Arylmethylene heterocyclic compounds as blockers of the Kv1.3 potassium shaker channel

Abstract

Compounds of Formula I or a pharmaceutically acceptable salt thereof are described, wherein the substituents are as defined herein. Also described are pharmaceutical compositions comprising the compounds or a pharmaceutically acceptable salt thereof, and methods of using the compounds or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 911,655, filed October 7, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] This patent disclosure contains copyrighted material. The copyright holder does not object to faxed copies of any patent document or patent disclosure appearing in the U.S. Patent and Trademark Office patent documents or records, but reserves all and all copyrights for any other means.

[0003] By incorporating references

[0004] All documents cited in this article are incorporated into this article in their entirety through citation. Invention Field

[0005] This invention relates primarily to the field of pharmaceutical science. More specifically, this invention relates to compounds and compositions that can be used as drugs, such as potassium channel blockers.

[0006] background

[0007] Voltage-gated Kv1.3 potassium (K + Kv1.3 channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, regulating a wide range of physiological processes, such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels can modulate membrane potential, thereby indirectly affecting calcium signaling in human effector memory T cells. Effector memory T cells are mediators of various conditions, including multiple sclerosis, type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, effector memory T cells increase Kv1.3 channel expression. In human B cells, naive and early memory B cells express low levels of Kv1.3 channels at rest. In contrast, class-switching memory B cells express high levels of Kv1.3 channels. Furthermore, Kv1.3 channels promote calcium homeostasis required for T cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G. et al., 2004). Trends Immunol. (565-569). Blocking the Kv1.3 channel in effector memory T cells inhibits activities such as calcium signaling, cytokine production (interferon-γ, interleukin-2), and cell proliferation.

[0008] Autoimmune diseases are a range of conditions caused by tissue damage resulting from the body's own immune system attacking the immune system. These diseases may affect a single organ, as in multiple sclerosis and type 1 diabetes, or multiple organs, as in rheumatoid arthritis and systemic lupus erythematosus. Treatment is often palliative, using anti-inflammatory and immunosuppressive drugs that can have serious side effects. The need for more effective therapies has led to the search for drugs that can selectively inhibit the function of effector memory T cells known to be associated with the etiology of autoimmune diseases. These inhibitors are thought to be able to improve the symptoms of autoimmune diseases without impairing the protective immune response. Effector memory T cells (TEMs) express large amounts of Kv1.3 channels and depend on these channels to perform their function. In vivo, Kv1.3 channel blockers paralyze TEMs at sites of inflammation and prevent them from being reactivated in inflamed tissue. Kv1.3 channel blockers do not affect the movement of naive and central memory T cells within lymph nodes. Inhibiting the function of these cells by selectively blocking Kv1.3 channels offers the potential to effectively treat autoimmune diseases with minimal side effects.

[0009] Multiple sclerosis (MS) is caused by autoimmune damage to the central nervous system (CNS). Symptoms include muscle weakness and paralysis, which severely impact patients' quality of life. MS progresses rapidly and unpredictably, ultimately leading to death. Kv1.3 channels are also highly expressed in autoreactive effector memory T cells from MS patients (Wulff H. et al., 2003, J. Clin. Invest. , 1703-1713; Rus H. et al., 2005, PNAS (11094-11099). Animal models of multiple sclerosis have been successfully treated using Kv1.3 channel blockers.

[0010] Compounds that are selective Kv1.3 channel blockers are therefore potential therapeutic agents as immunosuppressants or immune system modulators. The Kv1.3 channel is also considered a therapeutic target for treating obesity and enhancing peripheral insulin sensitivity in patients with type 2 diabetes. These compounds may also be used to prevent transplant rejection and to treat immune (e.g., autoimmune) and inflammatory conditions.

[0011] Tubulointerstitial fibrosis (TURF) is a progressive deposition of connective tissue in the renal parenchyma, leading to deterioration of renal function and participating in the pathology of chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation. It is a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes promotes their proliferation, leading to excessive stimulation of chronic inflammation and cellular immunity, which are involved in the underlying pathology of these kidney diseases and are contributing factors to the progression of TURF. Inhibition of lymphocyte Kv1.3 channel currents suppresses renal lymphocyte proliferation and improves the progression of renal fibrosis (Kazama I. et al., 2015). Mediators Inflamm. , 1-12).

[0012] Kv1.3 channels also play a role in gastrointestinal disorders, including inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease. Ulcerative colitis is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. Ulcerative colitis can impair quality of life and lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients are associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered a biomarker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy in UC. Current UC treatment regimens, including corticosteroids, salicylates, and anti-TNF-α agents, are insufficient for many patients (Hansen LK et al., 2014, 2014). J. Crohns Colitis Crohn's disease (1378-1391) is a type of IBD that can affect any part of the gastrointestinal tract. Crohn's disease is thought to result from intestinal inflammation caused by a T-cell-driven process triggered by normally safe bacteria. Therefore, Kv1.3 channel inhibition can be used to treat Crohn's disease.

[0013] Besides T cells, the Kv1.3 channel is also expressed in microglia, where it participates in the production of inflammatory cytokines and nitric oxide and in microglia-mediated neuronal killing. In humans, CD68 is also expressed in microglia of the frontal cortex of Alzheimer's disease patients and in multiple sclerosis brain injury. + Strong Kv1.3 channel expression was found in cells. It has been shown that Kv1.3 channel blockers may preferentially target harmful pro-inflammatory microglial function. Kv1.3 channels are expressed on activated microglia in infarcted rodents and the human brain. Higher Kv1.3 channel current densities were observed in acutely isolated microglia of the infarcted hemisphere in a stroke mouse model than in microglia isolated in the contralateral hemisphere (Chen Y.J. et al., 2017). Ann. Clin. Transl. Neurol., 147-161).

[0014] The expression of Kv1.3 channels is elevated in microglia in the brains of people with Alzheimer's disease, suggesting that Kv1.3 channels are pathologically relevant microglia targets in Alzheimer's disease (Rangaraju S. et al., 2015). J. Alzheimers Dis (797-808). Soluble AβO enhances microglial Kv1.3 channel activity. Kv1.3 channels are required for AβO-induced pro-inflammatory activation and neurotoxicity in microglia. Kv1.3 channel expression / activity is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of microglial Kv1.3 channels can affect hippocampal synaptic plasticity and reduce amyloid deposition in APP / PS1 mice. Therefore, Kv1.3 channels may be a therapeutic target for Alzheimer's disease.

[0015] Kv1.3 channel blockers can also be used to improve the pathology of cardiovascular conditions such as ischemic stroke, in which activated microglia significantly promote secondary dilation of the infarct.

[0016] Kv1.3 channel expression is involved in the control of proliferation, apoptosis, and cell survival in multiple cell types. These processes are crucial for cancer progression. In this context, Kv1.3 channels located in the inner mitochondrial membrane can interact with the apoptosis regulator Bax (Serrano-Albarras, A. et al., 2018, Expert Opin.Ther.Targets (101-105). Therefore, inhibitors of the Kv1.3 channel could be used as anticancer agents.

[0017] Many peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. Several selective and potent Kv1.3 channel peptide inhibitors have been developed. Synthetic derivatives of sea anemone toxins (shk) containing the non-natural amino acid shk-186 are among the most advanced peptide toxins. Shk has demonstrated efficacy in preclinical models and is currently in a Phase I clinical trial for the treatment of psoriasis. Shk can inhibit the proliferation of TEM cells, thereby improving symptoms in animal models of multiple sclerosis. Unfortunately, Shk also binds to closely associated Kvi channel subtypes found in the CNS and heart. Selective Kv1.3 channel inhibitors are needed to avoid potential cardiotoxicity and neurotoxicity. Furthermore, small peptides like shk-186 are rapidly cleared from the body after administration, resulting in short circulating half-lives and frequent dosing events. Therefore, there is a need to develop long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases.

[0018] Therefore, there is still a need to develop new Kv1.3 channel blockers as pharmaceutical agents. Summary of the Invention

[0019] In one aspect, a structure with Equation I is described. Compounds acting as potassium channel blockers, wherein various substituents are defined herein. Compounds of formula I described herein can block Kv1.3 potassium (K + These compounds are used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein can be used to treat conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and treatment methods have numerous clinical applications, including as pharmaceutical agents and methods for treating cancer, immune disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, kidney diseases, or combinations thereof.

[0020] In one respect, compounds of formula I or pharmaceutically acceptable salts thereof are described.

[0021] ;

[0022] in

[0023] Z is OR a NR a R b or NR b (C=O)R a ;

[0024] X1 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl or halocycloalkyl;

[0025] X2 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0026] X3 is H, halogen, fluoroalkyl, or alkyl;

[0027] Alternatively, X1 and X2 together with the carbon atoms to which they are attached can form an optionally substituted 6-aryl group;

[0028] Alternatively, X2 and X3 together with the carbon atoms they are attached to form an optional substituted 6-aryl group;

[0029] R3 is H, halogen, or alkyl;

[0030] Alternatively, X1 and R3 together with the carbon atoms to which they are attached can form an optionally substituted 6-aryl group;

[0031] R1 and R2 are each independently H, alkyl, or (CR6R7) n4 OR a (CR6R7) 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 Alternatively, R1 and R2, together with the carbon atoms they are attached to, can form 3-5 membered carbon rings.

[0032] R4 is H, alkyl, haloalkyl, 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 Optionally substituted saturated heterocycles, Optionally substituted aryl groups, Optionally substituted heteroaryl groups, Optionally substituted alkyl-aryl groups, Optionally substituted alkyl-heteroaryl groups, Optionally substituted alkyl-heterocyclic groups, Optionally substituted alkyl-cycloalkyl groups, or Optionally substituted cycloalkyl-alkyl groups.

[0033] Each occurrence of R5 is independently of H, alkyl, cycloalkyl, or oxo;

[0034] Or, two R5 groups together with the carbon atoms they are attached to form a 3-7 member saturated carbon ring that can be optionally substituted;

[0035] Or two R5 groups are attached to different carbon atoms on a carbon ring and together form a bond or an alkyl chain containing 1-3 carbons;

[0036] Each occurrence of R6 and R7 is independently H, alkyl, or cycloalkyl;

[0037] R a and R b Each occurrence of is independently H, alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl; or R a and R b Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

[0038] R c and R d Each occurrence of is independently H, alkyl, alkyl substituted with 1-4 substituents, each independently halogenated, OR8 or N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl or optionally substituted -cycloalkyl-alkyl; or R c and R d Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

[0039] Each occurrence of R8 is independently H, alkyl, or optionally substituted heterocycle; or two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from N, O, and S.

[0040] R9 is H, alkyl, halogen, or (CR6R7) n4 OR b ;

[0041] Where valence is permissible, X1, X2, X3, R1, R2, R3, R4, R5, R6, R7, R9, R a R b R c and R d The alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocyclic, aryl, and heteroaryl groups may, where applicable, be optionally substituted by 1 to 4 substituents, each of which is independently selected from alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, -(CH2). 0-2OR8, N(R8)2, (C=O)C 1-4 Alkyl, (C=O)N(R8)2, and oxo;

[0042] As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 3;

[0043] Each occurrence of n2 and n3 is an independent integer between 0 and 2; and

[0044] Each occurrence of n4 is an independent integer between 0 and 3.

[0045] In any of the embodiments described herein, each occurrence of n2 and n3 is an independent integer between 0 and 1.

[0046] In any of the embodiments described herein, structural motifs have , , , or The structure.

[0047] In any of the embodiments described herein, structural primitives have , or The structure.

[0048] In any of the embodiments described herein, structural primitives have The structure.

[0049] In any of the embodiments described herein, R1 and R2 appear at least once as H or alkyl.

[0050] In any of the embodiments described herein, R1 and R2 appear at least once as (CR6R7). n4 OR a (CR6R7) 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 .

[0051] In any of the embodiments described herein, at least one occurrence of R1 and R2 is OR aor NR a R b .

[0052] In any of the embodiments described herein, R1, R2, together with the carbon atoms to which they are attached, form a 3- to 5-membered carbon ring.

[0053] In any of the embodiments described herein, R1 and R2 are each independently H, Me, OH, CH2OH, NH2, NHMe, NMe2, CH2NH2, CONH2, CONHMe2, CONMe2, NH(C=O)Me, NMe(C=O)Me, , , , , or .

[0054] In any of the embodiments described herein, R4 is H, alkyl, haloalkyl, or cycloalkyl.

[0055] In any of the embodiments described herein, R4 is H, Me, or a fluoroethyl group.

[0056] In any of the embodiments described herein, R4 is (CR6R7). n4 OR c (CR6R7) n4 COR 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 (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 .

[0057] In any of the embodiments described herein, R4 is (CR6R7)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 SO2R c or SO2NR c R d .

[0058] In any of the embodiments described herein, R4 is (CH2)2OH, (CH2)2OMe, (C=O)H, (C=O)Me, (C=O)CH2OH, (C=O)CH2OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)NH2, (C=O)NHMe, (C=O)NMe2, (C=O)CH2NH2, (C=O)CH2NHMe, (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2OH, (C=O)CH(OH)CH2OMe, (C=O)(C=O)NMe2, (C=O)OMe, SO2Me, SO2Et, SO2CH2OH, SO2CH2OMe, SO2NH2, SO2NHMe, or SO2NMe2.

[0059] In any of the embodiments described herein, R4 is (C=O)R c (C=O)(CR6R7) 1-2 R c (C=O)(CR6R7) 1- 2OR c or SO2R c ; and R c The group is selected from H, alkyl, alkyl substituted with 1-4 substituents each independently selected from halogen, OR8 and N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl, and optionally substituted -cycloalkyl-alkyl.

[0060] In any of the embodiments described herein, R c Or R d It is H, Me, Et,

[0061] .

[0062] In any of the embodiments described herein, R c Or R d It is selected from the following heterocycles:

[0063]

[0064]

[0065]

[0066] Where the valence allows, the heterocycle may be optionally replaced by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0067] In any of the embodiments described herein, R, where valence allows, c Each of the substituents is optionally substituted with 1 to 4 substituents, which are cycloalkyl, spiroalkyl, or bicycloalkyl groups, and each substituent is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0068] In any of the embodiments described herein, R, where valence allows, c Each is optionally substituted by 1-4 substituents. Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0069] In any of the embodiments described herein, R4 is an optionally substituted saturated heterocycle, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted alkyl-aryl group, an optionally substituted alkyl-heteroaryl group, an optionally substituted alkyl-heterocycle, an optionally substituted cycloalkyl group, an optionally substituted alkyl-cycloalkyl group, or an optionally substituted cycloalkyl-alkyl group.

[0070] In any of the embodiments described herein, R4 is a heterocycle selected from the following:

[0071]

[0072]

[0073]

[0074] Where the valence allows, the heterocycle may be optionally replaced by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0075] In any of the embodiments described herein, R4 is a cycloalkyl group optionally substituted with 1 to 4 substituents, each substituent being independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0076] In any of the embodiments described herein, R4 is optionally substituted with 1 to 4 substituents, where the valence allows. Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0077] In any of the embodiments described herein, R4 is:

[0078]

[0079]

[0080]

[0081] Or its tautomers.

[0082] In any of the embodiments described herein, R5 appears at least once as H, alkyl, or cycloalkyl.

[0083] In any of the embodiments described herein, R5 occurs at least once as an oxidative form.

[0084] In any of the embodiments described herein, two R5 groups are attached to different carbon atoms on a carbon ring and together form a bond or an alkyl chain containing 1-3 carbons.

[0085] In any of the embodiments described herein, the two R5 groups together with the carbon atoms to which they are attached form a 3- to 7-membered substituted saturated carbocyclic ring.

[0086] In any of the embodiments described herein, R a and Rb At least one of them is independently H, alkyl, cycloalkyl, saturated heterocyclic, aryl or heteroaryl.

[0087] In any of the embodiments described herein, R a and R b Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0088] In any of the embodiments described herein, each occurrence of R6 and R7 is independently H or alkyl.

[0089] In any of the embodiments described herein, R9 is H, alkyl, or halogen.

[0090] In any of the embodiments described herein, R9 is (CR6R7). n4 OR b .

[0091] In any of the embodiments described herein, R9 is H, F, or OH.

[0092] In any of the embodiments described herein, Z is OR a NR a R b or NR b (C=O)R a .

[0093] In any of the embodiments described herein, Z is OH, OMe, NH2, NHMe, or NMe2.

[0094] In any of the embodiments described herein, Z is OH.

[0095] In any of the embodiments described herein, X1 is H, halogen, fluoroalkyl, or alkyl.

[0096] In any of the embodiments described herein, X1 is H, F, Cl, Br, Me, CF3, or CF2Cl.

[0097] In any of the embodiments described herein, X1 is Me or Cl.

[0098] In any of the embodiments described herein, X2 is H, halogen, fluoroalkyl, or alkyl.

[0099] In any of the embodiments described herein, X2 is H, F, Cl, Br, Me, CF3, or CF2Cl.

[0100] In any of the embodiments described herein, X2 is Cl.

[0101] In any of the embodiments described herein, X3 is H, F, Cl, Br, fluoroalkyl, or alkyl.

[0102] In any of the embodiments described herein, X3 is H, F, Cl, or CF3.

[0103] In any of the embodiments described herein, the structural portion Each of them was replaced by R3 The structure.

[0104] In any of the embodiments described herein, R3 is H or an alkyl group.

[0105] In any of the embodiments described herein, R3 is a halogen.

[0106] In any of the embodiments described herein, the compound has the structure of Formula II.

[0107] ;

[0108] R 3’ Each occurrence of is independently H, halogen, or alkyl; and

[0109] n6 is an integer between 0 and 2.

[0110] In any of the embodiments described herein, R 3’ The at least one occurrence of it is H or alkyl.

[0111] In any of the embodiments described herein, R 3’ The most frequent occurrence of halogen is halogen.

[0112] In any of the embodiments described herein, R8 appears at least once as H, alkyl, or optionally substituted heterocyclic ring.

[0113] In any of the embodiments described herein, R8 is H, Me, Et, Pr, Bu, or a heterocycle selected from the following:

[0114]

[0115]

[0116] Where the valence allows, the heterocycle may optionally be converted by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0117] In any of the embodiments described herein, the two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0118] In any of the embodiments described herein, n1 is 0, 1, 2, or 3.

[0119] In any of the embodiments described herein, n4 is 0, 1, or 2.

[0120] In any of the embodiments described herein, R c Or R d At least once, it is independently H, alkyl, alkyl substituted with 1-4 substituents each independently selected from halogen, OR8 and N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl or optionally substituted -cycloalkyl-alkyl.

[0121] In any of the embodiments described herein, R c and R d Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0122] In any of the embodiments described herein, R c Or R d The at least one occurrence of H, Me, Et,

[0123]

[0124] In any of the embodiments described herein, R c Or R d At least one occurrence of the substance is independently selected from the following heterocycles:

[0125]

[0126]

[0127]

[0128] Where the valence allows, the heterocycle may be optionally replaced by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0129] In any of the embodiments described herein, R, where valence allows, c Or R d Each of the following at least once is independently a cycloalkyl, spiroalkyl, or bicycloalkyl group, each optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0130] In any of the embodiments described herein, R, where valence allows, c Or R d Each of the at least one occurrence is independently represented by each of the substituted groups optionally being substituted by 1-4 substituents.

[0131] Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0132] In any of the embodiments described herein, the compound is selected from compounds 1-338 in Table 1.

[0133] In another aspect, pharmaceutical compositions are described that comprise at least one compound described in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0134] In another aspect, a method for treating a symptom in a mammalian species in need is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof described in any embodiment herein, wherein the symptom is selected from cancer, immune disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0135] In any of the embodiments described herein, the immune condition is transplant rejection or an autoimmune disease.

[0136] In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0137] In any of the embodiments described herein, the central nervous system (CNS) condition is Alzheimer's disease.

[0138] In any of the embodiments described herein, the inflammatory condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0139] In any of the embodiments described herein, the gastrointestinal condition is inflammatory bowel disease.

[0140] In any of the embodiments described herein, the metabolic condition is obesity or type II diabetes.

[0141] In any of the embodiments described herein, the cardiovascular condition is ischemic stroke.

[0142] In any of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0143] In any of the embodiments described herein, the condition is selected from 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.

[0144] In any of the embodiments described herein, the mammal species is human.

[0145] In another aspect, a method for blocking the Kv1.3 potassium channel in a desired mammalian species is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound described in any of the embodiments herein or a pharmaceutically acceptable salt thereof.

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

[0147] Any embodiment disclosed herein can be suitably combined with any other embodiment disclosed herein. Combinations of any embodiment disclosed herein with any other embodiment disclosed herein are explicitly contemplated. Specifically, the selection of one or more embodiments of a substituent can be suitably combined with the selection of one or more specific embodiments of any other substituent. Such combinations can be made in any one or more embodiments of the application described herein or in any formulation described herein. Invention Details

[0149] definition

[0150] The following are definitions of terms used in this specification. Unless otherwise stated, the initial definitions provided herein for a group or term apply individually or as part of another group throughout this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0151] The term "alkyl" (and "alk") refers to a straight-chain or branched alkane (hydrocarbon) group containing 1-12 carbon atoms, preferably 1-6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "(C 1- "C4) alkyl" refers to a straight-chain or branched alkane (hydrocarbon) group containing 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group that is substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents forming a group, such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NRb R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the group is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. In some embodiments, the group itself, such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic, and aryl, may optionally be substituted.

[0152] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2-12 carbon atoms and at least one carbon-carbon double bond. Exemplary examples of such groups include vinyl or allyl. The term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl, etc. E )-But-2-enyl, ( Z )-But-2-enyl, 2-methyl( E )-But-2-enyl, 2-methyl( Z )-But-2-enyl, 2,3-methyl-But-2-enyl, ( Z )-pent-2-enyl, ( E )-pent-1-enyl, ( Z )-hex-1-enyl, ( E )-pent-2-enyl, ( Z )-hex-2-enyl, ( E )-hex-2-enyl, ( Z )-hex-1-enyl, ( E )-hex-1-enyl, ( Z )-hex-3-enyl, ( E )-hex-3-enyl, and ( E)-Hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group that is substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, haloalkyl (i.e., alkyl groups with a single or multiple halogen substituents, such as CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R.b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutions may optionally be substituted.

[0153] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2-12 carbon atoms and at least one carbon-carbon triple bond. Exemplary examples of such groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, pent-1-alkynyl, pent-2-alkynyl, hex-1-alkynyl, hex-2-alkynyl, and hex-3-alkynyl. "Substituted alkynyl" refers to an alkynyl group substituted at any available linker with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NRd S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutions may optionally be substituted.

[0154] The term "cycloalkyl" refers to a fully saturated cycloalkyl group containing 1-4 rings and 3-8 carbons in each ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)Ra C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may optionally be substituted themselves. Exemplary substituents also include: spirolinked or fused cyclic substituents, particularly spirolinked cycloalkyl, spirolinked cycloalkenyl, spirolinked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may optionally be substituted themselves.

[0155] The term "cycloalkenyl" refers to a partially unsaturated cycloalkenyl group containing 1-4 rings and 3-8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)Re S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R eEach occurrence of the is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may optionally be substituted themselves. Exemplary substituents also include: spirolinked or fused cyclic substituents, particularly spirolinked cycloalkyl, spirolinked cycloalkenyl, spirolinked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may optionally be substituted themselves.

[0156] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of an aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthryl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, wherein two adjacent aromatic rings share two common carbon atoms. "Substituted aryl" refers to an aryl group that is substituted at any available connection point by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NRb R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the substituent is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may optionally be substituted themselves. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl groups, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may optionally be substituted themselves.

[0157] The term "biaryl" refers to two aryl groups connected by a single bond. The term "biheteroaryl" refers to two heteroaryl groups connected by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl and an aryl group connected by a single bond, and the term "aryl-heteroaryl" refers to an aryl and a heteroaryl group connected by a single bond. In some embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the size of the aryl or heteroaryl ring in the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl group is connected to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0158] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1-4 rings and 3-8 carbons per ring, or a cyclic aromatic hydrocarbon group having 1-5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloynyl, and aryl groups as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group that is substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloynyl, and substituted aryl groups. Exemplary substituents also include: spirolinked or fused cyclic substituents at any available connection point or one or more, particularly spirolinked cycloalkyl, spirolinked cycloalkenyl, spirolinked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may optionally be substituted themselves.

[0159] The terms "heterocycle" and "heterocyclic" refer to a fully saturated, partially or fully unsaturated, aromatic (i.e., "heteroaryl") cyclic group (e.g., 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring systems) having at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group can be independently saturated or partially or fully unsaturated. Each ring of a heterocyclic group containing heteroatoms can have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. (The term "heteroaryl-onium" refers to a heteroaryl group with a quaternary nitrogen atom and therefore a positive charge.) The heterocyclic group can be attached to the rest of the molecule at any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups include: aziridine, pyrrolidine, pyrrolyl, pyrazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopyrrolyl, 2-oxoaziridine, aziridine, hexahydrodiazazanyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide. Examples of bicyclic heterocyclic groups include: indolyl, indololinyl, isoyindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothiaphenyl, benzo[…]. d [1,3]dioxacyclopentenyl, dihydro-2H-benzo[ b [1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quininecycloyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indoleazinyl, benzofuranyl, benzofuranyl, dihydrobenzo[ dOxazole, chromone, coumarin, benzopyranyl, cyclolinyl, quinoxalinyl, indazole, pyrrolopyridyl, furanopyridyl (e.g., furano[2,3-c]pyridyl, furano[3,2-b]pyridyl or furano[2,3-b]pyridyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), triazinylazine, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include: carbazole, benzoindolyl, phenanthrolyl, acridine, phenanthidyl, xanthonyl, etc.

[0160] "Substituted heterocycle" and "substituted heterocyclic form" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group that is substituted at any available junction with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, 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 NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR dP(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of the is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may optionally be substituted themselves. Exemplary substituents also include: spirolinked or fused cyclic substituents at any available connection point, particularly spirolinked cycloalkyl, spirolinked cycloalkenyl, spirolinked heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may optionally be substituted themselves.

[0161] The term "oxo" refers to Substituents can be attached to carbocyclic or heterocyclic atoms. When an oxosubstituent is attached to a carbocyclic atom of an aromatic group (e.g., aryl or heteroaryl), the bonds on the aromatic ring can rearrange to satisfy valence requirements. For example, pyridine with a 2-oxosubstituent can have a structure... It also includes its tautomers. .

[0162] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, etc.

[0163] The term "dialkylamino" refers to a group having the structure -NRR', wherein R and R' are each independently an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined herein. R and R' may be the same or different in the dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to: dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, etc. In some embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to: aziridinyl, pyrrolyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-triazinyl, and tetrazolyl.

[0164] The term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0165] The term "substituted" refers to an embodiment in which a molecule, a molecular part, or a substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aryl, or any other group disclosed herein) is substituted by one or more substituents, preferably 1-6 substituents, at any available connection point, provided that the valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF3 or an alkyl group with CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)Ra C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e , where R a Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; b R c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c They optionally form heterocycles together with the N they are bonded to; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aryl. In the exemplary substituents described above, groups such as alkyl, cycloalkyl, alkenyl, ynyl, cycloalkenyl, heterocyclic, and aryl may optionally be substituted. The term "optionally substituted" refers to embodiments in which the molecule, molecular portion, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aryl, or any other group disclosed herein) may or may not be substituted by one or more of the aforementioned substituents.

[0166] Unless otherwise stated, it is assumed that any heteroatom with an unsaturated valence has enough hydrogen atoms to satisfy the compound.

[0167] The compounds of the present invention can form salts, which are also within the scope of the present invention. Unless otherwise stated, references to the compounds of the present invention should be understood to include references to their salts. As used herein, the term "salt" means an acidic and / or basic salt formed with inorganic and / or organic acids and bases. Furthermore, when the compounds of the present invention comprise a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids), zwitterions ("internal salts") can be formed and are included within the scope of "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, in the separation or purification steps that may be employed during the preparation process. Salts of the compounds of the present invention can be formed, for example, by reacting the compounds described herein with a certain amount of acid or base (e.g., equivalent) in, for example, a salt precipitation medium or an aqueous medium, followed by lyophilization.

[0168] Compounds of the present invention containing a basic moiety (e.g., but not limited to, amines, pyridines, or imidazole rings) can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include: acetates (such as those formed with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-heptyl sulfate, glycerol phosphates, hemisulfates, heptanate, hexanoate, hydrochloride, hydrobromide, and hydroiodic acid. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as toluenesulfonate, undecanoates, etc.

[0169] Compounds of the present invention containing an acidic moiety (e.g., but not limited to phenols or carboxylic acids) can form salts with a variety of organic and inorganic bases. Exemplary basic salts include: ammonium salts; alkali metal salts (such as sodium, lithium, and potassium salts); alkaline earth metal salts (such as calcium and magnesium salts); salts with organic bases (e.g., organic amines), such as benzathine penicillin, dicyclohexylamine, halamine (forming with N,N-bis(dehydrorosinyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glycamides, tert-butylamine; and salts with amino acids (such as arginine, lysine), etc. The basic nitrogen-containing group can be quaternized with a reagent, such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc.

[0170] Prodrugs and solvates of the compounds of this invention are also considered herein. As used herein, the term "prodrug" refers to a compound that undergoes chemical transformation through metabolism or a chemical process after administration to a subject to produce a compound of this invention or its salts and / or solvates. Solvates of the compounds of this invention include, for example, hydrates.

[0171] The compounds of the present invention and their salts or solvates may exist in their tautomers (e.g., as amides or imine ethers). All such tautomers are considered part of the present invention. As used herein, any shown structure of a compound includes its tautomers.

[0172] All stereoisomers of the compounds of this invention, including enantiomers and diastereomers (e.g., those that may exist due to asymmetric carbons on various substituents), are considered to be within the scope of this invention. Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with specific activity), or may, for example, be as racemates or mixed with all other or alternative stereoisomers. The chiral center of this invention may have an S or R configuration as defined in the International Union of Pure and Applied Chemistry (IUPAC) Recommendation 1974. Racemates may be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation using chiral column chromatography. Individual optical isomers may be obtained from racemates by any suitable method, including but not limited to conventional methods, such as forming salts with optically active acids followed by crystallization.

[0173] After preparation, the compounds of the present invention are preferably isolated and purified to obtain a composition containing 90% or more by weight, for example, 95% or more, or 99% or more of the compound (“substantially pure” compound), and then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also considered part of the present invention.

[0174] All configurational isomers of the compounds of this invention, whether in mixture form or in pure or substantially pure form, are considered within the scope of consideration. The definition of compounds of this invention includes cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0175] Throughout the specification, groups and their substituents can be selected to provide stable moieties and compounds.

[0176] Specific functional groups and chemical terms are defined in more detail herein. For the purposes of this invention, chemical elements are identified according to the CAS version of the periodic table, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in “Organic Chemistry,” Thomas Sorrell, University ScienceBooks, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0177] Certain compounds of this invention may exist as specific geometric or stereoisomers. This invention considers all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures, to fall within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in this invention.

[0178] According to the present invention, mixtures of isomers containing any number of isomer ratios can be used. For example, when only two isomers are combined, the present invention covers all mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily understand that similar ratios are considered for more complex isomer mixtures.

[0179] This invention also includes isotopically labeled compounds identical to those disclosed herein, but in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, […]. 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes such as… 3 H and 14 Those of C can be used for drug and / or substrate tissue distribution determination. Tritium substitution... 3 H, and carbon-14, i.e. 14 Carbon isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, heavier isotopes such as deuterium are also preferred. 2 H substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. Isotope-labeled compounds are typically prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents, following the schemes and / or the methods disclosed in the examples.

[0180] For example, if a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric isomer is then resolved by fractional crystallization or chromatographic methods known in the art, and the pure enantiomer is then recovered.

[0181] It should be understood that compounds described herein may be substituted with any number of substituents or functional portions. Generally, the term "substituted" refers to the substitution of a hydrogen group in a given structure with the group of a particular substituent, regardless of whether it is preceded by the term "optionally" or the substituents included in the formula of the invention. When more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituent of the organic compounds described herein that satisfies the heteroatom valence. Furthermore, the invention is not intended to be limited in any way by the permissible substituents of organic compounds. The combinations of substituents and variables contemplated in this invention are preferably those that result in the formation of stable compounds that can be used to treat, for example, proliferative diseases. As used herein, the term "stable" preferably means that a compound has sufficient stability to allow for manufacture and that it maintains its integrity for a sufficient period of detection, and preferably for the purposes detailed herein.

[0182] As used herein, the term “cancer” and equivalently “tumor” refers to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancer or tumor includes, but is not limited to: biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; kidney (renal) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other cancers and sarcomas. Cancer can be primary or metastatic. Diseases other than cancer may be associated with alternating mutations in components of the Ras signaling pathway, and the compounds disclosed herein may be used to treat these non-cancer diseases. Such non-cancerous diseases can include: neurofibromatosis; panther syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardiofacio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriofluidosis.

[0183] As used herein, "effective amount" means any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, effective amount is therapeutically effective amount. Therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the specific agent administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular agent without the need for excessive experimentation.

[0184] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammal species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including but not limited to non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and undomesticated animals.

[0185] compound

[0186] Novel compounds as Kv1.3 potassium channel blockers are described. The applicant has unexpectedly discovered that the disclosed compounds exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, the applicant has unexpectedly discovered that the disclosed compounds selectively block Kv1.3 potassium channels without blocking hERG channels, and therefore possess desirable cardiovascular safety properties.

[0187] In one respect, compounds of formula I or pharmaceutically acceptable salts thereof are described.

[0188] ;

[0189] in

[0190] Z is OR a NR a R b or NR b (C=O)R a ;

[0191] X1 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl or halocycloalkyl;

[0192] X2 is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;

[0193] X3 is H, halogen, fluoroalkyl, or alkyl;

[0194] Alternatively, X1 and X2 together with the carbon atoms to which they are attached can form an optionally substituted 6-aryl group;

[0195] Alternatively, X2 and X3 together with the carbon atoms they are attached to form an optional substituted 6-aryl group;

[0196] R3 is H, halogen, or alkyl;

[0197] Alternatively, X1 and R3 together with the carbon atoms to which they are attached can form an optionally substituted 6-aryl group;

[0198] R1 and R2 are each independently H, alkyl, or (CR6R7) n4 OR a (CR6R7) 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 Alternatively, R1 and R2, together with the carbon atoms they are attached to, can form 3-5 membered carbon rings.

[0199] R4 is H, alkyl, haloalkyl, 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 Rd Optionally substituted saturated heterocycles, Optionally substituted aryl groups, Optionally substituted heteroaryl groups, Optionally substituted alkyl-aryl groups, Optionally substituted alkyl-heteroaryl groups, Optionally substituted alkyl-heterocyclic groups, Optionally substituted alkyl-cycloalkyl groups, or Optionally substituted cycloalkyl-alkyl groups.

[0200] Each occurrence of R5 is independently of H, alkyl, cycloalkyl, or oxo;

[0201] Or, two R5 groups together with the carbon atoms they are attached to form a 3-7 member saturated carbon ring that can be optionally substituted;

[0202] Or two R5 groups are attached to different carbon atoms on a carbon ring and together form a bond or an alkyl chain containing 1-3 carbons;

[0203] Each occurrence of R6 and R7 is independently H, alkyl, or cycloalkyl;

[0204] R a and R b Each occurrence of is independently H, alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl; or R a and R b Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

[0205] R c and R d Each occurrence of is independently H, alkyl, alkyl substituted with 1-4 substituents, each independently halogenated, OR8 or N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl or optionally substituted -cycloalkyl-alkyl; or R c and R d Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

[0206] Each occurrence of R8 is independently H, alkyl, or optionally substituted heterocycle; or two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from N, O, and S.

[0207] R9 is H, alkyl, halogen, or (CR6R7) n4 ORa ;

[0208] Where valence permits, the alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted by 1 to 4 substituents, each of which is independently selected from alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl, (C=O)N(R8)2, and oxo;

[0209] As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 3;

[0210] Each occurrence of n2 and n3 is an independent integer between 0 and 2; and

[0211] Each occurrence of n4 is an independent integer between 0 and 3.

[0212] In some implementations, each occurrence of n2 and n3 is an independent integer from 0 to 2. In some implementations, n2 and n3 are each 0. In other implementations, n2 and n3 are each 1. In yet another implementation, n2 and n3 are each 2. In some implementations, n2 and n3 are 0 and 1 respectively. In some implementations, n2 and n3 are 0 and 2 respectively. In some implementations, n2 and n3 are 1 and 2 respectively.

[0213] In some implementation schemes, structural elements have , , or The structure contains various substituents as defined herein. In some embodiments, the structural motifs... have , , or The structure contains various substituents as defined herein. In some embodiments, the structural motifs... have The structure, wherein various substituents are as defined herein.

[0214] In any of the embodiments described herein, R a and R b Each occurrence of R can independently be H, alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl. In some embodiments, R a and R b At least one of them is independently H, alkyl, or cycloalkyl. In other embodiments, R a and R bAt least one of them is independently a saturated heterocycle, aryl, or heteroaryl. In other embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0215] In some embodiments, R1 and R2 are each H or an alkyl group. In some embodiments, both R1 and R2 are H. In some embodiments, at least one of R1 and R2 is an alkyl group, such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In some embodiments, R1 and R2 are H and an alkyl group, respectively.

[0216] In some implementations, R1 and R2 appear at least once in the form of (CR6R7). n4 OR a Or (CR6R7) n4 NR a R b In some implementations, R1 and R2 appear at least once in the form of (CR6R7). 0-2 NR a R b NR a R b Non-limiting examples include: NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, NHPr, NMePr, NEtPr, NH( iso -Pr) and N( iso -Pr)2. In some implementations, R1 and R2 appear at least once as (CR6R7). 0-2 OR a OR a Non-limiting examples include: OH, OMe, OEt, OPr, O- iso -Pr, Obu, O- tert -Bu and O- sec -Bu. In some implementations, at least one occurrence of R1 and R2 is OR a or NR a R b .

[0217] In some implementations, R1 and R2 appear at least once in the form of (CR6R7). 0-2 NR a (C=O)R b (CR6R7) n4 NR a SO2R b Or (CR6R7) 0-2 CONR aR 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). CONR a R b Non-limiting examples include: (C=O)NH2, (C=O)NHMe, (C=O)NMe2, (C=O)NHEt, (C=O)NMeEt, (C=O)NEt2, (C=O)NHPr, (C=O)NMePr, (C=O)NEtPr, (C=O)NH( iso -Pr) and (C=O)N( iso -Pr)2.

[0218] In other embodiments, R1, R2, together with the carbon atoms they are attached to, form a 3- to 5-membered carbon ring. In some specific embodiments, R1, R2, together with the carbon atoms they are attached to, form a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0219] In some implementations, R1 and R2 are each independently H, Me, OH, CH2OH, NH2, NHMe, NMe2, CH2NH2, CONH2, CONHMe2, CONMe2, NH(C=O)Me, NMe(C=O)Me, .

[0220] In some embodiments, R4 is H, alkyl, haloalkyl, or cycloalkyl. In some specific embodiments, R4 is H, Me, CF3, or fluoroethyl.

[0221] In other implementations, R4 is (CR6R7). n4 OR c (CR6R7) n4 COR c (C=O)(CR6R7) n4 R c (CR6R7) n4 COOR c (CR6R7) n4 NR c (C=O)R d (CR6R7) n4 (C=O)NRc 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 Or (CR6R7) n4 SO2NR c R d In some specific embodiments, n4 is 0. In other specific embodiments, n4 is 1 or 2. In some specific embodiments, R4 is (CR6R7)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 SO2R c or SO2NR c R dIn some specific implementations, CR6R7 is CH2, CHMe, CMe2, CHEt, or CEt2. In some specific embodiments, 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)NHMe, (C=O)NMe2, (C=O)CH2NH2, (C=O)CH2NHMe, (C=O)(C=O)NMe2, (C=O)OMe, SO2Me, SO2Et, SO2CH2OH, SO2CH2OMe, SO2NH2, SO2NHMe, or SO2NMe2. In other embodiments, R4 is (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2OH, or (C=O)CH(OH)CH2OMe.

[0222] In other implementations, 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 The group is selected from H, alkyl, alkyl substituted with 1-4 substituents each independently selected from halogen, OR8 and N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl, and optionally substituted -cycloalkyl-alkyl.

[0223] In some implementation schemes, R c Or R d It is H, Me, Et,

[0224]

[0225]

[0226] or .

[0227] In some implementation schemes, R cIt is selected from the following heterocycles:

[0228]

[0229]

[0230]

[0231] Where the valence allows, the heterocycle may optionally be converted by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0232] In some implementations, R, where valence allows, c Each of the substituents is optionally substituted with 1 to 4 substituents, which are cycloalkyl, spiroalkyl, or bicycloalkyl groups, and each substituent is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2, and oxo. In other embodiments, R... c Each can be substituted by 1-4 substituents at will. Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0233] In yet another embodiment, R4 is an optionally substituted saturated heterocycle, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted alkyl-aryl group, an optionally substituted alkyl-heteroaryl group, an optionally substituted alkyl-heterocyclic group, an optionally substituted alkyl-cycloalkyl group, or an optionally substituted cycloalkyl-alkyl group. In some specific embodiments, R4 is a heterocycle selected from the following:

[0234]

[0235]

[0236]

[0237] Where the valence allows, the heterocycle may optionally be converted by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0238] In yet another embodiment, where the valence allows, R4 is a cycloalkyl group optionally substituted with 1 to 4 substituents, each of which is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2, and oxo. In other embodiments, R4 is optionally substituted with 1-4 substituents, where the valence allows. Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0239] In some embodiments, R8 is H or an alkyl group. In other embodiments, R8 is an optionally substituted heterocycle. In yet another embodiment, two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising a nitrogen atom and 0-3 additional heteroatoms selected from N, O, and S, respectively.

[0240] In some specific implementations, R4 is:

[0241]

[0242]

[0243]

[0244] Or its tautomers.

[0245] In some embodiments, R5 is H, an alkyl group, or a cycloalkyl group. In some specific embodiments, R5 is H. In other specific embodiments, R5 is Me, Et, Pr, iso -Pr、Bu、 iso -Bu、 sec -Bu or tert -Bu. In other specific embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other specific embodiments, R5 is oxo.

[0246] In other embodiments, the two R5 groups together with the carbon atoms to which they are attached form a 3-7 member, optionally substituted, saturated carbocyclic ring. In yet another embodiment, the two R5 groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons.

[0247] In some embodiments, each occurrence of R6 and R7 is independently H or an alkyl group. In some specific embodiments, CR6R7 is CH2, CHMe, CMe2, CHEt, or CEt2. In some specific embodiments, CR6R7 is CH2.

[0248] In some embodiments, R9 is H, an alkyl group, or a halogen. In other embodiments, R9 is (CR6R7). n4 OR b In some specific implementations, R9 is H, F, or OH.

[0249] In any of the embodiments described herein, Z can be OR a NR a R b or NR b (C=O)R a In some embodiments, Z is OH, OMe, NH2, NHMe, or NMe2. In some embodiments, Z is OH.

[0250] In any of the embodiments described herein, X1 can be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X1 is a cycloalkyl or cycloalkenyl group. In some embodiments, X1 is H, F, Cl, Br, Me, CF3, or CF2Cl. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is Me or Cl.

[0251] In any of the embodiments described herein, X2 can be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X2 is H, F, Cl, Br, Me, CF3, or CF2Cl. In some embodiments, X2 is Cl or Br. In some embodiments, X2 is Cl.

[0252] In any of the embodiments described herein, X3 is H, F, Cl, Br, a fluoroalkyl group, or an alkyl group. In some embodiments, X3 is H, F, Cl, or CF3.

[0253] In some implementation schemes, the structural portion Each of them was replaced by R3

[0254] or The structure.

[0255] In some embodiments, the compound of formula I has the structure of formula II.

[0256] ;

[0257] Where n6 is an integer between 0 and 2; R3’ Each occurrence of R is independently H, halogen, or alkyl; other substituents are as defined herein. In some embodiments, R 3’ At least once, H or an alkyl group is present. Non-limiting examples of alkyl groups include: Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In other embodiments, R... 3’ The element present at least once is a halogen. In some embodiments, n6 is 0. In some embodiments, n6 is 1. In some embodiments, n6 is 2.

[0258] In any of the embodiments described herein, R3 is H, a halogen, or an alkyl group. In some embodiments, R3 is H. In other embodiments, R3 is an alkyl group such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In yet another embodiment, R3 is F, Cl, or Br.

[0259] In any of the embodiments described herein, R8 occurs at least once as H, an alkyl group, or an optionally substituted heterocycle. In some embodiments, R8 is H, Me, Et, Pr, Bu, or a heterocycle selected from the following:

[0260]

[0261]

[0262] Where the valence allows, the heterocycle may optionally be converted by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0263] In other embodiments, the two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0264] In some implementations, n1 is 0, 1, 2, or 3. In some specific implementations, n1 is 0 or 1. In some implementations, n4 is 0, 1, or 2. In some implementations, n4 is 0 or 1. In some specific implementations, n4 is 0.

[0265] In any of the embodiments described herein, R c Or R dAt least once, it is independently H, alkyl, alkyl substituted with 1-4 substituents each independently selected from halogen, OR8 and N(R8)2, 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-heterocyclic, optionally substituted -alkyl-cycloalkyl or optionally substituted -cycloalkyl-alkyl.

[0266] In some implementation schemes, R c and R d Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles, which contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

[0267] In some specific implementations, R c Or R d The at least one occurrence of H, Me, Et,

[0268]

[0269]

[0270] .

[0271] In some specific implementations, R c Or R d At least one occurrence of the substance is independently selected from the following heterocycles:

[0272]

[0273]

[0274]

[0275] Where the valence allows, the heterocycle may optionally be converted by one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH2, oxo, or (C=O)C groups. 1-4 Alkyl substitution.

[0276] In some specific implementations, R, where valence allows, c Or R d Each of the following at least once is independently a cycloalkyl, spiroalkyl, or bicycloalkyl group, each optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from alkyl, halogen, CN, -(CH2). 0-2OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0277] In some specific implementations, R, where valence allows, c Or R d Each of the at least one occurrence is independently represented by each of the substituted groups optionally being substituted by 1-4 substituents. Each of the substituents is independently selected from alkyl, halogen, CN, and -(CH2). 0-2 OR8, N(R8)2, (C=O)N(R8)2 and oxo.

[0278] In some embodiments, the compounds of Formula I are selected from compounds 1-338 shown in Table 1 below.

[0279] abbreviation

[0280] .

[0281] Preparation method

[0282] The following are general synthetic schemes for preparing the compounds of this invention. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to a person skilled in the art. Furthermore, the various steps in the synthesis may be carried out in an alternating order or sequence to obtain the desired compounds. The following reactions are illustrative of the preparation of some of the starting materials and compounds disclosed herein and are not limiting.

[0283] The following embodiments 1-9 describe synthetic routes that can be used to synthesize the compounds of the present invention, such as compounds having the structure of Formula I or precursors thereof. Those skilled in the art can contemplate various modifications to these methods to achieve results similar to those of the present invention given below. In the following embodiments, synthetic routes are described using I-4, I-6, I-4a, I-6a, I-7, I-7b, I-10, I-10a, and I-13 as examples. Other Formula I compounds can be prepared by using methods similar to those described in embodiments 1-9 or by methods known in the art. The general synthetic routes described in embodiments 1-9 and the examples described in the following Examples section illustrate methods for preparing the compounds described herein.

[0284] As shown in Scheme 1, compound I-4 can be prepared from compound I-1a or I-1b.

[0285]

[0286] Compounds I-1a, I-1b, I-2a, I-2b, and I-2c can be prepared by any method 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 alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in step i of Scheme 1, intermediate ketone I-3 can be synthesized in the presence of a Lewis acid by a Friedel-Crafts reaction of a protected phenol I-1a with a suitably protected acyl chloride I-2a. Non-limiting examples of Lewis acids include aluminum chloride III. Optionally, aryl bromide or iodide I-1b can be converted to the corresponding Grignard reagent, for example, by treatment with isopropyl magnesium chloride (R is isopropyl), or by treatment with butyllithium to the corresponding aryl lithium reagent (step ii). The resulting organometallic reagent reacts with Weinreb amide I-2b to form ketone I-3. Ketone I-3 can be reduced with a suitable reducing agent to give alcohol I-4 (step v). Non-limiting examples of suitable reducing agents include NaBH4. Alternatively, aryl bromide or iodide I-1b can be converted to the corresponding Grignard reagent, for example, by treatment with isopropyl magnesium chloride (R is isopropyl), or by treatment with butyllithium to the corresponding aryl lithium reagent, the resulting organometallic reagent reacting with aldehyde I-2c to give benzyl alcohol I-4 (step vi). Benzyl alcohol I-4 can be oxidized to ketone I-3 using an oxidizing agent such as Dess-Martin periodine. The protecting group in compound I-4 can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted to compound I using methods known in the art.

[0287] As shown in Scheme 2, compound I-6 can be prepared from compounds I-1b, I-2d or I-3.

[0288]

[0289] Compounds I-1b and 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, other alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in step i of Scheme 2, a compound having formula I (where R1 includes an amino group) (e.g., compound I-6) can be obtained from ketone I-3 by heating ketone I-3 with an alkyl sulfinimide, such as tert-butyl sulfinimide (i.e., R is alkyl such as tert-butyl) in the presence of a Lewis acid (e.g., tetraethanolamine) to form sulfinimide I-5. Sulphinimide I-5 is reduced with a reducing agent such as sodium borohydride or diisobutylaluminum hydride (DIBAL) to give sulfinimide I-6 (step ii). The single enantiomer of compound I-6 can be prepared by methods known in the art. Optionally, as shown in step iii, compound I-6 can be synthesized directly by forming a Grignard reagent or an organolithium reagent from I-1b, and reacting the formed Grignard reagent or organolithium reagent with sulfinimide I-2d (prepared from I-2c in Scheme 1 using methods known in the art). The protecting group in compound I-6 can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted to compound of formula I using methods known in the art.

[0290] As shown in Scheme 3, compounds I-3a, I-4a and I-6a can be prepared from compounds I-1d and I-2b, I-1d and I-2c, and I-1d and I-2d, respectively.

[0291]

[0292] Compounds I-1d, I-2b, I-2c, and I-2d can be prepared by any method known in the art. As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include: Me, allyl, Ac, Boc, other alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in steps i, ii, or iii of Scheme 3, a suitably protected phenol such as diethyl carbamate I-1d can be activated by lithiation at the ortho position of the carbamate and reacted with Weinreb amide I-2b (step i), aldehyde I-2c (step ii), or sulfinimide I-2d (step iii), as shown in Scheme 3. The protecting groups in compounds I-4a and I-6a can then be selectively removed, and the resulting compounds having free NH and / or phenolic OH groups can be optionally converted to compounds of formula I using methods known in the art. Ketone I-3a can be reduced with a suitable reducing agent (e.g., NaBH4) to give the corresponding alcohol (not shown). The protecting group of the resulting alcohol can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted into a compound of formula I using methods known in the art.

[0293] As shown in Scheme 4, compounds I-4, I-3'' and I-7 can be prepared from compound I-3.

[0294]

[0295] Compound I-3 can be prepared by the method shown in Scheme 1. As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include: Me, allyl, Ac, Boc, other alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art as suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in Scheme 4, for compounds of formula I where R1 = R2 = H (e.g., compound I-7), ketone I-3 is reduced to alcohol I-4 with a reducing agent (e.g., sodium borohydride) (step i). Alcohol I-4 is then reduced with a silane such as triethylsilane in the presence of a Lewis acid such as boron trifluoride diethyl ether or an acid such as trifluoroacetic acid to give compound I-7 (step ii). When the nitrogen protecting group is Boc, the nitrogen protecting group is removed under these conditions to give benzylcycloamine I-7. For compounds where R1 is alkyl, ketone I-3 is treated with a suitable alkyl-Grignard reagent (e.g., R1MeBr) to give alcohol I-3' (step iii). As shown in step iv of scheme 4, the OH group of alcohol I-3' can be removed by reduction with triethylsilane using a method similar to that used in step ii, to obtain compound I-3'' (the nitrogen protecting group is removed under these conditions when it is Boc). The protecting groups in compounds I-3'' and I-7 can then be selectively removed, and the resulting compound having a free phenolic OH group can be optionally converted into a compound of formula I using methods known in the art.

[0296] As shown in Scheme 5, compound I-7 can be prepared from compounds I-8 and I-9.

[0297]

[0298] 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. Non-limiting examples of protecting groups include: Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in Scheme 5, another route for preparing compounds of formula I in which R1 = R2 = H and n2 = n3 = 1 is to react benzylbromine I-8 with pyridineboronic acid or borate ester I-9 (R is H or alkyl) using a palladium catalyst such as tetrakis(triphenylphosphine)palladium to give benzylpyridine I-10 (step i). Pyridine I-10 is reduced by a reducing agent (e.g., hydrogen on platinum oxide in the presence of an acid (e.g., HCl) to give benzylpiperidine I-7b. Alternatively, vinyl borate I-9a can be used in a similar manner (steps iii and iv) to give compound I-7b. In steps I and iii, a base such as Na₂CO₃ can be used. The protecting groups in compounds I-7b can then be selectively removed, and the resulting compounds having free NH and phenolic OH groups can be optionally converted to compounds of formula I using methods known in the art.

[0299] As shown in Scheme 6, compound I-7 can be prepared from compounds I-1b and I-11.

[0300]

[0301] 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: Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in Scheme 6, another route for preparing compounds of formula I in which R1 = R2 = H is the hydroboration of exocyclic alkenyl cycloamine I-8, followed by coupling the resulting borate ester with bromo or iodophenol I-1b using a palladium catalyst (e.g., Pd(dppf)Cl2). The protecting group in compound I-7 can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted to a compound of formula I using methods known in the art.

[0302] As shown in Scheme 7, compound I-7 can also be prepared from compounds I-1b and I-12.

[0303]

[0304] 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: Me, allyl, Ac, Boc, other alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in Scheme 7, another route for preparing compounds of formula I in which R1 = R2 = H is the photooxidation reaction of bromophenol I-1b and bromomethylcycloamine I-12 under blue LED irradiation using a combination of tris(trimethylsilyl)silane, iridium, and nickel catalysts (e.g., Ir[dF(CF3)ppy]2(dtbbpy)PF6 and NiCl2, respectively). The protecting group in compound I-7 can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted to compound I using methods known in the art.

[0305] As shown in Scheme 8, compound I-13 can be prepared from compounds I-8 and I-2d.

[0306]

[0307] 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 alkoxy carbonyl, dialkylamino carbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH or NH2. Other substituents are as defined herein. As shown in Scheme 8, a compound of formula I having a substituent R9 can be reacted with a cyclic amine I-2d containing an electron-withdrawing group (EWG) such as an ester or nitrile with benzyl bromide I-8 in the presence of a base such as sodium hexamethyldisilazide to give compound I-13. Any suitable base can be used for this reaction. The ester or nitrile group (or other electron-withdrawing group) in compound I-13 can be converted to the range of R9 groups as defined herein by methods known in the art. The protecting group in the resulting compound having the desired R9 group can then be selectively removed, and the resulting compound having free NH and / or phenolic OH groups can be optionally converted to a compound of formula I by methods known in the art.

[0308] Compounds of formula I with other R1 and R2 substituents can be synthesized from ketone I-3 by, for example, reductive amination, Wittig reaction, followed by cyclopropanation or hydroboration, or from alcohol I-4 by conversion to the corresponding bromide and replacement of the bromide with a nucleophile.

[0309] As shown in Scheme 9, compounds of formula (I) where R1 is NH2, n2=1 and n3=1 (e.g., compounds I-16 and I-17) can be prepared from compounds I-1e and I-14.

[0310]

[0311] Compounds I-14 and I-1e can be prepared by any method known in the art. As shown in Scheme 9, the three-component reaction of phenol I-1e, pyridinaldehyde I-14, and acetamide is carried out by optionally heating all three components with aluminum trichloride under solvent-free conditions to give acetamide I-15. Hydrogenation on platinum oxide reduces pyridine to piperidine I-16, and acid hydrolysis gives amine I-17.

[0312] The reactions described in Schemes 1-9 can be carried out in suitable solvents. Suitable solvents include, but are not limited to, acetonitrile, methanol, ethanol, dichloromethane, DMF, THF, MTBE, or toluene. The reactions described in Schemes 1-9 can be carried out under an inert atmosphere, such as nitrogen or argon, or in a sealed tube. The reaction mixture can be heated in a microwave or heated to a high temperature. Suitable high temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 °C or higher, or the reflux / boiling temperature of the solvent used. Optionally, the reaction mixture can be cooled in a cold bath at temperatures below room temperature, such as 0, -10, -20, -30, -40, -50, -78, or -90 °C. The reaction can be carried out by removing the solvent or partitioning the organic solvent phase with one or more aqueous phases, each aqueous phase optionally containing NaCl, NaHCO3, or NH4Cl. The solvent in the organic phase can be removed by vacuum evaporation, and the resulting residue can be purified using silica gel column chromatography or HPLC.

[0313] Pharmaceutical Composition

[0314] The present invention also provides pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0315] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from compounds of Formula I as described herein and a pharmaceutically acceptable carrier or diluent.

[0316] In some embodiments, the composition is in the form of a hydrate, a solvate, or a pharmaceutically acceptable salt. The composition may be administered to the subject via any suitable route of administration, including but not limited to oral and parenteral administration.

[0317] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, relating to the carrying or transport of an investigational drug from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable,” meaning it is compatible with the other components of the formulation and harmless to the patient. Examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as butylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic and compatible substances used in pharmaceutical formulations. The term "carrier" refers to a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be blended with and blended with the compounds of the present invention so that there are no interactions that would significantly impair the desired pharmaceutical efficacy.

[0318] As described above, certain embodiments of the pharmaceutical agents of the present invention can be provided in the form of pharmaceutically acceptable salts. In this regard, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt of the compounds of the present invention. These salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or by reacting the purified compounds of the present invention in free base form with suitable organic or inorganic acids, and separating the resulting salts. Representative salts include: hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, and dodecyl sulfonate, etc. (See, for example, Berge et al., (1977) "Pharmaceutical Salts") J. Pharm. Sci. 66:1-19.)

[0319] Pharmaceutically acceptable salts of the subject compound include conventional non-toxic salts or quaternary ammonium salts of the compound, such as those derived from non-toxic organic or inorganic acids. Examples of such conventional non-toxic salts include those derived from inorganic acids, such as hydrochlorides, hydrobromic acids, sulfates, aminosulfonates, phosphates, nitrates, etc.; and salts prepared from organic acids such as acetic acid, butyric acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, etc.

[0320] In other cases, the compounds of the present invention may contain one or more acidic functional groups, thus enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic base addition salt of the compounds of the present invention. These salts can also be prepared in situ during the final separation and purification of the compounds, or by reacting the purified compounds in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine, respectively. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., ibid.).

[0321] Wetting agents, emulsifiers and lubricants such as sodium dodecyl sulfate, magnesium stearate and polyethylene oxide-polybutane copolymer, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0322] The formulations of the present invention include those suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can be conveniently present in unit dosage forms and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount will be in the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0323] Methods for preparing these formulations or compositions include the step of combining the compounds of the present invention with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and tightly combining the compounds of the present invention with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product.

[0324] Formulations of the present invention suitable for oral administration may be in the form of capsules, flat capsules, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth gum), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as soft lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered in the form of large pills, granules, or pastes.

[0325] In the solid dosage forms (capsules, tablets, pills, lozenges, powders, granules, etc.) for oral administration of the present invention, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; and wetting agents. The pharmaceutical composition may contain excipients such as glycerin; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, sodium carbonate, and sodium starch glycolate; solution blockers such as paraffin; absorption enhancers such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polybutane copolymers; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, which use excipients such as lactose or milk sugars and high molecular weight polyethylene glycol.

[0326] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutyl methyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch-hydroxyacetate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0327] The tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as tablets, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the field of pharmaceutical formulation. They may also be formulated to provide a slow or controlled release of the active ingredient therein, for example using different proportions of hydroxybutyl methylcellulose to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be immediately dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions in which they optionally release the active ingredient in a delayed manner only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymers and waxes. The active ingredient may also be in microencapsulated form, depending on the circumstances, together with one or more of the excipients described above.

[0328] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butanediol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, and mixtures thereof. Furthermore, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, may be used to solubilize the compounds.

[0329] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0330] In addition to active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0331] Dosage forms for topical or transdermal application of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds can be mixed under sterile conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0332] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0333] In addition to the compounds of this invention, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as propane and butane.

[0334] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention into the body. This dosage form can be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flow rate of the agents of the present invention through the skin. The rate of this flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0335] Ophthalmic preparations, ointments, powders, solutions, etc., are also within the scope of this invention.

[0336] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions before use. They may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0337] In some cases, to prolong the effect of a drug, it is desirable to slow down the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of a drug depends on its dissolution rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil medium. One strategy for reservoir injection involves using polyethylene oxide-polypropylene oxide copolymers, where the medium is fluid at room temperature and solidifies at body temperature.

[0338] Injectable reservoir formulations are prepared by forming microcapsule matrices of the subject compound within biodegradable polymers such as polylactide-polyglycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0339] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be given on their own or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0340] The compounds and pharmaceutical compositions of the present invention can be used for combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (therapeutic agents or methods) used in the combination regimen will take into account the compatibility of the desired therapeutic agents and / or methods and the desired therapeutic effect to be achieved. It should also be understood that the therapy used may achieve the desired effect on the same condition (e.g., the compounds of the present invention may be administered simultaneously with another therapeutic agent). Non-limiting examples of other therapeutic agents include biological and small molecule anticancer agents, immunomodulators, immunosuppressants, anti-inflammatory agents, anti-arthritis agents, corticosteroids, antidiarrheal agents, anticoagulants, and antithrombotic agents.

[0341] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritis symptoms in mammals (e.g., humans, livestock, and domesticated animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0342] The present invention also provides pharmaceutical packages or kits comprising one or more containers filled with one or more pharmaceutical composition ingredients of the present invention. Optionally, such containers may be accompanied by a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical or biological product, reflecting the approval of the manufacturing, using, or selling agency for human administration.

[0343] Administration to subjects

[0344] In another aspect, the present invention provides a method for treating a symptom in a mammalian species in need, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from formula I or a pharmaceutically acceptable salt thereof, wherein the symptom is selected from cancer, immune disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0345] In some implementations, the cancer is selected from bile duct cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0346] In some embodiments, the inflammatory condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some embodiments, the gastrointestinal condition is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0347] In some embodiments, the immune condition is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type 1 diabetes). In some embodiments, the central nervous system (CNS) condition is Alzheimer's disease.

[0348] In some embodiments, the metabolic condition is obesity or type II diabetes. In some embodiments, the cardiovascular condition is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0349] In some implementations, the mammal species is human.

[0350] In some implementations, the condition is selected from cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0351] In another aspect, a method for blocking the Kv1.3 potassium channel in a desired mammalian species is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the compounds described herein are selective in blocking Kv 1.3 potassium channels, with minimal or no off-target inhibitory activity against other potassium channels or against calcium or sodium channels. In some embodiments, the compounds described herein do not block hERG channels, thus exhibiting the desired cardiovascular safety properties.

[0353] Some aspects of the present invention relate to administering an effective amount of the composition to a subject to achieve a specific outcome. Therefore, small molecule compositions useful according to the methods of the present invention can be formulated in any manner suitable for pharmaceutical use.

[0354] The formulations of the present invention are administered in a pharmaceutically acceptable solution form, which may typically contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optional other therapeutic components.

[0355] For therapeutic use, an effective amount of the compound may be administered to the subject in any manner that allows the compound to be absorbed by appropriate target cells. The "administration" of the pharmaceutical compositions of the present invention may be accomplished by any method known to those skilled in the art. Specific routes of administration include, but are not limited to: oral, transdermal (e.g., via patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, vaginal, etc.). Injection may be a bolus or continuous infusion.

[0356] For example, pharmaceutical compositions according to the invention are typically administered intravenously, intramuscularly, or otherwise parenterally. They can also be administered via nasal application, inhalation, topical administration, oral administration, or as implants, and even rectal or vaginal administration is possible. Suitable liquid or solid pharmaceutical formulations are, for example, aqueous or saline solutions for injection or inhalation, microencapsulation, encochleating, coating onto microgold particles, contained in liposomes, atomized, aerosols, spheres for implantation into the skin, or onto dry, sharp objects for scraping into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations with prolonged release of the active compound, in which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers are conventionally used as described above. The pharmaceutical compositions are suitable for a variety of drug delivery systems. For a brief overview of current drug delivery methods, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

[0357] The concentration of the compounds contained in the compositions used in the methods of the present invention can be in the range of about 1 nM to about 100 μM. The effective dose is considered to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0358] The pharmaceutical composition is preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders, and suppositories. For the treatment of a patient, different dosages may be required depending on the activity of the compound, the route of administration, the purpose of administration (i.e., prevention or treatment), the nature and severity of the condition, the patient's age, and weight. A given dose can be administered via a single dose in the form of a single dosage unit or several smaller dosage units. The invention also contemplates repeated and multiple administrations at specific intervals of days, weeks, or months.

[0359] The composition may be administered either in its pure form or as a pharmaceutically acceptable salt. When used as a pharmaceutical, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be conveniently used to prepare their pharmaceutically acceptable salts. These salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Similarly, these salts may be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts with carboxylic acid groups.

[0360] Suitable buffers include: acetic acid and its salt (1-2% w / v); citric acid and its salt (1-3% w / v); boric acid and its salt (0.5-2.5% w / v); and phosphoric acid and its salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v); and thimerosal (0.004-0.02% w / v).

[0361] Compositions suitable for parenteral administration conveniently include sterile aqueous formulations that are isotonic with the recipient's blood. Water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solutions are among acceptable carriers and solvents. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, fixed-state mineral or non-mineral oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can be used to prepare injectable formulations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc., administration can be... Remington's Pharmaceutical Sciences Found at Mack Publishing Company, Easton, PA.

[0362] The compounds that can be used in this invention can be delivered in the form of a mixture of two or more such compounds. In addition to the combination of compounds, the mixture may also include one or more adjuvants.

[0363] There are multiple routes of administration. Of course, the specific mode of administration will depend on the specific compound selected, the age and general health of the subject, the specific condition being treated, and the dosage required for therapeutic efficacy. Generally, the method of the present invention can be implemented using any medically acceptable route of administration, i.e., any route that produces an effective level of response without causing clinically unacceptable side effects. Preferred routes of administration are as described above.

[0364] The composition can be readily available in unit dosage forms and can be prepared by any method known in the pharmaceutical field. All methods involve the step of combining the compound with a carrier constituting one or more auxiliary components. Typically, the composition is prepared by uniformly and tightly combining the compound with a liquid carrier, a finely chopped solid carrier, or both, and then shaping the product if desired.

[0365] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems avoid repeated administration of the compound, increasing convenience for both the subject and the physician. Many types of release delivery systems are available and are known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolic acid), copolyoxalate, polycaprolactone, polyesteramide, polyorthoester, polyhydroxybutyrate, and polyanhydride. For example, U.S. Patent No. 5,075,109 describes microcapsules containing the aforementioned polymers of a drug. Delivery systems also include non-polymer systems, such as: lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; tablets using conventional adhesives and excipients; partially fused implants; and so on. Specific examples include, but are not limited to: (a) erosion systems in which the reagents of the present invention are contained in a matrix-bound form, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152; and (b) diffusion systems in which the active component permeates from the polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Furthermore, pump-based hardware delivery systems may be used, some of which are suitable for implantation.

[0366] Efficacy determination of Kv1.3 potassium channel blockers

[0367] In some embodiments, the activity of the compounds described herein for Kv1.3 potassium channels is tested. In some embodiments, the electrophysiological activity of the compounds described herein for Kv1.3 potassium channels is tested. In some embodiments, the hERG electrophysiological activity of the compounds described herein is tested.

[0368] equivalent

[0369] The representative embodiments below are intended to aid in illustrating the invention and are not intended to, nor should they be construed as, limiting the scope of the invention. In fact, various modifications to the invention and many other embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entirety of this document, including the following embodiments and references to the scientific and patent literature cited herein. It should also be understood that the contents of these cited references are incorporated herein by reference to aid in illustrating the state of the art. The following embodiments contain important additional information, examples, and guidance that can be adapted to the practice of the invention in various embodiments and equivalents thereof. Example

[0370] Examples 1-76 describe various intermediates used in the synthesis of the representative Formula I compounds disclosed herein.

[0371] Example 1. Intermediate 1 (1-(4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl)acetone)

[0372]

[0373] Step a:

[0374] Under a nitrogen atmosphere at 0°C, SOCl2 (10 mL) was added dropwise to a stirred solution of 1-acetylpiperidin-4-carboxylic acid (2.00 g, 11.68 mmol) in a DCE (20 mL). The reaction solution was then heated to room temperature. After stirring for another 1.5 hours at room temperature, the resulting solution was concentrated under reduced pressure to obtain crude 1-acetylpiperidin-4-carboxyl chloride, which was used in the next step without further purification.

[0375] Step b:

[0376] Under a nitrogen atmosphere at room temperature, 1,2-dichloro-4-methoxybenzene (0.30 g, 1.69 mmol) was added to a solution of 1-acetylpiperidin-4-formyl chloride (0.39 g, 2.03 mmol) in DCE (20 mL). After stirring for 5 minutes, anhydrous AlCl3 (0.49 g, 3.73 mmol) was added in portions at 0 °C under a nitrogen atmosphere. The reaction mixture was heated to 50 °C and stirred under a nitrogen atmosphere for 2 hours. After cooling to 0 °C, the 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, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10 / 1), to give the crude product as a deep yellow solid. The crude product was purified by preparative HPLC under the following conditions: column: Sunfire Prep C18 OBD column, 10 μm, 19 × 250 mm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 56% B to 64% B over 9 minutes; detector: UV 254 / 210 nm; retention time: 6.98 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to give 1-(4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl)acetone (85.6 mg, 16%) as a grayish-white solid. 14 H 15 Cl2NO3 [M + H] + The calculated LCMS (ESI) values ​​are 316, 318 (3:2), and the measured values ​​are also 316, 318 (3:2). 1 H NMR (300 MHz, DMSO- d 6) 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).

[0377] Example 2. Intermediate 2 ((4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl)methyl ketone)

[0378]

[0379] Step a:

[0380] 1-[4-[(4,5-dichloro-2-hydroxyphenyl)carbonyl]piperidin-1-yl]ethyl-1-one (0.15 g, 0.48 mmol) was dissolved in an aqueous HCl solution (6... N The mixture in 15 mL was stirred at 105 °C for 4 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column 19 × 250 mm, 10 μm; mobile phase A: water with 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 20% B to 60% B over 9 minutes; detector: UV 254 / 210 nm; retention time: 8.5 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to give (4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl) methyl ketone (23.5 mg, 18%) as a yellow solid: C 12 H 13 Cl2NO2 [M + H] + The calculated LCMS (ESI) values ​​are 274, 276 (3:2), and the measured values ​​are also 274, 276 (3:2). 1 H NMR (300 MHz, DMSO- d 6) 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).

[0381] Example 3. Intermediate 3 (4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylic acid tert-butyl ester trifluoroacetic acid)

[0382]

[0383] Step a:

[0384] Under a nitrogen atmosphere at room temperature, K₂CO₃ (0.74 g, 5.36 mmol) and CH₃I (0.75 g, 5.36 mmol) were added to a stirred solution of 4-(4,5-dichloro-2-hydroxybenzoyl)piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.68 mmol) in DMF (10 mL). The reaction mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The resulting mixture was diluted with water (60 mL) at room temperature and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4 / 1), to give 4-(4,5-dichloro-2-methoxybenzoyl)piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 83%) as a pale yellow solid. 18 H 23 Cl2NO4[M + H] + The calculated LCMS (ESI) values ​​are 388, 390 (3:2), and the measured values ​​are also 388, 390 (3:2).

[0385] Step b:

[0386] At 0 °C, NaBH4 (0.25 g, 6.58 mmol) was added fractionally to a stirred solution of tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine-1-carboxylate (1.70 g, 4.38 mmol) in THF (20 mL). After stirring for another 1.5 hours, the reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30 / 1), to give tert-butyl 4-((4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl)cyclohexane-1-carboxylate (1.40 g, 82%) as a grayish-white solid. 18 H 25 Cl2NO4[M +H] + The calculated LCMS (ESI) values ​​are 390, 392 (3:2), and the measured values ​​are also 390, 392 (3:2). 1 H NMR (300MHz, DMSO- d 6) δ 7.41 (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).

[0387] Step c:

[0388] At 0 °C, PBr3 (3.50 g, 12.81 mmol) was added dropwise to a stirred solution of tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]piperidine-1-carboxylate (2.50 g, 6.41 mmol) in DCM (18 mL). After stirring for another 1 hour, the reaction solution was quenched at 0 °C with saturated NaHCO3 aqueous solution (30 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 to give crude 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine, which was used directly in the next step without further purification: C 13 H 16 BrCl2NO [M + H] + The calculated LCMS (ESI) values ​​are 352, 354, 356 (2:3:1), and the measured values ​​are 352, 354, 356 (2:3:1).

[0389] Step d:

[0390] At 0 °C, a solution of Boc₂O (1.90 g, 8.50 mmol) in DCM (5 mL) was added dropwise to a stirred solution of 4-[bromo(4,5-dichloro-2-methoxyphenyl)methyl]piperidine (2.00 g, 5.66 mmol) and Et₃N (0.90 g, 8.50 mmol) in DCM (20 mL). After stirring at 0 °C for another 1 hour, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10 / 1), to give tert-butyl 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate (0.30 g, 12% total for two steps): C 18 H 24 BrCl2NO3 [M + 1 - 56] +The calculated LCMS (ESI) values ​​are 396, 398, 400 (2:3:1), and the measured values ​​are 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).

[0391] Step e:

[0392] To a stirred solution of tert-butyl 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate (0.26 g, 0.58 mmol) in DMF (5 mL), NaN3 (0.11 g, 1.74 mmol) was added at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with water (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to one-quarter volume under reduced pressure. The residue was used directly in the next step without further purification: C 18 H 24 Cl2N4O3 [M + H] + The calculated LCMS (ESI) values ​​are 415, 417 (3:2), and the measured values ​​are 415, 417 (3:2).

[0393] Step f:

[0394] At room temperature, NH3 was added dropwise to a stirred solution of tert-butyl 4-[azido(4,5-dichloro-2-methoxyphenyl)methyl]piperidine-1-carboxylate (0.20 g, 0.48 mmol) and PPh3 (0.25 g, 0.96 mmol) in THF (2 mL). H2O (1 mL, 28% in H2O). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 30% aqueous ACN (with 0.05% TFA) to give tert-butyl 4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate trifluoroacetic acid (0.10 g, 45% total for two steps): C 18 H 26 Cl2N2O3 [M + H] + The calculated LCMS (ESI) values ​​are 389, 391 (3:2), and the measured values ​​are also 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).

[0395] Example 4. Intermediate 4 (1-(4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)acetone)

[0396]

[0397] Step a:

[0398] Under a nitrogen atmosphere and at room temperature, K₂CO₃ (0.87 g, 6.33 mmol) and CH₃I (0.90 g, 6.33 mmol) were added to a stirred solution of 1-[4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl]ethyl-1-one (1.00 g, 3.16 mmol) in DMF (10 mL). The reaction mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The resulting mixture was diluted with water (60 mL) at room temperature and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1), to give 1-[4-(4,5-dichloro-2-methoxybenzoyl)piperidin-1-yl]ethyl-1-one (1.00 g, 95%) as a pale yellow solid. 15 H 17Cl2NO3 [M + H] + The calculated LCMS (ESI) values ​​are 330, 332 (3:2), and the measured values ​​are 330, 332 (3:2).

[0399] Step b:

[0400] At 0 °C, NaBH4 (0.12 g, 3.18 mmol) was added in portions to a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidin-1-yl]ethyl-1-one (0.70 g, 2.12 mmol) in MeOH (5 mL). The reaction mixture was heated to room temperature and stirred for 3 hours. At 0 °C, the reaction mixture was quenched with saturated NH4Cl aqueous solution (30 mL), extracted with EA (3 × 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1), to give 1-(4-((4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl)piperidin-1-yl)ethyl one (0.46 g, 66%) as a yellow oil: C 15 H 19 Cl2NO3[M + H] + The calculated LCMS (ESI) values ​​are 332, 334 (3:2), and the measured values ​​are 332, 334 (3:2).

[0401] Step c:

[0402] At 0 °C, PBr3 (0.75 g, 2.77 mmol) was added dropwise to a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]piperidin-1-yl]ethyl-1-one (0.46 g, 1.38 mmol) in DCM (5 mL). After stirring at 0 °C for 1 hour, the reaction solution was quenched with water (30 mL) at 0 °C and extracted with EA (4 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2 / 1) to give 1-(4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)ethyl one (50 mg, 10%) as a yellow oil: C 15 H 18 BrCl2NO2 [M + H] +The calculated LCMS (ESI) values ​​are 394, 396, 398 (2:3:1), and the measured values ​​are 394, 396, 398 (2:3:1). 1 H NMR (300MHz, CD3OD) δ 7.57 (s, 1H), 7.15 (s, 1H), 5.14 (dd, J = 9.5, 2.4 Hz, 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).

[0403] Step d:

[0404] To a solution of 1-(4-(bromo(4,5-dichloro-2-hydroxyphenyl)methyl)piperidin-1-yl)acetone (50 mg, 0.13 mmol) in DMF (3 mL) at room temperature, add NaN3 (26 mg, 0.40 mmol). Heat the reaction mixture to 100 °C and stir for 8 hours. After cooling to room temperature, dilute the resulting mixture with water (20 mL) and extract with EA (3 × 25 mL). Wash the combined organic layers with brine (3 × 10 mL) and dry over anhydrous Na2SO4. Filter and concentrate the filtrate to one-quarter volume under reduced pressure. Use the residue directly for the next step without further purification: C 15 H 18 Cl2N4O2 [M + H] + The calculated LCMS (ESI) values ​​are 357, 359 (3:2), and the measured values ​​are also 357, 359 (3:2).

[0405] Step e:

[0406] To a solution of 1-[4-[azido(4,5-dichloro-2-methoxyphenyl)methyl]piperidin-1-yl]acetophenone (0.10 g, 0.28 mmol) in THF (4 mL), PPh3 (0.15 g, 0.56 mmol) and NH3·H2O (1 mL, 28% in H2O) were added at room temperature. The reaction mixture was stirred for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 29% ACN aqueous solution (with 0.05% TFA), to give 1-(4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)acetophenone (30 mg, 71% total for two steps): C 15 H 20 Cl2N2O2 [M + H] + The calculated LCMS (ESI) values ​​are 331, 333 (3:2), and the measured values ​​are 331, 333 (3:2). 1 H NMR (300 MHz, CD3OD) δ 7.47 (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).

[0407] Example 5. Intermediate 5 ( N -((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0408]

[0409] Step a:

[0410] At 0 °C, Boc₂O (14.90 g, 68.21 mmol) was added in portions to a stirred solution of (4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl) methyl ketone (17 g, 62.27 mmol) and Et₃N (31.44 g, 0.31 mol) in DCM (150 mL). The reaction solution was heated to room temperature and stirred for 4 hours at room temperature. The resulting 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 used directly in subsequent steps without further purification: C 17 H 21 Cl2NO4 [M +H] + The calculated LCMS (ESI) values ​​are 374, 376 (3:2), and the measured values ​​are also 374, 376 (3:2).

[0411] Step b:

[0412] Under a nitrogen atmosphere at room temperature, allyl bromide (14.48 g, 0.12 mmol) was added dropwise to a mixture of crude 4-(4,5-dichloro-2-hydroxybenzoyl)piperidine-1-carboxylate and K₂CO₃ (33.20 g, 0.24 mmol) in DMF (200 mL). The reaction mixture was heated to 40 °C and stirred for 12 hours. The resulting mixture was diluted with water (500 mL) and extracted with EA (2 × 500 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 residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1), to give tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate (15.40 g, 64% total for two steps) as a pale yellow solid: C 20 H 25 Cl2NO4 [M + H] + The calculated LCMS (ESI) value is 414, 416 (3:2), and the measured value is 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).

[0413] Step c:

[0414] Under a nitrogen atmosphere at room temperature, 2-methylpropane-2-sulfinamide (3.86 g, 31.85 mmol) was added fractionally to a stirred mixture of tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]piperidin-1-carboxylate (8.80 g, 21.24 mmol) and Ti(OEt)4 (21.51 g, 94.30 mmol) in THF (50 mL). The reaction mixture was heated to 70 °C and stirred under a nitrogen atmosphere for 16 hours. The resulting mixture was quenched with water (200 mL) at room temperature. A solid was formed and filtered. The filtrate was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain crude tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate. The crude product was used directly in subsequent steps without further purification: C 24 H 34 Cl2N2O4S [M + H] + The calculated LCMS (ESI) values ​​are 517, 519 (3:2), and the measured values ​​are 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, 9H).

[0415] Step d:

[0416] Under a nitrogen atmosphere and at 0 °C, NaBH4 (1.21 g, 31.86 mmol) was added in portions to a solution of crude tert-butyl piperidine-1-carboxylate in MeOH (80 mL). After addition, the reaction mixture was heated to room temperature and stirred under a nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (150 mL) at 0 °C and extracted with EA (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluted with 45% ACN aqueous solution (with 0.05% TFA), to give tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (6.58 g, 60% total for two steps): C 24 H 36 Cl2N2O4S[M + H] + The calculated LCMS (ESI) values ​​are 519, 521 (3:2), and the measured values ​​are also 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), 1.23 (s, 9H).

[0417] Step e:

[0418] At room temperature, TFA (20 mL) was added dropwise to a stirred solution of tert-butyl piperidine-1-carboxylate (6.58 g, 12.68 mmol) in DCM (100 mL). 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 system was adjusted to 9 at 0 °C with saturated NaHCO3 aqueous solution. 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 purified by reversed-phase chromatography, eluting with 35% ACN aqueous solution (with 0.05% TFA), to obtain a pale yellow oil. N -((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide (4.24 g, 80%):C 19 H 28 Cl2N2O2S [M + H] + The calculated LCMS (ESI) values ​​are 419, 421 (3:2), and the measured values ​​are also 419, 421 (3:2). 1 H NMR (300 MHz, DMSO- d 6+ D2O) 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).

[0419] Example 6. Intermediate 6 (( S )- N -(( R )-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method A

[0420]

[0421] Step a:

[0422] Under a nitrogen atmosphere at room temperature, tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate (5.16 g, 12.45 mmol) and Ti(OEt)4 (8.52 g, 37.36 mmol) in a stirred solution of tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate (50 mL) was added to... S 2-Methylpropane-2-sulfinamide (1.67 g, 13.70 mmol). The reaction solution was heated to 70 °C and stirred for 36 hours. After cooling to room temperature, the resulting solution was quenched with water (300 mL) at room temperature. A solid was formed and filtered. The filtrate was extracted with EA (2 × 500 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 residue was dried in a vacuum oven to obtain a pale yellow solid. S )-4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylic acid tert-butyl ester (6.00 g, 93%): C 24 H 34 Cl2N2O4S [M + H] + The calculated LCMS (ESI) values ​​are 517, 519 (3:2), and the measured values ​​are also 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, 2H), 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).

[0423] Step b:

[0424] Under a nitrogen atmosphere, at -65°C, for 30 minutes, to ( S4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidin-1-carboxylic acid tert-butyl ester (1.50 g, 2.90 mmol) was added dropwise to a solution of toluene (10 mL) with DIBAL-H (4.35 mL, 4.35 mmol, 1 M toluene solution). After addition, the reaction solution was stirred at -65 °C for 3 hours under a nitrogen atmosphere. The resulting solution was quenched with water (20 mL) at -65 °C and then diluted with a saturated aqueous solution of potassium sodium tartrate (200 mL). The aqueous layer was extracted with EA (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 45% ACN aqueous solution (with 0.05% TFA) to give 4-(( R )-(2-(allyloxy)-4,5-dichlorophenyl)(( S 1,1-Dimethylethylsulfinamidomethylpiperidine-1-carboxylic acid tert-butyl ester (0.78 g, 52%): C 24 H 36 Cl2N2O4S [M + H] + The calculated LCMS (ESI) values ​​are 519, 521 (3:2), and the measured values ​​are 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).

[0425] Step c:

[0426] At room temperature, to the stirred 4-(( R )-(2-(allyloxy)-4,5-dichlorophenyl)(( S1,1-Dimethylethylsulfinamidomethylpiperidine-1-carboxylic acid tert-butyl ester (16.00 g, 30.80 mmol) was added dropwise to a solution of TFA (30 mL) in DCM (120 mL). 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 system was adjusted to 8 at 0 °C with saturated NaHCO3 aqueous solution. 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 purified by reversed-phase chromatography, eluting with 35% ACN aqueous solution containing 10 mmol / L NH4HCO3, to obtain (…) as a yellow oil. S )- N -(( R )-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide (7.00 g, 46%): C 19 H 28 Cl2N2O2S [M + H] + The calculated LCMS (ESI) values ​​are 419, 421 (3:2), and the measured values ​​are also 419, 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).

[0427] Intermediate 6 (( S )- N -(( R )-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method B

[0428]

[0429] Step a:

[0430] Under a nitrogen atmosphere at 0°C, Br2 (98.04 g, 613.49 mmol) was added dropwise to a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL). The reaction solution was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous solution of Na2S2O3 (500 mL) at 0°C. The resulting mixture was extracted with EA (6 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4,5-dichlorophenol as a yellow oil. The crude product was used directly in subsequent steps without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.15 (s, 1H).

[0431] Step b:

[0432] Under a nitrogen atmosphere at room temperature, 3-bromoprop-1-ene (37.51 g, 310.06 mmol) was added dropwise to a stirred solution of 2-bromo-4,5-dichlorophenol (50.00 g, 206.71 mmol) and K₂CO₃ (57.14 g, 413.41 mmol) in DMF (500 mL). The reaction mixture was stirred for 16 hours at 40 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (1.5 L) and extracted with EA (3 × 0.5 L). The combined organic layers were washed with brine (4 × 0.5 L) 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, to give 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (40.00 g, 61%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ7.65 (s, 1H), 6.98 (s, 1H), 6.12-6.06 (m, 1H), 5.60-5.29 (m, 2H), 4.69-4.57(m, 2H).

[0433] Step c:

[0434] Under a nitrogen atmosphere, at -15°C, the solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (30.00 g, 106.39 mmol) in THF (800 mL) was added dropwise over 30 minutes. i-PrMgCl-LiCl (125 mL, 159.59 mmol, 1.3 M THF solution). The resulting mixture was stirred for an additional 0.5 hours at -15 °C under a nitrogen atmosphere. Then, 4-[[( S 4-[( )-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylic acid tert-butyl ester (33.67 g, 106.39 mmol). After addition, the reaction mixture was stirred at -15 °C for 2 hours. The reaction was quenched at -15 °C with saturated NH4Cl aqueous solution (100 mL) and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 100 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 (1 / 2), to give 4-[( R )-[4,5-Dichloro-2-(prop-2-en-1-yloxy)phenyl]([[( S 2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (34.00 g, 58%): C 24 H 36 Cl2N2O4S [M + H] + The calculated LCMS (ESI) values ​​are 519, 521 (3:2), and the measured values ​​are also 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).

[0435] Step d:

[0436] At room temperature, add 4-[( R )-[4,5-Dichloro-2-(prop-2-en-1-yloxy)phenyl]([[( S tert-butyl 2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylate (5.70 g, 10.97 mmol) was added dropwise to a mixture in DCM (40 mL) with TFA (10 mL). The reaction solution was stirred at room temperature for 1 hour. The mixture was neutralized to pH 9 with saturated NaHCO3 aqueous solution at 0 °C. The resulting mixture was extracted with EA (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography, eluting with 40% ACN aqueous solution containing 10 mmol / L NH4HCO3, to give a yellow solid. S )- N -[( R )-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (3.50 g, 68%): C 19 H 28 Cl2N2O2S [M + H] + The calculated LCMS (ESI) values ​​are 419, 421 (3:2), and the measured values ​​are also 419, 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).

[0437] Example 7. Intermediate 7 ( N -((2-hydroxynaphth-1-yl)(pyridin-4-yl)methyl)acetamide)

[0438]

[0439] Step a:

[0440] Under a nitrogen atmosphere, AlCl3 (0.49 g, 3.64 mmol) was added in fractional batches to a mixture of naphthalene-2-phenol (3.50 g, 24.28 mmol), acetamide (1.72 g, 29.13 mmol), and pyridine-4-carboxaldehyde (2.60 g, 24.28 mmol) under stirring at 110 °C. The reaction mixture was stirred at 110 °C for 8 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (60 mL). The aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (8 / 1), to obtain a light green solid. N -[(2-hydroxynaphth-1-yl)(pyridin-4-yl)methyl]acetamide (1.00 g, 14%): C 18 H 16 N₂O₂ [M + H] + The calculated LCMS (ESI) value is 293, and the measured value is 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 = 9.0Hz, 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).

[0441] Example 8. Intermediate 8 ( N -((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide trifluoroacetic acid)

[0442]

[0443] Step a:

[0444] At room temperature, an aqueous solution of HCl (6 mmol) was added to a stirred solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (0.50 g, 0.96 mmol) in 1,4-dioxane (5 mL). N , 0.5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was neutralized to pH 7 with saturated NaHCO3 aqueous solution and then concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 60% ACN aqueous solution containing 20 mmol / L NH4HCO3, to give tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(amino)methyl)piperidine-1-carboxylate (0.40 g, 90%) as a brown oil. 20 H 28 Cl2N2O3 [M + H] + The calculated LCMS (ESI) value is 415,417 (3:2), and the measured value is 415,417 (3:2).

[0445] Step b:

[0446] At 0 °C, TFAA (61 mg, 0.29 mmol) was added dropwise to a stirred solution of tert-butyl piperidine-1-carboxylate (0.11 g, 0.27 mmol) and Et3N (54 mg, 0.53 mmol) in DCM (3 mL). The reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was diluted with DCM (50 mL). The solution was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl piperidine-1-carboxylate (0.13 g, 95%) as a yellow solid: C 22 H 27 Cl2F3N2O4 [M + H] + The calculated LCMS (ESI) values ​​are 511, 513 (3:2), and the measured values ​​are 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).

[0447] Step c:

[0448] TFA (3 mL) was added dropwise to a solution of 0.13 g (0.25 mmol) of 4-((2-(allyloxy)-4,5-dichlorophenyl)(2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylic acid tert-butyl ester (3 mL) in DCM (3 mL) at room temperature. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid. N -((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide trifluoroacetic acid (0.10 g, 90%):C 17 H 19 Cl2F3N2O2 [M + H] + The calculated LCMS (ESI) values ​​are 411, 413 (3:2), and the measured values ​​are 411, 413 (3:2).

[0449] Example 9. Intermediate 9 (1-(allyloxy)-2-bromo-3,4,5-trichlorobenzene)

[0450]

[0451] Step a:

[0452] At room temperature, H₂O₂ (1.51 g, 44.39 mmol, 30%) and NaOH (1.78 g, 44.39 mmol) were added to a stirred solution of (3,4,5-trichlorophenyl)boric acid (5.00 g, 22.20 mol) in THF (15 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched at room temperature with a saturated aqueous solution of Na₂SO₃ (10 mL). The mixture was then quenched with an aqueous solution of HCl (1... NAcidify to pH 3. Extract the resulting mixture with EA (3 × 80 mL). Wash the combined organic layers with brine (2 × 80 mL) and dry to anhydrous Na₂SO₄. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with PE / EA (5 / 1), to give 3,4,5-trichlorophenol (4.30 g, 95%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl3) δ 6.92 (s, 2H).

[0453] Step b:

[0454] Under an argon atmosphere at room temperature, Br2 (3.70 g, 23.15 mol) was added dropwise to a stirred solution of 3,4,5-trichlorophenol (4.60 g, 23.30 mol) in AcOH (20 mL). After stirring for 6 hours, the reaction was quenched with saturated aqueous Na2SO3 solution (80 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with PE / EA (20 / 1), to give 2-bromo-3,4,5-trichlorophenol (2.40 g, 37%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ11.43 (s, 1H), 7.15 (s, 1H).

[0455] Step c:

[0456] At room temperature, allyl bromide (1.26 g, 10.42 mmol) was added to a stirred solution of 2-bromo-3,4,5-trichlorophenol (2.40 g, 8.69 mmol) and K₂CO₃ (2.40 g, 17.37 mmol) in DMF (15 mL). The reaction mixture was heated to 50 °C and stirred for 1 hour. The reaction mixture was diluted with EA (80 mL) and water (80 mL), and then extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (6 × 80 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with PE / EA (20 / 1), to give 2-bromo-3,4,5-trichloro-1-(prop-2-en-1-yloxy)benzene (1.80 g, 66%) as a pale yellow oil.

[0457] Example 10. Intermediate 10 (( S)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylic acid tert-butyl ester)

[0458]

[0459] Step a:

[0460] Under a nitrogen atmosphere at room temperature, 50.00 g (0.23 mol) of tert-butyl 4-formylpiperidine-1-carboxylate and ( S 2-Methylpropane-2-sulfinamide (43.00 g, 0.35 mmol) was added dropwise to a solution of Ti(OEt)4 (187.00 g, 0.82 mol) in THF (300 mL). The reaction solution was stirred for 4 hours at room temperature under a nitrogen atmosphere. The resulting solution was quenched with 200 mL of saturated NH4Cl aqueous solution at room temperature 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 to obtain ( ) as a grayish-white solid. S 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylic acid tert-butyl ester (67 g, 81%): C 15 H 28 N₂O₃S [M + H] + The calculated LCMS (ESI) value is 317, and the measured value is also 317. 1 H NMR (300 MHz, CDCl3) δ8.01 (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, 2H), 1.47 (s, 9H), 1.20 (s, 9H).

[0461] Example 11. Intermediate 11 (4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylic acid tert-butyl ester)

[0462]

[0463] Step a:

[0464] Under a nitrogen atmosphere at room temperature, Ti(OEt)₄ (50.00 g, 0.18 mmol) was added dropwise to a stirred solution of tert-butyl 4-formylpiperidin-1-carboxylate (20.00 g, 93.90 mmol) and 2-methylpropane-2-sulfinamide (17.00 g, 0.14 mol) in THF (300 mL). The reaction solution was stirred for 4 hours under a nitrogen atmosphere at room temperature. The resulting solution was quenched with saturated aqueous NH₄Cl solution (200 mL) at room temperature 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 to give tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidin-1-carboxylate (24.00 g, 80%) as a pale yellow solid. 15 H 28 N₂O₃S [M + H] + The calculated LCMS (ESI) value is 317, and the measured value is also 317.

[0465] Example 12. Intermediate 12 (( S )- N -((1-((R)-2,2-dimethyl-1,3-dioxacyclopentane-4-carbonyl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide)

[0466]

[0467] Step a:

[0468] At room temperature, TFA (30 mL) was added to a stirred solution of tert-butyl 4-formylpiperidin-1-carboxylate (9.00 g, 42.20 mmol) in DCM (60 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure. The crude product was used for subsequent steps without further purification: C6H 11 NO [M + H] + The calculated LCMS (ESI) value is 114, and the measured value is 114.

[0469] Step b:

[0470] Under a nitrogen atmosphere at room temperature, the mixture was stirred (4... RPiperidine-4-carboxylic acid (8.37 g, 57.27 mmol) and HATU (21.77 g, 57.26 mmol) in a solution of DMF (150 mL) were mixed with piperidine-4-carboxaldehyde (5.40 g, 47.72 mmol) and Et3N (72.43 g, 0.72 mol). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (100 mL) at room temperature and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in subsequent steps without further purification: C 12 H 19 NO4 [M + H] + The calculated LCMS (ESI) value is 242, and the measured value is 242.

[0471] Step c:

[0472] Under a nitrogen atmosphere at room temperature, 1-[(4) was stirred. R )-2,2-dimethyl-1,3-dioxacyclopentane-4-carbonyl]piperidine-4-carboxaldehyde (4.30 g, 17.82 mmol) and ( S 2-Methylpropane-2-sulfinamide (3.24 g, 26.73 mmol) was added to a solution of Ti(OEt)4 (12.20 g, 53.48 mmol) in THF (40 mL). The resulting mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:3), to give a pale yellow oil. S )- N -((1-(( R 2,2-Dimethyl-1,3-dioxacyclopentane-4-carbonyl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (4.37 g, 71%): C 16 H 28 N₂O₄S [M + H] + The calculated LCMS (ESI) value is 345, and the measured value is also 345. 1 HNMR (400 MHz, DMSO- d 6) 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).

[0473] Example 13. Intermediate 13 (2,2-dimethyl-1,3-dioxacyclopentane-4-carboxylic acid)

[0474]

[0475] Step a:

[0476] At room temperature, methyl 2,2-dimethyl-1,3-dioxacyclopentane-4-carboxylic acid (3.00 g, 18.73 mmol) was added in portions to a mixture of stirred KOH (2.10 g, 37.42 mmol) in H₂O (9 mL) and EtOH (18 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 4 with 10% aqueous H₃PO₄ solution. The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 2,2-dimethyl-1,3-dioxacyclopentane-4-carboxylic acid (1.80 g, 65%) as a colorless oil. 1 H NMR (400 MHz, DMSO- d 6) 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).

[0477] Example 14. Intermediate 14 (( R 2,2-Dimethyl-1,3-dioxacyclopentane-4-carboxylic acid

[0478]

[0479] Step a:

[0480] At room temperature, add in portions (4 g) of KOH (3.50 g, 62.38 mmol) to a stirred solution of H₂O (5 mL) and EtOH (10 mL). R Methyl 2,2-dimethyl-1,3-dioxane-4-carboxylate (5.00 g, 31.22 mmol). The reaction mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with H2O (10 mL) and acidified to pH 3 with 10% H3PO4 aqueous solution. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (4) a pale yellow oil. R 2,2-Dimethyl-1,3-dioxacyclopentane-4-carboxylic acid (3.00 g, 66%): C6H 10 O4 [M - H] + The calculated LCMS (ESI) value is 145, and the measured value is also 145. 1 H NMR (400 MHz, DMSO- d 6) δ 12.80 (br, 1H), 4.59-4.50 (m,1H), 4.27-4.10 (m, 1H), 4.00-3.91 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H).

[0481] Example 15. Intermediate 15 (1,2-Dichloro-3-iodo-4-methoxybenzene)

[0482]

[0483] Step a:

[0484] Under a nitrogen atmosphere at room temperature, diethylcarbamoyl chloride (62.39 g, 460.12 mmol) was added dropwise to a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol), DMAP (74.95 g, 613.50 mmol), and Et3N (62.08 g, 613.50 mmol) in DCM (500 mL). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The resulting mixture was diluted with water (300 mL) at room temperature 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (40 / 1), to obtain a yellow oil.N , N -Diethylcarbamate 3,4-dichlorophenyl dichlorocarbamate (72.00 g, 80%): C 11 H 13 Cl2NO2 [M + H] + The calculated LCMS (ESI) values ​​are 262, 264 (3:2), and the measured values ​​are also 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).

[0485] Step b:

[0486] Under a nitrogen atmosphere and at -78°C, diethylpropylamine (DIPA, 42.46 g, 419.64 mmol) was added dropwise to a solution of THF (400 mL) over 0.5 hours. n -BuLi (29.32 g, 457.79 mmol, 2.5 M hexane solution). After stirring at -78 °C for 20 minutes, the solution was then added dropwise over 20 minutes at -78 °C. N , N A solution of 3,4-dichlorophenyl diethylcarbamate (100.00 g, 381.49 mmol) in THF (100 mL) was added. After addition, the mixture was stirred for an additional 0.5 h at -78 °C under a nitrogen atmosphere. A solution of I2 (101.67 g, 400.56 mmol) in THF (50 mL) was added dropwise to the mixture at -78 °C over 0.5 h. The mixture was stirred for an additional 2 h at -78 °C. The mixture was quenched with a saturated aqueous solution of Na₂SO₃ (300 mL) at -78 °C 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (40 / 1), to obtain a grayish-white solid. N , N-Diethylcarbamate 3,4-dichloro-2-iodophenyl ester (117.00 g, 79%): C 11 H 12 Cl2INO2 [M + H] + The calculated LCMS (ESI) values ​​are 388, 390 (3:2), and the measured values ​​are also 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).

[0487] Step c:

[0488] At 0°C, the stirring... N , N A solution of 3,4-dichloro-2-iodophenyl diethylcarbamate (65.80 g, 169.58 mmol) in MeOH (100 mL) was added to a solution of NaOH (67.82 g, 1695.75 mmol) in H₂O (200 mL). The resulting mixture was heated to 50 °C and stirred for 10 hours. The pH of the solution was adjusted using an aqueous HCl solution (1... N Adjust the temperature to 6-7. At room temperature, dilute the reaction mixture with water (400 mL) and extract with EA (3 × 400 mL). Wash the combined organic layers with brine (3 × 100 mL) and dry over anhydrous Na₂SO₄. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with PE / EA (40 / 1) to give 3,4-dichloro-2-iodophenol (47.00 g, 96%) as a yellow oil. 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).

[0489] Step d:

[0490] Under a nitrogen atmosphere at room temperature, CH3I (73.70 g, 519.23 mmol) and K2CO3 (95.68 g, 692.31 mmol) were added to a stirred solution of 3,4-dichloro-2-iodophenol (100.00 g, 346.15 mmol) in DMF (300 mL). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 5 hours. The reaction mixture was diluted with water (500 mL) at room temperature and extracted with EA (3 × 600 mL). The combined organic layers were washed with brine (3 × 1000 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 (20 / 1), to give 1,2-dichloro-3-iodo-4-methoxybenzene (88.00 g, 84%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44(d, J = 8.9 Hz, 1H), 6.69 (d, J = 8.8 Hz (1H), 3.91 (s, 3H).

[0491] Example 16. Intermediate 16 (1-(allyloxy)-3,4-dichloro-2-iodobenzene)

[0492]

[0493] Step a:

[0494] At room temperature, 3-bromoprop-1-ene (15.70 g, 129.81 mmol) was added dropwise to a stirred solution of 3,4-dichloro-2-iodophenol (25.00 g, 86.54 mmol) and K₂CO₃ (35.88 g, 259.61 mmol) in DMF (100 mL). The resulting mixture was heated to 40 °C and stirred under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1), to give 1,2-dichloro-3-iodo-4-(prop-2-en-1-yloxy)benzene (16.00 g, 50%) as a yellow solid. 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).

[0495] Example 17. Intermediate 17 (4-(1-(4,5-dichloro-2-methoxyphenyl)vinyl)piperidine-1-carboxylic acid tert-butyl ester)

[0496]

[0497] Step a:

[0498] Under a nitrogen atmosphere at 0°C, NaH (0.12 g, 3.09 mmol, 60% mineral oil solution) was added in portions to a stirred solution of methyltriphenylphosphonium bromide (1.10 g, 3.09 mmol) in THF (15 mL). The reaction mixture was heated to room temperature and stirred for 15 minutes. Then, a solution of 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.06 mmol) in THF (3 mL) was added. The reaction mixture was stirred at room temperature for an additional 2 hours under a nitrogen atmosphere. The resulting mixture was quenched with a saturated aqueous solution of NH4Cl (40 mL) and extracted with EA (3 × 10 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, eluted with PE / EA (5 / 1), to give tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)vinyl]piperidine-1-carboxylate (0.50 g, 63%) as a pale yellow oil: C 19 H 25 Cl2NO3 [M + H] + The calculated LCMS (ESI) values ​​are 386, 388 (3:2), and the measured values ​​are also 386, 388 (3:2). 1H 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).

[0499] Example 18. Intermediate 18 (( S )- N -(( R )-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0500]

[0501] Step a:

[0502] Under a nitrogen atmosphere, at -65°C, 5-bromo-1,2-dichloro-3-fluorobenzene (4.00 g, 16.40 mmol) was added dropwise over 30 minutes to a solution of 5-bromo-1,2-dichloro-3-fluorobenzene in 50 mL of THF. i -PrMgCl·LiCl (25 mL, 32.80 mmol, 1.3 M THF solution). After stirring for another 30 minutes, a solution of B(OMe)3 (2.56 g, 24.60 mmol) in THF (10 mL) was added dropwise at -65 °C. After addition, the reaction mixture was stirred at -65 °C for 30 minutes under a nitrogen atmosphere. The resulting mixture was quenched with water (100 mL) at -65 °C and extracted with EA (2 × 300 mL). The combined organic layers were washed with brine (2 × 60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with a 50% aqueous solution of NH4HCO3 containing 10 mmol / L NH4HCO3, to give (3,4-dichloro-5-fluorophenyl)boronic acid (0.36 g, 94%) as a yellow solid: C6H4BCl2FO2 [M - H] + The calculated LCMS (ESI) values ​​are 207, 209 (3:2), and the measured values ​​are also 207, 209 (3:2). 1 H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H).

[0503] Step b:

[0504] Under air and at room temperature, H₂O₂ (2.54 g, 74.71 mmol, 30% aqueous solution) was added dropwise to a stirred mixture of (3,4-dichloro-5-fluorophenyl)boric acid (3.60 g, 18.66 mmol) and KOH (4.19 g, 74.71 mmol, 4.00 equivalents) in MeOH (20 mL). The reaction mixture was stirred for 2 hours under air and at room temperature. The resulting mixture was quenched with saturated NaHSO₃ aqueous solution (100 mL) at room temperature, and then acidified to pH 4 with citric acid. The resulting mixture was extracted with EA (2 × 400 mL). The combined organic layers were washed with brine (2 × 60 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1), to give 3,4-dichloro-5-fluorophenol (2.65 g, 70%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) 6.83(s, 1H), 6.64 (dd, J = 9.8, 2.8 Hz, 1H), 5.64 (s, 1H).

[0505] Step c:

[0506] Under a nitrogen atmosphere at room temperature, diethylcarbamoyl chloride (2.33 g, 17.24 mmol) was added dropwise to a stirred solution of 3,4-dichloro-5-fluorophenol (2.60 g, 14.36 mmol), Et3N (4.36 g, 43.09 mmol), and DMAP (3.51 g, 28.73 mmol) in DCM (20 mL). After stirring for 2 hours at room temperature under a nitrogen atmosphere, the reaction solution was quenched with water (130 mL) at room temperature and extracted with EA (2 × 200 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 purified by silica gel column chromatography, eluting with PE / EA (6 / 1), to obtain a grayish-white solid. N , N -Diethylcarbamate 3,4-dichloro-5-fluorophenyl ester (3.20 g, 70%): C 11 H 12 Cl2FNO2 [M + H] +The calculated LCMS (ESI) values ​​are 280 and 282 (3:2), while the measured values ​​are also 280 and 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).

[0507] Step d:

[0508] Under a nitrogen atmosphere, at -65°C, for 10 minutes... N , N 3,4-Dichloro-5-fluorophenyl diethylcarbamate (0.50 g, 1.79 mmol) was added to a solution of LDA (1.34 mL, 2.68 mmol, 2 M THF solution) in 10 mL of THF. After addition, the reaction solution was stirred at -65°C for 30 minutes, and then, under a nitrogen atmosphere, the solution was added dropwise over 10 minutes at -65°C. S A solution of 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate tert-butyl ester (0.85 g, 2.68 mmol) in THF (5 mL). After stirring for an additional 1 hour at -65°C under a nitrogen atmosphere, the resulting mixture was quenched with water (30 mL) at -65°C and extracted with EA (2 × 70 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 to obtain crude 4-(( R )-(3,4-dichloro-6-((diethylcarbamoyl)oxy)-2-fluorophenyl)(( S 1,1-Dimethylethylsulfinamidomethylpiperidine-1-carboxylic acid tert-butyl ester. The crude product can be used in subsequent steps without further purification: C 26 H 40 Cl2FN3O5S [M + H] + The calculated LCMS (ESI) value is 596,598 (3:2), and the measured value is 596,598 (3:2).

[0509] Step e:

[0510] At room temperature to 4-(( R )-(3,4-Dichloro-6-((diethylcarbamoyl)oxy)-2-fluorophenyl)(( SCrude tert-butyl 1,1-dimethylethylsulfinamidomethylpiperidine-1-carboxylate was added in portions to a solution of MeOH (20 mL) with NaOH (0.45 g, 11.32 mmol). The resulting mixture was heated to 50 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) at room temperature and acidified to pH 4 with citric acid. The resulting solution was extracted with EA (2 × 200 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 60% ACN aqueous solution (with 0.05% TFA) to give 4-[( S )-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)([[( R 2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 68% total for two steps): C 21 H 31 Cl2FN2O4S [M + H] + The calculated LCMS (ESI) values ​​are 497, 499 (3:2), and the measured values ​​are also 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).

[0511] Step f:

[0512] At room temperature to 4-[( S )-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)([[( R [2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (crude) was added dropwise to a solution of TFA (2 mL) in DCM (10 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was adjusted to pH 8 with saturated NaHCO3 aqueous solution and extracted with EA (2 × 80 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 to obtain crude (2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil. R )-N -[( S )-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (0.40 g, 83%). The crude product was used directly in subsequent steps without further purification: C 16 H 23 Cl2FN2O2S [M + H] + The calculated LCMS (ESI) values ​​are 397, 399 (3:2), and the measured values ​​are also 397, 399 (3:2). 1 H NMR (400 MHz, 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).

[0513] Example 19. Intermediate 19 ((2 R (1-Methyl-5-oxopyrrolidine-2-carboxylic acid lithium)

[0514]

[0515] Step a:

[0516] Under a nitrogen atmosphere at 0°C, the mixture was stirred (2... R Ethyl 5-oxopyrrolidine-2-carboxylate (0.50 g, 3.18 mmol) was added to a solution of NaH (0.25 g, 6.36 mmol, 60% mineral oil solution) in THF (4 mL). The resulting mixture was stirred at 0 °C for 10 min. Then MeI (0.90 g, 6.36 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched at 0 °C with water (3 mL). The resulting mixture was diluted with DCM (30 mL) and water (30 mL), and the aqueous layer was extracted with DCM (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 to give (2) a pale yellow oil. R ethyl 1-methyl-5-oxopyrrolidine-2-carboxylate (0.22 g, 40%): C8H 13 NO3 [M + H]+ LCMS (ESI) 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).

[0517] Step b:

[0518] Stirring at room temperature (2) R Ethyl 1-methyl-5-oxopyrrolidine-2-carboxylate (0.15 g, 0.95 mmol) in MeOH (2 mL) was mixed with a solution of LiOH·H₂O (48 mg, 1.15 mmol) in H₂O (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure to give (2...) as a grayish-white solid. R Lithium 1-methyl-5-oxopyrrolidine-2-carboxylate (0.15 g, crude) can be used directly in subsequent steps without further purification: C6H9NO3 [M + H] + The calculated LCMS (ESI) value is 144, and the measured value is 144.

[0519] Example 20. Intermediate 20 (1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene)

[0520]

[0521] Step a:

[0522] CH3I (2.51 g, 17.69 mmol) was added dropwise to a mixture of 4-chloro-3-iodophenol (3.00 g, 11.79 mmol) and K2CO3 (3.26 g, 23.59 mmol) in DMF (30 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (50 mL) and water (100 mL). The aqueous solution was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (6 × 30 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 (20 / 1) to give 1-chloro-2-iodo-4-methylbenzene (2.90 g, 92%) as a colorless oil. 1H 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).

[0523] Step b:

[0524] Under a nitrogen atmosphere, at -78°C, a solution of 1-chloro-2-iodo-4-methoxybenzene (1.00 g, 3.73 mmol) in THF (5 mL) was added dropwise. n -BuLi (2.2 mL, 5.59 mmol, 2.5 M hexane solution). The solution was stirred at -78 °C for 30 min under a nitrogen atmosphere. Then cyclobutanone (0.39 g, 5.59 mmol) was added to the solution. The resulting solution was stirred at -78 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl aqueous solution (3 mL). The resulting mixture was diluted with EA (30 mL) and water (30 mL), and 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 (3 / 1), to give 1-(2-chloro-5-methoxyphenyl)cyclobut-1-ol (0.56 g, 71%) as a pale yellow oil. 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), 2.50-2.37 (m, 2H), 2.23-2.12 (m, 1H), 1.78-1.66 (m, 1H).

[0525] Step c:

[0526] Under a nitrogen atmosphere at room temperature, BF3·Et2O (0.75 g, 5.27 mmol) was added to a stirred solution of 1-(2-chloro-5-methoxyphenyl)cyclobut-1-ol (0.56 g, 2.63 mmol) and Et3SiH (0.61 mg, 5.27 mmol) in DCM (3 mL). The solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20 / 1), to give 1-chloro-2-cyclobutyl-4-methoxyphenyl (0.49 g, 95%) as a colorless oil. 1 H NMR (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).

[0527] Step d:

[0528] Br2 (0.43 g, 2.69 mmol) was added dropwise to a stirred solution of 1-chloro-2-cyclobutyl-4-methoxybenzene (0.48 g, 2.44 mmol) in HOAc (5 mL) at room temperature. The solution was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous solution of Na2SO3 (2 mL) and 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 (20 / 1) to give 1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene (0.60 g, 72%) as a colorless liquid. 1 H 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),1.94-1.80 (m, 1H).

[0529] Example 21. Intermediate 21 (1-bromo-5-chloro-4-fluoro-2-(prop-2-en-1-yloxy)benzene)

[0530]

[0531] Step a:

[0532] Br2 (2.62 g, 16.40 mmol) was added to a stirred solution of 4-chloro-3-fluorophenol (2.00 g, 13.65 mmol) in DCM (15 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched at room temperature with a saturated aqueous solution of Na2SO3 (30 mL). The aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4-chloro-5-fluorophenol (3.40 g, crude) as a pale yellow oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 10.5 hours (z, 1 hour).

[0533] Step b:

[0534] 3-Bromoprop-1-ene (2.74 g, 22.65 mmol) was added dropwise to a mixture of 2-bromo-4-chloro-5-fluorophenol (3.40 g, 15.08 mmol) and K₂CO₃ (4.17 g, 30.17 mmol) in DMF (30 mL) under stirring at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture 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 × 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 (20 / 1) to give 1-bromo-5-chloro-4-fluoro-2-(prop-2-en-1-yloxy)benzene (2.40 g, 60%) as a colorless oil. 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).

[0535] Example 22. Intermediate 22 (8-[methoxy(methyl)carbamoyl]-3-azabicyclo[ 3.2.1 ] tert-butyl octane-3-carboxylate

[0536]

[0537] Step a:

[0538] 3-azabicyclic [ 3.2.1 Octo-8-carboxylate methyl hydrochloride (0.50 g, 2.43 mmol) and Et3N (0.98 g, 9.72 mmol) were added to a solution of Boc2O (0.80 g, 3.65 mmol) in DCM (6 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (20 mL) and water (30 mL). The aqueous solution was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure to give 3-tert-butyl-8-methyl-3-azabicyclo[] as a yellow oil. 3.2.1 Octane-3,8-dicarboxylate (0.65 g, crude) was used directly in the next step without further purification: C 14 H 23 NO4 [M + H - 15] + The calculated LCMS (ESI) value is 255, and the measured value is also 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).

[0539] Step b:

[0540] 3-tert-butyl-8-methyl-3-azabicyclo[ 3.2.1Octane-3,8-dicarboxylate (0.65 g, 2.41 mmol) in MeOH (5 mL) was mixed with a solution of NaOH (0.19 g, 4.83 mmol) in water (2 mL). The reaction was stirred at 40 °C for 1 hour. After cooling to room temperature, the resulting solution was diluted with EA (20 mL) and water (30 mL). The aqueous solution was acidified to pH 3 with citric acid and then extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was evaporated under reduced pressure to give 3-(tert-butoxycarbonyl)-3-azabicyclo[ 3.2.1 Octane-8-carboxylic acid (0.70 g, crude) was used directly in the next step without further purification: C 13 H 21 NO4[M + H -56] + The calculated LCMS (ESI) value is 200, and the measured value is 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).

[0541] Step c:

[0542] At room temperature, 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), and EDCI (0.79 g, 4.11 mmol) were added to a solution of DMF (6 mL). N,O -Dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et3N (0.55 g, 5.48 mmol). The reaction was stirred at room temperature for 16 hours. The reaction 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 (6 × 10 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 / EA (2 / 1) to give 8-[methoxy(methyl)carbamoyl]-3-azabicyclo[ 3.2.1 ]Tertiary butyl octane-3-carboxylate (0.43 g, 53%): C 15 H 26 N₂O₄[M + H - 56] + The calculated LCMS (ESI) value is 243, and the measured value is also 243. 1 H NMR (400 MHz, CDCl3) δ 3.91 (d, J = 47.8 Hz, 1H), 3.73 (d, J = 10.9 Hz, 3H), 3.69-3.39 (m,2H), 3.21 (d, J = 12.8 Hz, 3H), 3.03-2.84 (m, 1H), 2.74 (d, J = 17.2 Hz, 1H), 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).

[0543] Example 23. Intermediate 23 (( S )- N -[( R )-(4-bromo-5-chloro-2-methoxyphenyl)([1-[(4 R [2,2-Dimethyl-1,3-dioxacyclopentane-4-carbonyl]piperidin-4-yl]methyl]-2-methylpropane-2-sulfinamide]

[0544]

[0545] Step a:

[0546] MeI (10.26 g, 72.31 mmol) was added dropwise to a mixture of 3-bromo-4-chlorophenol (5.00 g, 24.10 mmol) and K₂CO₃ (9.99 g, 72.31 mmol) in THF (50 mL) under stirring at 40 °C. The reaction mixture was stirred at 40 °C for 16 hours. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE, to give 2-bromo-1-chloro-4-methoxybenzene (4.50 g, 84%) as a colorless oil. 1 HNMR (400 MHz, CD3OD) 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).

[0547] Step b:

[0548] AgOTf (2.55 g, 9.93 mmol) was added to a stirred solution of 2-bromo-1-chloro-4-methoxybenzene (2.00 g, 9.03 mmol) in DCM (20 mL) at room temperature. Following the addition, I₂ (2.52 g, 9.93 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with a saturated aqueous solution of Na₂SO₃ (50 mL) at room temperature and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (3 × 50 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, to give 1-bromo-2-chloro-4-iodo-5-methoxybenzene (2.50 g, 80%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.04 (s, 1H), 3.89 (s, 3H).

[0549] Step c:

[0550] Under a nitrogen atmosphere, at -90°C, 10.00 g (28.79 mmol) of 1-bromo-2-chloro-4-iodo-5-methoxybenzene in 20 mL of THF was added dropwise over 10 minutes. n-BuLi (11.5 mL, 28.75 mmol, 2.5 M hexane solution). The solution was stirred at the same temperature for 30 minutes. 4-[[( S A solution of tert-butyl 2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (9.10 g, 28.79 mmol) in THF (10 mL) was rapidly added to the above solution (reaction temperature increased from -90 °C to -70 °C). After addition, the reaction was stirred at -75 °C for an additional 1.5 h. The reaction was quenched by saturated NH4Cl aqueous solution (20 mL) and then diluted with water (100 mL). The aqueous phase was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 60% ACN aqueous solution containing 10 mmol / L NH4HCO4, to give 4-[( R )-(4-bromo-5-chloro-2-methoxyphenyl)([[( S 2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (12.40 g, 80%): C 22 H 34 BrClN2O4S [M + H] + The calculated LCMS (ESI) values ​​are 537, 539 (2:3:1), and the measured values ​​are also 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).

[0551] Step d:

[0552] At room temperature, add 4-[( R )-(4-bromo-5-chloro-2-methoxyphenyl)([[( Stert-butyl 2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylate (6.00 g, 11.19 mmol) was added dropwise to a solution in DCM (60 mL) with TFA (10 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was neutralized at room temperature with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous layer was extracted with DCM (3 × 200 mL). The combined organic layers were concentrated under reduced pressure to give a yellow oil. S )- N -[( R )-(4-bromo-5-chloro-2-methoxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (4.60 g, crude). The crude product was used directly in subsequent steps without further purification: C 17 H 26 BrClN2O2S [M+ H] + The calculated LCMS (ESI) values ​​are 437, 439 (2:3:1), and the measured values ​​are also 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, 1H), 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).

[0553] Step e:

[0554] Stirring at room temperature (4) R 2,2-Dimethyl-1,3-dioxane-4-carboxylic acid (1.70 g, 11.63 mmol) and HATU (4.43 g, 11.65 mmol) were added to a solution of DMF (10 mL). S )- N -[( R[4-Bromo-5-chloro-2-methoxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (3.40 g, 7.76 mmol) and Et3N (2.36 g, 23.29 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (60 mL) and extracted with EA (3 × 100 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 reversed-phase chromatography, eluting with 70% ACN aqueous solution containing 10 mmol / L NH4HCO3, to give ( ) as a grayish-white solid. S )- N -[( R )-(4-bromo-5-chloro-2-methoxyphenyl)([1-[(4 R [2,2-Dimethyl-1,3-dioxacyclopentane-4-carbonyl]piperidin-4-yl]methyl]-2-methylpropane-2-sulfinamide (3.80 g, 86%): C 23 H 34 BrClN2O5S [M + H] + The calculated LCMS (ESI) values ​​are 565, 567 (2:3:1), and the measured values ​​are 565, 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).

[0555] Example 24. Intermediate 24 (( S )- N -[( R )-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([1-[(4 R[2,2-Dimethyl-1,3-dioxacyclopentane-4-carbonyl]piperidin-4-yl]methyl]-2-methylpropane-2-sulfinamide]

[0556]

[0557] Step a:

[0558] Under a nitrogen atmosphere and at 0 °C, BBr3 (101.00 g, 405.90 mmol) was added dropwise to a stirred solution of 1-bromo-2-chloro-4-iodo-5-methoxybenzene (47.00 g, 135.30 mmol) in DCM (470 mL). The reaction solution was stirred for 20 hours at room temperature under a nitrogen atmosphere. The reaction was quenched with water (500 mL) at 0 °C and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-4-chloro-2-iodophenol (45.50 g, 95%) as a pale yellow solid, which was used in subsequent steps without further purification.

[0559] Step b:

[0560] Under a nitrogen atmosphere at room temperature, K₂CO₃ (39.14 g, 283.18 mmol) and allyl bromide (29.12 g, 240.70 mmol) were added dropwise to a stirred solution of 5-bromo-4-chloro-2-iodophenol (45.20 g, 141.59 mmol) in DMF (100 mL). The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The resulting 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 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE, to give 1-bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzene (28.50 g, 54%) as a colorless oil. 1 H NMR (400MHz, 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 = 10.7, 1.4 Hz, 1H), 4.59 (dq, J =4.6, 1.5 Hz, 2H).

[0561] Step c:

[0562] Under a nitrogen atmosphere, at -100°C, 10.00 g (26.78 mmol) of 1-bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzene (250 mL) was added dropwise to a stirred solution of 1-bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzene in THF (250 mL). n -BuLi (10.71 mL, 26.78 mmol, 2.5 M hexane solution). Under a nitrogen atmosphere, after stirring at -100 °C for 30 minutes, 4-[[( S A solution of tert-butyl 2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (8.47 g, 26.7 mmol) in THF (40 mL) was added dropwise to the above mixture at -100 °C. The resulting mixture was stirred at -100 °C for an additional 1 hour. The reaction was quenched at -100 °C with 200 mL of saturated NH4Cl aqueous solution. The aqueous layer was extracted with EA (3 × 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 70% ACN aqueous solution (with 0.05% TFA), to give 4-[( R )-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([[( S 2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (10.00 g, 60%): C 24 H 36 BrClN2O4S [M + H] + The calculated LCMS (ESI) values ​​are 563, 565 (2:3:1), and the measured values ​​are also 563, 565 (2:3:1). 1 H NMR (400 MHz, CDCl3) 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, 2H), 1.46 (s, 9H), 1.40-1.11 (m, 3H), 1.18 (s, 9H).

[0563] Step d:

[0564] Stirring at room temperature with 4-[( R )-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([[( S [2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (5.60 g, 9.96 mol) was added dropwise to a solution in DCM (50 mL) with TFA (10 mL). The reaction solution was stirred at room temperature for 0.5 h. The reaction was neutralized with a saturated aqueous solution of NaHCO3 at room temperature. The aqueous layer was extracted with EA (3 × 100 mL). The combined organic layers were concentrated under reduced pressure to give a pale yellow semi-solid. S )- N -[( R )-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (5.30 g, crude). The crude product was used directly in subsequent steps without further purification: C 19 H 28 BrClN2O2S [M + H] + The calculated LCMS (ESI) values ​​are 463, 465 (2:3:1), and the measured values ​​are 463, 465 (2:3:1). 1 H NMR (400 MHz, CDCl3) 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).

[0565] Step e:

[0566] Stirring at room temperature (4) R 2,2-Dimethyl-1,3-dioxacyclopentane-4-carboxylic acid (2.50 g, 17.13 mmol) and HATU (6.52 g, 17.13 mmol) were added to a solution of DMF (30 mL). S )- N -[( R[4-Bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (5.30 g, 11.42 mmol) and Et3N (3.47 g, 34.27 mmol). 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 × 100 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 reversed-phase chromatography, eluting with 70% ACN aqueous solution containing 10 mmol / L NH4HCO3, to give ( ) as a grayish-white solid. S )- N -[( R )-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([1-[(4 R [2,2-Dimethyl-1,3-dioxacyclopentane-4-carbonyl]piperidin-4-yl]methyl]-2-methylpropane-2-sulfinamide (3.80 g, 54%): C 25 H 36 BrClN2O5S [M + H] + The calculated LCMS (ESI) values ​​are 591, 593 (2:3:1), and the measured values ​​are also 591, 593 (2:3:1). 1 H NMR (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).

[0567] Example 25. Intermediate 25 (( S )- N -(( R)-(2-(allyloxy)-5-chloro-4-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0568]

[0569] Step a:

[0570] Under air atmosphere, NCS (31.00 g, 235.78 mmol) was added fractionally to a stirred solution of 2-bromo-5-methylphenol (42.00 g, 224.56 mmol) in 1,1,1,3,3,3-hexafluoroprop-2-ol (500 mL) at room temperature. The reaction solution was heated to 50 °C and stirred under air atmosphere for 16 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (50 / 1), to give 2-bromo-4-chloro-5-methylphenol (47.00 g, 90%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.93 (d, J = 0.8Hz, 1H), 2.32 (d, J = 0.7 Hz, 3H).

[0571] Step b:

[0572] Under air atmosphere, at room temperature, allyl bromide (29.00 g, 0.24 mol) was added dropwise to a mixture of 2-bromo-4-chloro-5-methylphenol (31.00 g, 0.14 mol) and K₂CO₃ (39.00 g, 0.28 mol) in DMF (300 mL). The reaction mixture was stirred at 40 °C for 16 hours under air atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (6 × 100 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 (100 / 1), to give 1-bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene (24.50 g, 66%) as a colorless oil. 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).

[0573] Step c:

[0574] Under a nitrogen atmosphere, at -90°C, 1-bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene (29.00 g, 0.12 mol) was added dropwise to a stirred solution of 1-bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene in 900 mL of THF. n -BuLi (48 mL, 0.12 mol, 2.5 M hexane solution). Under a nitrogen atmosphere, after stirring at -90 °C for 40 minutes, 4-[[( S A solution of tert-butyl 2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (35.57 g, 0.12 mol) in THF (80 mL) was added dropwise to a stirred solution over 20 minutes at -90 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 1 hour at -90 °C under a nitrogen atmosphere. The reaction was quenched at -90 °C with saturated aqueous NH4Cl solution (100 mL). The reaction solution was concentrated under reduced pressure to remove THF. The aqueous layer was extracted with EA (3 × 600 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1) to give 4-[( R )-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl]([[( S 2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (25.40 g, 44%): C 25 H 39 ClN2O4S [M + H] + The calculated LCMS (ESI) value is 499,501 (3:1), and the measured value is also 499,501 (3:1). 1H 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), 2.10-1.96 (m, 1H), 1.93-1.75 (m, 1H), 1.47(s, 9H), 1.37-1.21 (m, 3H), 1.12 (s, 9H).

[0575] Step d:

[0576] Stirring at room temperature with 4-[( R )-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl]([[( S [48.00 g, 95.77 mmol]-2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (TFA) was added dropwise to a solution in DCM (380 mL). The resulting mixture was stirred for an additional 1 hour at room temperature. The mixture was alkalized to pH 8 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow oil. S )- N -[( R )-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (33.10 g, 88%): C 20 H 31 ClN2O2S [M + 1] + The calculated LCMS (ESI) value is 399,401 (3:1), and the measured value is also 399,401 (3:1). 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.75 (s,1H), 6.08-5.93 (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 h z, 2H), 1.69–1.51 (m, 3H), 1.10 (s, 9H).

[0577] Example 26. Intermediate 26 ( N -[(1-acetylpiperidin-4-yl)(4,5-dichloro-2-methoxyphenyl)methylene]-2-methylpropane-2-sulfinamide)

[0578]

[0579] Step a:

[0580] Under a nitrogen atmosphere at room temperature, 2-methylpropane-2-sulfinamide (0.22 g, 1.82 mmol) was added to a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidin-1-yl]ethyl-1-one (0.30 g, 0.91 mmol) and Ti(OEt)4 (0.41 g, 1.82 mmol) in THF (10 mL). The resulting mixture was stirred at 70 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (3 × 50 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 purified by silica gel column chromatography, eluting with PE / EA (2 / 1), to obtain a pale yellow oil. N -[(1-acetylpiperidin-4-yl)(4,5-dichloro-2-methoxyphenyl)methylene]-2-methylpropane-2-sulfinamide (0.27 g, 68%): C 19 H 26 Cl2N2O3S[M + H] + The calculated LCMS (ESI) values ​​are 433, 435 (3:2), and the measured values ​​are 433, 435 (3:2).

[0581] Example 27. Intermediate 27 (( 2R,3S )-3-(benzoyloxy)oxacyclopentane-2-carboxylic acid)

[0582]

[0583] Step a:

[0584] At 0℃, towards ( 4R,5S 5-(hydroxymethyl)oxacyclopentane-2,4-diol (15.00 g, 111.83 mmol) in MeOH (130 mL) was added to a solution of H₂SO₄ (1.49 mL, 27.95 mmol, 97%) in MeOH (20 mL). The reaction was stirred at 0 °C to room temperature for 16 hours. The mixture was neutralized to pH 7 with a saturated aqueous solution of NaHCO₃. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 4), to obtain a pale yellow oil. 2S,3R 2-(hydroxymethyl)-5-methoxyoxacyclopentan-3-ol (15.00 g, 91%) 1 H NMR (400 MHz, DMSO- d 6) 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).

[0585] Step b:

[0586] Will( 2S,3R A solution of 2-(hydroxymethyl)-5-methoxyoxacyclopentan-3-ol (5.00 g, 33.75 mmol) and bis(trimethylsilyl)trifluoroacetamide (17.37 g, 67.48 mmol) in ACN (5 mL) was stirred at 80 °C for 5 hours. After cooling to room temperature, Et3SiH (19.62 g, 168.74 mmol) and TMSOTf (37.50 g, 168.72 mmol) were added to the above mixture in portions over 15 minutes at room temperature. 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 neutralized to pH 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA, to give ( ) as a pale yellow semi-solid. 2S,3R 2-(hydroxymethyl)oxacyclopentan-3-ol (1.40 g, 35%)1 H NMR (400 MHz, DMSO- d 6) 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).

[0587] Step c:

[0588] Stirring at room temperature 2S,3R TBDMSCl (1.66 g, 11.01 mmol) was added dropwise to a solution of 2-(hydroxymethyl)oxacyclopentan-3-ol (1.30 g, 11.01 mmol) and imidazole (0.76 g, 11.12 mmol) in DMF (8 mL). The resulting solution was stirred at room temperature for 0.5 h. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was purified by silica gel column chromatography, eluting with PE / EA (2 / 1) to obtain a colorless oil. 2S,3R )-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxacyclopentan-3-ol (1.54 g, 60%): 1 H NMR (400MHz, DMSO- d 6) 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).

[0589] Step d:

[0590] Stirring at room temperature 2S,3R )-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxacyclopentan-3-ol (0.82 g, 3.53 mmol) and benzoic acid (0.56 g, 4.59 mmol) were added to a solution of 2-[[(tert-butyldimethylsilyl)oxy]methyl]oxacyclopentan-3-ol (0.82 g, 3.53 mmol) and benzoic acid (0.56 g, 4.59 mmol) in THF (8 mL) with Ph3P (1.85 g, 7.05 mmol) and DEAD (1.23 g, 7.06 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture 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 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was purified by silica gel column chromatography, eluted with PE / EA (6 / 1), to give the product as a colorless oil. 2S,3S 2-[[(tert-butyldimethylsilyl)oxy]methyl]oxacyclopentane-3-ylbenzoate (1.00 g, 84%) 1 H NMR (400 MHz, 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).

[0591] Step e:

[0592] Stirring at room temperature 2S,3S 2-[[(tert-butyldimethylsilyl)oxy]methyl]oxacyclopentan-3-ylbenzoate (0.50 g, 1.49 mmol) was added to a solution of THF (3 mL) and HOAc (0.1 mL) with TBAF (2.97 mL, 2.970 mmol, 1 M THF solution). The reaction was stirred at room temperature for 3 hours. The reaction mixture 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 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was purified by silica gel column chromatography, eluting with PE / EA (1 / 4) to give the product as a colorless oil. 2S,3S 2-(hydroxymethyl)oxacyclopentane-3-ylbenzoate (0.30 g, 91%): 1 H NMR (400 MHz, DMSO-) d 6) δ 7.96-7.91 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (t, J = 7.6Hz, 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).

[0593] Step f:

[0594] Stirring at room temperature 2S,3S TEMPO (48 mg, 0.31 mmol) was added to a solution of (acetoxy)(phenyl)-λ3-iodoalkyl acetate (0.74 g, 2.30 mmol) in ACN (3 mL) and water (3 mL). The reaction was stirred at room temperature for 16 hours. The resulting mixture was quenched with saturated aqueous Na2SO3 solution (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1), to give a colorless oil. 2R,3S 3-(benzoyloxy)oxacyclopentane-2-carboxylic acid (0.20 g, 55%): 1 H NMR (400 MHz, DMSO- d 6) 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).

[0595] Example 28. Intermediate 28 (lithium 4-methyl-5-oxomorpholine-2-carboxylate)

[0596]

[0597] Step a:

[0598] SOCl2 (41 mL, 570.97 mmol) was added dropwise to a mixture of isoserine (50.00 g, 475.77 mmol) in MeOH (300 mL) under stirring at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give methyl 3-amino-2-hydroxypropionate (50.00 g, 71%) as a grayish-white solid: C4H9NO3[M + H] + The calculated LCMS (ESI) value is 120, and the measured value is also 120. 1 H NMR (400 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).

[0599] Step b:

[0600] Chloroacetyl chloride (21.33 g, 188.89 mmol) was added dropwise to a stirred solution of methyl 3-amino-2-hydroxypropionate (22.50 g, 188.89 mmol) and Et3N (57.34 g, 566.66 mmol) in DCM (300 mL) at room temperature. 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), to give methyl 3-(2-chloroacetamido)-2-hydroxypropionate (13.00 g, 35%) as a yellow solid: C6H 10 ClNO4[M + H] +The calculated LCMS (ESI) values ​​are 196, 198 (3:1), and the measured values ​​are 196, 198 (3:1). 1 H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.08 (s, 2H), 3.84 (s, 3H), 3.79-3.62 (m, 2H), 3.26 (s, 1H).

[0601] Step c:

[0602] Under a nitrogen atmosphere at room temperature, methyl 3-(2-chloroacetamido)-2-hydroxypropionate (5.00 g, 25.56 mmol) was added to a stirred solution of methyl 3-(2-chloroacetamido)-2-hydroxypropionate in 300 mL of THF. t -BuOK (5.74 g, 51.15 mmol). 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 to the reaction. The mixture was stirred at room temperature for another 2 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA, to give methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.90 g, 20%) as a pale yellow semi-solid: C7H 11 NO4[M + H] + The calculated LCMS (ESI) value is 174, and the measured value is also 174. 1 H NMR (400 MHz, CD3OD) δ 4.61 (dd, J = 7.5, 4.8 Hz, 1H), 4.30 (d, J = 16.5 Hz, 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).

[0603] Step d:

[0604] A solution of LiOH·H₂O (73 mg, 1.73 mmol) in water (1 mL) was added to a stirred solution of methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.15 g, 0.87 mmol) in MeOH (3 mL) at room temperature. The reaction solution was stirred at 40 °C for 1 hour. The reaction was concentrated under reduced pressure to give lithium 4-methyl-5-oxomorpholine-2-carboxylate (0.14 g, crude) as a grayish-white solid, which was used directly in the next step without further purification: C₆H₉NO₄[M + H] + The calculated LCMS (ESI) value is 160, and the measured value is 160.

[0605] Example 29. Intermediate 29 (3-[methoxy(methyl)carbamoyl]-8-azabicyclo[ 3.2.1 ] tert-butyl octane-8-carboxylate

[0606]

[0607] Step a:

[0608] Stirring 8-azabicyclo[ at room temperature] 3.2.1 Methyl octane-3-carboxylate (1.00 g, 5.91 mmol) and Et3N (1.20 g, 11.86 mol) were added to a solution of Boc2O (1.60 g, 7.33 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The separated aqueous solution was extracted with EA (3 × 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 to give 8-tert-butyl-3-methyl-8-azabicyclo[] as a pale yellow oil. 3.2.1 Octane-3,8-dicarboxylate (1.30 g, 99%): C 14 H 23 NO4 [M + H -15] + The calculated LCMS (ESI) value is 255, and the measured value is 255.

[0609] Step b:

[0610] 8-tert-butyl-3-methyl-8-azabicyclo[ 3.2.1Octane-3,8-dicarboxylate (1.30 g, 4.83 mol) in MeOH (5 mL) was mixed with a solution of NaOH (0.39 g, 9.65 mol) in H₂O (0.5 mL). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 × 20 mL). The combined aqueous layers were acidified to pH 3 with citric acid and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give (8-[(tert-butoxy)carbonyl]-8-azabicyclo[ 3.2.1 Octane-3-carboxylic acid (1.20 g, 97%): C 13 H 21 NO4 [M + Na] + The calculated LCMS (ESI) value is 278, and the measured value is also 278. 1 H NMR (300 MHz, CDCl3) 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).

[0611] Step c:

[0612] At room temperature, 8-[(tert-butoxy)carbonyl]-8-azabicyclo[ 3.2.1 Octane-3-carboxylic acid (1.20 g, 4.70 mmol) and Et3N (0.95 g, 9.40 mmol) were added to a solution in DCM (10 mL) along with CDI (0.91 g, 5.64 mmol) and N. ,O 3-Methoxy(methyl)amine hydrochloride (0.69 g, 7.05 mmol). 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), to give 3-[methoxy(methyl)carbamoyl]-8-azabicyclo[ 3.2.1 Octane-8-carboxylic acid tert-butyl ester (1.10 g, 69% total over three steps): C 15 H 26 N₂O₄ [M + H - 56] + The calculated LCMS (ESI) value is 243, and the measured value is also 243. 1H 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).

[0613] Example 30. Intermediate 30 (3-[methoxy(methyl)carbamoyl]azacyclobutane-1-carboxylic acid tert-butyl ester)

[0614]

[0615] Step a:

[0616] Et3N (1.20 g, 11.93 mmol) and N were added to a stirred solution of 1-[(tert-butoxy)carbonyl]azacyclobutane-3-carboxylic acid (2.00 g, 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 mL) at room temperature. ,O 3-Methoxy(methyl)amine hydrochloride (0.90 g, 14.91 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1), to give tert-butyl 3-[methoxy(methyl)carbamoyl]azacyclobutane-1-carboxylate (2.10 g, 78%) as a pale yellow oil: C 11 H 20 N₂O₄ [M + H - 56] + The calculated LCMS (ESI) value is 189, and the measured value is also 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).

[0617] Example 31. Intermediate 31 (4-fluoro-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester)

[0618]

[0619] Step a:

[0620] Et3N (2.50 g, 24.27 mmol) and N were added to a stirred solution of 1-[(tert-butoxy)carbonyl]-4-fluoropiperidine-4-carboxylic acid (2.00 g, 8.09 mmol) and CDI (2.60 g, 16.18 mmol) in DCM (10 mL) at room temperature. ,O -Methoxy(methyl)amine hydrochloride (1.00 g, 16.18 mmol). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3 / 1), to give tert-butyl 4-fluoro-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.50 g, 57%) as a colorless oil: C 13 H 23 FN2O4 [M + H - 56] + The calculated LCMS (ESI) value is 235, and the measured value is also 235. 1 H NMR (400 MHz, 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).

[0621] Example 32. Intermediate 32 (5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate lithium)

[0622]

[0623] Step a:

[0624] Boc₂O (0.17 g, 0.76 mmol) was added to a stirred solution of ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.64 mmol) and Et₃N (0.19 g, 1.91 mmol) in DMF (1 mL) at room temperature. The resulting solution was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with a 55% aqueous solution of NH₄HCO₃ containing 10 mmol / L to give ethyl 5-[[(tert-butoxy)carbonyl]amino]-1,3,4-oxadiazole-2-carboxylate (0.10 g, 55%) as a pale yellow oil: C 10 H 15 N3O5 [M + H - 56] + The calculated LCMS (ESI) value is 202, and the measured value is also 202. 1 H NMR (400 MHz, DMSO- d 6) δ 4.38 (q, J = 7.1 Hz, 2H), 1.46 (d, J = 3.1 Hz, 9H), 1.32 (t, J = 7.1 Hz, 3H).

[0625] Step b:

[0626] To a stirred solution of ethyl 5-[[(tert-butoxycarbonyl)amino]-1,3,4-oxadiazole-2-carboxylate (0.16 g, 0.62 mmol) in MeOH (2 mL), an aqueous solution of LiOH·H₂O (78 mg, 1.87 mmol) in MeOH (3 mL) was added, followed by a solution of LiOH·H₂O (48 mg, 1.15 mmol) in H₂O (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give lithium 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate (0.16 g, crude) as a grayish-white solid, which was used directly in the next step without further purification: C8H 11 N3O5 [M + H] + The calculated LCMS (ESI) value is 230, and the measured value is also 230. 1 H NMR (400 MHz, DMSO- d 6) δ8.53 (s, 1H), 2.50 (s, 9H).

[0627] Example 33. Intermediate 33 (3-iodo-1-(triphenylmethyl)-1 H -pyrazole)

[0628]

[0629] Step a:

[0630] 3-Iodine-1 was stirred at room temperature H 3-Pyrazole (0.50 g, 2.59 mmol) was added to a solution in DCM (5 mL) with TrtCl (0.86 g, 3.09 mmol) and Et3N (0.52 g, 5.16 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (12 / 1), to give 3-iodo-1-(triphenylmethyl)-1-pyrazole as a grayish-white solid. H -Pyrazole (0.60 g, 48%): 1 H NMR (400MHz, CDCl3) δ 7.19-7.10 (m, 15H), 6.42 (d, J = 2.5 Hz, 2H).

[0631] Example 34. Intermediate 34 (4-iodo-1-(triphenylmethyl)-1 H -pyrazole)

[0632]

[0633] Step a:

[0634] 4-Iodine-1 was stirred at room temperature H 4-Iodo-1-(triphenylmethyl)-1-pyrazole (0.50 g, 2.59 mmol) was added to a solution in DCM (5 mL) with TrtCl (0.86 g, 3.09 mmol) and Et3N (0.52 g, 5.16 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10 / 1), to give 4-iodo-1-(triphenylmethyl)-1-pyrazole as a grayish-white solid. H -Pyrazole (0.80 g, 64%): 1 H NMR (400MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.45 (s, 1H), 7.40-7.35 (m, 9H), 7.07-7.00 (m, 6H).

[0635] Example 35. Intermediate 35 (( S Lithium 3-methoxy-2-(triphenylmethoxy)propionate

[0636]

[0637] Step a:

[0638] Stirring at room temperature (2) S Methyl 2-ethylene oxide (2.00 g, 19.59 mmol) was added to a solution of Mg(OSO2CF3)2 (3.15 g, 9.80 mmol) in MeOH (15 mL). The resulting mixture was stirred at 40 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10 / 1), to give (2) a pale yellow oil. S Methyl 2-hydroxy-3-methoxypropionate (1.50 g, 46%): C5H 10 O4 [M + H] + The calculated LCMS (ESI) value is 135, and the measured value is also 135. 1 H NMR (400 MHz, CDCl3) δ 4.34 (t, J = 3.4Hz, 1H), 3.83 (s, 3H), 3.75-3.65 (m, 2H), 3.41 (s, 3H), 2.65 (brs, 1H).

[0639] Step b:

[0640] Stirring at room temperature (2) S Methyl 2-hydroxy-3-methoxypropionate (0.70 g, 5.22 mmol) and DMAP (64 mg, 0.52 mmol) were added to a solution of pyridine (8 mL) with TrtCl (1.60 g, 5.74 mmol). The resulting solution was heated 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 × 30 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), to give (2) a grayish-white solid. S Methyl 3-methoxy-2-(triphenylmethoxy)propionate (0.80 g, 33%) 1 H NMR (400 MHz, DMSO- d6) δ7.45-7.19 (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).

[0641] Step c:

[0642] Stirring at room temperature (2) S Methyl 3-methoxy-2-(triphenylmethoxy)propionate (0.80 g, 2.13 mmol) was added to a solution of LiOH·H₂O (0.45 g, 10.63 mmol) in water (3 mL) in MeOH (8 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give ( S Lithium 3-methoxy-2-(triphenylmethoxy)propionate (0.80 g, crude) was used directly in the next step without further purification: C 23 H 22 O4 [M + Na] + The calculated LCMS (ESI) value is 385, and the measured value is 385.

[0643] Example 36. Intermediate 36 (lithium 1-oxo-1,2-dihydroisoquinoline-4-carboxylate)

[0644]

[0645] Step a:

[0646] 1-oxo-2- H Methyl isoquinoline-4-carboxylate (0.20 g, 1.00 mmol) was added to a solution of LiOH·H₂O (84 mg, 2.00 mmol) in 3 mL of water in MeOH (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give lithium 1-oxo-1,2-dihydroisoquinoline-4-carboxylate (0.20 g, crude), which was used directly in the next step without further purification: C 10 H7NO3 [M - H] + The calculated LCMS (ESI) value is 188, and the measured value is 188.

[0647] Example 37. Intermediate 37 (Lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate)

[0648]

[0649] Step a:

[0650] 5-ethynyl-6-oxo-1 H Methyl pyridine-3-carboxylate (0.18 g, 1.00 mmol) was dissolved in 2 mL of MeOH and then dissolved in 3 mL of water containing 84 mg of LiOH·H₂O. The resulting mixture was stirred at 40 °C for 0.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate (0.20 g, crude), which was used directly in the next step without further purification: C₇H₄N₂O₃ [M-H] + The calculated LCMS (ESI) value is 163, and the measured value is 163.

[0651] Example 38. Intermediate 38 ( N -[( R )-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide)

[0652]

[0653] Step a:

[0654] Stirring at room temperature with 4-[( R )-[4,5-Dichloro-2-(prop-2-en-1-yloxy)phenyl]([[( S [2-methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 0.96 mmol) was added to a solution of 1,4-dioxane (8 mL) with an aqueous solution of HCl (4 mmol). N , 2 mL). The reaction solution was stirred at room temperature for 20 minutes. The pH of the reaction solution was adjusted to 8 at room temperature with saturated Na2CO3 aqueous solution. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-[( R 4,5-Dichloro-2-(prop-2-en-1-yloxy)phenyl]methyl]piperidine-1-carboxylic acid tert-butyl ester (0.40 g, crude) was used directly in the next step without further purification: C 20 H 28 Cl2N2O3 [M + H] +The calculated LCMS (ESI) values ​​are 415, 417 (3:2), and the measured values ​​are also 415, 417 (3:2).

[0655] Step b:

[0656] 4-[( R 4-(dichloro-2-(prop-2-en-1-yloxy)phenyl]methyl]piperidin-1-carboxylic acid tert-butyl ester (0.40 g, 0.96 mmol) and Et3N (0.29 g, 2.89 mmol) were added to a solution of 4-[(dichloro-2-(prop-2-en-1-yloxy)phenyl]methyl]piperidin-1-carboxylic acid tert-butyl ester (0.40 g, 0.96 mmol) in DCM (5 mL) and TFAA (0.24 g, 1.16 mmol) were added. 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 extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-[( R )-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylic acid tert-butyl ester (0.40 g, crude), which was used directly in the next step without further purification: C 22 H 27 Cl2F3N2O4 [M + Na] + The calculated LCMS (ESI) values ​​are 533, 535 (3:2), and the measured values ​​are also 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).

[0657] Step c:

[0658] Stirring at room temperature with 4-[( R0.40 g (0.78 mmol) of tert-butyl piperidine-1-carboxylate (0.40 g, 0.78 mmol) was added to a solution of TFA (2 mL) in DCM (2 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 50% ACN aqueous solution containing 10 mmol / L NH4HCO3, to give a pale yellow solid. N -[( R )-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide (0.30 g, 76% total for three steps): C 17 H 19 Cl2F3N2O2[M + H] + The calculated LCMS (ESI) values ​​are 411, 413 (3:2), and the measured values ​​are 411, 413 (3:2).

[0659] Example 39. Intermediate 39 (lithium 2-(oxetane-3-yloxy)acetate)

[0660]

[0661] Step a:

[0662] Under a nitrogen atmosphere and at 0°C, oxadiazon-3-ol (19.52 g, 263.47 mmol) was added dropwise to a mixture of NaH (12.65 g, 316.16 mmol, 60%) in THF (300 mL) under stirring. The reaction solution was stirred at room temperature for 0.5 h under a nitrogen atmosphere. Ethyl 2-bromoacetate (44.00 g, 263.47 mmol) was added dropwise to the above mixture under a nitrogen atmosphere and at 0°C. The reaction mixture was stirred at room temperature for an additional 2 h. The resulting mixture was quenched with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were 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 chromatography, eluted with PE / EA (5 / 1), to give ethyl 2-(oxetane-3-yloxy)acetate (25.00 g, 59%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ4.79-4.72 (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).

[0663] Step b:

[0664] LiOH·H₂O (0.29 g, 6.89 mmol) was added to a solution of ethyl 2-(oxetane-3-yloxy)acetate (1.00 g, 6.24 mmol) in THF (2 mL) and MeOH (2 mL) under stirring at 0 °C. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give 0.70 g (crude) 2-(oxetane-3-yloxy)acetate as a grayish-white solid, which was 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).

[0665] Example 40. Intermediate 40 (( R Lithium 3-methoxy-2-(triphenylmethoxy)propionate

[0666]

[0667] Step a:

[0668] Stirring at room temperature (2) R Methyl 2-ethylene oxide (1.00 g, 9.80 mmol) was added to a solution of Mg(OSO2CF3)2 (1.58 g, 4.90 mmol) in MeOH (10 mL). The resulting mixture was stirred at 40 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10 / 1), to give (2) a pale yellow oil. R Methyl 2-hydroxy-3-methoxypropionate (0.90 g, 55%): C5H 10 O4 [M + H] + The calculated LCMS (ESI) value is 135, and the measured value is also 135. 1 H NMR (400 MHz, CDCl3) δ 4.33 (t, J = 3.7Hz, 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).

[0669] Step b:

[0670] Stirring at room temperature (2) R Methyl 2-hydroxy-3-methoxypropionate (0.50 g, 3.73 mmol) and DMAP (46 mg, 0.37 mmol) were added to a solution of pyridine (4 mL) with TrtCl (1.14 g, 4.10 mmol). The resulting solution was stirred at 80 °C for 24 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10 / 1), to give (2) a grayish-white solid. R Methyl 3-methoxy-2-(triphenylmethoxy)propionate (0.60 g, 34%) 1 H NMR (400 MHz, DMSO- d 6) 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), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H).

[0671] Step c:

[0672] Stirring at room temperature (2) R Methyl 3-methoxy-2-(triphenylmethoxy)propionate (0.60 g, 1.59 mmol) in MeOH (6 mL) was dissolved in 2 mL of water containing LiOH·H₂O (0.33 g, 7.97 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to obtain ( R Lithium 3-methoxy-2-(triphenylmethoxy)propionate (0.80 g, crude) was used directly in the next step without further purification: LCMS (ESI) calculated values ​​for C 23 H 22 O4 [M + Na] - : 385, measured value 385.

[0673] Example 41. Intermediate 41 ((1 R 5 S 6 R )-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[ 3.1.0 tert-butyl hexane-3-carboxylate)

[0674]

[0675] Step a:

[0676] Stirring at room temperature (1) R 5 S 6 R )-3-[(tert-butoxy)carbonyl]-3-azabicyclic[ 3.1.0 Hexane-6-carboxylic acid (0.50 g, 2.20 mmol), HOBt (0.45 g, 3.30 mmol), and EDCI (0.63 g, 3.30 mmol) were added to a solution of DMF (6 mL). N , O -Dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et3N (0.45 g, 4.40 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution 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 (6 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by reversed-phase chromatography, eluting with 70% ACN aqueous solution (with 0.05% TFA) to give (1) a pale yellow oil. R 5 S 6 R )-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[ 3.1.0 ]Tertiary butyl hexane-3-carboxylate (0.30 g, 45%): C 13 H 22 N₂O₄[M + H - 56] + The calculated LCMS (ESI) value is 215, and the measured value is also 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).

[0677] Example 42. Intermediate 42 (4-[methoxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylic acid tert-butyl ester)

[0678]

[0679] Step a:

[0680] PtO2 (0.40 g, 1.75 mmol) and HCl (6 mmol) were added to a stirred solution of 2-methylpyridin-4-carboxylic acid (2.00 g, 14.58 mmol) in MeOH (10 mL) at room temperature. N (1 mL). The reaction was degassed three times under hydrogen and stirred at 30 °C for 16 hours under H2 (50 atm). The reaction was filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-methylpiperidine-4-carboxylate (2.00 g, 96%) as a pale yellow oil, which was used directly in the next step without further purification: C8H 15 NO2 [M + H] + The calculated LCMS (ESI) value is 158, and the measured value is 158. 1 H NMR (400 MHz, CD3OD)δ3.51-3.43 (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, 1H), 1.37 (d, J = 6.5 Hz, 3H).

[0681] Step b:

[0682] Boc₂O (4.16 g, 19.06 mmol) was added to a mixture of methyl 2-methylpiperidin-4-carboxylate (2.00 g, 12.72 mmol) and Et₃N (2.57 g, 25.40 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture 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 (2 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 1-tert-butyl-4-methyl-2-methylpiperidin-1,4-dicarboxylate (3.3 g, crude) as a pale yellow oil, which was used directly in the next step without further purification. 13 H 23 NO4 [M + H - 56] + LCMS (ESI) 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).

[0683] Step c:

[0684] A solution of NaOH (1.03 g, 25.75 mmol) in water (2 mL) was added to a stirred solution of 1-tert-butyl-4-methyl-2-methylpiperidine-1,4-dicarboxylate (3.30 g, 12.82 mmol) in MeOH (10 mL) at room temperature. The reaction solution was stirred at 40 °C for 1 hour. The reaction solution was diluted with water (50 mL). The aqueous solution was acidified to pH 3 with citric acid and then extracted with EA (3 × 50 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 reversed-phase chromatography, eluting with 23% ACN aqueous solution (with 0.05% TFA) to give 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-4-carboxylic acid (2.20 g, 71%) as a pale yellow semi-solid. 12 H 21NO4[M + H -56] + The calculated LCMS (ESI) value is 188, and the measured value is 188.

[0685] Step d:

[0686] Add to a stirred solution of 1-[(tert-butoxy)carbonyl]-2-methylpiperidin-4-carboxylic acid (1.80 g, 7.40 mmol), HOBt (1.50 g, 11.10 mmol), and EDCI (1.80 g, 11.10 mmol) in DCM (10 mL) at room temperature. N , O -Dimethylhydroxyamine hydrochloride (1.08 g, 11.10 mmol) and Et3N (1.50 g, 14.80 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 mL). The aqueous solution was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 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 / EA (4 / 1), to give tert-butyl 4-[methoxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylate (1.50 g, 71%) as a pale yellow oil: C 14 H 26 N₂O₄[M + H] + LCMS (ESI) calculated value: 287; Measured value: 287; 1 H NMR (400 MHz, CDCl3) δ 4.04-3.92 (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).

[0687] Example 43. Intermediate 43a (containing the cis isomer and racemic form of 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylic acid tert-butyl ester); Intermediate 43b (containing the trans isomer and racemic form of 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylic acid tert-butyl ester).

[0688]

[0689] Step a:

[0690] Under a nitrogen atmosphere and at 0°C, 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (2.76 g, 9.78 mmol) was added dropwise to a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene in 10 mL of THF. i -PrMgCl (4.86 mL, 9.72 mmol, 2 M THF solution). The reaction mixture was stirred at 0 °C for 30 min. Then, 4-[methoxy(methyl)carbamoyl]-2-methylpiperidin-1-carboxylic acid tert-butyl ester (1.40 g, 4.89 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The resulting mixture was quenched with saturated NH4Cl aqueous solution (5 mL) and diluted with water (30 mL). The aqueous solution 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 chromatography, eluted with PE / EA (4 / 1), to give tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidin-1-carboxylate (0.50 g, 24%) as a pale yellow semi-solid. 21 H 27 Cl2NO4[M + H -56] + The calculated LCMS (ESI) values ​​are 372, 374 (3:2), and the measured values ​​are also 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-hydroxybenzoyl)-2-methylpiperidine-1-carboxylate (1.00 g, 53%) was obtained as a pale yellow oil: C 18 H 23 Cl2NO4[M + H - 56] + The calculated LCMS (ESI) values ​​are 332, 334 (3:2), and the measured values ​​are also 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).

[0691] 3-Bromoprop-1-ene (0.47 g, 3.86 mmol) was added to a mixture of tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)-2-methylpiperidin-1-carboxylate (1.00 g, 2.56 mmol) and K₂CO₃ (0.71 g, 5.15 mmol) in DMF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and 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, eluted with PE / EA (10 / 1), to give tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidin-1-carboxylate (1.00 g, 90%) as a pale yellow oil. The total amount of tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidin-1-carboxylate was 1.50 g (72%).

[0692] Step b:

[0693] 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidin-1-carboxylic acid tert-butyl ester (1.50 g, 3.51 mmol) was separated under SFC conditions as follows: 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: 3.29 min; RT2: 3.85 min.

[0694] The first peak was obtained at 3.29 minutes, from which tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate (0.50 g, 45%) containing two cis enantiomers was isolated as a pale yellow semi-solid: C 21 H 27 Cl2NO4[M + H -56] + LCMS (ESI) calculated values: 372, 374 (3:2), measured values: 372, 374 (3:2); A second peak was obtained at 3.85 min, from which tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate (0.40 g, 36%) containing two trans enantiomers was separated as a pale yellow semi-solid: C21 H 27 Cl2NO4[M + H -56] + The calculated LCMS (ESI) values ​​are 372, 374 (3:2), and the measured values ​​are 372, 374 (3:2).

[0695] Example 44. Intermediate 44 ((2,3-dichloro-6-methoxyphenyl)(piperidin-4-yl)methanoltrifluoroacetic acid)

[0696]

[0697] Step a:

[0698] Under a nitrogen atmosphere and at 0 °C, Br2 (98.04 g, 613.49 mmol) was added dropwise to a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL). The reaction solution was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous solution of Na2S2O3 (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a mixture (100 g, crude) of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol as a yellow oil. The crude product was used directly in subsequent steps without further purification.

[0699] Step b:

[0700] MeI (16.5 mL, 116.05 mmol, 2 equivalents) was added dropwise to a crude mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (32 g, 125.04 mmol, 1 equivalent) with K₂CO₃ (54.9 g, 396.87 mmol, 3 equivalents) in MeCN (210 mL) at 0 °C. 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, to give 2-bromo-3,4-dichloro-1-methoxybenzene (8.7 g, 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-bromo-4,5-dichloro-2-methoxybenzene (24.3 g, 71.77%) was given as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H).

[0701] Step c:

[0702] Under a nitrogen atmosphere, at 0°C, 2-bromo-3,4-dichloro-1-methoxybenzene (0.80 g, 3.13 mmol) was added dropwise to a solution of 2-bromo-3,4-dichloro-1-methoxybenzene in 8 mL of THF. i -PrMgCl (2.0 mL, 19.76 mmol, 2 M THF solution). The reaction solution was stirred at 0 °C for 0.5 h. Then, under a nitrogen atmosphere, a solution of 4-formylpiperidin-1-carboxylic acid tert-butyl ester (0.67 g, 3.13 mmol) in THF (2 mL) was added dropwise at 0 °C. After stirring at 0 °C for another 0.5 h, the reaction mixture was heated to room temperature and stirred at a nitrogen atmosphere for another 0.5 h. The reaction was quenched with saturated NH4Cl aqueous solution (40 mL) and extracted with EA (2 × 40 mL). The organic layers were combined 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 / 2), to give 4-[(2,3-dichloro-6-methoxyphenyl)(hydroxy)methyl]piperidin-1-carboxylic acid tert-butyl ester (1.00 g, 82%) as a grayish-white foam. 18 H 25 Cl2NO4 [M + Na] + The calculated LCMS (ESI) values ​​are 412, 414 (3:2), and the measured values ​​are also 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), 2.70 (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).

[0703] Step d:

[0704] TFA (2 mL) was added to a solution of 0.50 g (1.28 mmol) of 4-[(2,3-dichloro-6-methoxyphenyl)(hydroxy)methyl]piperidin-1-carboxylic acid tert-butyl ester (5 mL) in DCM at room temperature. The reaction solution was stirred at room temperature for 1 hour and concentrated to obtain (2,3-dichloro-6-methoxyphenyl)(piperidin-4-yl)methanoltrifluoroacetic acid (0.60 g, crude): C 13 H 17 Cl2NO2 [M + H] + The calculated LCMS (ESI) values ​​are 290, 292 (3:2), and the measured values ​​are 290, 292 (3:2).

[0705] Example 45. Intermediate 45 (( S )- N -(( R )-(2-(allyloxy)-4-chloro-5-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0706]

[0707] Step a:

[0708] Under a nitrogen atmosphere, Br2 (0.56 g, 3.51 mmol) was added dropwise to a solution of HOAc (5 mL) containing 0.50 g, 3.51 mmol, while 3-chloro-4-methylphenol was stirred at room temperature. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated aqueous Na2SO3 solution (50 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (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 chromatography, eluting with PE / EA (5 / 1), to give 2-bromo-5-chloro-4-methylphenol (0.70 g, 90%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.06 (s, 1H), 5.46 (s, 1H), 2.30 (s, 3H).

[0709] Step b:

[0710] 3-Bromoprop-1-ene (0.50 g, 4.11 mmol) was added to a mixture of 2-bromo-5-chloro-4-methylphenol (0.70 g, 3.16 mmol) and K₂CO₃ (0.87 g, 6.32 mmol) in DMF (5 mL) at room temperature. The reaction mixture was heated to 40 °C and stirred for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (2 × 15 mL). The combined organic layers were washed with brine (3 × 10 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, to give 1-bromo-4-chloro-5-methyl-2-(prop-2-en-1-yloxy)benzene (0.45 g, 54%) as a grayish-white solid. 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).

[0711] Step c:

[0712] Under a nitrogen atmosphere, at -65°C, 1.64 mmol of 1-bromo-4-chloro-5-methyl-2-(prop-2-en-1-yloxy)benzene (0.43 g) in THF (4 mL) was added dropwise. n -BuLi (0.76 mL, 1.90 mmol, 2.5 M hexane solution). After stirring for 30 minutes, 4-[[( S A solution of tert-butyl 2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (0.40 g, 1.26 mmol) in THF (2 mL). The resulting mixture was heated to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution (30 mL). 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 chromatography, eluting with PE / EA (1 / 5) to give 4-(( R)-(2-(allyloxy)-4-chloro-5-methylphenyl)((( S )-tert-butylsulfinyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 30%): C 25 H 39 ClN2O4S [M + H] + The calculated LCMS (ESI) value is 499,501 (3:1), and the measured value is 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).

[0713] Step d:

[0714] Stirring at room temperature 4-(( R )-(2-(allyloxy)-4-chloro-5-methylphenyl)((( S 0.18 g, 0.38 mmol) of tert-butyl(-tert-butyl)-1-carboxylic acid (TFA) was added to a solution of 4 mL DCM. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with 20 mL of saturated NaHCO3 aqueous solution at room temperature and extracted with DCM (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 to obtain a pale yellow oil. S )- N -(( R )-(2-(allyloxy)-4-chloro-5-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.10 g, 70%):C 20 H 31 ClN2O2S [M + H] + The calculated LCMS (ESI) value is 399,401 (3:1), and the measured value is 399,401 (3:1).

[0715] Example 46. Intermediate 46 (1-bromo-4,5-dichloro-3-fluoro-2-(prop-2-en-1-yloxy)benzene)

[0716]

[0717] Step a:

[0718] Under a nitrogen atmosphere at room temperature, NCS (1.37 g, 10.24 mmol) was added to a solution of 3-chloro-2-fluorophenol (1.50 g, 10.23 mmol) in MeCN (60 mL) and TFA (1.00 mL). 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 chromatography, eluting with PE / EA (5 / 1), to give 3,4-dichloro-2-fluorophenol (1.60 g, 86%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.64 (s, 1H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1H).

[0719] Step b:

[0720] Br2 (1.55 g, 9.72 mmol) was added dropwise to a stirred solution of 3,4-dichloro-2-fluorophenol (1.60 g, 8.84 mmol) in AcOH (20 mL) at room temperature. The reaction solution 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 × 50 mL). The organic phase was washed with saturated aqueous Na2SO3 solution (2 × 50 mL), saturated aqueous NaHCO3 solution (2 × 50 mL), and brine (2 × 50 mL). The solution was then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1), to give 6-bromo-3,4-dichloro-2-fluorophenol (1.80 g, 78%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ7.45 (d, J = 2.3 Hz, 1H).

[0721] Step c:

[0722] 3-Bromoprop-1-ene (1.26 g, 10.39 mmol) was added to a mixture of 6-bromo-3,4-dichloro-2-fluorophenol (1.80 g, 6.97 mmol) and K₂CO₃ (2.00 g, 14.47 mmol) in DMF (20 mL) at room temperature. The reaction mixture was then stirred at 40 °C for 3 hours. The reaction mixture was diluted with water (80 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (3 × 30 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-4,5-dichloro-3-fluoro-2-(prop-2-en-1-yloxy)benzene (1.70 g, 82%) as a colorless liquid. 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, 1.5Hz, 1H), 4.70-4.60 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ -121.32.

[0723] Example 47. Intermediate 47 (( R Lithium 2-methoxy-3-(triphenylmethoxy)propionate

[0724]

[0725] Step a:

[0726] Stirring at room temperature (2) R Methyl 2,3-dihydroxypropionate (0.50 g, 4.16 mmol) and (chlorodiphenylmethyl)benzene (3.50 g, 12.5 mmol) were added in portions to a solution in DCM (4 mL) with DMAP (30 mg, 0.25 mmol) and Et3N (1.26 g, 12.5 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 25 mL). The combined organic layers were washed with brine (3 × 5 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 (8 / 1), to give (2) a grayish-white solid. RMethyl 2-methoxy-3-(triphenylmethoxy)propionate (0.10 g, 6%). 1 HNMR (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).

[0727] Step b:

[0728] Stirring at room temperature (2) R Methyl 2-hydroxy-3-(triphenylmethoxy)propionate (0.50 g, 1.38 mmol) and CH3I (1 mL) were added fractionally to a solution of Et2O (5 mL) with Ag2O (0.96 g, 4.14 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 5 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), to give (2) a grayish-white solid. R Methyl 2-methoxy-3-(triphenylmethoxy)propionate (0.40 g, 77%): C 24 H 24 O4 [M + Na] + The calculated LCMS (ESI) value is 399, and the measured value is also 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).

[0729] Step c:

[0730] Stirring at room temperature (2) R A solution of LiOH·H₂O (9 mg, 0.4 mmol) in H₂O (1 mL) was added to a mixture of methyl 2-methoxy-3-(triphenylmethoxy)propionate (50 mg, 0.13 mmol) in MeOH (2 mL). The resulting mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure to obtain (2... RLithium 2-methoxy-3-(triphenylmethoxy)propionate (50 mg, crude). The crude product was used directly in subsequent steps without further purification: C 23 H 22 O4 [M + Na] + The calculated LCMS (ESI) value is 385, and the measured value is 385.

[0731] Example 48. Intermediate 48 ((2 S Lithium 2-methoxy-3-(triphenylmethoxy)propionate

[0732]

[0733] Step a:

[0734] Stirring at room temperature (2) S Methyl 2,3-dihydroxypropionate (1.00 g, 8.32 mmol) and (chlorodiphenylmethyl)benzene (2.50 g, 9.16 mmol) in DCM (10 mL) were mixed with Et3N (1.26 g, 12.5 mmol) and DMAP (61 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (15 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 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 as a grayish-white solid with PE / EA (5 / 1) to give (2 S Methyl 2-hydroxy-3-(triphenylmethoxy)propionate (1.00 g, 33%) 1 H NMR (400MHz, 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).

[0735] Step b:

[0736] In an air atmosphere, at room temperature, the mixture was stirred (2) SMethyl 2-hydroxy-3-(triphenylmethoxy)propionate (0.50 g, 1.38 mmol) and CH3I (1 mL) were added fractionally to a solution of Et2O (5 mL) with Ag2O (0.96 g, 4.14 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was 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 chromatography, eluting with PE / EA (6 / 1), to give (2) a grayish-white solid. S Methyl 2-methoxy-3-(triphenylmethoxy)propionate (0.40 g, 77%): C 24 H 24 O4[M + Na] + The calculated LCMS (ESI) value is 399, and the measured value is also 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), 3.97 (dd, J = 5.4, ​​4.0 Hz, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 3.45-3.36 (m, 2H).

[0737] Step c:

[0738] In an air atmosphere, at room temperature, the mixture was stirred (2) S Methyl 2-methoxy-3-(triphenylmethoxy)propionate (0.20 g, 0.53 mmol) in MeOH (3 mL) was mixed with a solution of LiOH·H₂O (38 mg, 1.59 mmol) in H₂O (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain (2-)-methyl 2-methoxy-3-(triphenylmethoxy)propionate as a grayish-white solid. S 2-Methoxy-3-(triphenylmethoxy)propionic acid (0.10 g, crude). The crude product was used directly in subsequent steps without further purification: C 23 H 22 O4 [M + Na] + The calculated LCMS (ESI) value is 385, and the measured value is 385.

[0739] Example 49. Intermediate 49 (4-(1-(4,5-dichloro-2-methoxyphenyl)-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester)

[0740]

[0741] Step a:

[0742] Under a nitrogen atmosphere, at -78°C, a mixture of (methoxymethyl)triphenylphosphonium chloride (12.36 g, 36.06 mmol) in THF (60 mL) was added dropwise. n -BuLi (10.30 mL, 25.75 mmol, 2.5 M hexane solution). The resulting mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. A solution of tert-butyl 4-(4,5-dichloro-2-methoxybenzoyl)piperidine-1-carboxylate (2.00 g, 5.15 mmol) in THF (5 mL) was added dropwise over 5 min at -78 °C. The resulting mixture was stirred at -78 °C for an additional 2 h. The reaction was quenched at 0 °C with saturated NH4Cl aqueous solution (80 mL). The resulting mixture was extracted with EA (3 × 50 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, eluted with PE / EA (1 / 1), to give tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-methoxyvinyl]piperidine-1-carboxylate (1.60 g, 59%) as a pale yellow oil: C 20 H 27 Cl2NO4 [M + H] + The calculated LCMS (ESI) value is 416,418 (3:2), and the measured value is 416,418 (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).

[0743] Step b:

[0744] 4-[( E[4,5-Dichloro-2-methoxyphenyl]piperidine-1-carboxylic acid tert-butyl ester (1.80 g, 4.32 mmol) was added dropwise to a solution of 1,4-dioxane (10 mL) with an aqueous solution of HCl (6... N (10 mL). The resulting mixture was then heated to room temperature and stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude mixture was used directly in subsequent steps without further purification: C 14 H 17 Cl2NO2 [M + H] + The calculated LCMS (ESI) values ​​are 302 and 304 (3:2), while the measured values ​​are also 302 and 304 (3:2).

[0745] Step c:

[0746] Boc₂O (1.62 g, 7.445 mmol) was added dropwise to a mixture of 2-(4,5-dichloro-2-methoxyphenyl)-2-(piperidin-4-yl)acetaldehyde (1.50 g, 4.96 mmol) stirred in THF (15 mL) and saturated NaHCO₃ aqueous solution (20 mL) at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. The resulting mixture was extracted with EA (3 × 30 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 to give tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-oxoethyl]piperidin-1-carboxylic acid (1.30 g, 65%) as a pale yellow oil: C 19 H 25 Cl2NO4 [M + H] + The calculated LCMS (ESI) values ​​are 402 and 404 (3:2), while the measured values ​​are also 402 and 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, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.67 (dd, J = 8.9, 1.7Hz, 1H), 2.82-2.71 (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).

[0747] Example 50. Intermediate 50 (4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)amino]methyl]-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester)

[0748]

[0749] Step a:

[0750] Under a nitrogen atmosphere, at -10°C, (methoxymethyl)triphenylphosphonium chloride (1508 mg, 4.40 mmol) was added dropwise to a solution of THF (7 mL). n -BuLi (2.5 mL, 38.46 mmol, 2.5 M hexane solution). The solution was stirred at 0 °C for 1 hour. Then, under a nitrogen atmosphere, a solution of tert-butyl 2,2-dimethyl-4-oxopiridine-1-carboxylate (1 g, 4.40 mmol) in THF (5 mL) was added dropwise at -20 °C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with EA (2 × 20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1), to give tert-butyl 4-(methoxymethylene)-2,2-dimethylpiperidine-1-carboxylate (0.80 g, 71%) as a colorless oil: C 14 H 25 NO3 [M + H] + The calculated LCMS (ESI) value is 256, and the measured value is also 256. 1 ¹H NMR (300 MHz, M ethanol) δ 5.97 (d, J = 24.0Hz, 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).

[0751] Step b:

[0752] At room temperature, an aqueous HCl solution (4 mmol) was added to a solution of 0.80 g (3.13 mmol) of 4-(methoxymethylene)-2,2-dimethylpiperidin-1-carboxylic acid tert-butyl ester in THF (10 mL). N , 5 mL). The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was then alkalized to pH 9 with a saturated aqueous NaHCO3 solution, and Boc2O (821 mg, 3.76 mmol) was added. The mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (2 × 15 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (2 / 1), to give tert-butyl 4-formyl-2,2-dimethylpiperidine-1-carboxylate (360 mg, 48%) as a colorless oil: C 13 H 23 NO3 [M + H] + The calculated LCMS (ESI) value is 242, and the measured value is 242.

[0753] Step c':

[0754] DIEA (49.70 g, 384.46 mmol) was added to a stirred solution of 2-bromo-4,5-dichlorophenol (31.00 g, 128.15 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (32.00 g, 192.23 mmol) in DCM (100 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (200 mL). The resulting mixture was extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50 / 1), to give [2-(2-bromo-4,5-dichlorophenoxymethoxy)ethyl]trimethylsilane (44.00 g, 83%) as a pale yellow oil: 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).

[0755] Step c:

[0756] Under a nitrogen atmosphere, at -10°C, [2-(2-bromo-4,5-dichlorophenoxymethoxy)ethyl]trimethylsilane (the product of step c') (0.69 g, 1.86 mol) was added dropwise to a solution of [2-(2-bromo-4,5-dichlorophenoxymethoxy)ethyl]trimethylsilane (the product of step c') in THF (7 mL). i -PrMgCl (0.2 mL, 1.61 mmol, 2 M THF solution). The reaction mixture was stirred at -10 °C for 0.5 h under a nitrogen atmosphere. A solution of tert-butyl 4-formyl-2,2-dimethylpiperidin-1-carboxylate (300 mg, 1.24 mmol) in THF (3 mL) was added dropwise to the resulting solution at -10 °C under a nitrogen atmosphere. The reaction mixture was heated to room temperature and stirred under a nitrogen atmosphere for 2 h. The resulting mixture was quenched with 40 mL of saturated NH4Cl aqueous solution. The resulting mixture was extracted with EA (3 × 10 mL). The organic phases were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9 / 1), to give tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)(hydroxy)methyl]-2,2-dimethylpiperidin-1-carboxylic acid (0.20 g, 30%) as a colorless oil: C 25 H 41 Cl2NO5Si [M +H] + The calculated LCMS (ESI) value is 534,536 (3:2), and the measured value is also 534,536 (3:2). 1 H NMR (300MHz, 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).

[0757] Step d:

[0758] At room temperature, 0.18 g (0.34 mmol) of tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)(hydroxy)methyl]-2,2-dimethylpiperidin-1-carboxylate tert-butyl ester (DCM) in DCM (8 mL) was added in three portions with Dys-Martin reagent (0.14 g, 0.34 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of Na₂SO₃ and then extracted with DCM (2 × 10 mL). The organic phase was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 0.16 g (crude) of 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)carbonyl]-2,2-dimethylpiperidin-1-carboxylate tert-butyl ester (DCM): C 25 H 39 Cl2NO5Si [M + H] + The calculated LCMS (ESI) values ​​are 532, 534 (3:2), and the measured values ​​are 532, 534 (3:2).

[0759] Step e:

[0760] At room temperature, 2-methylpropane-2-sulfinamide (44 mg, 360 mmol) and Ti(OEt)4 (0.90 g, 3.95 mmol) were added in one step to a solution of 0.16 g crude 4-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]benzoyl)-2,2-dimethylpiperidin-1-carboxylic acid tert-butyl ester in THF (10 mL). The reaction mixture was stirred at 70 °C for 15 h under a nitrogen atmosphere. The reaction mixture was quenched with water (50 mL). A solid was formed and filtered. The filtrate was extracted with EA (2 × 40 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)imino]methyl]-2,2-dimethylpiperidine-1-carboxylate (0.20 g, crude): C 29 H 48 Cl2N2O5SSi [M + Na] + The calculated LCMS (ESI) values ​​are 657, 659 (3:2), and the measured values ​​are also 657, 659 (3:2).

[0761] Step f:

[0762] Under a nitrogen atmosphere at room temperature, 4-[(1 E 0.20 g (0.31 mmol) of tert-butyl 2-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)imino]methyl]-2,2-dimethylpiperidin-1-carboxylic acid was added in five portions to a solution of NaBH4 (58 mg, 1.54 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with 10 mL of saturated NH4Cl aqueous solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with PE / EA (1 / 1), to give 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)amino]methyl]-2,2-dimethylpiperidin-1-carboxylic acid tert-butyl ester (75 mg, 37%) as a colorless oil. 29 H 50 Cl2N2O5SSi [M +Na] + The calculated LCMS (ESI) value is 659, 661 (3:2), and the measured value is 659, 661 (3:2).

[0763] Example 51. Intermediate 51 (( S )- N -(( R )-(6-(allyloxy)-2,3-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0764]

[0765] Step a:

[0766] Under a nitrogen atmosphere, at -65°C, a solution of 1,2-dichloro-3-iodo-4-(prop-2-en-1-yloxy)benzene (1.25 g, 3.80 mmol) in THF (10 mL) was added... n- BuLi (1.2 mL, 3.80 mmol, 2.5 M hexane solution). After stirring at -65°C for 30 minutes under a nitrogen atmosphere, 4-[[( SA solution of tert-butyl 2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (0.80 g, 2.53 mmol) in THF (5 mL). After addition, the reaction mixture was stirred at -65 °C for an additional 1 hour under a nitrogen atmosphere. The reaction was quenched with water (40 mL) at -65 °C and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, washed with PE / EA (7 / 1), to give 4-(( R )-(6-(allyloxy)-2,3-dichlorophenyl)((( S )-tert-butylsulfinyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 57%): C 24 H 36 Cl2N2O4S [M + H] + The calculated LCMS (ESI) values ​​are 519, 521 (3:2), and the measured values ​​are also 519, 521 (3:2). 1 H NMR (400 MHz, CDCL3) δ7.34 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 9.0, 4.9 Hz, 1H), 6.11-5.94 (m, 1H), 5.49-5.28 (m, 2H), 4.79 (t, J = 9.7 Hz, 1H), 4.68-4.50 (m, 3H), 4.36-3.91 (m,3H), 2.77-2.47 (m, 2H), 2.40-2.29 (m, 1H), 2.18-2.02 (m, 1H), 1.46 (s, 9H), 1.34-1.22 (m, 1H), 1.04 (s, 9H).

[0767] Step b:

[0768] Stirring at room temperature with 4-[( R )-[2,3-Dichloro-6-(prop-2-en-1-yloxy)phenyl]([[( S[2-Methylpropane-2-sulfinyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 1.54 mmol) was added to a solution of TFA (1.5 mL) in DCM (6 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (6 mL) and neutralized to pH 8 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow oil. S )- N -[( R )-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (0.60 g, 74%): C 19 H 28 Cl2N2O2S [M + H] + The calculated LCMS (ESI) values ​​are 419 and 421 (3:2), while the measured values ​​are also 419 and 421 (3:2). 1 H NMR (400 MHz, CDCl3) δ 7.36-7.31 (m, 1H), 6.81-6.76 (m, 1H), 6.11-5.95 (m, 1H), 5.49-5.34 (m, 2H), 4.81 (t, J = 10.0Hz, 1H), 4.67-4.50 (m, 3H), 3.26 (d, J = 12.5 Hz, 1H), 3.08 (d, J = 12.4 Hz,1H), 2.68-2.36 (m, 5H), 2.13 (t, J = 10.7 Hz (1H), 1.04 (s, 9H).

[0769] Example 52. Intermediate 52 (Lithium 4-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylate)

[0770]

[0771] Step a:

[0772] 5-oxo-4 HCH3I (15.2 g, 1.08 mol) was added to a mixture of pyrazin-2-carboxylic acid (3.00 g, 21.41 mmol) and K2CO3 (14.8 g, 1.07 mol) in DMF (30 mL). The resulting mixture was stirred at 40 °C for 16 hours under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EA (5 × 60 mL). The combined organic layers were washed with brine (5 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-methyl-5-oxopyrazin-2-carboxylate (2.50 g, 69%) as a dark brown solid: C7H8N2O3[M + H]. + The calculated LCMS (ESI) value is 169, and the measured value is also 169. 1 H NMR (400 MHz, CD3OD) δ 8.48 (s,1H), 8.02 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H).

[0773] Step b:

[0774] A solution of LiOH (0.26 g, 10.71 mmol) in H₂O (1 mL) was added to a stirred mixture of methyl 4-methyl-5-oxopyrazine-2-carboxylate (0.60 g, 3.57 mmol) in MeOH (7 mL) at room temperature. After stirring for 20 hours at room temperature, the resulting mixture was concentrated under reduced pressure. The crude product was used directly in subsequent steps without further purification. C₆H₆N₂O₃ [M + H] + The calculated LCMS (ESI) value is 155, and the measured value is 155.

[0775] Example 53. Intermediate 53 (1-bromo-4-methyl-2-(prop-2-en-1-yloxy)benzene)

[0776]

[0777] Step a:

[0778] K₂CO₃ (2.96 g, 21.41 mmol) and 3-bromoprop-1-ene (1.94 g, 16.04 mmol) were added to a stirred solution of 2-bromo-5-methylphenol (2.00 g, 10.69 mmol) in DMF (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture 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 (3 × 30 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) to give 1-bromo-4-methyl-2-(prop-2-en-1-yloxy)benzene (1.29 g, 53%) as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.69 (dd, J = 7.9, 2.0 Hz, 1H), 6.16-6.02 (m, 1H), 5.40-5.30 (m, 1H), 5.28-5.20 (m, 1H), 4.60 (d, J = 5.0 Hz, 2H), 2.32 (s, 3H).

[0779] Example 54. Intermediate 54 (4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylic acid tert-butyl ester)

[0780]

[0781] Step a:

[0782] At room temperature, 3-methylpyridin-4-carboxylic acid (2.00 g, 14.58 mmol) and HCl (6 mmol) were stirred. N, PtO2 (0.33 g, 1.46 mmol) was added to a mixture of 3 mL of MeOH (15 mL). The resulting mixture was stirred at 50 °C for 12 hours under a H2 (50 atm) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 3-methylpiperidin-4-carboxylate HCl (2.30 g, 90%): C8H2O as a yellow oil. 15 NO2 [M + H] + LCMS (ESI) calculated value: 158, measured value: 158 ；1 H NMR (400 MHz, DMSO- d 6) δ 3.86-3.69 (m, 2H), 3.64 (s, 3H), 3.15-2.90 (m, 2H), 2.83 (q, J = 5.7 Hz, 1H), 2.35-2.23 (m, 1H), 1.91-1.81 (m,2H), 0.93 (d, J = 7.2 Hz, 3H).

[0783] Step b:

[0784] Boc₂O (4.79 g, 21.95 mmol) was added to a solution of methyl 3-methylpiperidin-4-carboxylate (2.30 g, 14.63 mmol) and Et₃N (2.96 g, 29.26 mmol) in THF (15 mL) and MeOH (30 mL) under stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours. The resulting mixture was diluted with EA (50 mL) and water (30 mL). The aqueous solution was 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. The residue was purified by reversed-phase chromatography, eluting with 20% ACN aqueous solution (with 0.05% TFA) to give 1-tert-butyl-4-methyl-3-methylpiperidin-1,4-dicarboxylate (2.90 g, 77% total from two steps): C 13 H 23 NO4[M + H - 15] + The calculated LCMS (ESI) value is 243, and the measured value is also 243. 1 H NMR (400 MHz, CDCl3) δ 4.02 (s, 1H), 3.80 (dd, J = 13.3, 1.5 Hz, 1H), 3.70 (s,3H), 3.31-2.81 (m, 2H), 2.62 (dt, J = 10.5, 4.3 Hz, 1H), 2.27-2.15 (m, 1H), 1.92-1.77 (m, 1H), 1.75-1.58 (m, 1H), 1.47 (s, 9H), 0.90 (dd, J = 6.8, 2.5Hz, 3H).

[0785] Step c:

[0786] A solution of NaOH (0.83 g, 20.98 mmol) in H₂O (4 mL) was added to a stirred solution of 1-tert-butyl-4-methyl-3-methylpiperidine-1,4-dicarboxylate (2.70 g, 10.49 mmol) in MeOH (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and acidified to pH 3 with citric acid. The mixture was extracted with EA (3 × 50 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 to give 1-[(tert-butoxy)carbonyl]-3-methylpiperidine-4-carboxylic acid (1.30 g, 63%) as a yellow oil. 12 H 21 NO4[M + Na] + The calculated LCMS (ESI) value is 266, and the measured value is also 266. 1 H NMR (400 MHz, DMSO- d 6) δ12.24 (s, 1H), 3.88 (s, 1H), 3.70 (dd, J = 13.1, 3.6 Hz, 1H), 3.09-2.65 (m,2H), 2.56 (dt, J = 10.0, 4.5 Hz, 1H), 2.19-2.08 (m, 1H), 1.65-1.49 (m, 2H), 1.39 (s, 9H), 0.80 (d, J = 6.9 Hz, 3H).

[0787] Step d:

[0788] At room temperature, EDCI (1.30 g, 6.78 mmol), Et3N (0.55 g, 5.43 mmol), and N were added to a stirred mixture of 1-[(tert-butoxy)carbonyl]-3-methylpiperidin-4-carboxylic acid (1.10 g, 4.52 mmol) and HOBt (0.91 g, 6.78 mmol) in DMF (10 mL). ,O-Methoxy(methyl)amine (0.30 g, 4.97 mmol). The reaction solution was stirred at room temperature for 12 hours. The resulting solution was quenched with water (50 mL) at room temperature and extracted with EA (2 × 50 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 purified by silica gel column chromatography, eluting with PE / EA (4 / 1) to give tert-butyl 4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylate (1.00 g, 77%) as a colorless oil: C 14 H 26 N₂O₄[M + H - 56] + LCMS (ESI) calculated value: 231; Measured value: 231; 1 H NMR (400 MHz, CDCl3) δ 4.17-3.89 (m, 2H), 3.86-3.76 (m, 1H), 3.73 (s, 3H), 3.29-3.13 (m, 4H), 3.13-2.94 (m, 2H), 2.24-2.09 (m, 1H), 2.06-1.87 (m, 1H), 1.48 (s, 9H), 0.93 (d, J = 7.0 Hz, 3H).

[0789] Example 55. Intermediate 55 ((3S,4S)-rel-4-(2-(prop-2-en-1-yloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester; (3R,4S)-rel-4-(2-(prop-2-en-1-yloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester)

[0790]

[0791] Step a:

[0792] Under a nitrogen atmosphere and at 0°C, 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (2.12 g, 7.68 mmol) was added dropwise to a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene in 10 mL of THF. i-PrMgCl (3.84 mL, 7.68 mmol, 2 M THF solution). The reaction was stirred at 0 °C for 30 min. Then, a solution of tert-butyl 4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylate (1.10 g, 3.84 mmol) in THF (8 mL) was added dropwise to the solution. After the addition, the resulting solution was stirred at 0 °C for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL). The reaction mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous solution was then 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 to give a mixture of tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylate and tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)-3-methylpiperidine-1-carboxylate. The residue was dissolved in DMF (10 mL), and K₂CO₃ (0.88 g, 6.37 mmol) and allyl bromide (0.77 g, 6.37 mmol) were added at room temperature. The resulting 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 (6 × 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, eluted with PE / EA (10 / 1), to give tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-3-methylpiperidin-1-carboxylic acid (0.90 g, 55%) containing two cis enantiomers as a pale yellow oil: C 21 H 27 Cl2NO4[M + H - 56] + The calculated LCMS (ESI) values ​​are 372, 374 (3:2), and the measured values ​​are also 372, 374 (3:2). 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.06 (s, 1H), 6.15-5.97 (m, 1H), 5.52-5.38 (m, 2H), 4.69-4.54 (m, 2H), 4.25-4.03 (m, 1H), 4.01-3.86 (m, 1H),3.68-3.52 (m, 1H), 3.12-2.94 (m, 1H), 2.91-2.76 (m, 1H), 2.24-2.10 (m, 1H),2.01-1.84 (m, 1H), 1.76-1.55 (m, 1H), 1.55-1.39 (m, 9H), 0.85 (d, J = 6.5 Hz, 3H).

[0793] 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.12 g, 7%) containing two trans enantiomers was isolated as a pale yellow oil: C 21 H 27 Cl2NO4[M + Na] + The calculated LCMS (ESI) values ​​are 450 and 452 (3:2), while the measured values ​​are also 450 and 452 (3:2). 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.07 (s, 1H), 6.11-5.93 (m, 1H), 5.44 (q, J = 11.2 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.19-4.10 (m, 1H), 3.92 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 13.1 Hz, 1H), 2.87-2.78 (m, 1H), 2.23-2.08 (m, 1H), 1.97-1.82 (m, 1H), 1.76-1.58 (m, 1H), 1.56-1.32 (m, 9H), 0.82-0.75 (m, 3H).

[0794] Example 56. Intermediate 56 ((2 S )-1-Methyl-5-oxopyrrolidine-2-carboxylic acid)

[0795]

[0796] Step a:

[0797] Under a nitrogen atmosphere, at 0°C, the mixture was stirred (2... S 5-oxopyrrolidine-2-carboxylic acid tert-butyl ester (0.50 g, 2.70 mmol) was added to a solution of NaH (0.22 g, 5.40 mmol, 60% mineral oil solution) in THF (5 mL). The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. MeI (1.15 g, 8.10 mmol) was added dropwise to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water (40 mL) and extracted with EA (3 × 50 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 reversed-phase chromatography, eluting with 50% ACN aqueous solution (with 0.05% TFA), to give (2) a pale yellow oil. S 1-Methyl-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester (0.34 g, 63%): C 10 H 17 NO3 [2M + H] + The calculated LCMS (ESI) value is 399, and the measured value is also 399. 1 H NMR (400 MHz, CDCl3) δ 4.09-3.92 (m, 1H), 2.87 (s, 3H), 2.57-2.43 (m, 1H), 2.43-2.24 (m, 2H), 2.13-1.98 (m, 1H), 1.50 (s, 9H).

[0798] Step b:

[0799] Stirring at room temperature (2) S 1-Methyl-5-oxopyrrolidine-2-carboxylic acid ter...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in Structural parts have The structure; R1 and R2 are each independently H, C1-C6 alkyl, or (CR6R7). n4 OH, (CR6R7) 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 ; R4 is H, C1-C6 alkyl, halo-C1-C6 alkyl, (CR6R7) n4 OR c (CR6R7) n4 (C=O)R c (C=O)(CR6R7) n4 R c (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 Optionally selected by 1-4 independently chosen C1-C6 alkyl groups, halogens, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo-substituted 3-7 membered monocyclic and 7-11 membered bicyclic saturated heterocyclic or 5-7 membered monocyclic or 7-11 membered bicyclic heteroaryl, or -C1-C6 alkyl-phenyl; Each occurrence of R5 is independently of H, C1-C6 alkyl, or oxo; Or two R5 groups are attached to different carbon atoms on the ring and together form a bond or an alkyl chain containing 1-3 carbons; Each occurrence of R6 and R7 is independently H or C1-C6 alkyl; R a Each occurrence of is independently H or C1-C6 alkyl; R b Each occurrence of H is independently a C1-C6 alkyl group optionally substituted with 1-4 halogens, or a 5-7 membered monocyclic heteroaryl group; or R a and R b Together with the nitrogen atoms to which they are attached, they form 3-7 membered monocyclic heterocycles, wherein the heterocycles are optionally composed of 1-4 atoms, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo substituents are used to replace nitrogen atoms and 0-3 additional heteroatoms selected from N, O and S respectively; R c Each occurrence of the compound is independently H, a C1-C6 alkyl group, substituted with 1-4 C1-C6 alkyl groups, each independently substituted with a halogen, OR8, or N(R8)2 group, or a C3-C7 cycloalkyl group, a 3-7 membered monocyclic or 7-11 membered bicyclic saturated heterocyclic group, a phenyl group, or a 5-7 membered monocyclic or 7-11 membered bicyclic heteroaryl group, each optionally substituted with 1-4 substituents, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo; R d Each occurrence of is independently H or C1-C6 alkyl; Or R c and R d Together with the nitrogen atoms to which they are attached, they form 3-7 membered monocyclic or 7-11 membered bicyclic saturated heterocycles, which are optionally composed of 1-4 atoms, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo substituents are used to replace nitrogen atoms and 0-3 additional heteroatoms selected from N, O and S respectively; Each occurrence of R8 is independently H or C1-C6 alkyl; R9 is H, C1-C6 alkyl, or halogen; As long as the valence allows, each occurrence of n1 is an independent integer between 0 and 3; Each occurrence of n2 and n3 is an independent integer between 0 and 2; and Each occurrence of n4 is an independent integer between 0 and 3.

2. The compound according to claim 1, wherein each occurrence of n2 and n3 is an independent integer from 0 to 1.

3. The compound according to claim 1, wherein the structural motif have or The structure.

4. The compound according to claim 1, wherein the structural motif have or The structure.

5. The compound according to claim 1, wherein the structural motif have The structure.

6. The compound according to any one of claims 1-5, wherein at least one occurrence of R1 and R2 is H or C1-C6 alkyl.

7. The compound according to any one of claims 1-5, wherein at least one occurrence of R1 and R2 is (CR6R7). n4 OH, (CR6R7) 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 .

8. The compound according to claim 7, wherein at least one occurrence of R1 and R2 is OH or NR. a R b .

9. The compound according to any one of claims 1-5, wherein R1 and R2 are each independently H, Me, OH, CH2OH, NH2, NHMe, NMe2, CH2NH2, CONH2, CONHMe2, CONMe2, NH(C=O)Me, NMe(C=O)Me, , , , or .

10. The compound according to any one of claims 1-5, wherein R4 is H, C1-C6 alkyl, or halo-C1-C6 alkyl.

11. The compound according to claim 10, wherein R4 is H, Me, or a fluoroethyl group.

12. The compound according to any one of claims 1-5, wherein R4 is (CR6R7). n4 OR c (CR6R7) n4 COR c (C=O)(CR6R7) n4 R c (CR6R7) n4 (C=O)NR c R d (CR6R7) n4 (C=O)(C=O)NR c R d (C=O)(CR6R7) n4 OR c Or (CR6R7) n4 SO2R c .

13. The compound according to claim 12, wherein R4 is (CR6R7)2OR c (C=O)R c (C=O)(CR6R7) 1-2 R c (C=O)NR c R d (CR6R7) n4 (C=O)(C=O)NR c R d (C=O)(CR6R7) 1-2 OR c or SO2R c .

14. The compound according to claim 13, wherein R4 is (CH2)2OH, (CH2)2OMe, (C=O)H, (C=O)Me, (C=O)CH2OH, (C=O)CH2OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)NH2, (C=O)NHMe, (C=O)NMe2, (C=O)CH2NH2, (C=O)CH2NHMe, (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2OH, (C=O)CH(OH)CH2OMe, (C=O)(C=O)NMe2, (C=O)OMe, SO2Me, SO2Et, SO2CH2OH or SO2CH2OMe.

15. The compound according to claim 13, wherein 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 The C1-C6 alkyl group is selected from H, and is substituted with 1-4 substituents selected independently from halogens, OR8, and N(R8)2; or is selected from C3-C7 cycloalkyl, 3-7 membered monocyclic saturated heterocyclic, phenyl, or 5-7 membered monocyclic heteroaryl, each optionally substituted with 1-4 substituents selected independently from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo.

16. The compound according to claim 13, wherein R c It is H, Me, Et, , , 。 17. The compound according to claim 13, wherein R c It is selected from the following heterocycles: Where the valence allows, the heterocycle may optionally be converted by one or more cyano groups, halogens, OH, NH2, oxo groups, or (C=O)C groups. 1-4 Alkyl substitution.

18. The compound according to claim 13, wherein R, where the valence permits, c It is a C3-C7 cycloalkyl group optionally substituted with 1-4 substituents, each of which is independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2 and oxo.

19. The compound according to claim 18, wherein R, where the valence permits, c Each can be substituted by 1-4 substituents at will. Each of the substituents is independently selected from C1-C6 alkyl, halogen, CN, -(CH2) 0-2 OR8, N(R8)2 and oxo.

20. The compound according to any one of claims 1-5, wherein R4 is optionally composed of 1-4 molecules, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo-substituted 3-7 membered monocyclic or 7-11 membered bicyclic saturated heterocyclic or 5-7 membered monocyclic or 7-11 membered bicyclic heteroaryl, or -C1-C6 alkyl-phenyl.

21. The compound of claim 20, wherein R4 is a heterocycle selected from: Where the valence allows, the heterocycle may optionally be converted by one or more cyano groups, halogens, OH, NH2, oxo groups, or (C=O)C groups. 1-4 Alkyl substitution.

22. The compound according to any one of claims 1-5, wherein R4 is Or its tautomers.

23. The compound according to any one of claims 1-5, wherein R5 appears at least once as H or C1-C6 alkyl.

24. The compound according to any one of claims 1-5, wherein at least one occurrence of R5 is oxosubstituted.

25. The compound according to any one of claims 1-5, wherein the two R5 groups are attached to different carbon atoms on the ring and together form a bond or an alkyl chain containing 1-3 carbons.

26. The compound according to any one of claims 1-5, wherein R a and R b At least one of them is independently H or C1-C6 alkyl.

27. The compound according to any one of claims 1-5, wherein R a and R b Together with the nitrogen atoms to which they are attached, they form 3-7 membered monocyclic heterocycles, wherein the heterocycles are optionally composed of 1-4 atoms, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0- 2OR8, N(R8)2, (C=O)C 1-4 The alkyl and oxo substituents are substituted and contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

28. The compound according to any one of claims 1-5, wherein R9 is H or F.

29. The compound according to any one of claims 1-5, wherein R8 is H, Me, Et, Pr or Bu.

30. The compound according to any one of claims 1-5, wherein n4 is 0, 1 or 2.

31. The compound according to any one of claims 1-5, wherein R c At least once, it is independently H, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with 1-4 substituents each independently selected from halogens, OR8, and N(R8)2, or a C3-C7 cycloalkyl group, a 3-7 membered monocyclic or 7-11 membered bicyclic saturated heterocyclic group, a phenyl group, or a 5-7 membered monocyclic or 7-11 membered bicyclic heteroaryl group, each optionally substituted with 1-4 substituents, each substituent independently selected from C1-C6 alkyl groups, halogens, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 Alkyl and oxo.

32. The compound according to any one of claims 1-5, wherein R c and R d Together with the nitrogen atoms to which they are attached, they form 3-7 membered monocyclic or 7-11 membered bicyclic saturated heterocycles, which are optionally composed of 1-4 atoms, each independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2, (C=O)C 1-4 The alkyl and oxo substituents are substituted and contain a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

33. The compound according to any one of claims 1-5, wherein R c The at least one occurrence of H, Me, Et, 。 34. The compound according to any one of claims 1-5, wherein R c At least one occurrence of the substance is independently selected from the following heterocycles: Where the valence allows, the heterocycle may optionally be converted by one or more cyano groups, halogens, OH, NH2, oxo groups, or (C=O)C groups. 1-4 Alkyl substitution.

35. The compound according to any one of claims 1-5, wherein R, where the valence permits, c The at least one occurrence of the substance is independently a C3-C7 cycloalkyl group optionally substituted with 1-4 substituents, each of which is independently selected from C1-C6 alkyl, halogen, CN, -(CH2). 0-2 OR8, N(R8)2 and oxo.

36. The compound according to any one of claims 1-5, wherein R, where the valence permits, c Each of the at least one occurrence is independently represented by each of the substituted groups optionally being substituted by 1-4 substituents. Each of the substituents is independently selected from C1-C6 alkyl, halogen, CN, -(CH2) 0-2 OR8, N(R8)2 and oxo.

37. A compound selected from: 。 38. A pharmaceutical composition comprising at least one compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

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