Arylheterobicyclic compounds as blockers of the Kv1.3 potassium shaker channel

Abstract

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

Description

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. filed on 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 the reproduction of any copy of the patent document or patent disclosure appearing in the U.S. Patent and Trademark Office patent documents or records, but otherwise reserves all and all copyright rights.

[0003] By incorporating via reference

[0004] All references cited in this article are incorporated herein by reference in their full text. Technical Field

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

[0006] Background of the Invention: Voltage-gated Kv1.3 potassium (K + Kv1.3 channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and regulate a wide range of physiological processes, such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels can modulate membrane potential and thereby indirectly affect calcium signaling in human effector memory T cells (“TEMs”). TEMs are mediators of several diseases, including multiple sclerosis (“MS”), type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, TEMs increase the expression of Kv1.3 channels. In human B cells, naïve and early memory B cells express low levels of Kv1.3 channels when they are quiescent. Conversely, class-switched 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 (e.g., interferon-γ, interleukin-2), and cell proliferation.

[0007] Autoimmune diseases are a group of conditions caused by tissue damage resulting from the body's own immune system attacking the tissues. These diseases can affect a single organ, as in MS 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, which can have serious side effects. The need for more effective therapies has led to research into drugs that can selectively inhibit the function of TEMs (transferases) known to be involved in the etiology of autoimmune diseases. These inhibitors are thought to be able to improve the symptoms of autoimmune diseases without compromising the protective immune response. TEMs express a large number of Kv1.3 channels, and their function depends on these channels. In vivo, Kv1.3 channel blockers paralyze TEMs at sites of inflammation and prevent them from reactivating in inflamed tissues. Kv1.3 channel blockers do not affect the intranodal motility of naïve and central memory T cells. Inhibiting the function of these cells by selectively blocking Kv1.3 channels offers the potential for effective treatment of autoimmune diseases with minimal side effects.

[0008] MS is caused by autoimmune damage to the central nervous system (“CNS”). Symptoms include muscle weakness and paralysis, which severely impact patients’ quality of life. MS progresses rapidly and unpredictably, ultimately leading to death. Kv1.3 channels are also highly expressed in autoreactive TEMs from MS patients (Wulff H. et al., 2003, J. Clin. Invest., 1703-1713; Rus H. et al., 2005, PNAS, 11094-11099). Animal models of MS have been successfully treated with Kv1.3 channel blockers.

[0009] Compounds that are selective Kv1.3 channel blockers are therefore potential therapeutic agents as immunosuppressants or modulators of the immune system. Kv1.3 channels are also considered therapeutic targets 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 treat immune (e.g., autoimmune) and inflammatory conditions.

[0010] Tubulointerstitial fibrosis (TURF) is a progressive deposition of connective tissue in the renal parenchyma, leading to renal function decline and involving 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 the Kv1.3 channel in lymphocytes can promote its proliferation, leading to excessive stimulation of chronic inflammation and cellular immunity. It is involved in the underlying pathology of these kidney diseases and is a contributing factor to the progression of TURF. Inhibition of lymphocyte Kv1.3 channel currents suppressed renal lymphocyte proliferation and improved the progression of renal fibrosis (Kazama I. et al., 2015, Mediators Inflamm., 1-12).

[0011] Kv1.3 channels also play a role in gastrointestinal diseases, including inflammatory bowel diseases (“IBDs”) such as ulcerative colitis (“UC”) and Crohn’s disease. UC is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. UC can impair quality of life and can lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients are associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered to act as a biomarker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy in UC. Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNF-α agents, are insufficient for many patients (Hansen LK et al., 2014, J. Crohn’s Colitis, 1378-1391). Crohn’s disease is a type of IBD that can affect any part of the gastrointestinal tract. Crohn’s disease is thought to result from intestinal inflammation caused by a T-cell-driven process induced by normally safe bacteria. Therefore, Kv1.3 channel inhibition could be used to treat Crohn's disease.

[0012] Besides T cells, the Kv1.3 channel is also expressed in microglia, where it is involved in the production of inflammatory cytokines and nitric oxide, as well as microglia-mediated neuronal killing. In humans, the Kv1.3 channel has been found in microglia of the frontal cortex in Alzheimer's disease patients and in CD68 cells of multiple sclerosis brain injury. + Strong expression on cells. It has been shown that Kv1.3 channel blockers may preferentially target detrimental pro-inflammatory microglial function. Kv1.3 channels are expressed on activated microglial cells in infarcted rodent and human brains. Higher Kv1.3 channel current densities were observed in acutely isolated microglial cells of the infarcted hemisphere in a stroke mouse model than in isolated microglial cells of the contralateral hemisphere (Chen YJ et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0013] Kv1.3 channel expression is elevated in microglia of the human Alzheimer's disease brain, suggesting that Kv1.3 channels are a pathologically relevant microglia target in Alzheimer's disease (Rangaraju S. et al., 2015, J. Alzheimers Dis., 797-808). Soluble AβO enhances Kv1.3 channel activity in microglia. 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 the human Alzheimer's disease brain. Pharmacological targeting of Kv1.3 channels in microglia 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.

[0014] 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.

[0015] Kv1.3 channel expression is involved in the control of proliferation, apoptosis, and cell survival in various 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 Kv1.3 channels could potentially be used as anticancer agents.

[0016] Several peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. Several selective and potent peptide inhibitors of Kv1.3 channels have been developed. A synthetic derivative (shk-186) of stichodactyla toxin (“shk”), containing non-natural amino acids, is the most advanced peptide toxin. Shk has demonstrated efficacy in preclinical models and is currently in a Phase I clinical trial for the treatment of psoriasis. Shk inhibits the proliferation of TEM, leading to improved condition in MS animal models. Unfortunately, Shk also binds to closely related Kv1.3 channel subtypes found in the CNS and heart. Selective inhibitors of Kv1.3 channels are needed to avoid potential cardiotoxicity and neurotoxicity. Furthermore, small peptides such as shk-186 are rapidly cleared from the body after administration, resulting in a short circulating half-life and frequent dosing events. Therefore, there is a need to develop long-acting selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory conditions.

[0017] Therefore, there is still a need to develop new Kv1.3 channel blockers as drugs. Invention Overview

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

[0020] On one hand, compounds of formula I or their pharmaceutically acceptable salts are described.

[0021]

[0022] in

[0023] Y is C(R2)2, NR1, or O;

[0024] Z is OR a ;

[0025] X1 is H, halogen, or alkyl;

[0026] X2 is H, halogen, CN, alkyl, cycloalkyl, halocycloalkyl, or haloalkyl;

[0027] X3 is H, halogen, haloalkyl, or alkyl;

[0028] Alternatively, X1 and X2 together with the carbon atoms to which they are attached can form optionally substituted 5- or 6-membered aryl groups;

[0029] Alternatively, X2 and X3 together with the carbon atoms to which they are attached can form optional substituted 5- or 6-membered aryl groups;

[0030] Each occurrence of R1 is independently H, alkyl, alkenyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, aryl, heteroaryl, (CR6R7) n6 OR a (CR6R7) n6 N(R a 2. (C=O)R a (C=O)OR a (CR6R7) n6 (C=O)NR a R b SO2Ra Or (CR6R7) n6 - Heterocyclic rings;

[0031] Each occurrence of R2 is independently of H, halogen, CN, alkyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, (CR6R7) n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a 2. NR a (CR6R7) n6 OR a (C=O)NR a (CR6R7) n6 OR a (C=O)R a (CR6R7) n6 (C=O)NR a R b aryl or heteroaryl, wherein each R2 may be connected to On any one of the carbon ring atoms;

[0032] R3 is H, alkyl, or halogen;

[0033] Each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0034] R a and R b Each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl; or R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted heterocycles;

[0035] The heterocycle contains 1-3 heteroatoms, each selected from N, O, and S;

[0036] X1, X2, X3, R1, R2, R3, R6, R7, R a and R b The alkyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by 1-4 substituents, wherein the substituents are each independently selected from alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, CN, R8, OR8, and -(CH2). 1-2OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8 and oxidative oxidation (where valence state allows);

[0037] Each occurrence of R8 is independently H, alkyl, cycloalkyl, or a heterocycle optionally substituted with an alkyl group; or two R8 groups together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with an alkyl group and containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O, and S.

[0038] n1 is an integer between 0 and 1;

[0039] n² is an integer between 0 and 2;

[0040] n3 is an integer between 0 and 3;

[0041] n4 is an integer from 1 to 2; and

[0042] n6 is an integer between 0 and 3.

[0043] In any of the embodiments described herein, the structural portion have The structure.

[0044] In any of the embodiments described herein, the structural portion have The structure.

[0045] In any of the embodiments described herein, this structural portion have The structure.

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

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

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

[0049] In any of the embodiments described herein, the structural portion have The structure.

[0050] In any of the embodiments described herein, R1 is H, alkyl, alkenyl, cycloalkyl, heteroalkyl, or cyclohexaalkyl.

[0051] In any of the embodiments described herein, R1 is aryl or heteroaryl.

[0052] In any of the embodiments described herein, R1 is (C=O)R a (C=O)OR a SO2R a (CR6R7) n6 OR a (CR6R7) n6 N(R a 2. (CR6R7) n6 (C=O)NR a R b Or (CR6R7) n6 - Heterocyclic rings.

[0053] In any of the embodiments described herein, R1 is (C=O)R a .

[0054] In any of the embodiments described herein, R a and R b Each is independently H, alkyl, or alkyl substituted with one or more OR8 groups.

[0055] In any of the embodiments described herein, R8 is H or an alkyl group.

[0056] In any of the embodiments described herein, R1 is selected from H, -CH3, -(CH2)2OH, -(CH2)2NH2, -CONH2, -CONHMe, -CONMe2, -CONEt2, SO2Me and SO2Et.

[0057] In any of the embodiments described herein, R1 is selected from...

[0058]

[0059] In any of the embodiments described herein, R1 is selected from...

[0060]

[0061] In any of the embodiments described herein, R2 appears at least once as H, halogen, CN, alkyl, heteroalkyl, cycloalkyl, cyclohexaalkyl, OR a N(R1)2, (C=O)R a (C=O)NR a R b , aryl or heteroaryl.

[0062] In any of the embodiments described herein, R2 appears at least once in (CR6R7). n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)R a (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a 2. NR a (CR6R7) n6 OR a (C=O)NR a (CR6R7) n6 OR a Or (CR6R7) n6 (C=O)NR a R b .

[0063] In any of the embodiments described herein, R2 appears at least once.

[0064]

[0065] In any of the embodiments described herein, R2 appears at least once as a heteroalkyl, cyclohexaalkyl,

[0066]

[0067] In any of the implementations described herein, n1 is 0.

[0068] In any of the embodiments described herein, n1 is 1.

[0069] In any of the embodiments described herein, n2 is 0 or 1.

[0070] In any of the embodiments described herein, n3 is 0, 1, or 2.

[0071] In any of the embodiments described herein, n4 is 1.

[0072] In any of the embodiments described herein, n6 is 0, 1, or 2.

[0073] In any of the embodiments described herein, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or Obu.

[0074] In any of the embodiments described herein, Z is OH, OMe, or OEt.

[0075] In any of the embodiments described herein, Z is OH.

[0076] In any of the embodiments described herein, X1 is H, halogen, Me, or Et.

[0077] In any of the embodiments described herein, X1 is H, F, Cl, Br, or Me.

[0078] In any of the embodiments described herein, X1 is H or Cl.

[0079] In any of the embodiments described herein, X2 is H, halogen, fluoroalkyl, or alkyl.

[0080] In any of the embodiments described herein, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0081] In any of the embodiments described herein, X2 is H or Cl.

[0082] In any of the embodiments described herein, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0083] In any of the embodiments described herein, X3 is H or Cl.

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

[0085] In any of the embodiments described herein, R3 is an alkyl group.

[0086] In any of the embodiments described herein, R3 is a halogen.

[0087] In any of the embodiments described herein, R3 is H, F, Cl, or Me.

[0088] In any of the embodiments described herein, the structural portion have The structure.

[0089] In any of the embodiments described herein, the compound has the structure of formula II' or II:

[0090]

[0091] Where R 3’ Independently H, halogen, or alkyl; and

[0092] n5 is an integer between 0 and 3.

[0093] In any of the embodiments described herein, n5 is 0, 1, or 2.

[0094] In any of the implementations described herein, n5 is 0.

[0095] In any of the embodiments described herein, R 3’ It is H or alkyl.

[0096] In any of the embodiments described herein, R 3’ It is halogen.

[0097] In any of the embodiments described herein, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or OBu.

[0098] In any of the embodiments described herein, Z is OH, OMe, or OEt.

[0099] In any of the embodiments described herein, Z is OH.

[0100] In any of the embodiments described herein, R a Or R b It appears at least once independently as H, alkyl, cycloalkyl, saturated heterocyclic, aryl or heteroaryl.

[0101] In any of the embodiments described herein, R a Or R b The at least one occurrence of is independently H, Me, Et, Pr or selected from

[0102] Heterocyclic compounds; wherein, when the valence state permits, the heterocycle is optionally converted by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution.

[0103] 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 comprising the nitrogen atoms and 0-3 additional heteroatoms each selected from N, O, and S.

[0104] In any of the embodiments described herein, the heterocycle is selected from...

[0105]

[0106] In any of the embodiments described herein, the compound is selected from compounds 1-62 shown in Table 4.

[0107] In any of the embodiments described herein, the compounds are selected from compounds 63-78, 83-85, 87-88, 90-94, 96-97, 99-104, 109-176, 180-208, 213-220, and 223-293 shown in Table 5.

[0108] In another aspect, pharmaceutical compositions are described, comprising at least one compound according to any of the embodiments described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0109] In another aspect, methods for treating diseases in mammalian species in need are described, including administering a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any embodiment described herein to the mammalian species, wherein the disease is selected from cancer, immunological diseases, central nervous system (CNS) diseases, inflammatory diseases, gastrointestinal diseases, metabolic diseases, cardiovascular diseases, and kidney diseases.

[0110] In any of the implementation methods described herein, the immunological condition is transplant rejection or an autoimmune disease.

[0111] In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0112] In any of the embodiments described herein, the central nervous system symptom is Alzheimer's disease.

[0113] In any of the embodiments described herein, the inflammatory condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neurological disease.

[0114] In any of the embodiments described herein, the gastrointestinal disease is inflammatory bowel disease.

[0115] In any of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0116] In any of the implementation methods described herein, the cardiovascular condition is ischemic stroke.

[0117] In any of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0118] In any of the embodiments described herein, the disease is selected from cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin diseases, inflammatory neurological diseases, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0119] In any of the embodiments described herein, the mammal species is human.

[0120] In another aspect, a method for blocking the Kv1.3 potassium channel in mammalian species in need of this is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any embodiment described herein.

[0121] In any of the embodiments described herein, the mammal species is human.

[0122] Any embodiment disclosed herein may be suitably combined with any other embodiment disclosed herein. Combinations of any embodiment disclosed herein with any other embodiment disclosed herein are expressly contemplated. Specifically, the selection of one or more embodiments of a substituent may be suitably combined with the selection of one or more particular embodiments of any other substituent. Such combinations may be made in any one or more embodiments of the application described herein or in any formula described herein. Invention Details

[0124] definition

[0125] The following are definitions of terms used in this specification. Unless otherwise stated, the initial definitions provided herein for groups or terms, either alone or as part of another group, apply throughout this specification to that group or term. 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.

[0126] The terms "alkyl" and "alk" refer to straight-chain or branched alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, 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 to 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 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 a polyhalogen substituent, 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 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 Rc and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c The N atoms bonded to them may optionally form heterocycles, and R e Each occurrence of the group is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. In some embodiments, the groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic, and aryl may optionally be substituted.

[0127] The term "heteroalkyl" refers to a straight-chain or branched alkyl group, preferably having 2 to 12 carbons in the chain, more preferably 2 to 10 carbons, wherein one or more carbons have been replaced by heteroatoms selected from S, O, P, and N. Exemplary heteroalkyl groups include, but are not limited to, alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides, etc. The group can be a terminal group or a bridging group.

[0128] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary examples of such groups include vinyl or allyl groups. The term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl-(E)-but-2-enyl, 2-methyl-(Z)-but-2-enyl, 2,3-dimethylbut-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-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 connection point with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, haloalkyl (i.e., alkyl with a single or multiple halogen substituents, such as CF3 or 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 NRb 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 The N atoms bonded to them may optionally form heterocycles; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutes may optionally be substituted.

[0129] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, propynyl-2-alkynyl, butynyl, butynyl-2-alkynyl, pentynyl, pentynyl-2-alkynyl, hexynyl, hexynyl-2-alkynyl, or hexynyl-3-alkynyl. "Substituted alkynyl" refers to an alkynyl group that is substituted at any available linker with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent, or a polyhalogen substituent, 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 NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NRb 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 The N atoms bonded to them may optionally form heterocycles; and R e Each occurrence of the substance is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substitutes may optionally be substituted.

[0130] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings, each with 3 to 8 carbons. "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 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 a polyhalogen substituent, 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)ORe 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 The N atoms bonded to them may optionally form heterocycles; 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 or fused cyclic substituents, particularly fused cycloalkyl, fused cycloalkenyl, fused 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.

[0131] The term "heterocyclic alkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, and oxygen, preferably one to three heteroatoms. Each ring is preferably 3 to 10-membered, more preferably 4 to 7-membered. Examples of suitable heterocyclic alkyl substituents include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazyl, tetrahydropyranyl, morpholinyl, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,4-oxazacycloheptane, and 1,4-oxothiocycloheptane. The group can be a terminal group or a bridging group.

[0132] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted at any available junction with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent, or a polyhalogen substituent, 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 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; bR c and R d Each occurrence of R is independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or R. b and R c The N atoms bonded to them may optionally form heterocycles; 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 or fused cyclic substituents, particularly fused cycloalkyl, fused cycloalkenyl, fused 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.

[0133] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, especially a monocyclic or bicyclic group, such as phenyl, biphenyl, or naphthyl. When containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined 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 one to three 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 a polyhalogen substituent, 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 cOC(=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 The N atoms bonded to them may optionally form heterocycles; and R e Each occurrence of the group 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.

[0134] 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 attached to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0135] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings, each with three to eight carbon atoms, or a cyclic aromatic hydrocarbon group having one to five 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 one to four 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 cyclic substituents that are screwed or fused at any of the available one or more connection points, particularly screwed cycloalkyl, screwed cycloalkenyl, screwed 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.

[0136] The terms "heterocyclic" and "heterocyclic" refer to fully saturated, partially or fully unsaturated, aromatic (i.e., "heteroaryl") cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic rings) having at least one heteroatom in at least one carbon-containing ring. Each ring of a heterocyclic group can be independently saturated, 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 "heteroarylium" refers to a heteroaryl group carrying a quaternary nitrogen atom and thus a positive charge. Heterocyclic groups can be attached to the remainder of the molecule at any heteroatom or carbon atom in the ring or cyclic system. Exemplary monocyclic heterocyclic groups include azirrobutyl, pyrrolyl, pyrrolyl, pyrazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolyl, oxazolyl, oxazolyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopyrrolodinyl, 2-oxopyrrolodinyl, 2-oxazirrobutylyl, 2-oxopyrrolodinyl, and 2-oxazirrobutylyl. basic, nitrogen-based basalt, hexahydrodiaza Bicyclic heterocyclic groups include indole, indolyl, isoydinyl, benzothiazolyl, triazolyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxazolyl, tetrahydro-1,1-dioxothiophene, etc. Exemplary bicyclic heterocyclic groups include indole, indololinyl, isoydinol, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothiaphene, benzo[d][1,3]dioxacyclopentenyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl, quininecycloyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indoleazinyl, etc. Benzofuranyl, benzofuranyl, dihydrobenzo[d]oxazole, crenoyl, coumarinyl, benzopyranyl, cenolinyl, quinoxalinyl, indazole, pyrrolopyridyl, furanopyridyl (such as furano[2,3-c]pyridyl, furano[3,2-b]pyridyl] or furano[2,3-b]pyridyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazine-aza Examples of tricyclic heterocyclic groups include carbazole, benzoindolyl, phenanthrenerolinyl, acridine, phenanthridine, xanthonyl, etc.

[0137] "Substituted heterocycle" and "substituted heterocycle" (such as "substituted heteroaryl") refer to a heterocycle or heterocyclic 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 a polyhalogen substituent, 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)ORd 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 The N atoms bonded to them may optionally form heterocycles; 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 or fused cyclic substituents at any available connection point, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl substituents, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may optionally be substituted themselves.

[0138] 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 be rearranged to satisfy valence requirements. For example, pyridine with a 2-oxosubstituent can have... The structure, which also includes its tautomer forms.

[0139] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, or 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.

[0140] The term "dialkylamino" refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic. R and R' may be the same or different in the dialkylamino moiety. Examples of dialkylamino include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di-n-propylamino, diisopropylamino, dicyclopropylamino, di-n-butylamino, di-tert-butylamino, dinepentylamino, di-n-pentylamino, dihexylamino, dicyclohexylamino, 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 structure include, but are not limited to, acridine, pyrrolidine, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0141] The term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0142] 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 at any available connection point with one or more substituents, preferably one to six substituents where the valence state permits. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent, or a polyhalogen substituent, 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, halogen-substituted alkyl, 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 bP(=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 The N atoms bonded to them may optionally form heterocycles; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aryl. In the foregoing exemplary substituents, 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 foregoing substituents.

[0143] Unless otherwise stated, it is assumed that any heteroatom with an unsatisfied valence has a hydrogen atom sufficient to satisfy the valence.

[0144] The compounds of the present invention can form salts, which are also within the scope of the present invention. Unless otherwise stated, reference to a compound of the present invention should be understood to include reference to its salts. The term "one or more salts" as used herein refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when the compounds of the present invention contain a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids or phenols), zwitterions ("internal salts") can be formed and included in the term "one or more salts" as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps that can be used in 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 an acid or base (such as an equivalent) in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium followed by lyophilization.

[0145] Compounds of the present invention containing a basic moiety, such as, but not limited to, an amine, pyridine, or an imidazole ring, 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, glucoheptanoate, glycerophosphates, hemisulfates, heptanates, hexanoates, and hydrochlorides. Hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, neopentanoate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate (e.g., toluenesulfonate), undecanoate, etc.

[0146] Compounds of the present invention containing an acidic moiety, such as, 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 benzylamine, dicyclohexylamine, hydrabamine (formed from N,N-bis(dehydroabidiamine)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glycamide, and tert-butylamine, as well as salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), etc.

[0147] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, undergoes a chemical transformation via metabolism or a chemical process to produce a compound of the present invention or a salt thereof and / or a solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0148] The compounds of the present invention, as well as their salts or solvates, may exist in their tautomer forms (e.g., as amides or imino ethers). All such tautomer forms are considered part of the invention herein. As used herein, any described structure of a compound includes its tautomer form.

[0149] All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomers and diastereomers, are considered to be within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with specific activities), or may be mixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974. Racemate forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by any suitable method, including but not limited to conventional methods, such as forming a salt with an optically active acid followed by crystallization.

[0150] The compounds of the present invention are preferably isolated and purified after their preparation to obtain a compound containing, by weight, 90% or more, for example, 95% or more, or 99% or more (“substantially pure” compounds), which are subsequently used or formulated as described herein. Such “substantially pure” compounds of the present invention are also considered to be part of the present invention herein.

[0151] All configurational isomers of the compounds of this invention are considered, whether in mixtures or in pure or substantially pure form. 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 heterocyclic rings.

[0152] Throughout this specification, selectable groups and their substituents may be used to provide stable moieties and compounds.

[0153] The definitions and chemical terms for specific functional groups are described in more detail herein. For the purposes of this invention, chemical elements are determined according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as descriptions of specific functional groups and reactivity, are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999).

[0154] Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling 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 intended to be included in this invention.

[0155] According to the present invention, mixtures of isomers containing any ratio of multiple isomers can be used. For example, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all within the scope of this invention when only two isomers are mixed. Those skilled in the art will readily understand that similar ratios are considered for more complex mixtures of isomers.

[0156] This invention also includes isotopically labeled compounds that are identical to those disclosed herein, but in the presence of one or more atoms replaced by atoms with 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, respectively, as follows: 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. The compounds of the present invention, or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, incorporating radioactive isotopes such as… 3 H and 14 Those of type C can be used for drug and / or substrate tissue distribution determination. Tritium (i.e.,...) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages derived from greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. Isotope-labeled compounds can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents by implementing the schemes and / or procedures disclosed in the examples below.

[0157] For example, if a specific enantiomer of the compound of the present invention is desired, 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 salt is then resolved by fractional crystallization or chromatographic methods known in the art, and the pure enantiomer is subsequently recovered.

[0158] It should be understood that compounds described herein may be substituted with any number of substituents or functional portions. Generally, the term “substituted”, whether prefixed with the term “optionally”, and with substituents contained in the formula of this invention, refers to the substitution of a hydrogen group in a given structure with a specified substituent group. When more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. The term “substituted” as used herein is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and 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 (which satisfy the valence state of the heteroatom). Furthermore, this 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 for treatment, for example, the treatment of proliferative diseases. The term “stable” as used herein preferably refers to a compound that has sufficient stability to allow for manufacture and maintains its integrity for a period of time sufficient to be detected and preferably for the purposes detailed herein.

[0159] As used herein, the term “cancer” and its equivalent “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. 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 lung cancer); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; kidney (renal) cancer; sarcoma; skin cancer; testicular cancer; and thyroid cancer; as well as other cancers and sarcomas. Cancer can be primary or metastatic. Non-cancer diseases may be associated with mutational alterations 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 may include: neurofibromatosis; panther syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardiofacial skin syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphocytic proliferative syndrome; and capillary malformations—arteriovenous malformations.

[0160] 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 determine the effective amount of a particular agent empirically without conducting excessive experiments.

[0161] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In another embodiment, the subject is a human. In still 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.

[0162] compound

[0163] Novel compounds as Kv1.3 potassium channel blockers are described herein. The applicant has surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, the applicant has surprisingly discovered that the compounds disclosed herein selectively block Kv1.3 potassium channels without blocking hERG channels, thereby exhibiting desirable cardiovascular safety.

[0164] On one hand, compounds of formula I or their pharmaceutically acceptable salts are described.

[0165]

[0166] in

[0167] Y is C(R2)2, NR1, or O;

[0168] Z is OR a ;

[0169] X1 is H, halogen, or alkyl;

[0170] X2 is H, halogen, CN, alkyl, cycloalkyl, halocycloalkyl, or haloalkyl;

[0171] X3 is H, halogen, haloalkyl, or alkyl;

[0172] Alternatively, X1 and X2 together with the carbon atoms to which they are attached can form optionally substituted 5- or 6-membered aryl groups;

[0173] Alternatively, X2 and X3 together with the carbon atoms to which they are attached can form optional substituted 5- or 6-membered aryl groups;

[0174] Each occurrence of R1 is independently H, alkyl, alkenyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, aryl, heteroaryl, (CR6R7) n6 OR a (CR6R7) n6 N(R a 2. (C=O)R a (C=O)OR a (CR6R7) n6 (C=O)NR a R b SO2R a Or (CR6R7) n6 - Heterocyclic rings;

[0175] Each occurrence of R2 is independently of H, halogen, CN, alkyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, (CR6R7) n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)R a (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a 2. NR a (CR6R7) n6 OR a (C=O)NR a (CR6R7) n6 OR a (C=O)R a (CR6R7) n6 (C=O)NR a R b aryl or heteroaryl, wherein each R2 may be connected to On any one of the carbon ring atoms;

[0176] R3 is H, alkyl, or halogen;

[0177] Each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0178] R a and R b Each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl; or

[0179] R a and R bTogether with the nitrogen atoms to which they are attached, they form optionally substituted heterocycles;

[0180] Heterocycles consist of 1-3 heteroatoms, each selected from N, O, and S;

[0181] X1, X2, X3, R1, R2, R3, R6, R7, R a and R b The alkyl, cycloalkyl, heteroalkyl, cyclohexaalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected independently from alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, CN, R8, OR8, -(CH2) wherever applicable. 1-2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, NR8(C=O)R8 and oxo (where the valence state allows) substituents;

[0182] Each occurrence of R8 is independently H, alkyl, cycloalkyl, or a heterocycle optionally substituted with an alkyl group; or two R8 groups together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with an alkyl group and including the nitrogen atom and 0-3 additional heteroatoms each selected from N, O, and S.

[0183] n1 is an integer between 0 and 1;

[0184] n² is an integer between 0 and 2;

[0185] n3 is an integer between 0 and 3;

[0186] n4 is an integer between 1 and 2; and

[0187] n6 is an integer between 0 and 3.

[0188] In some implementation schemes, the structural portion have The structure. In some specific implementations, the structural part have The structure.

[0189] In some implementation schemes, the structural portion have The structure. In some specific implementations, the structural part have The structure.

[0190] In some implementations, n1 is 1. In some implementations, n1 is 0. In some implementations, n2 is an integer from 0 to 2. In some implementations, n2 is an integer from 1 to 2. In some implementations, n2 is 0. In some implementations, n2 is either 1 or 2. In some implementations, n2 is 1.

[0191] In some implementation schemes, the structural portion have The structure. In some implementations, the structural parts have The structure.

[0192] In some implementation schemes, the structural portion have The structure. In some implementations, the structural parts have The structure.

[0193] In some implementations, Y is C(R2)2. In other implementations, Y is NR1. In still other implementations, Y is 0.

[0194] In some implementation schemes, the structural portion have The structure. In some specific implementations, the structural part have The structure. In some specific implementations, the structural part have The structure. In some specific implementations, the structural part have The structure. In some specific implementations, the structural part have The structure.

[0195] In some specific implementation schemes, the structural part have The structure. In some specific implementations, this structure is partially... have The structure. In some implementations, this structure is partially... have The structure. In some implementations, this structure is partially... have The structure. In some implementations, this structure is partially... have The structure.

[0196] In some embodiments, R1 is H, alkyl, alkenyl, cycloalkyl, heteroalkyl, or cyclohexaalkyl.

[0197] In some embodiments, R1 is H. In some embodiments, R1 is an alkyl group, such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In other embodiments, R1 is a cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0198] In some embodiments, R1 is a heteroalkyl group. In some specific embodiments, R1 is an alkyl ether, a secondary or tertiary alkylamine, or an alkyl sulfide, such as -CH2-CH2-OMe, -CH2-CH2-OEt, -CH2-CH2-OPr, -CH2-CH2-SMe, -CH2-CH2-SEt, -CH2-CH2-SPr, -CH2-CH2-NHMe, -CH2-CH2-NMe2, -CH2-CH2-NEtMe, or -CH2-CH2-NEt2. In some embodiments, R1 is a cyclohexane. Non-limiting examples of cyclohexanes include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,4-oxazacycloheptane, and 1,4-oxothionylheptane.

[0199] In some embodiments, R1 is aryl or heteroaryl. In some embodiments, R1 is (C=O)R. a (C=O)OR a (C=O)NR a R b SO2R a (CR6R7) n6 OR a Or (CR6R7) n6 N(R a 2. In some implementations, R1 is (CR6R7). n6 (C=O)NR a R b SO2R a Or (CR6R7) n6 - Heterocyclic ring. In some specific implementations, R1 is (C=O)R a In some specific implementation schemes, R a and R b Each is independently H, alkyl, or alkyl substituted with one or more OR8 groups.

[0200] In some specific implementations, R8 is H or an alkyl group.

[0201] In some embodiments, R1 is selected from H, -CH3, -(CH2)2OH, -(CH2)2NH2, -CONH2, -CONHMe, -CONMe2, -CONEt2, SO2Me, or SO2Et. In other embodiments, R1 is selected from...

[0202] In some other implementations, R1 is selected from...

[0203]

[0204] In some embodiments, R2 is at least once H, CN, alkyl, heteroalkyl, cycloalkyl, or cyclohexaalkyl. In some embodiments, R2 is at least once H. In some embodiments, R2 is at least once alkyl, such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In other embodiments, R2 is at least once cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R2 is at least once aryl or heteroaryl.

[0205] In some implementations, R2 appears at least once in (CR6R7). n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)R a (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a 2. NR a (CR6R7) n6 OR a (C=O)NR a (CR6R7) n6 OR a Or (CR6R7) n6 (C=O)NR a R b In some implementations, each R2 can be connected to R2 appears at least once on any of the carbon ring atoms. In some specific embodiments, R2 appears at least once in the following order: -CH3, -CH2-OH, -CH2-CH2-OH, -CH(OH)-CH3, -CH2-NH2.

[0206]

[0207] In some implementations, R2 occurs at least once as OR a In some implementations, R2 occurs at least once in N(R1)2. In some implementations, R2 occurs at least once in (C=O)R. a In some implementations, R2 occurs at least once in (C=O)NR. a R bIn some embodiments, R2 occurs at least once as an aryl group. In some embodiments, R2 is a heteroaryl group. In some embodiments, R2 occurs at least once as a heteroalkyl or cyclohexaalkyl group. In some embodiments, R2 is a heteroalkyl group. In some specific embodiments, R2 is an alkyl ether, a secondary or tertiary alkylamine, or an alkyl sulfide, such as -CH2-CH2-OMe, -CH2-CH2-OEt, -CH2-CH2-OPr, -CH2-CH2-SMe, -CH2-CH2-SEt, -CH2-CH2-SPr, -CH2-CH2-NHMe, -CH2-CH2-NMe2, -CH2-CH2-NEtMe, or -CH2-CH2-NEt2. In some embodiments, R2 is a cyclohexaalkyl group. Non-limiting examples of cyclohexaalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,4-oxazacycloheptane, and 1,4-oxothionecycloheptane. In some embodiments, R2 appears at least once.

[0208]

[0209] In some implementations, n1 is 0. In some implementations, n1 is 1. In some implementations, n2 is 0. In some implementations, n2 is 1. In some implementations, n3 is 0, 1, 2, or 3. In some implementations, n3 is 0. In some implementations, n3 is 1. In some implementations, n3 is 2. In some implementations, n4 is 1. In some implementations, n4 is 2. In some implementations, n6 is 0. In some implementations, n6 is 1. In some implementations, n6 is 2. In some implementations, n6 is 3.

[0210] In some embodiments, R8 is H or an alkyl group. In other embodiments, R8 is an optionally substituted heterocycle. In still other embodiments, two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O, and S.

[0211] In some implementations, Z is OR a In some embodiments, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or OBu. In some embodiments, Z is OH.

[0212] In some embodiments, X1 is H, a halogen, or an alkyl group. In any of the embodiments described herein, X1 may be H or an alkyl group. In some embodiments, X1 is Me, Et, Pr, i-Pr, or Bu. In some embodiments, X1 is H or a halogen. In other embodiments, X1 is an alkyl group. In some embodiments, X1 is H, F, Cl, Br, or Me. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is F or Cl. In some embodiments, X1 is F. In some embodiments, X1 is H.

[0213] In some embodiments, X2 is H, a halogen, CN, an alkyl group, a haloalkyl group, a cycloalkyl group, or a halocycloalkyl group. In any of the embodiments described herein, X2 may be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X2 is H or a halogen. In other embodiments, X2 is a fluoroalkyl group or an alkyl group. In other embodiments, X2 is a cycloalkyl group. In some embodiments, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is F. In some embodiments, X2 is CF3. In some embodiments, X2 is CF2Cl. In some embodiments, X2 is Cl.

[0214] In some embodiments, X3 is H, a halogen, an alkyl group, or a haloalkyl group. In any of the embodiments described herein, X3 may be H, a halogen, a fluoroalkyl group, or an alkyl group. In some embodiments, X3 is H or a halogen. In other embodiments, X3 is a fluoroalkyl group or an alkyl group. In some embodiments, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X3 is H, F, or Cl. In some embodiments, X3 is F or Cl. In some embodiments, X3 is F. In some embodiments, X3 is CF3. In some embodiments, X3 is CF2Cl. In some embodiments, X3 is Cl.

[0215] In some implementation schemes, the structural portion have The structure.

[0216] In any of the embodiments described herein, R3 is H, an alkyl group, or a halogen. In some embodiments, R3 is a halogen. In some embodiments, R3 is H, a halogen, or an alkyl group. Non-limiting examples of alkyl groups include Me, Et, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. In some embodiments, R3 is H.

[0217] In some embodiments, the compound of formula I has the structure of formula II' or II.

[0218]

[0219] Each occurrence of R3 is independently H, halogen, or alkyl, n5 is an integer from 0 to 3, and other substituents are as defined herein.

[0220] In some implementations, Z is OR a In some embodiments, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or OBu. In some embodiments, Z is OH.

[0221] In some implementations, n5 is an integer from 0 to 3. In some implementations, n5 is an integer from 1 to 3. In some implementations, n5 is 0. In some implementations, n5 is 1 or 2. In some implementations, n5 is 1. In some implementations, R... 3’ It is H or an alkyl group. In some embodiments, R 3’ It is H. In some implementations, R 3’ It is an alkyl group. In some embodiments, R 3’ It is halogen.

[0222] In any of the embodiments described herein, R a Or R b The presence of at least one of the following independently constitutes H, alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl. In some embodiments, R a Or R b The occurrence of at least one of these independently is H, Me, Et, Pr, or Bu. In some implementations, R a Or R b At least one occurrence of independently selected from The heterocycle; wherein the heterocycle is optionally surrounded by an alkyl group, OH group, oxo group, or (C=O)C group. 1-4 Alkyl substitution (where the valence state allows).

[0223] In some implementation schemes, R a and R bTogether with the nitrogen atoms to which they are attached, they form optional substituted heterocycles comprising the nitrogen atoms and 0-3 additional heteroatoms each selected from N, O, and S.

[0224] In some implementations, the heterocycle is selected from...

[0225]

[0226] In some embodiments, the compounds of Formula I are selected from compounds 1-62 shown in Table 4 below.

[0227] In some embodiments, the compounds of Formula I are selected from compounds 63-78, 83-85, 87-88, 90-94, 96-97, 99-104, 109-176, 180-208, 213-220, and 223-293 shown in Table 5 below.

[0228] abbreviation

[0229] ACN Acetonitrile

[0230] Alloc allyloxycarbonyl

[0231] Boc or boc tert-butoxycarbonyl

[0232] DCM dichloromethane

[0233] DIEA N,N-Diisopropylethylamine

[0234] DIPA diisopropylamine

[0235] DMF 4-Dimethylaminopyridine

[0236] EA (ethyl acetate)

[0237] EDCI or EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0238] Fmoc fluoreneoxycarbonylamide

[0239] HATU N-[(dimethylamino)(3H-1,2,3-triazolo(4,4-b)pyridin-3-yloxy)methylene]-N-methylmethane hexafluorophosphate

[0240] LiHMDS (Lithium Hexamethyldisiloxane)

[0241] HOBT 1-Hydroxybenzotriazole

[0242] PE petroleum ether

[0243] TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium

[0244] TEA Triethylamine

[0245] TFA (trifluoroacetic acid)

[0246] THF Tetrahydrofuran

[0247] Troc 2,2,2-trichloroethoxycarbonyl

[0248] TsOH is p-toluenesulfonic acid.

[0249] Preparation method

[0250] The following are general synthetic schemes for manufacturing the compounds of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art could use to manufacture 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 performed in an alternating order or sequence to obtain one or more desired compounds. All references cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrative and not limiting of the preparation of some of the starting materials and compounds disclosed herein.

[0251] The following embodiments 1-8 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 will envision various modifications to these methods to achieve results similar to those of the present invention given below. In the following embodiments, compounds having the structure of Formula I or precursors thereof are used as examples to describe the synthetic routes. The general synthetic routes described in embodiments 1-8 and the examples described in the following Examples section illustrate methods for preparing the compounds described herein.

[0252] The compounds I-1a and I-2 shown below in Scheme 1 can be prepared and / or are commercially available by any method known in the art. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxy carbonyl, dialkylamino carbonyl, or another protecting group known in the art suitable for use as a protecting group for OH and amine groups. Other substituents are defined herein. As shown in Scheme 1, the core of a compound of Formula I can be synthesized from a suitable substituted bromobenzene or iodobenzene I-1a, which is converted to the corresponding borate I-1b by metallization with, for example, n-butyllithium and reaction with a trialkyl borate ester such as trimethyl borate. Ketone ester I-2 reacts with a base such as LiHMDS and N-phenyltrifluoromethanesulfonylimide to form enol trifluoromethanesulfonate I-3. Enol trifluoromethanesulfonate I-3 and boric acid I-1b were coupled in the presence of a catalyst such as 1,1′-bis(diphenylphosphino)-ferrocene palladium(II) chloride (Pd(dppf)Cl2) to give cyclic amine I-4. Hydrogenation of I-4 over a catalyst such as platinum oxide yielded saturated cyclic amine ester I-5a. Selective removal of the protecting group on the nitrogen of compound I-5a provided the corresponding cyclic amine ester I-5c. The protecting group in compound I-5c can subsequently be removed, and the resulting compound having a free phenolic OH group can optionally be converted to compounds of formula I using methods known in the art.

[0253]

[0254] The compound I-1a shown below in Scheme 2 can be prepared and / or is commercially available by any method known in the art. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxy carbonyl, dialkylamino carbonyl, or another protecting group known in the art suitable for use as an OH protecting group. Other substituents are defined herein. As shown in Scheme 2, compounds of formula I in which n1 = 1 can be prepared by the alternative routes shown herein. Iodobenzene or bromobenzene I-1a is coupled with pyridine borate I-6 in the presence of a palladium catalyst such as Pd(dppf)Cl2 to form 4-arylpyridinium ester I-8, or coupled with cyanopyridinium borate I-7 to form 4-arylpyridinium nitrile I-9. Hydrogenation of ester I-8 on a catalyst such as platinum oxide provides 4-arylpiperidine I-5b. The protecting group in compound I-5b can then be removed, and the resulting compound having a free phenol OH group can optionally be converted into a compound of formula I using methods known in the art.

[0255]

[0256] As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art as suitable for use as an OH protecting group. Other substituents are defined herein. The intermediates, aminomethyl heterocycles I-12a and I-12b, can be obtained by several routes shown in Scheme 3 below. For compounds of formula I where n1 = 1, pyridinium nitrile I-9 (as shown in Scheme 2) can be converted to primary amide I-10 by hydrolysis with a basic peroxide, or reduced to aminomethylpyridine I-11 by a borane-tetrahydrofuran complex. The pyridine ring of I-10 or I-11 is hydrogenated over a catalyst such as platinum oxide in the presence of an acid such as hydrochloric acid or acetic acid to produce the corresponding piperidine I-13 or I-12a, respectively. Alternatively, hydrogenation of I-9 under similar conditions directly yields I-12a. In methods applicable to all ring sizes, ester I-5c (as shown in Scheme 1) is converted to primary amide I-13 by heating it in methanol with ammonia in a sealed container. Reduction of amide I-13 with borane-methyl sulfide provides diamine I-12b. The protecting groups in compounds I-12a, I-12b, and I-13 can optionally be removed to provide compounds of formula I using methods known in the art.

[0257]

[0258] As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as an OH protecting group. Other substituents are defined herein. Diamine I-12b can be used to prepare bicyclic amide I-17 via one of the two routes shown in Scheme 4 below. Using peptide coupling agents such as EDCI / HOBT, TBTU, or HATU with carboxylic acid R… a Acylation of I-12b with CO2H is selectively carried out on a primary amine to obtain I-14. Acylation of I-14 on a cyclic amine with chloroacetyl chloride yields chloroacetamide I-15, which is cyclized in a polar solvent such as DMF with a base such as cesium carbonate to form piperazine I-16. If the protecting group is methyl, deprotection of the phenol with boron tribromide, for example, yields I-17. Alternatively, selective protection of the primary amine of I-12b (e.g., with a Boc group) yields I-18. Acylation with chloroacetyl chloride to I-19 and cyclization with a base followed by simultaneous deprotection of the amine and phenol yields a similar sequence, which can be converted to carboxylic acid R under standard conditions. a CO2H acylation provides I-17. Compound I-20 can be used to provide compounds with other R4 groups on nitrogen via standard methods.

[0259]

[0260] 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 another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. As shown in Scheme 5 below, a compound of formula I in which Y is oxygen was synthesized. The cyclic amine ester I-5c (as shown in Scheme 1) was reduced to alcohol I-21 under heating with, for example, borane-tetrahydrofuran. I-21 was coupled with a potassium salt of 2-epoxyethylene carboxylic acid using a reagent such as HATU, TBTU, or EDC / HOBt to form an epoxy amide I-22. Treatment of the epoxide I-22 with a base (such as sodium hydride) in an inert solvent (such as THF) resulted in cyclization to I-23. The hydroxymethyl group in I-23 can be converted to other substituents by standard methods. Removal of the protecting group provides a free phenol.

[0261]

[0262] 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 another protecting group known in the art as suitable for use as an OH protecting group. Other substituents are defined herein. Compounds of Formula I having a ring system in which Y is N (e.g., 8-phenyl-octahydro-4H-pyrido[1,2-a]pyrazin-4-one (I-27) substituted with R2 at C3) are obtained from amino alcohol I-21 by one of the two routes shown in Scheme 6 below. Acylation of I-21 with a suitably protected amino acid using a coupling agent such as HATU, TBTU, or EDC / HOBT (as shown in Scheme 5) yields amide I-24. Typically, the amino group is protected with Boc, but other protecting groups such as alloc, troc, or Fmoc may also be used. Primary alcohols are oxidized to aldehydes I-25 using Dess-Martin reagents or Swern oxidation conditions. Removing the amine protecting group with TFA leads to cyclization to I-26, followed by reduction of the imine double bond by hydrogenation or with sodium borohydride. In an alternative procedure, the amine of I-21 is first protected with a Boc group to form I-28, which is then oxidized to the aldehyde I-29 using a Dess-Martin reagent. This aldehyde I-29 undergoes reductive amination with an amino acid ester in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride to obtain I-30. Removal of the Boc protecting group on the nitrogen atom followed by heating with a base (such as triethylamine) in a solvent (such as ethanol) leads to cyclization to I-27. I-27 can be further modified by derivatization of the amine using standard methods and removal of the protecting group to obtain a free phenol, forming additional compounds of formula I.

[0263]

[0264] As shown in Scheme 7, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art as suitable for use as an OH and amine group. Other substituents are defined herein. Compounds of formula I having a ring system in which Y is N are prepared from protected amino esters I-5a (as shown in Scheme 1) via the route shown in Scheme 7 below. Ester I-5a is first hydrolyzed to a carboxylic acid and converted to Weinreb amide I-31 by treatment with N,O-dimethylhydroxylamine and a coupling agent such as carbonyl diimidazole or EDC / HOBT. I-31 reacts with the Grignard reagent R2MgBr to form ketone I-32. The protecting group on the nitrogen is then selectively removed. When PG is Boc, the removal of the Boc group can be achieved by using TFA. Cyclic amines are acylated with protected amino acids such as Boc-glycine to obtain amide I-33. Removal of the Boc group with TFA, while simultaneously cyclizing the amine onto a ketone, forms a cyclic imine I-34. Reduction of the imine with sodium borohydride yields a cyclic amine I-35, which can be further modified at the amine nitrogen by, for example, acylation or alkylation using standard methods. Removal of protecting groups from phenols to obtain free phenols can be performed before or after the derivatization of the amine.

[0265]

[0266] As shown in Scheme 8, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl, or another protecting group known in the art as suitable for use as an OH protecting group. Other substituents are defined herein. The stereoselective synthesis of intermediate I-5d is as shown in Scheme 8 below. Enantiomeric pure piperidinone I-36 was synthesized from protected L-aspartic acid and Michaelis acid by the method described in Org. Syn., 2008, 85, 147, and subsequently converted to enol trifluoromethanesulfonate I-37 by treatment with trifluoromethanesulfonic anhydride and base according to the procedure described in Syn. Lett. 2009, 71-74. This enol trifluoromethanesulfonate I-37 was coupled with borate I-1b using a palladium catalyst (such as Pd(dppf)Cl2) to obtain I-39. Hydrogenation of I-17 over a catalyst (such as platinum oxide) yielded piperidinone I-40, which is mainly the 2S,4S enantiomer, and reduction of the amide using a boron methyl sulfide complex to provide enantiomerically pure I-5d, which can be used for the synthesis outlined in schemes 3, 4, 5, 6 and 7.

[0267]

[0268] The reactions described in Schemes 1-8 above can be carried out in suitable solvents. Suitable solvents include, but are not limited to, ACN, methanol, ethanol, DCM, DMF, THF, MTBE, or toluene. The reactions described in Schemes 1-8 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 to an elevated temperature. Suitable elevated 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. Alternatively, 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 into 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.

[0269] Pharmaceutical Composition

[0270] The present invention also provides pharmaceutical compositions comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0271] In another aspect, the present invention provides a compound comprising at least one compound selected from Formula I described herein, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.

[0272] 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.

[0273] As used herein, the phrase "medicinal carrier" refers to 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 a subject pharmaceutical agent 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 serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; 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 solutions; and other non-toxic, 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 mixed with and mixed with the compounds of the present invention in a manner that does not involve interactions that would significantly impair the desired pharmaceutical efficiency.

[0274] As described above, specific embodiments of the pharmaceutical preparations of the present invention can be provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" in this context refers to the relatively non-toxic, inorganic and organic acid salts 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 their 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 laurylsulfonate, etc. See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.

[0275] Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as those derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochlorides, hydrobroms, 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, etc.

[0276] In other respects, the compounds of the present invention may contain one or more acidic functional groups, thereby enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases 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 alone with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative bases or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, aluminum, 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., above.

[0277] Wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate, magnesium stearate and polyethylene oxide-polybutane copolymer, as well as colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0278] 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 may be conveniently available in unit dosage forms and may 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 will generally be the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount will be from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0279] Methods for preparing these formulations or compositions include the steps 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 dispersed solid carrier, or both, and subsequently shaping the product if desired.

[0280] 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), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil 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, etc., 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.

[0281] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, 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; humectants, such as... Glycerin; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarders 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 include a buffer. Similar solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0282] Tablets may optionally be prepared by compression or molding with one or more excipients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxybutyl methyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets may be manufactured by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0283] The pharmaceutical compositions of the present invention, in tablet and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules, may optionally be prepared by scoring or by coating and shelling, such as enteric coating and other coatings known in the field of pharmaceutical formulation. They may also be formulated, for example, with different proportions of hydroxybutyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile, to provide a slow or controlled release of the active ingredient therein. 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 dissolved in sterile water or certain other sterile injectable media immediately before use. These compositions may also optionally contain a light-blocking agent and may be compositions that optionally release one or more active ingredients in a delayed manner, either alone or preferably in a specific portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, (if suitable) together with one or more of the above-described excipients.

[0284] 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, EA, 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, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. Furthermore, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, may be used to dissolve the compounds.

[0285] 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.

[0286] In addition to the active compound, the suspension 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.

[0287] Dosage forms for topical or transdermal application of the compounds used in 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 necessary preservatives, buffers, or propellants.

[0288] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may 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.

[0289] 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 additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane.

[0290] Transdermal patches offer the added advantage of controlled delivery of the compounds of the present invention into the body. Such dosage forms can be manufactured by dissolving or dispersing the pharmaceutical agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agent of the present invention across the skin. The rate of such flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0291] Ophthalmic preparations, ointments, powders, solutions, etc., are also considered to be within the scope of this invention.

[0292] Pharmaceutical compositions of the present invention suitable for parenteral administration include one or more of the compounds of the present invention in combination with: one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions; or sterile powders that can be reconstituted into sterile injectable solutions or dispersions before use, which may contain antioxidants, buffers, bacteriostatic agents or solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0293] In some cases, to prolong the effect of a drug, it is desirable to slow 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 the drug then depends on its dissolution rate, which in turn can depend 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.

[0294] Injectable depot forms are manufactured by forming microcapsule matrices of the subject compound within biodegradable polymers such as polylactide-polyglycolic acid. The drug release rate can be controlled based on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot-type injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0295] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be provided as is (pure) 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.

[0296] The compounds and pharmaceutical compositions of the present invention can be used in combination therapies, meaning that the compounds and pharmaceutical compositions can be administered simultaneously, before, or after one or more other desired treatments or medical procedures. The specific combination (therapy or procedure) of the therapy used in the combination regimen will take into account the compatibility of the desired therapy and / or procedure and the desired therapeutic effect to be achieved. It should also be understood that the therapy used can achieve the desired effect for the same condition (e.g., the compounds of the present invention can be administered simultaneously with another anticancer agent).

[0297] The compounds of this invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritis in mammals (e.g., humans, livestock, and domesticated animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0298] The present invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Optionally, associated with such one or more containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical or biological product, reflecting approval for human administration by the manufacturing, using, or selling agency.

[0299] administered to subjects

[0300] In another aspect, the present invention provides a method for treating a disease in a mammalian species in need of such treatment, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from those of formula I or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, immunological diseases, central nervous system diseases, inflammatory diseases, gastrointestinal diseases, metabolic diseases, cardiovascular diseases, and kidney diseases.

[0301] In some implementation schemes, 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.

[0302] In some implementations, the inflammatory condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neurological disorder. In some implementations, the gastrointestinal condition is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0303] In some implementations, the immunological condition is transplant rejection or an autoimmune disease (such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type 1 diabetes). In some implementations, the central nervous system (CNS) condition is Alzheimer's disease.

[0304] In some implementations, the metabolic condition is obesity or type 2 diabetes. In some implementations, the cardiovascular condition is ischemic stroke. In some implementations, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0305] In some implementations, the mammal species is human.

[0306] In some implementation schemes, the disease is selected from cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin diseases, inflammatory neurological diseases, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0307] In another aspect, methods for blocking the Kv1.3 potassium channel in mammalian species in need are described, including administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compounds described herein selectively block Kv 1.3 potassium channels while exhibiting 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 and therefore possess desirable cardiovascular safety.

[0309] Some aspects of the present invention relate to administering an effective amount of the composition to a subject to achieve a specific outcome. Small molecule compositions useful according to the method of the present invention can thus be formulated in any manner suitable for pharmaceutical use.

[0310] The formulations of the present invention are administered in the form of a pharmaceutically acceptable solution, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0311] 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 (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, vaginal, etc.). Injection may be by bolus injection or continuous infusion.

[0312] For example, pharmaceutical compositions according to the invention are typically administered intravenously, intramuscularly, or otherwise parenterally. They can also be administered intranasally, by inhalation, topically, or orally, as implants; even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical formulations are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, atomized, aerosols, pellets for implantation under the skin, or dried onto a sharp object to be rubbed into the skin. Pharmaceutical compositions also include formulations of granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or prolonged-release active compounds, 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. 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 cited here and incorporated into this article.

[0313] The concentration of compounds contained in the compositions used in the methods of the present invention can be from about 1 nM to about 100 μM. The effective dose is believed to be from about 10 picomoles / kg to about 100 micromoles / kg.

[0314] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders, and suppositories. For patient treatment, 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 disease, and the patient's age and weight. Administration of a given dosage can be done by a single dose in the form of a single dosage unit or by several smaller dosage units. The invention also contemplates repeated and multiple administrations at specific intervals of days, weeks, or months.

[0315] The composition may be administered as is (pure) or as a pharmaceutically acceptable salt. When used as a medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutical salts may be conveniently used to prepare their pharmaceutically acceptable forms. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, TsOH (p-toluenesulfonic acid), tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Similarly, such salts may be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts with carboxylic acid groups.

[0316] 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).

[0317] Compositions suitable for parenteral administration conveniently include sterile aqueous formulations that are isotonic with the recipient's blood. Acceptable mediators and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile mineral or non-mineral oil, including synthetic monoglycerides or diglycerides, can be used. Furthermore, fatty acids such as oleic acid can be used to prepare injectable formulations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc., are available at Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0318] The compounds that can be used in this invention can be delivered in the form of a mixture of more than two such compounds. In addition to the combination of compounds, the mixture may further include one or more adjuvants.

[0319] Multiple routes of administration are possible. Of course, the specific mode of administration chosen 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 manner of administration, i.e., any manner that produces an effective level of response without causing clinically unacceptable side effects. Preferred methods of administration are as described above.

[0320] The composition can be readily available in unit dosage form 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 dispersed solid carrier, or both, and subsequently shaping the product if desired.

[0321] Other delivery systems may include timed-release, delayed-release, or sustained-release delivery systems. Such systems avoid repeated administration of the compound, improving convenience for both the patient 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. Microcapsules containing the aforementioned polymers of a drug are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include non-polymer systems, which are: 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-coated systems; compressed tablets using conventional adhesives and excipients; partially fused implants; and so on. Specific examples include, but are not limited to: (a) erosional 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 can be used, some of which are suitable for implantation.

[0322] Determination of the effectiveness of Kv1.3 potassium channel blockers

[0323] In some embodiments, the compounds described herein are tested for their activity against Kv1.3 potassium channels. In some embodiments, the compounds described herein are tested for their Kv1.3 potassium channel electrophysiology. In some embodiments, the compounds described herein are tested for their hERG electrophysiology.

[0324] Equivalent solution

[0325] The representative embodiments described below are intended to help illustrate the invention and are not intended to, and should not be construed as limiting the scope of the invention. In fact, various modifications and many other embodiments of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document (including the following embodiments and references to scientific and patent literature cited herein). It should also be understood that the contents of these cited references are incorporated herein by reference to help illustrate the state of the prior art. The following embodiments contain important additional information, illustrations, and guidance, which can be adapted to the practice of the invention in various embodiments and their equivalents. Example

[0326] Examples 1-7 describe various intermediates used to synthesize representative compounds of Formula I disclosed herein.

[0327] Example 1. Intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) and Intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene)

[0328]

[0329] Step a:

[0330] 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) at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched at 0 °C with a saturated aqueous solution of Na2S2O3 (500 mL). 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 provide 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 the next step without further purification.

[0331] 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) and K₂CO₃ (54.9 g, 396.87 mmol, 3 equivalents) in ACN (210 mL) at 0 °C. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE to provide intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) (8.7 g, 25.7%) as a white solid. 1¹H NMR (300MHz, 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 intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene) (24.3 g, 71.77%) as a white solid: 1 H NMR (300MHz, CDCl3) δ7.64(s,1H),6.99(s,1H),3.91(s,3H).

[0332] Example 2. Intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid)

[0333]

[0334] Step a:

[0335] NaOH (75 g, 1.88 mol) was added fractionally to a stirred solution of 3,4-dichlorophenol (120 g, 0.74 mol) in THF (400 mL) under a nitrogen atmosphere at room temperature, followed by stirring for 30 min. N,N-diethylcarbamoyl chloride (150 g, 1.11 mol) was added over 40 min, followed by stirring for 15 h. The reaction mixture was poured into water (1.5 L) and extracted with PE (2 × 800 mL). The combined organic phases were washed with brine (500 mL) and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide N,N-diethylcarbamate 3,4-dichlorophenyl ester (213 g, crude) as a yellow oil: [C] 11 H 13 LCMS (ESI) [M+H] calculated using Cl2NO2 + : 262,264(3:2), actual measurement 262,264(3:2); 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 8.8Hz, 1H), 7.30 (d, J = 2.7Hz, 1H), 7.03 (dd, J = 8.8, 2.7Hz, 1H), 3.50-3.34 (m, 4H), 1.32-1.17 (m, 6H).

[0336] Step b:

[0337] n-BuLi (131 mL, 0.33 mmol) was added dropwise to a solution of DIPA (32 g, 0.32 mol) in THF (400 mL) at -65 °C under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour. A solution of N,N-diethylcarbamate 3,4-dichlorophenyl ester (77 g, 0.29 mol) in THF (200 mL) was added dropwise, followed by stirring for 1 hour. After 1 hour, a solution of I2 (82 g, 0.32 mol) in THF (200 mL) was added dropwise. The resulting mixture was stirred at -65 °C for an additional 30 minutes. The reaction was quenched at room temperature by adding an aqueous solution of NH4Cl (300 mL). The resulting mixture was extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Three additional batches (3 x 77 g of N,N-diethylcarbamate 3,4-dichlorophenyl ester) were reacted and processed similarly, and then combined with the previous batch. The resulting residue was pulped in PE (500 mL) and subsequently filtered to provide 300 g of N,N-diethylcarbamate 3,4-dichloro-2-iodophenyl ester. The filtrate was purified by silica gel column chromatography eluted with PE / EA (50 / 1) to provide another 75 g of pure product. N,N-diethylcarbamate 3,4-dichloro-2-iodophenyl ester (375 g, 83% after 2 steps) was obtained as a grayish-white solid: [C] 11 H 12 LCMS(ESI)[M+H] calculated using Cl2INO3 + :388,390(3:2), actual measurement 388,390(3:2); 1 H NMR (400MHz, CDCl3) δ7.48(d,J=8.8Hz,1H),7.08(d,J=8.8Hz,1H),3.55(q,J=7 .2Hz, 2H), 3.42 (q, J = 7.1Hz, 2H), 1.34 (t, J = 7.1Hz, 3H), 1.25 (t, J = 7.1Hz, 3H).

[0338] Step c:

[0339] To a stirred solution of 200 g (0.52 mol) of N,N-diethylcarbamate 3,4-dichloro-2-iodophenyl ester in EtOH (1.50 L), NaOH (165 g, 4.1 mol) was added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice water (1.5 L). The mixture was then acidified with an aqueous HCl solution (6N) to pH 3. The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (800 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide LCMS(ESI) [MH] of 202 g (crude) of 3,4-dichloro-2-iodophenol as a brown oil, calculated against C₆H₃Cl₂IO. - : 287,289(3:2), actual measurement 287,289(3:2).

[0340] Step d:

[0341] To a stirred solution of 220 g (0.76 mol) of 3,4-dichloro-2-iodophenol in DMF (700 mL), K₂CO₃ (210 g, 1.52 mol) and MeI (119 g, 0.84 mol) were added. The resulting mixture was stirred at room temperature for 5 hours. Another batch (100 g of 3,4-dichloro-2-iodophenol) was reacted similarly and combined with the previous batch. The resulting mixture was diluted with water (5 L) at room temperature. The resulting mixture was then extracted with EA (3 × 1 L). The combined organic layers were washed with brine (4 × 400 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was pulped in PE (300 mL) and then filtered to provide 128 g of the desired product. The filtrate was purified by silica gel column chromatography eluted with PE / EA (40 / 1) to provide an additional 64 g of the desired product. 1,2-Dichloro-3-iodo-4-methoxybenzene (192 g, 78% after 2 steps) was obtained as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.44 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H).

[0342] Step e:

[0343] i-PrMgCl (182 mL, 0.36 mol) was added dropwise to a solution of 1,2-dichloro-3-iodo-4-methoxybenzene (100 g, 0.33 mol) in 1.2 L of THF under a nitrogen atmosphere at 0 °C. The reaction mixture was then stirred at 0 °C for 1 hour. B(OMe)3 (86 g, 0.83 mol) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature over 1 hour and stirred at room temperature for another 1 hour. Subsequently, an aqueous solution of H2SO4 (5%, 500 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was extracted with EA (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was stirred in DCM (200 mL) and subsequently filtered to provide intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid) (55 g, 76%) as an off-white solid: against C 15 H 16 LCMS(ESI)[MH] calculated using Cl2N2O4 - :219,221(3:2), actual measurement 219,221(3:2); 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 5.65 (s, 2H), 3.89 (s, 3H).

[0344] Example 3. Intermediate 4 ((2S)-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester)

[0345]

[0346] Step a:

[0347] LiHMDS (9.87 mL, 9.87 mmol, 1 M in THF) was added dropwise to a solution of (2S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (2.0 g, 8.22 mmol) in THF (15 mL) for 10 min at -65 °C under a nitrogen atmosphere. After stirring for 0.5 h, 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (4.41 g, 12.35 mmol) in THF (5 mL) was added dropwise at -65 °C. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched at room temperature with a saturated aqueous solution of NH4Cl (50 mL). The resulting mixture was extracted with EA (3 × 50 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 to provide intermediate 4 ((2S)-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester) (3 g, crude) as a yellow oil, which was used directly in the next step without further purification: for C 12 H 16 LCMS(ESI) calculated by F3NO7S [M+H-56] + 320, actual measurement 320.

[0348] Example 4. Intermediate 5 (1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methylaminebis(trifluoroacetic acid))

[0349]

[0350] Step a:

[0351] Under a nitrogen atmosphere, Na₂CO₃ (5.25 g, 49.53 mmol) and Pd(dppf)Cl₂·CH₂Cl₂ (0.67 g, 0.83 mmol) were added to a solution of intermediate 1 (Example 1) (5.00 g, 16.51 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-carboxynitrile (3.80 g, 16.51 mmol) in 1,4-dioxacyclohexane (80 mL) and H₂O (20 mL). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was poured into water (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 eluted with PE / EA (3 / 1) to provide 4-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carboxynitrile (3.00 g, 65%) as an off-white solid: [C] 13LCMS(ESI)[M+H] calculated using H8Cl2N2O + :279,281(3:2), actual measurement 279,281(3:2); 1 H NMR (400MHz, CDCl3) δ 8.80 (dd, J = 5.0, 0.9Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 8.9Hz, 1H), 7.46 (dd, J = 5.0, 1.7Hz, 1H), 6.92 (d, J = 9.0Hz, 1H), 3.77 (s, 3H).

[0352] PtO2 (0.50 g, 2.16 mmol) was added fractionally to a stirred mixture of 4-(2,3-dichloro-6-methoxyphenyl)pyridin-2-carboxynitrile (3.00 g, 10.75 mmol) in MeOH (400 mL) and concentrated HCl (12 M, 40.00 mL) at room temperature. The reaction mixture was degassed at 30 °C under a hydrogen atmosphere (50 atm) and stirred for 48 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 40% ACN in water (with 0.05% TFA) to provide intermediate 5(1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methylaminebis(trifluoroacetic acid)) (2.8 g, 50%) as an off-white solid. 13 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O + :289,291(3:2), actual measurement 289,291(3:2); 1 H NMR (400MHz, CD3OD) δ7.36(d,J=9.0Hz,1H),6.95(d,J=9.0Hz,1H),3.85(s,3H),3.66-3.52(m,1H),3.25-3.16(m ,1H),2.83-2.73(m,1H),2.73-2.62(m,3H),2.48-2.33(m,1H),2.16-1.98(m,1H),1.58(dd,J=31.4,12.8Hz,2H).

[0353] Example 5. Intermediate 6 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0354]

[0355] Step a:

[0356] Boc₂O (0.43 g, 2.00 mmol) was added to a stirred mixture of 1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methylaminetrifluoroacetic acid (intermediate 5, Example 4) (1.00 g, 2.59 mmol) and TEA (0.75 g, 7.50 mmol) in DCM (15.00 mL) at -50 °C under a nitrogen atmosphere. The resulting mixture was stirred at -50 °C under a nitrogen atmosphere for 1 h and then quenched with NH₃·H₂O (2 mL), diluted with water (20 mL), and 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. The residue was purified by silica gel column chromatography with hexane / EA (1 / 1) elution to provide N-[[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate tert-butyl ester (0.6 g, 62%) as an off-white solid: against C 18 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :389,401(3:2), actual measurement 389,401(3:2).

[0357] Step b:

[0358] At 0 °C, 0.60 g (1.54 mmol) of N-[[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]tert-butyl carbamate and 0.47 g (4.62 mmol) of TEA in DCM (10 mL) were added with chloroacetyl chloride (0.19 g (2.00 mmol), and the reaction was stirred at room temperature for 1 h. The resulting reaction mixture was concentrated to provide N-[[1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]tert-butyl carbamate (0.7 g, crude) as a yellow oil: [C] 20 H 27 LCMS(ESI)[M+H] calculated using Cl3N2O4 + :465,467(1:1), actual measurement 465,467(1:1).

[0359] Step c:

[0360] Cs₂CO₃ (0.98 g, 3.00 mmol) was added to a solution of N-[[1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate tert-butyl (0.70 g, 1.50 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred at 50 °C for 16 h, diluted with water (20 mL), and subsequently 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 with PE / EA (1:1) elution to provide tert-butyl 8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (0.30 g, 46%) as a yellow oil. 8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (0.30 g, 0.70 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: from 30% B to 30% B over 13 min; detector: UV 254 / 210 nm; retention time: RT1: 9.048 min; RT2: 11.244 min. The enantiomer (0.12 g, 18%) of (8S,9aR)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester, as a yellow oil, was obtained at 9.048 min: [C] 20 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :429,431(3:2), measured 429,431(3:2). Slower elution of enantiomers (0.12 g, 18%) of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as yellow oil was obtained at 11.244 min: [Reference to C] 20 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :429,431(3:2), actual measurement 429,431(3:2). 1H NMR (400MHz, CDCl3) δ7.31(d,J=8.9Hz,1H),6.75(d,J=8.9Hz,1H),5.32(s,1H),4.92-4.80(m,1H),4.27(d,J=18.4Hz,1H),4.17-3. 88(m,2H),3.80(s,3H),3.77-3.59(m,1H),3.59-3.47(m,1H),2.73-2.62(m,1H),2.46-2.07(m,2H),1.71-1.64(m,2H),1.50(s,9H).

[0361] Step d:

[0362] BBr3 (0.13 mL, 0.527 mmol) was added dropwise to a solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazin-2-carboxylic acid tert-butyl ester (0.12 g, 0.279 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h, quenched with water (1 mL), diluted with saturated NaHCO3 (10 mL), and subsequently extracted with EA (3 × 20 mL). The combined organic layers were concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mM ammonium formate), mobile phase B: CAN; flow rate: 60 mL / min; gradient: from 25% B to 45% B over 7 min; detector: UV 254 / 210 nm; retention time: 6.5 min. Fractions containing the desired product were combined and concentrated under reduced pressure to provide intermediate 6((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) (65.1 mg, 74%) as a grayish-white solid: [The text abruptly ends here, so the translation stops as well.] 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :315,317(3:2), actual measurement 315,317(3:2). 1¹H NMR (400MHz, methanol-d⁴) δ 7.20 (d, J = 8.7Hz, 1H), 6.71 (d, J = 8.8Hz, 1H), 4.83–4.70 (m, 1H), 3.79–3.63 (m, 1H), 3.60–3.49 (m, 1H), 3.43 (s, 2H), 3.24 (dd, J = 13.4, 5.1Hz, 1H), 2.86–2.61 (m, 2H), 2.56–2.32 (m, 2H), 1.72–1.58 (m, 2H).

[0363] Example 6. Intermediate 7 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester)

[0364]

[0365] Step a:

[0366] Under a nitrogen atmosphere, 3.09 g (8.23 mmol) of 2-methyl 1-tert-butyl 4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylic acid (intermediate 4, Example 3), 1.40 g (6.34 mmol) of 2,3-dichloro-6-methoxyphenyl)boronic acid (intermediate 3, Example 2), and 2.02 g (19.06 mmol) of Na₂CO₃ in dioxane (15 mL) and H₂O (3 mL) was added to a stirred solution of Pd(dppf)Cl₂·CH₂Cl₂ (0.10 g, 0.12 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 h. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution 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 with PE / EA (4 / 1) elution to provide (2S)-4-(2,3-dichloro-6-methoxyphenyl)-2,3-dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.30 g, 51%) as a pale yellow oil: [C] 18 H 21 LCMS (ESI) [M+H] calculated using Cl2NO5 + 402, 404 (3:2), actual measurement 402, 404 (3:2); 1H NMR (400MHz, CD3OD) δ7.48(d,J=8.9Hz,1H),7.00(d,J=9.0Hz,1H),5.82-5.64(m,1H ),5.27-5.11(m,1H),4.50-4.21(m,2H),3.93-3.74(m,6H),1.47(d,J=15.9Hz,9H).

[0367] Step b:

[0368] A solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2,5-dihydropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (1.30 g, 3.23 mmol) and PtO2 (0.22 g, 0.970 mmol) in HOAc (8 mL) was stirred at room temperature for 16 hours under a hydrogen atmosphere (1.5 atm). The reaction was filtered, and the filtrate was concentrated under reduced pressure to provide intermediate 7 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester) (1.30 g, 99%) as a pale yellow oil: [The text abruptly ends here, so the translation stops as well.] 18 H 23 LCMS (ESI) [M+H] calculated using Cl2NO5 + 404,406(3:2), actual measurement 404,406(3:2); 1 H NMR (400MHz, CD3OD) δ7.42(d,J=9.0,1.2Hz,1H),6.98(d,J=9.0Hz,1H),4.48-4.38(m,1H),4.30-4.18(m,1H),3.86(d, J=2.2Hz,3H),3.80(d,J=3.7Hz,3H),3.71-3.57(m,1H),3.35-3.29(m,1H),2.70-2.41(m,2H),1.47(d,J=14.2Hz,9H).

[0369] Example 7. Intermediate 8 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide)

[0370]

[0371] Step a:

[0372] BH3·Me2S (2.97 mL, 29.68 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate 7, Example 6) (6.00 g, 14.84 mmol) in THF (20 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred at 70 °C for 2 h. The reaction was quenched at 0 °C with MeOH (5 mL) and then an aqueous solution of HCl (6 N, 5 mL) was added. The resulting solution was stirred at 70 °C for 1 h. The reaction was concentrated under reduced pressure to provide [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methanol hydrochloride (5.0 g, crude) as a pale yellow oil, which was used directly for the next step without further purification: C 12 H 15 LCMS (ESI) [M+H] calculated using Cl2NO2 + 276,278(3:2), actual measurement 276,278(3:2).

[0373] Step b:

[0374] Boc₂O (3.80 g, 17.41 mmol) was added to a stirred solution of [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methanol hydrochloride (5.0 g, 15.99 mmol) and TEA (3.22 g, 31.82 mmol) in DCM (20 mL). The reaction was stirred at room temperature for 1 h. The reaction solution was diluted with EA (50 mL) and water (50 mL). The aqueous solution was 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 reversed-phase chromatography with 75% CAN elution in water containing 10 mmol / L NH4HCO3 to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.90 g, 32% by two steps) as a grayish-white solid: [C] 17 H 23 LCMS (ESI) [M+H] calculated using Cl2NO4 + 376,378(3:2), actual measurement 376,378(3:2); 1H NMR (400MHz, CD3OD) δ7.39(d,J=8.9Hz,1H),6.97(d,J=9.0Hz,1H),4.62(s,1H),4.08-3.91(m,1H ), 3.87 (s, 3H), 3.85-3.63 (m, 4H), 2.77-2.46 (m, 1H), 2.28-2.11 (m, 1H), 1.50 (d, J = 11.2Hz, 9H).

[0375] Step c:

[0376] At room temperature, tert-butyl (2.57 g, 6.06 mmol) of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.90 g, 5.050 mmol) in a stirred solution in DCM (10 mL) was added to a mixture of 2S,4R-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.90 g, 5.050 mmol). The reaction was stirred for 1 h and then quenched with saturated aqueous solution of Na₂S₂O₃ (30 mL). The mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with saturated aqueous solution of NaHCO₃ (3 × 30 mL) and brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g, crude) as a pale yellow oil, which was used directly in the next step without further purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 17 H 21 LCMS (ESI) [M+H] calculated using Cl2NO4 + 374,376(3:2), actual measurement 374,376(3:2).

[0377] Step d:

[0378] At room temperature, TEA (1.28 g, 12.65 mmol) and NaBH(AcO)3 (2.15 g, 10.14 mmol) were added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.90 g, 5.08 mmol) and methyl 2-aminoacetic acid hydrochloride (0.96 g, 7.65 mmol) in DCM (20 mL). The reaction was stirred for 2 h and then quenched with water (50 mL). The mixture was 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 reversed-phase chromatography with elution of 45% ACN (0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.80 g, 79% total from 2 steps) as a yellow foam: [C] 20 H 28 LCMS(ESI)[M+H] calculated using Cl2N2O5 + 447,449(3:2), actual measurement 447,449(3:2); 1 H NMR (400MHz, CD3OD) δ7.46(d,J=8.7Hz,1H),7.03(d,J=9.0Hz,1H),4.28(s,1H),4.23-3.95(m,3 H), 3.90 (d, J = 9.3Hz, 6H), 3.87-3.71 (m, 2H), 3.41-3.35 (m, 2H), 2.49-2.32 (m, 2H), 1.53 (s, 9H).

[0379] Step e:

[0380] TFA (3 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.80 g, 4.02 mmol) in DCM (15 mL). The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure. The resulting mixture was dissolved in EtOH (10 mL) and TEA (1.23 g, 12.16 mmol) was added thereto. The reaction was stirred at 70 °C for 1 h. The reaction mixture was diluted with water (50 mL). The mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (1.10 g, 87%) as a yellow oil: [C] 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + 315,317(3:2), actual measurement 315,317(3:2); 1 H NMR (400MHz, CD3OD) δ7.43(d,J=9.0Hz,1H),7.00(d,J=9.0Hz,1H),4.40-4.26(m,1H),4.15-4.05(m,1H),3.90-3.79 (m,4H),3.59-3.46(m,2H),3.43-3.39(m,1H),3.39-3.36(m,1H),2.61(dd,J=13.0,10.3Hz,1H),2.26-2.06(m,2H).

[0381] Step f:

[0382] BBr3 (3.50 g, 13.97 mmol) was added dropwise to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (1.10 g, 3.49 mmol) in DCM (10 mL) at room temperature. The reaction was stirred for 2 h and then quenched with MeOH (10 mL). The mixture was filtered, and the filter cake was washed with EA (3 × 5 mL) and dried under reduced pressure to provide intermediate 8 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide) (1.00 g, 63%) as an off-white solid. 13 H 14 LCMS(ESI)[M+H] calculated using Cl2N2O2+ 301, 303 (3:2), actual measurement 301, 303 (3:2); 1 H NMR (400MHz, CD3OD) δ7.29(d,J=8.8Hz,1H),6.79(d,J=8.8Hz,1H),4.44-4.28(m,1H),4.28-4.18(m,1H),4.18-4.0 5(m,1H),3.98-3.84(m,3H),3.71-3.55(m,1H),3.19(t,J=11.9Hz,1H),2.49(q,J=11.5Hz,1H),2.37-2.24(m,1H).

[0383] Example 8. Intermediate 9 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester) and intermediate 10 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carboxylic acid tert-butyl ester).

[0384]

[0385] Step a:

[0386] EDCI (120 g, 622 mmol), DMAP (76.0 g, 622 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (Missell's acid) (60.0 g, 414 mmol) were added to a stirred solution of (3S)-4-(tert-butoxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid (120 g, 415 mmol) in DCM (1.50 L) at -8 °C. The resulting mixture was stirred at -8 °C for 3 h under a nitrogen atmosphere. The resulting mixture was washed with a saturated aqueous solution of KHSO4 (2 × 1 L) and brine (2 × 1 L). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (3.70 L) to provide a 0.1 M solution, which was refluxed for 16 h. After cooling to room temperature, the mixture was washed with a saturated aqueous solution of KHSO4 (2 × 1 L) and brine (2 × 1 L). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide (2S)-4,6-dioxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (123 g, 94%) as a grayish-white solid: [C] 15 H 23 LCMS(ESI)[M+H] calculated by NO6 + :314, actual measurement 314; 1H NMR (400MHz, CDCl3) δ5.12-5.03(m,1H),3.63-3.32(m,2H),3.10-3.01(m,1H),2.89-2.79(m,1H),1.58(s,9H),1.49(s,9H).

[0387] Step b:

[0388] DIEA (83 mL, 645 mmol) was added dropwise to a solution of (2S)-4,6-dioxopiperidine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (50.0 g, 160 mmol) in DCM (500 mL) at 0 °C. The resulting reaction was stirred at 0 °C for 10 min, followed by dropwise addition of trifluoromethanesulfonic anhydride (54.0 g, 191 mmol) at 0 °C. The reaction was then heated to room temperature and stirred for an additional 2 h. The reaction was quenched at 10 °C with a saturated aqueous solution of NaHCO3 (100 mL). The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phases 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 with PE / EA (5 / 1) elution to provide (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (39.0 g, 55%) as a yellow solid: [C] 16 H 22 LCMS(ESI)[M+H] calculated by F3NO8S + :446, actual measurement 346 [M+H-100] + ; 1 H NMR (300MHz, CDCl3) δ6.03 (d, J = 2.2 Hz, 1H), 5.01 (dd, J = 6.3, 2.6 Hz, 1H), 3.27-2.98 (m, 2H), 1.57 (s, 9H), 1.47 (s, 9H).

[0389] Step c:

[0390] Pd(dppf)Cl2·CH2Cl2 (2.66 g, 3.26 mmol) was added to a stirred mixture of (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (39.0 g, 78.8 mmol), 2,3-dichloro-6-methoxyphenylboronic acid (20.0 g, 81.5 mmol), and Na2CO3 (17.0 g, 163 mmol) in dioxane (400 mL) and H2O (100 mL) under a nitrogen atmosphere at room temperature. The suspension was degassed under vacuum and purged three times under a nitrogen atmosphere. The reaction was then stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted in EA (500 mL) and washed with brine (2 × 500 mL). The organic phase was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (2 / 1) elution to provide (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylic acid 1,2-di-tert-butyl ester (31.0 g, 72%) as a pale yellow liquid: [C] 22 H 27 LCMS (ESI) [M+H] calculated using Cl2NO6 + : 472,474 (3:2), actual measurement 372,374 [M+H-100] + (3:2); 1 H NMR (300MHz, CDCl3) δ7.42(d,J=8.9Hz,1H),6.80(d,J=9.0Hz,1H),5.92(d,J=2.7Hz,1H),4.95(dd,J=7 .2,1.8Hz,1H),3.78(s,3H),3.14(d,J=17.6Hz,1H),2.90(d,J=18.2Hz,1H),1.60(s,9H),1.50(s,9H).

[0391] Step d:

[0392] PtO2 (6.26 g, 27.6 mmol) was added fractionally to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylic acid tert-butyl ester (31.0 g, 65.6 mmol) in EA (400 mL) and AcOH (100 mL) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 16 h, filtered, and the filter cake was subsequently washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (2 / 1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-2-carboxylic acid tert-butyl ester (20.8 g, 76%) as a pale yellow liquid: [C] 17 H 21 LCMS (ESI) [M+H] calculated using Cl2NO4 + :374,376(3:2), actual measurement 374,376(3:2); 1 H NMR (300MHz, CDCl3) δ7.36(d,J=8.9Hz,1H),6.79(d,J=8.9Hz,1H),4.12-3.92(m,2H),3.85(s,3H),3.03( dd,J=17.7,11.2Hz,1H),2.57-2.34(m,2H),2.28-2.09(m,1H),1.86-1.63(m,1H),1.51(d,J=2.1Hz,9H).

[0393] Step e:

[0394] BH3Me2S (14.2 mL, 187 mmol, 10 M in Me2S solution) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidin-2-carboxylic acid tert-butyl ester (20.8 g, 50.0 mmol) in THF (200 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at 70 °C for 4 h. The reaction was quenched at 0 °C with MeOH (50 mL). The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL) and HCl (6 N, 100 mL). The resulting solution was stirred at 70°C for 1 hour and then concentrated under reduced pressure to provide [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanol as a pale yellow liquid, which was used directly in the next step (20.0 g, crude) without further purification: [The text abruptly ends here, so the translation stops as well.] 13 H 17 LCMS (ESI) [M+H] calculated using Cl2NO2 +:290,292(3:2), actual measurement 290,292(3:2).

[0395] Step f:

[0396] Boc₂O (17.7 mL, 81.1 mL) was added to a stirred solution of [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanol (20.0 g, 68.9 mmol) and TEA (28.7 mL, 284 mmol) in DCM (200 mL) at room temperature. The reaction was stirred at room temperature for 1 h and then diluted with water (100 mL). The aqueous solution was extracted with DCM (2 × 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. The residue was purified by silica gel column chromatography with PE / EA (1 / 1) elution to provide intermediate 9 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester) (13.0 g, 43%) as a pale yellow liquid: [C] 18 H 25 LCMS (ESI) [M+H] calculated using Cl2NO4 + :390,392(3:2), measured 334,336[M+H–56] + (3:2); 1 H NMR (400MHz, CDCl3) δ7.30 (d, J = 9.4Hz, 1H), 6.75 (d, J = 8.9Hz, 1H), 3.82 (s, 3H), 3.80-3.56 (m, 5H), 3.54 -3.40(m,1H),2.40-2.24(m,1H),2.06-1.96(m,1H),1.87-1.74(m,1H),1.60-1.55(m,1H),1.53(s,9H).

[0397] Step g:

[0398] Dess-Martin reagent (1.80 g, 4.31 mmol) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester (1.40 g, 3.58 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 h. The resulting mixture was quenched with saturated aqueous solution of Na₂S₂O₄ (10 mL) and NaHCO₃ (30 mL). The solution was 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 to provide intermediate 10 ((2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidin-1-carboxylic acid tert-butyl ester) (1.30 g, crude): [C] 18 H 23 LCMS (ESI) calculated using Cl2NO4 [M+H-56] + :332,334(3:2), actual measurement 332,334(3:2); 1 H NMR (400MHz, CD3OD) δ9.52(d,J=1.4Hz,1H),7.39(d,J=9.0Hz,1H),6.97(d,J=9.0Hz,1H),4.02-3.90(m, 1H), 3.90-3.64 (m, 5H), 3.26-3.10 (m, 1H), 2.45-2.22 (m, 2H), 1.93-1.57 (m, 2H), 1.51 (d, J = 5.8Hz, 9H).

[0399] Example 9. Intermediate 11 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0400]

[0401] Step a:

[0402] TEA (0.510 g, 5.04 mmol) and NaBH(OAc)3 (1.42 g, 6.70 mmol) were added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidin-1-carboxylic acid tert-butyl ester (1.30 g, 3.35 mmol) (Intermediate 10, Example 8) and glycine methyl ester hydrochloride (0.640 g, 5.09 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA (20 mL) and water (20 mL). The aqueous solution was extracted with EA (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 35% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]piperidine-1-carboxylic acid tert-butyl trifluoroacetate (1.00 g, 52%) as a colorless liquid: [C] 21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :461,463(3:2), actual measurement 461,463(3:2); 1 H NMR (400MHz, CD3OD) δ7.41(d,J=8.8Hz,1H),6.99(d,J=8.9Hz,1H),4.20(s,1H),4.12–3.96(m,2H),3.88(d,J=1.2Hz,6H),3.76-3 .54(m,2H),3.54-3.37(m,2H),3.22-3.10(m,1H),2.41(d,J=13.2Hz,1H),2.00-1.87(m,2H),1.69(d,J=13.3Hz,1H),1.57(s,9H); 19 F NMR (376MHz, CD3OD) δ-77.31 (s, 3F).

[0403] Step b:

[0404] TFA (4 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]piperidine-1-carboxylic acid tert-butyl trifluoroacetic acid (1.00 g, 1.74 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL) and TEA (0.530 g, 5.24 mmol) was added. The reaction was stirred at 80 °C for 1 h and then diluted with EA (50 mL) and water (30 mL). The aqueous solution was extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide intermediate 11 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) (0.550 g, crude) as a grayish-white foam: [C] 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :329,331(3:2), actual measurement 329,331(3:2). 1 H NMR (400MHz, CD3OD) δ7.39(d,J=9.0Hz,1H),6.97(d,J=9.0Hz,1H),4.78(ddd,J=13.3,4.4,2.2Hz,1H),3.85(s,3H),3.80-3.68(m,1H),3.63-3.54(m ,1H),3.52(d,J=2.0Hz,2H),3.30(d,J=5.2Hz,1H),2.86(dd,J=13.3,8.4H z,1H),2.71(td,J=13.2,3.0Hz,1H),2.41-2.23(m,2H),1.72-1.62(m,2H).

[0405] Example 10. Intermediate 12 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0406]

[0407] Step a:

[0408] BBr3 (4.19 g, 16.7 mmol) was added to a stirred solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one (intermediate 11, Example 9) (0.550 g, 1.67 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 h. The reaction was quenched with MeOH (2 mL), and the resulting solution was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and alkalized to pH 8 with TEA. After concentration under reduced pressure, the residue was purified by reversed-phase chromatography with elution of 36% ACN in water (with 10 mM NH4HCO3) to provide a crude product. Fractions containing the desired product were combined and concentrated under reduced pressure to provide intermediate 12 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) (0.250 g, 47%) as a grayish-white solid: [C] 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :315,317(3:2), actual measurement 315,317(3:2); 1 H NMR (400MHz, CD3OD) δ7.20(d,J=8.8Hz,1H),6.72(d,J=8.8Hz,1H),4.81-4.73(m,1H),3.76-3.63(m,1H),3.60-3 .49(m,1H),3.44(s,2H),3.24(dd,J=13.4,5.1Hz,1H),2.81-2.61(m,2H),2.56-2.31(m,2H),1.70-1.59(m,2H).

[0409] Example 11. Intermediate 13 ((7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one)

[0410]

[0411] Step a:

[0412] Boc₂O (1.14 g, 5.24 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide (2.00 g, 5.24 mmol) and TEA (1.59 g, 15.7 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 1 hour, diluted with water (50 mL), and extracted with EA (3 × 40 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 provide (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a pale yellow solid, which was used directly in the next step without further purification (2.10 g, crude): [The text abruptly ends here, so the translation stops as well.] 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :401,403(3:2), actual measurement 401,403(3:2).

[0413] Step b:

[0414] Allyl bromide (0.760 g, 6.28 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-carboxylic acid tert-butyl ester (2.10 g, 5.23 mmol) and K₂CO₃ (1.45 g, 10.5 mmol) in DMF (40 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (100 mL), and subsequently extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (5 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a pale yellow solid, which was used directly in the next step without further purification (2.10 g, crude): [The text abruptly ends here, so the translation stops as well.] 21 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :441,443(3:2), actual measurement 441,443(3:2).

[0415] Step c:

[0416] TFA (10 mL) was added to a stirred solution of (7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-carboxylic acid tert-butyl ester (2.00 g, 4.53 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with 60% ACN in water (with 10 mM NH4HCO3) to provide intermediate 13 ((7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one) (1.50 g, 66% after three steps) as a pale yellow liquid: [The text abruptly ends here, so the translation stops as well.] 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :341,343(3:2), actual measurement 341,343(3:2); 1 H NMR (400MHz, CDCl3) δ7.32(d,J=8.9Hz,1H),6.76(d,J=9.0Hz,1H),6.09-5.95(m,1H),5.43-5.30(m,2H),4.59-4.44(m,2H),4 .30-4.14(m,2H),3.83-3.72(m,1H),3.67-3.53(m,2H),3.50-3.38(m,2H),2.64(dd,J=12.7,10.2Hz,1H),2.24-2.06(m,2H).

[0417] Example 12. Intermediate 14 (8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-4-one)

[0418]

[0419] Step a:

[0420] At room temperature, [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanol (Intermediate 9, Example 8) (2.20 g, 7.58 mmol) and TEA (2.30 g, 22.7 mmol) were added to a stirred solution of glycidyl acid (0.668 g, 7.58 mmol) and HATU (3.17 g, 8.34 mmol) in DMF (20.0 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, diluted with water (100 mL), and extracted with EA (2 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The reaction was purified by reversed-phase chromatography with 33% ACN in water (eluting with 10 mM NH4HCO3) to provide [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-1-(ethylene oxide-2-carbonyl)piperidin-2-yl]methanol (1.10 g, 40%) as a grayish-white semi-solid: [C] 16 H 19 LCMS(ESI) [M+1] calculated using Cl2NO4 + 360, 362 (3:2), actual measurement 360, 362 (3:2); 1 H NMR (400MHz, CD3OD) δ7.39(d,J=8.9Hz,1H),6.99(d,J=9.0Hz,1H),4.49-3.93(m,3H),3.85(s,3H),3.83-3.57(m,3H ),3.08-2.94(m,1H),2.94-2.79(m,1H),2.81-2.56(m,1H),2.18-1.89(m,2H),1.85-1.54(m,1H),1.39-1.28(m,1H).

[0421] Step b:

[0422] t-BuOK (0.516 g, 4.61 mmol) was added to a stirred solution of [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-1-(ethylene oxide-2-carbonyl)piperidin-2-yl]methanol (1.10 g, 3.05 mmol) in THF (10.0 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. The resulting mixture was quenched with water (100 mL) 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 reversed-phase chromatography with 40% ACN (with 0.05% TFA) in water to provide intermediate 14 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-4-one) (0.450 g, 50%) as a yellow liquid: [Reference to C] 16 H 19 LCMS(ESI) [M+1] calculated using Cl2NO4 + 360, 362 (3:2), actual measurement 360, 362 (3:2); 1 H NMR (400MHz, CD3OD) δ7.38 (d, J = 9.0, 1H), 6.96 (d, J = 9.0, 1H), 4.78-4.65 (m, 1H), 4.20-4.10 (m, 1H), 4.05-3.94 (m, 2H), 3.94-3. 87(m,2H),3.84(d,J=6.7Hz,3H),3.77-3.68(m,1H),3.53-3.44(m,1H),2.81-2.68(m,2H),2.40-2.28(m,1H),1.80-1.52(m,2H).

[0423] Example 13. Intermediate 15 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindoleazine-5,7-dione)

[0424]

[0425] Step a:

[0426] TEA (26.6 g, 263 mmol) was added dropwise to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step b) (40.0 g, 95.7 mmol), TsCl (21.9 g, 115 mmol), and DMAP (3.51 g, 28.7 mmol) in DCM (400 mL). The resulting mixture was stirred at room temperature under nitrogen for 4 hours and then diluted with water (300 mL). The aqueous solution was extracted with DCM (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. The residue was purified by silica gel column chromatography eluted with PE / EA (3 / 1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (42.5 g, 75%) as an off-white solid: [C] 24 H 29 LCMS (ESI) calculated by Cl2NO6S [M+H-100] + :430,432(3:2), actual measurement 430,432(3:2); 1 H NMR (300MHz, CD3OD) δ7.82(d,J=7.9Hz,2H),7.48(d,J=7.9Hz,2H),7.42(d,J=9.0Hz,1H),6.99(d,J=9.0Hz,1H),4.47-4.28(m ,1H),4.19-3.97(m,3H),3.89(s,3H),3.76-3.56(m,2H),2.69(q,J=11.1Hz,1H),2.47(s,3H),2.26-2.07(m,1H),1.42(s,9H).

[0427] Step b:

[0428] KCN (2.95 g, 45.3 mmol) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (12.0 g, 22.6 mmol) in DMSO (20 mL). The resulting solution was stirred at 80 °C for 1 h, diluted with saturated aqueous solution of NaHCO3 (100 mL), and subsequently extracted with EA (3 × 100 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 chromatography with PE / EA (2 / 1) elution to provide (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.50 g, 40%) as an off-white solid: [C] 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :385,387(3:2), actual measurement 385,387(3:2); 1 H NMR (400MHz, CD3OD) δ7.44(d,J=9.0Hz,1H),7.02(d,J=9.0Hz,1H),4.17-4.04(m,2H),3.95-3.90 (m,4H),3.69-3.64(m,1H),3.21-3.19(m,1H),2.88-2.67(m,2H),2.35-2.30(m,1H),1.53(s,9H).

[0429] Step c:

[0430] AcOH (4 mL) was added to a stirred solution of (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (9.30 g, 24.1 mmol) in concentrated HCl (20 mL). The reaction was stirred at 100 °C for 1 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Subsequently, DCM (20 mL), TEA (12.2 g, 121 mmol), and Boc₂O (5.79 g, 26.6 mmol) were added sequentially to the crude product. The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 65% ACN (with 0.1% FA) in water to provide [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetic acid (9.00 g, 92%) as an off-white solid: [C] 18 H 23LCMS (ESI) [M+H] calculated using Cl2NO5 + :404,406(3:2), actual measurement 404,406(3:2); 1 H NMR(300MHz,CD3OD)δ7.42(d,J=9.0Hz,1H),6.99(d,J=9.0Hz,1H),4.28-3.99(m,2H),3.89(s, 3H),3.84-3.80(m,1H),3.70-3.58(m,1H),3.17-2.87(m,1H),2.63-2.30(m,3H),1.51(s,9H).

[0431] Step d:

[0432] At room temperature, DMAP (4.08 g, 33.4 mmol) and EDCI (6.40 g, 33.5 mmol) were added to a stirred solution of [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetic acid (9.00 g, 22.3 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Mischel acid) (4.81 g, 33.4 mmol) in DCM (50.0 mL). The reaction was stirred at room temperature for 3 h. The resulting solution was diluted with DCM (100 mL), washed with aqueous HCl solution (1 M, 2 × 100 mL) and brine (3 × 100 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (30 mL) and stirred at 90 °C for 1 h. The resulting solution was diluted with water (100 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 purified by silica gel column chromatography eluted with PE / EA (2 / 1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (9.00 g, 85%) as a pale yellow liquid: against C 22 H 29 LCMS (ESI) [M+H] calculated using Cl2NO6 + :474,476(3:2), actual measurement 474,476(3:2); 1H NMR (300MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.76(d,J=9.0Hz,1H),4.29-3.99(m,4H),4.17-4.01(m,1H),3.85(s,3 H),3.81-3.68(m,1H),3.55-3.36(m,3H),2.85-2.80(m,1H),2.49-2.25(m,2H),1.50(s,9H),1.29(t,J=7.2Hz,3H).

[0433] Step e:

[0434] TFA (10 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (9.00 g, 19.0 mmol) in DCM (40 mL). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to provide ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]-3-oxobutyrate (9.00 g, crude) as a yellow liquid, which was used directly in the next step without further purification: [The text abruptly ends here, so the translation stops as well.] 17 H 21 The calculated LCMS(ESI)[M+H]+ of Cl2NO4 was 374,376 (3:2), and the actual measured value was 374,376 (3:2).

[0435] Step f:

[0436] K₂CO₃ (16.7 g, 120 mmol) was added to a stirred solution of ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]-3-oxobutyrate (9.00 g, 24.1 mmol) in MeOH (50 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then neutralized to pH 7 with aqueous HCl (1 M) and extracted with EA (3 × 100 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 purified by silica gel column chromatography eluted with EA to provide intermediate 15 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindoleazine-5,7-dione) (5.00 g, 80% total from both steps) as a pale yellow solid: [C] 15 H 15 LCMS(ESI)[M+H] calculated using Cl2NO3 + :328,330(3:2), actual measurement 328,330(3:2);1 H NMR (300MHz, CDCl3) δ7.38 (d, J = 8.9, 1H), 6.81 (d, J = 9.0, 1H), 4.40-4.12 (m, 2H), 4.12-3.98 (m,1H),3.85(s,3H),3.83-3.71(m,1H),3.34(s,2H),2.96-2.76(m,1H),2.74-2.29(m,3H).

[0437] Example 14. Intermediate 16 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indoleazine-5-one)

[0438]

[0439] Step a:

[0440] t-BuOK (136 mL, 1 M in THF) was added dropwise to a solution of methyltriphenylphosphanium bromide (48.7 g, 136 mmol) in THF (400 mL) for 30 minutes at -10 °C under a nitrogen atmosphere. Subsequently, (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) (17.0 g, 45.4 mmol) in THF (50 mL) was added dropwise to the mixture at -10 °C. The resulting mixture was stirred under nitrogen at room temperature for 2 hours, quenched at 0 °C with a saturated aqueous solution of NH4Cl (200 mL), and extracted with EA (3 × 300 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 with PE / EA (5 / 1) elution to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (8.50 g, 43%) as a colorless liquid: [C] 18 H 23 LCMS (ESI) calculated with Cl2NO3 [M+H-56] + :316,318(3:2), actual measurement 316,318(3:2); 1H NMR (400MHz, CD3OD) δ7.42(d,J=9.0Hz,1H),7.00(d,J=9.0Hz,1H),5.95-5.77(m,1H),5.25-5.05(m,2H),4.40-4.27(m,1H) ,4.18-4.02(m,1H),3.88(s,3H),3.83-3.80(m,1H),3.70-3.62(m,1H),2.52-2.39(m,1H),2.32-2.21(m,1H),1.47(s,9H).

[0441] Step b:

[0442] TFA (9 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (3.60 g, 9.67 mmol) in DCM (36 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine (3.60 g, crude) as a yellow liquid, which was used directly for the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 13 H 15 LCMS(ESI)[M+H] calculated using Cl2NO + :272,274(3:2), actual measurement 272,274(3:2).

[0443] Step c:

[0444] To a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine (3.60 g, 13.2 mmol) and TEA (4.02 g, 39.7 mmol) in DMF (30 mL), 3-butenoic acid (1.37 g, 15.9 mmol) and diethyl cyanophosphonate (3.12 g, 17.2 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours, quenched with water (100 mL) at room temperature, and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (5 × 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 provide 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidone-1-yl]but-3-en-1-one (2.60 g, 79% after two steps) as a pale yellow liquid: [C] 17 H 19 LCMS (ESI) [M+H] calculated using Cl2NO2 +:340,342(3:2), actual measurement 340,342(3:2); 1 H NMR (300MHz, CDCl3) δ7.35(d,J=8.8Hz,1H),6.78(d,J=8.9Hz,1H),6.11-5.82(m,2H),5.36-5.07(m,4 H), 4.73-4.34 (m, 1H), 4.18-3.94 (m, 2H), 3.92-3.59 (m, 4H), 3.16 (d, J = 6.6Hz, 2H), 2.59-2.23 (m, 2H).

[0445] Step d:

[0446] Grubbs second-generation catalyst (0.260 g, 0.30 mmol) was added to a stirred mixture of 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine-1-yl]but-3-en-1-one (2.60 g, 7.64 mmol) in DCM (26 mL) at room temperature. The resulting mixture was stirred at 40 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA to provide intermediate 16 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indoleazine-5-one) (2.20 g, 74%) as a brown solid. 15 H 15 LCMS (ESI) [M+H] calculated using Cl2NO2 + :312,314(3:2), actual measurement 312,314(3:2); 1 H NMR(400MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.75(d,J=8.9Hz,1H),5.94-5.82(m,2H),4 .33-4.20(m,3H),3.79(s,3H),3.55-3.50(m,1H),3.07-2.98(m,2H),2.27-2.13(m,2H).

[0447] Example 15. Intermediate 17 ((2R,8aR)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,8,8a-tetrahydro-1H-indoleazine-5-one)

[0448]

[0449] Step a:

[0450] DBU (10 mL, 66.9 mmol) was added to a stirred mixture of (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indoleazine-5-one (intermediate 16, Example 14) (2.20 g, 7.05 mmol) in toluene (15 mL) at room temperature. The resulting mixture was stirred at 90 °C for 16 h, diluted with water (100 mL), and extracted with EA (3 × 40 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 EA to provide intermediate 17 ((2R,8aR)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,8,8a-tetrahydro-1H-indolinazine-5-one) (1.50 g, 61%) as an off-white solid. 15 H 15 LCMS (ESI) [M+H] calculated using Cl2NO2 + :312,314(3:2), actual measurement 312,314(3:2); 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.9Hz,1H),6.78(d,J=9.0Hz,1H),6.61-6.55(m,1H),6.06-6.02(m,1H),4.28-4.11(m,1H),4 .01-3.94(m,1H),3.94-3.87(m,1H),3.84(s,3H),3.80-3.71(m,1H),2.58-2.49(m,1H),2.45-2.40(m,1H),2.34-2.20(m,2H).

[0451] Example 16. Intermediate 18 ((6R,7aR)-6-(2,3-dichloro-6-methoxyphenyl)-hexahydropyrrolizin-3-one)

[0452]

[0453] Step a:

[0454] At room temperature, 2.00 g (5.34 mmol) of tert-butyl 2-(triphenyl-λ5-phosphanylidene)acetate (1.79 g (5.34 mmol) was added to a solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) in DCM (30 mL). The reaction was stirred at room temperature under a nitrogen atmosphere for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (2 / 1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.65 g, 72%) as an off-white solid: [C] 20 H 25 LCMS (ESI) [M+Na] calculated using Cl2NO5 + :452,454(3:2), actual measurement 452,454(3:2); 1 H NMR (300MHz, CDCl3) δ7.35(d,J=8.9Hz,1H),6.99-6.95(m,1H),6.77(d,J=9.0Hz,1H),6.00-5.92(m,1H),4.68-4. 34(m,1H),4.26-4.03(m,1H),3.82(s,6H),3.80-3.70(m,2H),2.45-2.16(m,1H),2.32-2.29(m,1H),1.50(s,9H).

[0455] Step b:

[0456] PtO2 (50.0 mg, 0.220 mmol) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.450 g, 1.05 mmol) in MeOH (6 mL). The mixture was degassed under reduced pressure and purged three times with hydrogen. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (1.5 atm). The mixture was then filtered and concentrated under reduced pressure to provide (2R,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.450 g, crude) as a colorless liquid, which was used directly in the next step without purification: [The text abruptly ends here, so the translation stops as well.] 20 H 27 LCMS (ESI) [M+H] calculated using Cl2NO5 +:432,434(3:2), actual measurement 432,434(3:2); 1 H NMR (300MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.77(d,J=8.9Hz,1H),4.11-3.91(m,2H),3.8 6(s,3H),3.80-3.62(m,5H),2.46-2.14(m,5H),2.09-1.95(m,1H),1.50(d,J=7.7Hz,9H).

[0457] Step c:

[0458] TFA (1.50 mL) was added to a solution of (2R,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.500 g, 1.16 mmol) in DCM (5 mL) at room temperature. The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOH (15 mL) and TEA (3 mL, 21.6 mmol) was added. The resulting mixture was stirred at 80 °C for 48 h and then concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 65% ACN in water (with 0.05% TFA) to provide intermediate 18 ((6R,7aR)-6-(2,3-dichloro-6-methoxyphenyl)-hexahydropyrrolizin-3-one) (0.250 g, 72%) as a pale yellow solid. 14 H 15 LCMS (ESI) [M+H] calculated using Cl2NO2 + :300,302(3:2), actual measurement 300,302(3:2); 1 H NMR (400MHz, CD3OD) δ7.41(d,J=9.0Hz,1H),6.99(d,J=9.0Hz,1H),4.59-4.47(m,1H),4.21-4.13(m,1H),3.86-3.78(m,4H),3.30 -3.22(m,1H),2.86-2.74(m,1H),2.62-2.52(m,1H),2.46-2.35(m,1H),2.24-2.15(m,1H),1.98-1.89(m,1H),1.89-1.79(m,1H).

[0459] Example 17. Intermediate 19 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-3-oxo-hexahydropyrrolizine-2-carboxylic acid)

[0460]

[0461] Step a:

[0462] L-proline (31.0 mg, 0.27 mmol) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) (1.00 g, 2.67 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (Missell's acid) (0.380 g, 2.67 mmol), and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (etidin) (0.67 g, 2.67 mmol) in ACN (10 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours and then concentrated under reduced pressure. The residue was diluted with MeOH (10 mL), filtered, and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 50% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.20 g, 89%) as a pale yellow liquid. 23 H 29 LCMS(ESI)[M+H] calculated using Cl2NO7 + :502, 504 (3:2), actual measured 502, 504 (3:2); 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.9Hz,1H),6.79(d,J=8.9Hz,1H),4.94-4.76(m,1H),4.54-4.44(m,1H),4.08-3.96(m,1H),3. 91(s,3H),3.85-3.73(m,2H),2.67-2.55(m,1H),2.55-2.44(m,1H),2.28-2.14(m,2H),1.89(s,3H),1.80(s,3H),1.46(s,9H).

[0463] Step b:

[0464] A solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.39 mmol) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL) and alkalized to pH 8 with TEA (1 mL). The resulting mixture was stirred at 80 °C for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 35% ACN in water (with 0.05% TFA) to provide intermediate 19 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-3-oxo-hexahydropyrrolizidine-2-carboxylic acid) (0.780 g, 95%) as a pale yellow liquid. 15 H 15 LCMS (ESI) [M+H] calculated using Cl2NO4 + :344,346(3:2), actual measurement 344,346(3:2); 1 H NMR (300MHz, CDCl3) δ7.34(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.88-4.62(m,1H),4.58-4.37(m,1H),4.18 -4.01(m,1H),4.00-3.63(m,5H),3.41-3.24(m,1H),2.87-2.67(m,1H),2.40-2.09(m,2H),1.99-1.70(m,1H).

[0465] Example 18. Intermediate 20 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-1-(hydroxymethyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one)

[0466]

[0467] Step a:

[0468] m-CPBA (4.59 g, 26.6 mmol) was added to a stirred mixture of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 16, step a) (3.30 g, 8.86 mmol) in a DCM (25 mL) at room temperature. After 2 hours, the reaction was quenched with a saturated aqueous solution of Na₂S₂O₃ (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO₃ (3 × 30 mL) and brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(ethylene-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.50 g, crude) as a pale yellow liquid, which was used directly in the next step without further purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 18 H 23 LCMS (ESI) [M+Na] calculated using Cl2NO4 + :410,412(3:2), actual measurement 410,412(3:2).

[0469] Step b:

[0470] A mixture of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(ethylene-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.30 g, 8.50 mmol) and TsOH (0.150 g, 0.850 mmol) in MeOH (25 mL) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 45% ACN (with 0.05% TFA) in water to provide intermediate 20 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-1-(hydroxymethyl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one) (1.70 g, 57% after two steps) as a pale yellow solid: [The text abruptly ends here, so the translation stops as well.] 14 H 15 LCMS (ESI) [M+H] calculated using Cl2NO4 + :332,334(3:2), actual measurement 332,334(3:2); 1 H NMR(400MHz, CDCl3)δ7.35(d,J=8.9Hz,1H),6.78(d,J=8.9,1H),4.88-4.48(m,1H),4.42- 4.27(m,1H),4.16-3.80(m,7H),3.49-3.36(m,1H),2.29-2.18(m,1H),2.11-1.87(m,1H).

[0471] Examples 19-108 describe the synthesis of representative compounds of Formula I disclosed herein.

[0472] Example 19. Compound 1 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one)

[0473]

[0474] Step a:

[0475] EDCI (32 mg, 0.17 mmol) and HOBT (23 mg, 0.17 mmol) were added to a stirred solution of glycolic acid (9 mg, 0.12 mmol) in DMF (1.00 mL) at room temperature. After five minutes, TEA (34 mg, 0.33 mmol) and (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one (intermediate 6, Example 5) (35 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD, Column 30×150mm, 5μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: from 17% B to 45% B over 7 minutes; detector: UV 220nm; retention time: 6.97 minutes. Fractions containing the desired product were combined and concentrated under reduced pressure to provide compound 1 ((8R,9aR)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) (15.6 mg, 38%) as a grayish-white solid: [The text abruptly ends here, so the translation stops as well.] 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :373,375(3:2), actual measurement 373,375(3:2). 1¹H NMR (400MHz, methanol-d⁴) δ 7.20 (d, J = 8.8Hz, 1H), 6.71 (d, J = 8.8Hz, 1H), 4.77–4.65 (m, 1H), 4.45–3.87 (m, 5H), 3.82–3.42 (m, 3H), 2.82–2.70 (m, 1H), 2.52–2.34 (m, 2H), 1.80–1.58 (m, 2H); (400M Hz, CD3OD) δ7.20(d,J=8.8Hz,1H),6.71(d,J=8.8Hz,1H),4.74(d,J=13.3Hz,1H),4.41-3.87( m,5H),3.86-3.39(m,3H),2.76(td,J=13.2,3.0Hz,1H),2.54-2.32(m,2H),1.83-1.54(m,2H).

[0476] Example 20. Compound 2 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyethyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0477]

[0478] Step a:

[0479] DIEA (38 mg, 0.30 mmol) was added dropwise to a stirred mixture of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide (intermediate 8, Example 7) (30 mg, 0.10 mmol) and 2-bromoethanol (50 mg, 0.39 mmol) in ACN (1 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridgeShield RP18 OBD Column 30×150mm, 5μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: from 15% B to 40% B over 7 min; detector: UV 254 / 220nm; retention time: 6.92 min. Fractions containing the desired product were collected and concentrated under reduced pressure to provide compound 2 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyethyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one) (15 mg, 41%) as a grayish-white solid. 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O3 +:345,347(3:2), Actual measurement: 345,347(3:2); 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.46-4.29(m,1H),4.24-4.09(m,1H),4.03-3.83(m,1H),3.78-3.62(m,3H),3. 39(t,J=10.6Hz,1H),3.35-3.25(m,1H),3.11(d,J=16.8Hz,1H),2.85-2. 67(m,2H),2.53-2.33(m,1H),2.22(q,J=11.5Hz,1H),2.16-2.04(m,1H).

[0480] Example 21. Compounds 3-11, 14-17, 19-25, 27-29, 31-35, 37-42, 44-45, 47-49, 51, 53-54, 56 and 58-59

[0481] The following compounds were prepared in a manner similar to that of compound 1 (Example 19) or compound 2 (Example 20) and / or by methods known in the art.

[0482] Table 1

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494] Example 22. Compound 61 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxyhexahydroindoleazine-5(1H)-one isomer 1) and compound 62 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxyhexahydroindoleazine-5(1H)-one isomer 2)

[0495]

[0496] Step a:

[0497] TEA (3.55 g, 35.081 mmol, 2.00 equivalent) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step b) (6.6 g, 17.541 mmol, 1.00 equivalent), TsCl (3.68 g, 19.295 mmol, 1.10 equivalent), and DMAP (214 mg, 1.754 mmol, 0.10 equivalent) in DCM (60 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was 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 eluted with PE / EA (3:1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (6.6 g, 64%): [C] 24 H 29 LCMS (ESI) [M+H] calculated by Cl2NO6S + :530,532(3:2), actual measurement 530,532(3:2); 1 ¹H NMR (300MHz, chloroform-d) δ 7.82 (d, J = 8.2Hz, 2H), 7.38–7.33 (m, 3H), 6.78 (d, J = 9.0Hz, 1H), 4.43–4.42 (m, 1H), 4.21–3.95 (m, 2H), 3.90–3.85 (m, 2H), 3.75–3.73 (m, 3H), 2.70–2.66 (m, 1H), 2.48–2.46 (m, 4H), 2.20–2.17 (m, 1H), 1.41 (s, 9H).

[0498] Step b:

[0499] KCN (245 mg, 3.770 mmol, 2.00 equivalence) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.885 mmol, 1.00 equivalence) in DMSO (10 mL). The reaction was stirred at 80 °C for 1 h. The resulting mixture was diluted with saturated NaHCO3 (100 mL). The resulting mixture was extracted with EA (3 × 200 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 chromatography with PE / EA (3:1) elution to provide (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.4 g, 47%) as an off-white solid: [C] 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :385,387(3:2), actual measurement 385,387(3:2); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.44 (d, J = 9.0Hz, 1H), 7.02 (d, J = 9.0Hz, 1H), 4.17–4.04 (m, 2H), 3.92–3.86 (m, 4H), 3.71–3.63 (m, 1H), 3.19–3.15 (m, 1H), 2.88–0.67 (m, 2H), 2.33–2.31 (m, 1H), 1.53 (s, 9H).

[0500] Step c:

[0501] AcOH (4 mL) was added to a stirred solution of (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 5.191 mmol, 1.00 equivalence) in HCl (20 mL). The reaction was stirred at 100 °C for 1 h. The reaction was concentrated under reduced pressure. DCM (20 mL), TEA (2.63 g, 25.991 mmol, 5.01 equivalence), and Boc₂O (2.27 g, 10.382 mmol, 2.00 equivalence) were added sequentially to the residue. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 65% ACN (with 0.1% FA) in water to provide [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetic acid (1.8 g, 86%) as an off-white solid: [C]18 H 23 LCMS (ESI) [M+H] calculated using Cl2NO5 + :404,406(3:2), actual measurement 404,406(3:2); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.42 (d, J = 9.0Hz, 1H), 6.99 (d, J = 9.0Hz, 1H), 4.29–4.02 (m, 2H), 3.90 (s, 3H), 3.84–3.59 (m, 2H), 3.14–2.94 (m, 1H), 2.67–2.30 (m, 3H), 1.51 (s, 9H).

[0502] Step d:

[0503] At room temperature, DMAP (0.66 g, 5.442 mmol, 1.00 equivalence) and EDCI (0.78 g, 4.081 mmol, 1.50 equivalence) were added to a stirred solution of [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetic acid (1.1 g, 2.721 mmol, 1.00 equivalence) in DCM (10 mL) and Michaelis-Menten acid (0.59 g, 4.081 mmol, 1.50 equivalence). The reaction was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL), and the resulting mixture was stirred at 90 °C for 16 h. Subsequently, TsOH (243 mg, 1.36 mmol, 0.50 equivalence) was added. The reaction mixture was stirred at 100 °C 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 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 65% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 77%) as a yellow oil: against C 22 H 29 LCMS (ESI) [M+H] calculated using Cl2NO6 + :474,476(3:2), actual measurement 474,476(3:2); 1¹H NMR (400MHz, chloroform-d) δ 7.33 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 4.29–3.99 (m, 4H), 3.85 (s, 3H), 3.81–3.57 (m, 2H), 3.51–3.41 (m, 3H), 2.85–2.79 (m, 1H), 2.49–2.15 (m, 2H), 1.49 (s, 9H), 1.31–1.28 (m, 3H).

[0504] Step e:

[0505] TFA (1.5 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.632 mmol, 1.00 equivalent) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to provide ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]-3-oxobutyrate (300 mg, crude) as a yellow oil: [C] 17 H 21 LCMS (ESI) [M+H] calculated using Cl2NO4 + :374,376(3:2), actual measurement 374,376(3:2).

[0506] Step f:

[0507] Ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]-3-oxobutyrate (300 mg, 0.802 mmol, 1.00 equivalence) in MeOH (3 mL) was added to a stirred solution of LiOH·H₂O (67 mg, 1.603 mmol, 2.00 equivalence) and H₂O (1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography with 50% ACN (with 0.05% TFA) in water to provide (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindoleazine-5,7-dione (90 mg, 34%) as a yellow oil: [C] 15 H 15 LCMS(ESI)[M+H] calculated using Cl2NO3 + :328,330(3:2), actual measurement 328,330(3:2); 1¹H NMR (400MHz, chloroform-d) δ 7.38 (dd, J = 8.9, 2.4Hz, 1H), 6.80 (dd, J = 9.0, 3.4Hz, 1H), 4.30–4.05 (m, 2H), 3.85–3.83 (m, 4H), 3.40–3.23 (m, 2H), 2.90–2.61 (m, 2H), 2.58–2.28 (m, 2H), 2.13–2.10 (m, 1H).

[0508] Step g:

[0509] BBr3 (0.9 mL, 10 Equivalents) was added to a stirred solution of (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindoleazine-5,7-dione (300 mg, 0.609 mmol, 1.00 equivalent) in DCM (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (2 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography with 20% ACN in water (with 10 mmol / L NH4HCO3) to provide (2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-hexahydroindoleazine-5,7-dione (180 mg, 58%) as an off-white solid: [C] 14 H 13 LCMS(ESI)[M+H] calculated using Cl2NO3 + :314,316(3:2), actual measurement 314,316(3:2); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.29–7.24 (m, 1H), 6.79–6.74 (m, 1H), 4.61 (s, 2H), 4.50–4.04 (m, 3H), 3.91–3.71 (m, 1H), 2.86–2.74 (m, 1H), 2.63–2.30 (m, 2H), 2.18–2.06 (m, 1H).

[0510] Step h:

[0511] To a stirred solution of (2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-hexahydroindoleazine-5,7-dione (180 mg, 0.516 mmol, 1.00 equivalence, 90%) in THF (2 mL), NaBH4 (39 mg, 1.026 mmol, 1.99 equivalence) was added. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (3 mL). The resulting mixture was extracted with EA (3 × 10 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 chiral HPLC under the following conditions: column: CHIRALPAK IE, 2*25cm, 5μm; mobile phase A: Hex (0.1% FA), mobile phase B: EtOH; flow rate: 20mL / min; gradient: from 20B to 20B over 11 min; 220 / 254nm; retention times: 6.98 min and 8.68 min. A faster elution of the isomer (10 mg, 2%) of compound 61 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxy-hexahydro-1H-indoleazine-5-one isomer 1) as a grayish-white solid was obtained: [The text abruptly ends here, so the translation stops as well.] 14 H 15 LCMS(ESI)[M+H] calculated using Cl2NO3 + :316,318(3:2), actual measurement 316,318(3:2); 1 H NMR (400MHz, methanol-d4) δ7.25(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.20-4.05(m,4H),3.57-3.52(m, 1H),2.76-2.70(m,1H),2.47-2.34(m,2H),2.28-2.21(m,1H),2.11-2.02(m,1H),1.52-1.43(m,1H).

[0512] Slower elution isomer of compound 62 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxy-hexahydro-1H-indoleazine-5-one isomer 2) as a grayish-white solid was obtained (45 mg, 43%): [C] 14 H 15 LCMS(ESI)[M+H] calculated using Cl2NO3 + :316,318(3:2), actual measurement 316,318(3:2); 1¹H NMR (400MHz, methanol-d⁴) δ 7.25 (d, J = 8.8Hz, 1H), 6.75 (d, J = 8.8Hz, 1H), 4.29–4.21 (m, 1H), 4.13–4.06 (m, 2H), 3.78–3.72 (m, 1H), 3.52–3.46 (m, 1H), 2.79–2.73 (m, 1H), 2.44–2.35 (m, 2H), 2.28–2.13 (m, 2H), 1.53–1.44 (m, 1H).

[0513] Example 23. Compounds 63-64 were prepared in a manner similar to the examples disclosed herein and / or in a manner similar to that known in the art.

[0514]

[0515]

[0516] Example 24. Compounds 65-78 were prepared in a manner similar to the examples disclosed herein and / or in a manner similar to that known in the art.

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523] Example 25. Compound 57 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one) and compound 36 ((3R,8S,9aR)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0524]

[0525] Step a:

[0526] At room temperature, [4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanol (cis, racemic) (0.190 g, 0.67 mmol) and TEA (0.140 g, 1.34 mmol) were added to a stirred solution of (4R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (0.180 g, 0.74 mmol) and HATU (0.280 g, 0.74 mmol) in DMF (2 mL). The reaction was stirred for 0.5 hours, and the resulting mixture was purified directly by reversed-phase chromatography using 55% elution with ACN in 0.05% TFA aqueous solution to provide (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidin-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (cis, a mixture of two diastereomers) (0.230 g, 71%) as a pale yellow solid. 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :517,519(3:2), actual measurement 517,519(3:2); 1 H NMR (400MHz, CDCl3) δ7.36-7.29(m,1H),6.80-6.72(m,1H),4.94-4.64(m,1H),4.56-4.12(m,3H),4.12-3.90(m,1H),3.90-3.72(m,4H) ,3.72-3.30(m,2H),3.10-2.97(m,1H),2.64-2.28(m,1H),2.24-1.95(m,3H),1.79-1.65(m,3H),1.65-1.53(m,3H),1.52-1.47(m,9H).

[0527] Step b:

[0528] At room temperature, 0.230 g (0.44 mmol) of tert-butyl (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidin-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester was added to a stirred solution in DCM (1.00 mL). The reaction was stirred for 1 h, quenched with an aqueous solution of Na₂SO₃ (1 mL), diluted with water (20 mL), and extracted with EA (2 × 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 reversed-phase chromatography with 70% elution of ACN in 0.05% TFA aqueous solution to provide (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidin-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (cis, a mixture of two isomers) (0.150 g, 65%) as a yellow oil. (For C...) 24 H 32 LCMS(ESI)[M+1] calculated from Cl2N2O6 + 515,517(3:2), actual measurement 515,517(3:2); 1 H NMR (400MHz, CDCl3) δ9.55 (d, J = 25.0Hz, 1H), 7.42-7.30 (m, 1H), 6.82-6.73 (m, 1H), 4.99-4.79 (m, 1H), 4.58-4.41 (m, 1H), 4.38-4.19 (m, 2 H),4.19-3.93(m,1H),3.94-3.65(m,4H),3.63-3.26(m,1H),2.66-2.32(m,1H),2.35-1.76(m,3H),1.79-1.64(m,3H),1.63-1.40(m,12H).

[0529] Step c:

[0530] TFA (0.5 mL) was added to a stirred solution of (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(dihydroxymethyl)piperidin-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.150 g, 0.29 mmol) in DCM (2 mL) at room temperature. The reaction was stirred for 2 h and concentrated under reduced pressure to provide 8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-1H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (0.110 g, crude) as a yellow oil, which was used directly for the next step without purification: C 16 H 18 LCMS(ESI)[M+1] calculated from Cl2N2O3 + 357,359(3:2), actual measurement 357,359(3:2).

[0531] Step d:

[0532] PtO2 (20 mg) was added to a stirred solution of 8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-1H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (0.110 g, 0.31 mmol) in MeOH (2 mL). The reaction was stirred at H2 (1.5 atm) for 1 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography eluting with 26% ACN in 0.05% TFA aqueous solution to provide (3R)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (80.0 mg, 72%) as a yellow oil: [C] 16 H 20 LCMS(ESI)[M+1] calculated from Cl2N2O3 + 359,361(3:2), actual measurement 359,361(3:2).

[0533] Step e:

[0534] BBr3 (0.560 g, 2.23 mmol) was added to a stirred solution of (3R)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (80.0 mg, 0.22 mmol) in DCM (2 mL). The reaction was stirred for 2 h, quenched with MeOH (2 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD Column, 5 μm, 19 × 150 mm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 28% B to 40% B over 7 min; detector: UV: 254 / 220 nm; retention time: 6.30 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide (3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (18.0 mg, 23%) as a grayish-white solid: [C] 15 H 18 LCMS(ESI)[M+1] calculated from Cl2N2O3 + 345,347(3:2), actual measurement 345,347(3:2). 1 H NMR (400MHz, CD3OD) δ7.23(d,J=8.8Hz,1H),6.73(d,J=8.8Hz,1H),4.84-4.67(m,1H),4.21-3.96(m,3H),3.93 -3.68(m,2H),3.68-3.47(m,1H),3.39-3.35(m,1H),2.90-2.72(m,1H),2.62-2.34(m,2H),1.91-1.61(m,2H).

[0535] Step f:

[0536] 3R)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, a mixture of two isomers) (12 mg, 0.04 mmol) was separated by chiral preparative HPLC under the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (with 0.2% IPA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: from 20% B to 20% B over 14 min; detector: UV 220 / 254 nm; retention time 1: 7.51 min; retention time 2: 11.52 min. The faster eluting isomer obtained at 7.51 min provided compound 57 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one) (1.9 mg, 16%) as a grayish-white solid. 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :345,347(3:2), actual measurement 345,347(3:2); 1 H NMR (400MHz, CD3OD) δ7.19(d,J=8.7Hz,1H),6.71(d,J=8.8Hz,1H),4.82-4.73(m,1H),3.96-3.84(m,2H),3.72-3.54( m,2H),3.45(dd,J=5.7,3.9Hz,1H),3.36-3.34(m,1H),2.82-2.62(m,2H),2.53-2.24(m,2H),1.66(t,J=11.9Hz,2H). A slower-eluting isomer was obtained at 11.52 min to provide compound 36 ((3R,8S,9aR)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one) (2.6 mg, 21%) as a grayish-white solid: [Reference to C] 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :345,347(3:2), actual measurement 345,347(3:2); 1H NMR (400MHz, CD3OD) δ7.19(d,J=8.7Hz,1H),6.71(d,J=8.8Hz,1H),4.79-4.71(m,1H),3.96( dd,J=11.0,6.6Hz,1H),3.83(dd,J=11.0,3.8Hz,1H),3.77-3.71(m,1H),3.55-3.47(m,1H),3 .45(dd,J=6.6,3.7Hz,1H),3.18(dd,J=13.4,5.0Hz,1H),3.01(dd,J=13.5,5.2Hz,1H),2.71 (td,J=13.1,2.9Hz,1H),2.62-2.58(m,1H),2.53-2.39(m,1H),1.60(dt,J=13.2,3.4Hz,2H).

[0537] Example 26. Compound 46 ((3S,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one)

[0538]

[0539] Step a:

[0540] At room temperature, tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidin-1-carboxylic acid (intermediate 10, Example 8) (200 mg, 0.51 mmol) and L-alanine methyl ester (63.0 mg, 0.620 mmol) in a stirred solution in DCM (2 mL) were added with TEA (100 mg, 1.03 mmol) and NaBH(AcO)3 (330 mg, 1.54 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) and then extracted with EA (3 × 20 mL). The combined organic phases 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 reversed-phase chromatography with 45% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropyl-2-yl]amino]methyl)piperidine-1-carboxylic acid tert-butyl ester (180 mg, 73%) as a yellow oil: against C 22 H 32 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :475,477(3:2), actual measurement 475,477(3:2);1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.77(d,J=8.9Hz,1H),4.28-4.15(m,2H),3.87(s,3H),3.84(s,3H),3.72-3.59(m,1H),3.5 5-3.33(m,2H),3.09(d,J=12.4Hz,1H),2.40-2.25(m,1H),2.01-1.83(m,2H),1.64(d,J=7.1Hz,2H),1.53(s,9H),1.48(d,J=3.8Hz,3H).

[0541] Step b:

[0542] TFA (1 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropyl-2-yl]amino]methyl)piperidin-1-carboxylic acid tert-butyl ester (180 mg, 0.39 mmol) in DCM (2 mL). The reaction solution was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO3 aqueous solution (5 mL), diluted with water (10 mL), and extracted separately with EA (3 × 10 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 provide methyl (2S)-2-([[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]amino)propionate (0.20 g, crude) as a yellow oil, which was used directly in the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 17 H 24 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :375,377(3:2), actual measurement 375,377(3:2).

[0543] Step c:

[0544] TEA (160 mg, 1.60 mmol) was added to a stirred solution of (2S)-2-([[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]amino)propionate (200 mg, 0.53 mmol) in EtOH (2 mL). The reaction solution was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 55% ACN in water (with 10 mM NH4HCO3) to provide (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-methyl-octahydropyrido[1,2-a]pyrazin-4-one (50.0 mg, 38% after two steps) as a yellow oil: [C] 16 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :343,345(3:2), actual measurement 343,345(3:2); 1 HNMR(400MHz, CDCl3)δ7.31(d,J=8.9Hz,1H),6.75(d,J=9.0Hz,1H),4.90-4 .79(m,1H),3.82(s,3H),3.77-3.64(m,1H),3.58(q,J=7.0Hz,1H),3.45-3. 37(m,1H),3.21(dd,J=13.3,5.1Hz,1H),3.00-2.89(m,1H),2.61(td,J=12. 8,2.8Hz,1H),2.48-2.27(m,2H),1.72-1.54(m,2H),1.47(d,J=7.0Hz,3H).

[0545] Step d:

[0546] To a stirred solution of glycolic acid (16.0 mg, 0.22 mmol), HOBT (29.0 mg, 0.22 mmol), and EDCI (42.0 mg, 0.219 mmol) in DMF (1 mL), (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-methyl-octahydropyrido[1,2-a]pyrazin-4-one (50 mg, 0.15 mmol) and TEA (44.0 mg, 0.44 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one (90 mg, crude) as a yellow oil, which was used directly in the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :401,403(3:2), actual measurement 401,403(3:2).

[0547] Step e:

[0548] BBr3 (0.25 mL) was added to a stirred solution of (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one (90.0 mg, 0.22 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 h, quenched with MeOH (2 mL) at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% to 49% over 8 min; detector: UV 254 / 220 nm; retention time: 6.58 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 46 ((3S,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) (8.7 mg, 15% after two steps) as a grayish-white solid: [C] 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4+ :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.21(d,J=8.8Hz,1H),6.73(d,J=8.8Hz,1H),5.00-4.94(m,1H),4.78-4.69(m,1H),4.65-4.40(m,1H),4.40-4.14(m,2H),3. 95(dd,J=14.5,4.5Hz,1H),3.75-3.52(m,2H),3.09-2.64(m,1H),2.57-2 .38(m,1H),2.38-2.20(m,1H),1.83-1.52(m,3H),1.47(d,J=7.1Hz,2H).

[0549] Example 27. Compound 12 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyloctahydro-4H-pyrido[1,2-a]pyrazin-4-one)

[0550]

[0551] (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one was prepared using D-alanine methyl ester in the same manner as in the previous examples.

[0552] BBr3 (0.25 mL) was added to a stirred solution of (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one (70.0 mg, 0.17 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 h, quenched with MeOH (2 mL) at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% to 48% over 8 min; detector: UV 254 / 220 nm; retention time: 7.13 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 12 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) (6.6 mg, 15% total from both steps) as a grayish-white solid: [C] 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.20(d,J=8.8Hz,1H),6.69(d,J=8.8Hz,1H),5.02-4.92(m,1H),4.74-4.54(m,1H),4.50-4.30(m,1H),4.30-4. 18(m,2H),3.94-3.66(m,2H),3.62(d,J=11.7Hz,1H),2.86-2.73(m,1H),2.60-2.33(m,2H),1.74-1.51(m,3H),1.45(d,J=7.1Hz,2H).

[0553] Example 28. Compound 83 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 1) and compound 84 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 2)

[0554]

[0555] Step a:

[0556] LiOH·H₂O (600 mg, 14.3 mmol) was added to a solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.00 g, 4.78 mmol) in MeOH (20 mL) and H₂O (1.00 mL) at room temperature. The reaction was stirred at room temperature for 12 h. The reaction was then acidified to pH 3 with saturated aqueous citric acid, and the mixture was extracted with EA (3 × 30 mL). The combined organic phases were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylic acid (1.90 g, 89%) as a pale yellow solid. 18 H 23 LCMS (ESI) [M+H] calculated using Cl2NO5 + :404,406(3:2), actual measurement 404,406(3:2); 1 H NMR (400MHz, CD3OD) δ7.38(d,J=9.0Hz,1H),6.97(d,J=8.9Hz,1H),4.25-4.20(m,1H),3.86(s, 3H),3.82-3.47(m,3H),2.60-2.56(m,1H),2.18-1.99(m,1H),1.99-1.81(m,2H),1.40(s,9H).

[0557] Step b:

[0558] A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylic acid (1.00 g, 2.47 mmol), EDCI (710 mg, 3.71 mmol), and HOBT (500 mg, 3.71 mmol) in DMF (10 mL) was stirred for 30 min at room temperature. TEA (1.03 mL, 10.19 mmol) and N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.95 mmol) were added to the above solution at room temperature. The reaction was stirred for 3 h at room temperature. The resulting mixture was diluted with water (40 mL) and then 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 eluted with EA / PE (1 / 1) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester (400 mg, 36%) as a pale yellow oil: against C 20 H 28 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :447,449(3:2), actual measurement 447,449(3:2); 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.8Hz,1H),6.75(d,J=8.9Hz,1H),4.86-4.52(m,1H),4.17-3.88(m,1H),3. 82(s,3H),3.79(s,3H),3.66-3.62(m,2H),3.21(s,3H),2.66-2.36(m,1H),2.14-1.77(m,3H),1.49(s,9H).

[0559] Step c:

[0560] MeMgBr (3.58 mL, 3.58 mmol, 1 M in THF) was added to a solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.89 mmol) in THF (4 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with EA (2 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide tert-butyl (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidine-1-carboxylate (0.36 g, crude) as a pale yellow oil, which was used directly in the next step without further purification: [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 19 H 25 LCMS (ESI) [M+H] calculated using Cl2NO4 + :402,404(3:2), actual measurement 402,404(3:2).

[0561] Step d:

[0562] TFA (1 mL) was added dropwise to a stirred solution of (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidin-1-carboxylic acid tert-butyl ester (360 mg, 0.90 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to provide 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]acetone (280 mg, crude) as a pale yellow oil, which was used directly in the next step without further purification: C 14 H 17 LCMS (ESI) [M+H] calculated using Cl2NO2 + :302,304(3:2), actual measurement 302,304(3:2); 1 H NMR (400MHz, CD3OD) δ7.45(d,J=9.0Hz,1H),7.02(d,J=9.0Hz,1H),4.27(dd,J=12.8,3.4Hz,1H),3.90-3.88(m,1H),3.87(s,3H ),3.57-3.50(m,1H),3.16(td,J=13.1,3.3Hz,1H),2.65-2.43(m,2H),2.41-2.32(m,1H),2.29(s,3H),1.82(d,J=14.3Hz,1H).

[0563] Step e:

[0564] At room temperature, TEA (0.39 mL, 3.82 mmol) and 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]acetone (280 mg, 0.93 mmol) were added to a solution of [(tert-butoxycarbonyl)amino]acetic acid (240 mg, 1.39 mmol) and HATU (530 mg, 1.39 mmol) in DMF (3 mL). The reaction was stirred at room temperature for 2 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 (5 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidin-1-yl]-2-oxoethyl] tert-butyl carbamate (500 mg, crude) as a yellow oil, which was used directly in the next step without further purification: [C] 21 H 28 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :459,461(3:2), actual measurement 459,461(3:2); 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.77(d,J=8.9Hz,1H),4.44(s,1H),4.10-4.01(m,2H),3.83(s,3H),3.75 -3.66(m,2H),3.60-3.47(m,1H),2.52-2.32(m,1H),2.23(s,3H),2.18-2.08(m,1H),2.01-1.89(m,2H),1.47(s,9H).

[0565] Step f:

[0566] TFA (1 mL) was added to a solution of N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidin-1-yl]-2-oxoethyl] tert-butyl carbamate (500 mg, 1.09 mmol) in DCM (4 mL) at room temperature. The reaction was stirred at room temperature for 30 min. The reaction mixture was alkalized to pH 7 with aqueous NaHCO3 solution. Subsequently, the resulting mixture was extracted with DCM (2 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one (360 mg, crude) as a pale yellow oil: against C 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :341,343(3:2), actual measurement 341,343(3:2); 1 H NMR (400MHz, CD3OD) δ7.41(d,J=9.0Hz,1H),6.98(d,J=9.0Hz,1H),4.81-4.72(m,1H),4.27-4.18(m,2H),3.84(s,3H),2.83 (s,2H),2.74(td,J=13.1,3.0Hz,1H),2.39-2.26(m,2H),2.16-2.08(m,1H),2.06(t,J=1.7Hz,3H),1.64(d,J=13.3Hz,1H).

[0567] Step g:

[0568] PtO2 (24.0 mg, 0.11 mmol) was added to a solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one (360 mg, 1.06 mmol) in MeOH (2 mL) at room temperature. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (1.5 atm). The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 32% MeCN in water (with 0.05% TFA) to provide (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-octahydropyrido[1,2-a]pyrazin-4-one as a pale yellow oil; trifluoroacetic acid (300 mg, 73%): [The text abruptly ends here, so the translation stops as well.] 16 H20 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :343,345(3:2), actual measurement 343,345(3:2); 1 H NMR (400MHz, CD3OD) δ7.41(d,J=8.9Hz,1H),6.98(d,J=8.8Hz,1H),4.65-4.51(m,1H),4.44-4.33(m,1H),3.86-3.81(m,4H),3.68- 3.55(m,3H),3.26-3.11(m,1H),2.24-2.11(m,1H),1.99-1.90(m,1H),1.78-1.69(m,1H),1.53-1.43(m,1H),1.36(d,J=6.6Hz,3H).

[0569] Step h:

[0570] At room temperature, (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-octahydropyrido[1,2-a]pyrazin-4-one (350 mg, 1.02 mmol) and TEA (310 mg, 3.06 mmol) were added to a solution of methoxyacetic acid (120 mg, 1.33 mmol) in DMF (3 mL) and HATU (580 mg, 1.53 mmol). The reaction was stirred at room temperature for 2 hours, poured into water (40 mL), and extracted with EA (2 × 30 mL). The combined organic phases were washed with brine (4 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 25% B to 55% B over 7 min; detector: UV 220 nm; retention time 1: 6.35 min; retention time 2: 6.55 min. A faster elution of the enantiomer (80.0 mg, 25%) as a pale yellow foam at 6.35 min was obtained for C 19 H 24 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :415,417(3:2), actual measurement 415,417(3:2); 1H NMR (400MHz, CDCl3) δ7.27(d,J=9.1Hz,1H),6.71(d,J=9.2Hz,1H),5.65-5.18(m,1H),5.03-4.60(m,2H),4.56-3.89(m,3H),3.8 6-3.61(m,4H),3.59-3.19(m,4H),2.67(t,J=12.8Hz,1H),2.44-2.17(m,2H),1.62(dd,J=38.6,13.0Hz,2H),1.50-1.23(m,3H). The slower elution of the enantiomer (80 mg, 25%) of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 2 as a pale yellow foam was obtained at 6.55 min: [C] 19 H 24 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :415,417(3:2), actual measurement 415,417(3:2); 1 H NMR (400MHz, CDCl3) δ7.29(d,J=8.9Hz,1H),6.74(d,J=8.9Hz,1H),5.67-5.19(m,1H),4.97-4.60(m,2H),4.41-3.93(m,3H),3.80(s ,3H),3.74-3.47(m,2H),3.40(s,3H),2.76(t,J=12.7Hz,1H),2.45-2.07(m,2H),1.63(dd,J=54.4,13.0Hz,2H),1.39-1.16(m,3H).

[0571] Step i:

[0572] BBr3 (0.15 mL, 1.59 mmol) was added to a solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 1 or (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 2 (80.0 mg, 0.19 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched with MeOH (5 mL). The mixture was concentrated under reduced pressure. The residues were purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30×150mm, 5μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: from 23% B to 50% B over 7 minutes; detector: UV 220nm; retention time: 4.15 minutes for both (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 1 and (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 2. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 83 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 1) (33.4 mg, 45%) as a grayish-white solid. 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.19(d,J=8.8Hz,1H),6.69(d,J=8.7Hz,1H),4.79-4.65(m,2H),4.37-4.17(m,2H),4.09-4.05(m,1H),3.95-3.66(m,2H),3 .50(d,J=11.2Hz,1H),2.80(td,J=13.0,2.9Hz,1H),2.54-2.34(m,2H),1 .71(dd,J=35.1,12.6Hz,1H),1.57(d,J=13.3Hz,1H),1.47-1.32(m,3H).

[0573] The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 84 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 2) as a grayish-white solid (41.4 mg, 56%): against C 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.21(d,J=8.8Hz,1H),6.73(d,J=8.8Hz,1H),4.85-4.59(m,2H),4.41-4.10(m,3H),3 .90-3.57(m,3H),2.90-2.70(m,1H),2.56-2.35(m,2H),1.68(dd,J=29.2,13.1Hz,2H),1.39-1.19(m,3H).

[0574] Example 29. Compound 85 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one)

[0575]

[0576] Step a:

[0577] At room temperature, TEA (340 mg, 3.36 mmol) and NaBH(AcO)3 (570 mg, 2.69 mmol) were added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) (500 mg, 1.34 mmol) and D-alanyl ester hydrochloride (370 mg, 2.65 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 2 h, quenched with water (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 reversed-phase chromatography with 45% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropyl-2-yl]amino]methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 48%) as a yellow oil: against C21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + 461,463(3:2), actual measurement 461,463(3:2); 1 H NMR (400MHz, CD3OD) δ7.46(d,J=9.0Hz,1H),7.03(d,J=9.0Hz,1H),4.31-4.10(m,3H),3.92(s,3H),3.89(s,3H), 3.88-3.71(m,2H),3.45-3.37(m,1H),3.24-2.90(m,1H),2.53-2.33(m,2H),1.63(d,J=7.2Hz,3H),1.52(s,9H).

[0578] Step b:

[0579] TFA (1 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropyl-2-yl]amino]methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.65 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 h. The resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (5 mL) and TEA (200 mg, 1.95 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the resulting mixture was diluted with water (30 mL). The solution was 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 to provide (3S,7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (220 mg, 95%) as a yellow oil: against C 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + 329,331(3:2), actual measurement 329,331(3:2); 1 H NMR(400MHz,CD3OD)δ7.43(d,J=9.0Hz,1H),7.00(d,J=9.0Hz,1H),4.35-4.27(m,2H),3 .85(s,3H),3.64-3.48(m,4H),3.26-3.12(m,2H),2.90-2.79(m,1H),1.48-1.44(m,3H).

[0580] Step c:

[0581] BBr3 (550 mg, 2.20 mmol) was added to a stirred solution of (3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (120 mg, 0.36 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 1 h. The reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 12% ACN (with 0.05% TFA) in water to provide compound 85 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one) (80.0 mg, 51%) as a pale yellow oil. 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + 315,317(3:2), actual measurement 315,317(3:2); 1 H NMR (400MHz, CD3OD) δ7.31(d,J=8.8Hz,1H),6.79(d,J=8.8Hz,1H),4.50-4.33(m,1H),4.26 -4.04(m,2H),3.84-3.58(m,2H),3.27-3.07(m,2H),2.54-2.18(m,2H),1.70-1.59(m,3H).

[0582] Example 30. Compound 60 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0583]

[0584] At room temperature, (3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (compound 85, Example 29) (50.0 mg, 0.16 mmol) and TEA (40.0 mg, 0.40 mmol) were added to a stirred solution of glycolic acid (12.0 mg, 0.159 mmol), EDCI (36.0 mg, 0.19 mmol), and HOBT (26.0 mg, 0.19 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (0.5 mL) and purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 40% B over 7 min; detector: UV 254 / 220 nm; retention time: 6.73 min. Fractions containing the desired product were collected and concentrated under reduced pressure to provide compound 60 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one) (14.5 mg, 24%) as a grayish-white solid. 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 + 373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.26(d,J=8.7Hz,1H),6.77(d,J=8.8Hz,1H),4.45-4.21(m,4H),4.21-4.10(m,2 H), 4.01-3.70 (m, 1H), 3.64-3.47 (m, 1H), 3.26-3.17 (m, 1H), 2.44-2.09 (m, 2H), 1.51 (d, J = 7.0Hz, 3H).

[0585] Example 31. Compound 87 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methylhexahydropyrrolo[1,2-a]pyrazine-4(1H)-one isomer 1) and compound 88 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methylhexahydropyrrolo[1,2-a]pyrazine-4(1H)-one isomer 2)

[0586]

[0587] Step a:

[0588] At room temperature, 2.00 g (4.95 mmol) of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate 7, Example 6) in MeOH (20 mL) was added to a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate 7, Example 6) in H2O (1 mL). The reaction was then stirred at room temperature for 12 h and acidified to pH 3 with citric acid (30 mL), followed by extraction with EA (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-carboxylic acid (1.60 g, 83%) as a grayish-white foam: [C] 17 H 21 LCMS (ESI) [M+Na] calculated using Cl2NO5 + :412,414(3:2), actual measurement 412,414(3:2); 1 H NMR(400MHz, CDCl3)δ7.35(d,J=8.9Hz,1H),6.77(d,J=9.0Hz,1H),4.58-4.39(m,1H),4 .27-4.13(m,1H),3.92-3.73(m,5H),3.01-2.65(m,1H),2.57-2.35(m,1H),1.50(s,9H).

[0589] Step b:

[0590] EDCI (1.03 g, 5.38 mmol) and HOBT (720 mg, 5.38 mmol) were added to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-carboxylic acid (1.40 g, 3.59 mmol) in DMF (15 mL) at room temperature. After 30 min, N,O-dimethylhydroxylamine hydrochloride (700 mg, 7.18 mmol) and TEA (3 mL, 24.6 mmol) were added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h, diluted with water (80 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 eluted with PE / EA (1 / 4) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.10 g, 71%) as a pale yellow oil: [C] 19 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :433,435(3:2), actual measurement 433,435(3:2); 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.9Hz,1H),6.74(d,J=8.9Hz,1H),4.78(s,1H),4.20-4.08(m,1H),4.00-3. 87(m,1H),3.82(d,J=3.4Hz,3H),3.80-3.66(m,4H),3.25(s,3H),2.64-2.35(m,2H),1.47(d,J=11.1Hz,9H).

[0591] Step c:

[0592] MeMgBr (7.62 mL, 7.614 mmol, 1 M solution in THF) was added to a solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.10 g, 2.54 mmol) in THF (10 mL) at 0 °C. The reaction was stirred at room temperature under a nitrogen atmosphere for 1 h and quenched with a saturated aqueous solution of NH4Cl (10 mL), followed by extraction with EA (3 × 50 mL). The combined organic phases were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (630 mg, 89%) as a yellow oil: [C] 18 H 23 LCMS (ESI) [M+Na] calculated using Cl2NO4 + :410,412(3:2), actual measurement 410,412(3:2); 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.9Hz,1H),6.78(d,J=8.9Hz,1H),4.43(t,J=8.7Hz,1H),4.27-4.17(m,1H),3.93(t,J =10.3Hz,1H),3.87-3.68(m,4H),2.60-2.45(m,1H),2.40-2.28(m,1H),2.22(d,J=5.1Hz,3H),1.48(d,J=11.7Hz,9H).

[0593] Step d:

[0594] TFA (1 mL) was added to a solution of (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (630 mg) in DCM (4 mL) at room temperature. The reaction was stirred at room temperature for 30 min and then concentrated under reduced pressure to provide 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetone (470 mg, crude) as a pale yellow oil, which was used directly for the next step without purification: [The text abruptly ends here, so the translation stops as well.] 13 H 15 LCMS (ESI) [M+H] calculated using Cl2NO2 + :288,290(3:2), actual measurement 288,290(3:2).

[0595] Step e:

[0596] To a solution of [(tert-butoxycarbonyl)amino]acetic acid (390 mg, 2.20 mmol) and HATU (840 mg, 2.20 mmol) in DMF (5 mL), 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]acetone (420 mg, 1.47 mmol) and TEA (0.6 mL, 6.05 mmol) were added. The reaction was then stirred at room temperature for 1 hour and poured into water (30 mL), followed by extraction with EA (2 × 50 mL). The combined organic phases were washed with brine (4 × 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 with EA / PE (3 / 2) elution to provide N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidone-1-yl]-2-oxoethyl] tert-butyl carbamate (580 mg, 80% by two steps) as an off-white solid: [C] 20 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :445,447(3:2), actual measurement 445,447(3:2); 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.9Hz,1H),6.79(d,J=9.0Hz,1H),4.66(t,J=8.8Hz,1H),4.36-4.24(m,1H), 4.08-3.89(m,3H),3.84(s,3H),3.66(t,J=8.8Hz,1H),2.51-2.33(m,2H),2.24(s,3H),1.47(d,J=5.2Hz,9H).

[0597] Step f:

[0598] TFA (1 mL) was added to a solution of N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-yl]-2-oxoethyl] tert-butyl carbamate (580 mg, 1.31 mmol) in DCM (4 mL) at room temperature. The reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to provide (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,8aH-pyrrolo[1,2-a]pyrazin-4-one (660 mg, crude) as a pale yellow oil, which was used directly for the next step without further purification: C 15 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 +:327,329(3:2), actual measurement 327,329(3:2).

[0599] Step g:

[0600] NaBH4 (150 mg, 4.05 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,8aH-pyrrolo[1,2-a]pyrazin-4-one (660 mg, 2.02 mmol) in MeOH (5 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The resulting mixture was diluted with NH4Cl (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 50% ACN in water (with 0.05% TFA) to provide (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (380 mg, 88% total from both steps) as a pale yellow oil: [C] 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :329,331(3:2), actual measurement 329,331(3:2); 1 H NMR (400MHz, CD3OD) δ7.46 (dd, J=9.0, 1.7Hz, 1H), 7.04 (dd, J=12.9, 8.9Hz, 1H), 4.46-4.25 (m, 2H), 4. 17-4.01(m,1H),3.95-3.72(m,6H),3.67-3.46(m,1H),2.40-2.14(m,2H),1.43(dd,J=6.3,4.9Hz,3H).

[0601] Step h:

[0602] A solution of methoxyacetic acid (150 mg, 1.64 mmol) and HATU (620 mg, 1.64 mmol) in DMF (8 mL) was stirred for 30 min at room temperature. Then, TEA (1 mL, 7.12 mmol) and (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (360 mg, 1.09 mmol) were added to the mixture at room temperature. The reaction was stirred for 1 h at room temperature, diluted with water (30 mL), and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (5 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one (350 mg, 80%) as a pale yellow oil, which was used directly in the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :401,403(3:2), actual measurement 401,403(3:2).

[0603] Step i:

[0604] BBr3 (5 mL) was slowly added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one (300 mg, 0.75 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 50 min. The reaction was quenched with MeOH (5 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: SunFire PrepC18 OBD Column, 19×150mm 5μm 10nm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 25mL / min; gradient: from 23% B to 48% B over 11 min; UV: detector 220nm; retention time 1: 10.05 min, retention time 2: 10.6 min. The fraction containing the desired product at 10.05 min provided compound 87 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one isomer 1) (35 mg, 12.54%) as a grayish-white solid. 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4+ :373,375(3:2), actual measurement 373,375(3:2); 1 ¹H NMR (400MHz, CD3OD) δ 7.27 (d, J = 8.8Hz, 1H), 6.76 (d, J = 8.8Hz, 1H), 4.43–4.15 (m, 3H), 4.07–3.79 (m, 6H), 2.98–2.81 (m, 1H), 2.16–2.07 (m, 1H), 1.33 (d, J = 5.2Hz, 3H); fractions containing the desired product were combined at 10.60 min to provide compound 88 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one isomer 2) (55 mg, 19.71%) as a grayish-white solid. 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),4.43-4.15(m,4H),4.14-4.02(m,1H),4. 01-3.85(m,2H),3.83-3.66(m,2H),2.58-2.53(m,1H),2.40(dt,J=11.8,6.7Hz,1H),1.35(d,J=6.2Hz,3H).

[0605] Example 32. Compound 18((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza -5-keto)

[0606]

[0607] Step a:

[0608] At room temperature, tert-butyl pyrrolidine-1-carboxylate (Example 7, step c) (1.90 g, 5.08 mmol) and methyl 3-aminopropionate hydrochloride (500 mg, 1.39 mmol) in a stirred solution in DCM (20 mL) were added with TEA (430 mg, 4.25 mmol) and NaBH(AcO)3 (600 mg, 2.83 mmol). The reaction was stirred for 2 h, quenched with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 45% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-hydroxyphenyl)-2-[[(3-methoxy-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 48%) as a yellow oil: against C 21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + 461,463(3:2), actual measurement 461,463(3:2); 1 H NMR(400MHz,CD3OD)δ7.46(d,J=9.0Hz,1H),7.03(d,J=9.0Hz,1H),4.24-4.12(m,2H),3.91(s,3H),3.88 -3.69(m,6H),3.46-3.36(m,3H),2.95-2.82(m,2H),2.51-2.36(m,1H),2.36-2.33(m,1H),1.53(s,9H).

[0609] Step b:

[0610] TFA (2 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-hydroxyphenyl)-2-[[(3-methoxy-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.26 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and LiOH·H₂O (33.0 mg, 0.78 mmol) was added. The reaction was stirred at 40 °C for 1 h and concentrated under reduced pressure. The crude product was dissolved in DMF (3 mL) and HATU (200 mg, 0.52 mmol) was added. The resulting solution was stirred at room temperature for 1 h, diluted with water (30 mL), and 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 reversed-phase chromatography with elution of 50% ACN in water (with 0.05% TFA) to provide (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrrolo[1,2-a][1,4]diaza as a yellow oil. -5-one (30.0 mg, 35%): for C 15 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O2 + 329,331(3:2), actual measurement 329,331(3:2); 1 H NMR (400MHz, CD3OD) δ7.45(d,J=9.0Hz,1H),7.02(d,J=9.0Hz,1H),4.44-4.34(m,1H),4.27-4.14(m,1H),3.92-3.86(m, 5H),3.67-3.55(m,2H),3.31-3.16(m,2H),3.16-3.04(m,1H),2.80-2.70(m,1H),2.61-2.49(m,1H),2.46-2.36(m,1H).

[0611] Step c:

[0612] At room temperature, (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrrolo[1,2-a][1,4]diaza -5-one (30.0 mg, 0.09 mmol) was added to a stirred solution of BBr3 (91.0 mg, 0.37 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 1 h. The reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with 20% ACN (with 0.05% TFA) in water to provide (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrrolo[1,2-a][1,4]diaza as a colorless oil. 5-Ketotrifluoroacetic acid (30.0 mg, 77%): [The text abruptly ends here, likely due to an incomplete translation or a formatting error.] 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + 315,317(3:2), actual measurement 315,317(3:2); 1 HNMR (400MHz, CD3OD) δ7.32(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),4.55-4.42(m,1H),4.05-3.96(m,1H),3.8 0-3.70(m,1H),3.70-3.43(m,4H),3.31-3.18(m,2H),2.77-2.62(m,1H),2.56-2.41(m,1H),2.36-2.16(m,1H).

[0613] Step d:

[0614] At room temperature, (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrrolo[1,2-a][1,4]diaza was added to a stirred solution of glycolic acid (6 mg, 0.08 mmol), HOBT (11.0 mg, 0.08 mmol), and EDCI (16.0 mg, 0.08 mmol) in DMF (1 mL). 5-ketotrifluoroacetic acid (30.0 mg, 0.07 mmol) and TEA (21.0 mg, 0.21 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with MeOH (0.5 mL) and purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 15% B to 45% B over 8 minutes; detector: UV 254 / 220 nm; retention time: 6.98 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 18(8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a grayish-white solid. -5-one)(8.7 mg, 33%): for C 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 + 373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.77-4.58(m,1H),4.40-4.24(m, 2H),4.17-3.75(m,5H),3.30-2.94(m,1H),2.92-2.78(m,1H),2.78-2.57(m,3H),2.43-2.26(m,1H).

[0615] Example 33. Compound 90((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diaza -5-keto)

[0616]

[0617] Step a:

[0618] t-BuOK (2.22 mL, 2.22 mmol, 1 M in THF) was added dropwise to a stirred mixture of (methoxymethyl)triphenylphosphonium chloride (770 mg, 2.23 mmol) in THF (5 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 15 min. Then, (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) (420 mg, 1.12 mmol) in THF (1 mL) was added. The reaction was stirred at 0 °C for 1 h, followed by dilution with EA (30 mL) and water (30 mL). The 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. The residue was purified by reversed-phase chromatography with elution of 70% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyvinyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 59%) as a yellow oil: [C] 19 H 25 LCMS (ESI) [M+H] calculated using Cl2NO4 + 402, 404 (3:2), actual measurement 402, 404 (3:2); 1 H NMR(400MHz,CD3OD)δ7.47-7.39(m,1H),7.03-6.95(m,1H),4.85-4.58(m,1H),4.58-4.20(m,1H) ,4.14-3.68(m,4H),3.66-3.46(m,4H),2.91-2.16(m,2H),1.87-1.61(m,2H),1.57-1.43(m,9H).

[0619] Step b:

[0620] TsOH·H₂O (71.0 mg, 0.37 mmol) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyvinyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.75 mmol) in acetone (5 mL). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was diluted with water (20 mL). The aqueous solution was extracted with EA (2 × 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 provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, crude) as a yellow oil, which was used directly for the next step without further purification: C 18 H 23 LCMS (ESI) [M+H] calculated using Cl2NO4 + 388,340 (3:2), actual measurement 388,340 (3:2);

[0621] Step c:

[0622] At room temperature, TEA (160 mg, 1.62 mmol) and NaBH(AcO)3 (340 mg, 1.62 mmol) were added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg, 0.54 mmol) and methyl 2-aminoacetate hydrochloride (140 mg, 1.08 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 1 h, diluted with water (20 mL), and extracted with EA (2 × 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 reversed-phase chromatography with elution of 35% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[(2-methoxy-2-oxoethyl)amino]ethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 48% after two steps) as a pale yellow oil: [C] 21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + 461,463(3:2), actual measurement 461,463(3:2);

[0623] Step d:

[0624] At room temperature, [2-[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]ethyl](2-methoxy-2-oxoethyl)amino (aminyl) (110 mg, 0.24 mmol) and TEA (72.0 mg, 0.72 mmol) were added to a stirred solution of methoxyacetic acid (43.0 mg, 0.48 mmol) and HATU (180 mg, 0.48 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction was purified by reversed-phase chromatography with elution of 40% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[2-[2-methoxy-N-(2-methoxy-2-oxoethyl)acetamido]ethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (50.0 mg, 39%) as a pale yellow oil: [C] 24 H 34 LCMS(ESI)[M+H] calculated using Cl2N2O7 + 533,535(3:2), actual measurement 533,535(3:2); 1 H NMR (400MHz, CD3OD) δ7.43(d,J=8.9Hz,1H),7.00(d,J=9.1Hz,1H),4.44-3.98(m,6H),3.95 -3.70(m,8H),3.55-3.41(m,4H),2.69-2.57(m,1H),2.10-1.63(m,4H),1.58-1.46(m,9H).

[0625] Step e:

[0626] TFA (1 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[2-methoxy-N-(2-methoxy-2-oxoethyl)acetamito]ethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.09 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and LiOH H2O (20.0 mg, 0.47 mmol) in water (0.5 mL). The reaction was stirred at 40 °C for 1 hour. The reaction was concentrated under reduced pressure to provide (N-[2-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]ethyl]-2-methoxyacetamyl)acetic acid (50.0 mg, crude) as a yellow solid, which was used directly in the next step without further purification: [The reaction proceeded to] C 18 H 24LCMS(ESI)[M+H] calculated using Cl2N2O5 + 419,421(3:2), actual measurement 419,421(3:2).

[0627] Step f:

[0628] A solution of (N-[2-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]ethyl]-2-methoxyacetamyl)acetic acid (50.0 mg, 0.12 mmol) and HATU (45.0 mg, 0.12 mmol) in DMF (0.50 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water (0.2 mL). The reaction solution was purified by reversed-phase chromatography with elution of 35% ACN in water (with 0.05% TFA) to provide (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(2-methoxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diaza as a pale yellow oil. -5-one (25.0 mg, 65% after two steps): against C 18 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O4 + 401,403(3:2), actual measurement 401,403(3:2); 1 H NMR(400MHz,CD3OD)δ7.43(d,J=9.0Hz,1H),7.00(d,J=9.0Hz,1H),4.45-3.98(m, 6H),3.97-3.67(m,7H),3.60-3.37(m,4H),2.10-1.86(m,2H),1.82-1.67(m,1H).

[0629] Step g:

[0630] At room temperature, (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(2-methoxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diaza 5-one (25.0 mg, 0.06 mmol) was added to a stirred solution of BBr3 (94.0 mg, 0.37 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 1 h. The reaction was quenched with MeOH (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30 × 150 mm 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 15% B to 45% B over 7 min; detector: UV 220 nm; retention time: 6.92 min. Fractions containing the desired product were combined and concentrated under reduced pressure to provide compound 90((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diaza as a grayish-white solid. -5-one)(7.8 mg, 34%): for C 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 + 373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.25 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.47-3.97 (m, 8H), 3.86-3.67 (m, 2H), 3.10-2.65 (m, 1H), 2.35-1.85 (m, 3H).

[0631] Example 34. Compound 91((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyloctahydro-5H-pyrrolo[1,2-a][1,4]diaza -5-keto isomer 1) and compound 92((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyloctahydro-5H-pyrrolo[1,2-a][1,4]diaza -5-KetoIsomer 2)

[0632]

[0633] Step a:

[0634] To a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 7, step c) (300 mg, 0.80 mmol) and methyl 3-amino-2-methylpropionate (110 mg, 0.96 mmol) in DCM (4 mL), NaOAc (130 mg, 1.60 mmol) and NaBH(OAc)3 (500 mg, 2.40 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL) and then extracted with EA (3 × 20 mL). The combined organic phases 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 reversed-phase chromatography with 55% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(3-methoxy-2-methyl-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 80%) as a pale yellow oil: against C 22 H 32 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :475,477(3:2), actual measurement 475,477(3:2); 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.9Hz,1H),6.78(d,J=9.0Hz,1H),4.26-4.08(m,1H),3.86(s,3H),3.83-3.72(m,4H),3 .67(t,J=9.6Hz,1H),3.54-3.38(m,2H),3.25-3.00(m,4H),2.48-2.24(m,2H),1.49(d,J=3.5Hz,9H),1.38-1.29(m,3H).

[0635] Step b:

[0636] To a stirred solution of methoxyacetic acid (110 mg, 1.26 mmol) and HATU (480 mg, 1.26 mmol) in DMF (4 mL), tert-butyl pyrrolidine-1-carboxylate (400 mg, 0.84 mmol) and TEA (250 mg, 2.52 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, diluted with water (30 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 with elution of 60% ACN (with 0.05% TFA) in water to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[2-methoxy-N-(3-methoxy-2-methyl-3-oxopropyl)acetamido]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 65%) as a yellow oil: against C 25 H 36 LCMS(ESI)[M+H] calculated using Cl2N2O7 + :547,549(3:2), actual measurement 547,549(3:2); 1 H NMR (400MHz, CDCl3) δ7.34(d,J=8.9Hz,1H),6.78(d,J=8.9Hz,1H),4.31-4.12(m,4H),4.12-3.93(m,1H),3.90(d,J=4.1H z,3H),3.78-3.60(m,6H),3.43(s,3H),3.13-2.83(m,3H),2.39-2.15(m,2H),1.50(d,J=19.1Hz,9H),1.25-1.10(m,3H).

[0637] Step c:

[0638] TFA (1.5 mL) was added to a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[2-methoxy-N-(3-methoxy-2-methyl-3-oxopropyl)acetamido]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.55 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to provide methyl 3-(N-[[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamido)-2-methylpropionate (0.30 g, crude) as a yellow oil, which was used directly in the next step without further purification: C 20 H 28 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :447,449(3:2), actual measurement 447,449(3:2).

[0639] Step d:

[0640] At room temperature, methyl 3-(N-[[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamyl)-2-methylpropionate (300 mg, 0.67 mmol) in MeOH (3 mL) was added to a stirred solution of LiOH·H2O (1 mL) in H2O (56.0 mg, 1.34 mmol). The resulting mixture was stirred at 40 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in DMF (3 mL) and HATU (380 mg, 1.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, diluted with water (30 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 with elution of 30% ACN in water (with 0.05% TFA) to provide (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a yellow oil. -5-one (60.0 mg, 27% after two steps): against C 19 H 24 Calculation of LCMS(ESI)[M+H] using Cl2N2O4 + :415,417(3:2), actual measurement 415,417(3:2); 1H NMR (400MHz, CDCl3) δ7.41-7.35(m,1H),6.83-6.77(m,1H),4.49-4.35(m,1H),4.34-4.03(m,3H),4.01 -3.82(m,4H),3.82-3.50(m,4H),3.47(s,3H),3.33-2.95(m,2H),2.59-2.18(m,2H),1.39-1.27(m,3H).

[0641] Step e:

[0642] At room temperature, (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza 5-one (60.0 mg, 0.14 mmol) was added to a stirred solution of BBr3 (0.5 mL) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30 × 150 mm 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% to 40% over 8 min; detector: UV 254 / 220 nm; retention time 1: 8.68 min, retention time 2: 8.98 min. The fraction containing the desired product was collected at 8.68 min and concentrated under reduced pressure to provide compound 91((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a grayish-white solid. -5-keto isomer 1)(3.8 mg, 2%): [The text abruptly ends here, likely due to an incomplete translation or a formatting error.] 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.65-4.36(m,1H),4.36-4.29(m,2H),4.29-4.10(m,2H),4.09-3.98(m,2 H),3.82-3.51(m,2H),3.29-3.18(m,1H),3.00-2.87(m,1H),2.76-2.63(m,1H),2.30(dt,J=12.8,6.6Hz,1H),1.29(dd,J=18.8,7.5Hz,3H). The fraction containing the desired product was collected at 8.98 min and concentrated under reduced pressure to provide compound 92((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a grayish-white solid. -5-keto isomer 2)(2 mg, 1%). For C 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.71-4.27(m,3H),4.19-3.97(m,3 H), 3.98-3.57 (m, 2H), 3.23-3.10 (m, 1H), 2.88-2.63 (m, 3H), 2.42-2.29 (m, 1H), 1.21 (d, J = 7.0Hz, 3H).

[0643] Example 35. Compound 93((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza -5-keto)

[0644]

[0645] Step a:

[0646] At room temperature, 400 mg (1.07 mmol) of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylate (Example 7, step c) and (3R)-3-aminobutyric acid (170 mg, 1.60 mmol) in a stirred solution in DCM (5 mL) were added to HOAc (0.06 mL, 1.020 mmol) and NaBH(AcO)3 (680 mg, 3.21 mmol). The reaction was stirred at room temperature for 1 hour. The resulting mixture 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 concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 50% ACN (with 0.05% TFA) in water to provide (3R)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]amino)butyric acid (300 mg, 55%) as a pale yellow oil: against C 21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :461,463(3:2), actual measurement 461,463(3:2); 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 4.23-4.00 (m, 2H), 3.87 (s, 3H), 3.81-3.69 (m, 2H), 3.32-3. 23(m,1H),3.20(d,J=11.7Hz,1H),3.04-2.94(m,1H),2.63-2.43(m,2H),2.38-2.22(m,2H),1.49(s,9H),1.34(d,J=6.6Hz,3H).

[0647] Step b:

[0648] To a stirred solution of methoxyacetic acid (79.0 mg, 0.88 mmol) and HATU (300 mg, 0.88 mmol) in DMF (3 mL), (3R)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]amino)butyric acid (270 mg, 0.59 mmol) and TEA (0.24 mL, 2.41 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, diluted with water (50 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 with elution of 50% ACN (with 0.05% TFA) in water to provide (3R)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamyl)butyric acid (220 mg, 63%) as a pale yellow oil: against C 24 H 34 LCMS(ESI)[M+H] calculated using Cl2N2O7 + :533,535(3:2), actual measurement 533,535(3:2); 1 H NMR(400MHz, CDCl3) δ7.33(dd,J=20.6,10.4Hz,1H),6.77(dd,J=16.2,9.2Hz,1H),4.40-4.01(m,3H),4.00-3.83(m,4H),3.84- 3.63(m,3H),3.59-3.37(m,4H),3.10-2.86(m,1H),2.63-2.40(m,2H),2.34-2.07(m,2H),1.58-1.43(m,9H),1.35-1.26(m,3H).

[0649] Step c:

[0650] TFA (0.50 mL) was added to a stirred solution of (3R)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamyl)butyric acid (220 mg, 0.41 mmol) in DCM (2 mL). The reaction was stirred for 1 h and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL), and TEA (130 mg, 1.237 mmol) and HATU (240 mg, 0.619 mmol) were added sequentially at room temperature. The resulting mixture was stirred for 1 h, diluted with water (80 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 with elution of 48% ACN in water (with 0.05% TFA) to provide (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a pale yellow oil. -5-one (140 mg, 74%): for C 19 H 24 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :415,417(3:2), actual measurement 415,417(3:2).

[0651] Step d:

[0652] At room temperature, (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza 5-one (70.0 mg, 0.17 mmol) was added dropwise to a stirred mixture in DCM (1 mL) with BBr3 (0.25 mL). The resulting mixture was stirred at room temperature for 1 h, then quenched with MeOH (5 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 40% B over 7.00 min; detector: UV 220 nm; retention time: 7.03 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 93((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a grayish-white solid. -5-keto)(19.7 mg, 29%): for C 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.25(d,J=8.6Hz,1H),6.75(d,J=8.6Hz,1H),4.83-4.69(m,1H),4.43-4.06(m,5H),4.06-3 .92(m,1H),3.81-3.52(m,2H),3.12-2.71(m,2H),2.69-2.45(m,1H),2.26(d,J=54.0Hz,1H),1.36-1.22(m,3H).

[0653] Example 36. Compound 94((3S,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza -5-keto)

[0654]

[0655] Step a:

[0656] At room temperature, 400 mg (1.07 mmol) of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-carboxypyrrolidine-1-carboxylic acid (Example 7, step c) and (3S)-3-aminobutyric acid (170 mg, 1.60 mmol) in a stirred solution in DCM (5 mL) were added to HOAc (0.06 mL, 1.02 mmol) and NaBH(AcO)3 (680 mg, 3.21 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) 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 concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 50% ACN (with 0.05% TFA) in water to provide (3S)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]amino)butyric acid (220 mg, 40%) as a pale yellow oil: against C 21 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O5 + :461,463(3:2), actual measurement 461,463(3:2); 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.9Hz,1H),6.78(d,J=9.0Hz,1H),4.18-4.02(m,2H),3.87(s,3H),3.83-3.66(m,2 H),3.18-2.93(m,2H),2.93-2.80(m,1H),2.62-2.51(m,2H),2.44-2.26(m,2H),1.48(s,9H),1.33(d,J=6.5Hz,3H).

[0657] Step b:

[0658] To a stirred solution of methoxyacetic acid (64.0 mg, 0.72 mmol) and HATU (280 mg, 0.72 mmol) in DMF (3 mL), (3S)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]amino)butyric acid (220 mg, 0.48 mmol) and TEA (140 mg, 1.43 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, diluted with water (20 mL), 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 reversed-phase chromatography with elution of 50% ACN (with 0.05% TFA) in water to provide (3S)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamyl)butyric acid (140 mg, 50%) as a pale yellow oil: against C 24 H 34 LCMS(ESI)[M+H] calculated using Cl2N2O7 + :533,535(3:2), actual measurement 533,535(3:2); 1 H NMR (400MHz, CDCl3) δ7.39-7.31(m,1H),6.82-6.73(m,1H),4.38-4.28(m,1H),4.28-4.13(m,2H),4.00-3.86(m, 4H),3.86-3.60(m,3H),3.58-3.37(m,4H),3.20-3.09(m,1H),2.63-2.16(m,4H),1.50(s,9H),1.35-1.26(m,3H).

[0659] Step c:

[0660] TFA (0.5 mL) was added to a stirred solution of (3S)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-yl]methyl]-2-methoxyacetamyl)butyric acid (140 mg, 0.26 mmol) in DCM (2 mL). The reaction was stirred for 1 h and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and TEA (0.11 mL, 1.082 mmol) and HATU (150 mg, 0.394 mmol) were added sequentially at room temperature. The resulting reaction was stirred for 1 h, diluted with water (50 mL), and extracted with EA (3 × 20 mL). The combined organic phases 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 with elution of 45% ACN in water (with 0.05% TFA) to provide (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a pale yellow oil. -5-one (70.0 mg, 58%): for C 19 H 24 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :415,417(3:2), actual measurement 415,417(3:2).

[0661] Step d:

[0662] At room temperature, (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza 5-one (70.0 mg, 0.17 mmol) was added dropwise to a stirred mixture in DCM (1 mL) with BBr3 (0.25 mL). The resulting mixture was stirred under nitrogen for 1 h. The reaction was quenched with MeOH (5 mL) at 0 °C. 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, 30 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 40% B over 7 min; detector: UV 220 nm; retention time: 7.03 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 94((3S,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diaza as a grayish-white solid. -5-keto)(17.7 mg, 27%): for C 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :387,389(3:2), actual measurement 387,389(3:2); 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.70-4.57(m,1H),4.41-4.25(m, 2H),4.26-3.69(m,5H),3.09-2.90(m,2H),2.78-2.53(m,2H),2.46-2.28(m,1H),1.36-1.24(m,3H).

[0663] Example 37. Compound 55 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide)

[0664]

[0665] Step a:

[0666] Trimethylsilyl isocyanate (17 mg, 0.14 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (intermediate 8 free base, Example 7) (30.0 mg, 0.10 mmol) and TEA (30.0 mg, 0.29 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 38% B over 8 min; detector: UV 220 nm; retention time: 6.40 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 55 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide) (17.0 mg, 47%) as a grayish-white solid: [C] 14 H 15 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :344,346(3:2), actual measurement 344,346(3:2); 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.48-4.27(m,3H),4.21-4.13(m,1H),3.96-3.87(m,1H) ,3.82(d,J=17.7Hz,1H),3.59(t,J=11.4,9.7Hz,1H),2.88(dd,J=13.2,10.5Hz,1H),2.45-2.42(m,1H),2.22-2.13(m,1H).

[0667] Example 38. Compounds 96-97 were prepared in a manner similar to that described for compound 55.

[0668]

[0669] Example 39. Compound 30 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-N,N-dimethyl-4-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-formamide)

[0670]

[0671] Step a:

[0672] N,N-diisopropylethylamine (150 mg, 1.15 mmol) and 4-nitrobenzene chloroformate (84.0 mg, 0.42 mmol) were added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide (intermediate 8, Example 7) (200 mg, 0.52 mmol) in DCM (2 mL). The resulting solution was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (20 mL) and then extracted with EA (3 × 20 mL). The combined organic phases 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 reversed-phase chromatography with elution of 45% ACN (with 0.05% TFA) in water to provide (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid 4-nitrobenzene ester (110 mg, 42%) as a pale yellow solid: against C 20 H 17 LCMS(ESI)[M+H] calculated using Cl2N3O6 + :466,468(3:2), actual measurement 466,468(3:2); 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.34(d,J=8.5Hz,2H),7.50(d,J=8.5Hz,2H),7.36(d,J=8.8Hz,1H),6.85(d,J=8.8 Hz, 1H), 4.57-4.09 (m, 3H), 4.09-3.81 (m, 3H), 3.49 (t, J = 10.4Hz, 1H), 3.05 (dt, J = 72.4, 11.8Hz, 1H), 2.31-2.08 (m, 2H).

[0673] Step b:

[0674] At room temperature, K₂CO₃ (18 mg, 0.13 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-carboxylic acid 4-nitrobenzene ester (30.0 mg, 0.06 mmol) and dimethylamine (9 mg, 0.19 mmol) in DMF (1 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction was filtered, and the filtrate was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 25% to 50% over 8 min; detector: UV 254 / 220 nm; retention time: 5.85 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 30 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-N,N-dimethyl-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide) (14.0 mg, 55.53%) as a grayish-white solid: [Reference to C] 16 H 19 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :372,374(3:2), actual measurement 372,374(3:2); 1 H NMR (400MHz, CD3OD) δ7.26(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),4.37-4.25(m,1H),4.19(dd,J=11.4,9.2Hz,1H),4.13-4.04 (m,2H),4.03-3.94(m,1H),3.85(d,J=17.6Hz,1H),3.60-3.52(m,1H),2.97-2.84(m,7H),2.39-2.36(m,1H),2.20-2.11(m,1H).

[0675] Example 40. Compounds 99-104 were prepared in a manner similar to that described for compound 30.

[0676]

[0677]

[0678]

[0679] Example 41. Compound 105 ((7S,9aR)-7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one isomer 1) and compound 106 ((7S,9aS)-7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one isomer 2)

[0680]

[0681] Step a:

[0682] At room temperature under a nitrogen atmosphere, Na₂CO₃ (2.10 g, 19.81 mmol) and Pd(dppf)Cl₂·CH₂Cl₂ (540 mg, 0.66 mmol) were added to a solution of 1,2-dichloro-3-iodo-4-methoxybenzene (2.00 g, 6.60 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-carboxynitrile (1.52 g, 6.60 mmol) in dioxane (20 mL) and H₂O (5 mL). The suspension was degassed under vacuum and purged three times under a nitrogen atmosphere. Subsequently, the reaction was stirred at 80 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (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 eluted with PE / EA (3 / 1) to provide 5-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carboxynitrile (1.50 g, 81%) as a yellow solid: against C 13 LCMS(ESI)[M+H] calculated using H8Cl2N2O + :279,281(3:2), actual measurement 279,281(3:2); 1 H NMR (400MHz, CDCl3) δ8.63 (dd, J=1.9, 1.1Hz, 1H), 7.83-7.75 (m, 2H), 7.54 (d, J=9.0Hz, 1H), 6.92 (d, J=9.0Hz, 1H), 3.77 (s, 3H).

[0683] Step b:

[0684] PtO2 (0.40 g, 1.76 mmol) was added to a stirred mixture of 5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-carboxynitrile (1.00 g, 3.58 mmol) in HCl (3.00 mL, 6 M) and MeOH (30 mL) at room temperature. The reaction mixture was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere (1.5 atm). The reaction was filtered and concentrated under reduced pressure to provide 1-[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methylamine (1.50 g, crude) as a pale yellow oil, which was used directly in the next step without further purification: [The text abruptly ends here, so the translation stops here as well.] 13 H 12 LCMS(ESI)[M+H] calculated using Cl2N2O + :283,285(3:2), actual measurement 283,285(3:2).

[0685] Step c:

[0686] Boc₂O (1.16 g, 5.30 mmol) was added to a solution of 1-[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methylamine (1.50 g, 5.30 mmol) in DCM (15 mL) and TEA (1.84 mL, 18.2 mmol) at room temperature. The reaction was stirred for 2 h, diluted with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (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 eluted with PE / EA (4 / 1) to provide N-[[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methyl]carbamate tert-butyl ester (0.80 g, 58% total for both steps) as a colorless oil: [C] 18 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :383,385(3:2), actual measurement 383,385(3:2); 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),7.61(dd,J=8.0,2.2Hz,1H),7.48(d,J=8.9Hz,1H),7.38(d,J=8.0 Hz, 1H), 6.89 (d, J = 9.0Hz, 1H), 5.65-5.60 (brs, 1H), 4.55 (d, J = 5.2Hz, 2H), 3.75 (s, 3H), 1.51 (s, 9H).

[0687] Step d:

[0688] Benzyl bromide (1.34 g, 7.85 mmol) was added to a solution of N-[[4-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methyl]carbamate tert-butyl ester (0.60 g, 1.57 mmol) in MeCN (15 mL) at room temperature. The reaction was stirred at 80 °C for 12 h. Subsequently, the reaction mixture was concentrated under reduced pressure to provide 1-benzyl-2-[[(tert-butoxycarbonyl)amino]methyl]-4-(2,3-dichloro-6-methoxyphenyl)pyridine-1-onium bromide (1.00 g, crude) as a light brown oil, which was used directly for the next step without purification: [The text abruptly ends here, so the translation stops here as well.] 25 H 27 LCMS (ESI) calculated from BrCl2N2O3 [M] + :473,475(3:2), actual measurement 473,475(3:2).

[0689] Step e:

[0690] NaBH4 (200 mg, 5.29 mmol) was added fractionally to a solution of 1-benzyl-2-[[(tert-butoxycarbonyl)amino]methyl]-5-(2,3-dichloro-6-methoxyphenyl)pyridine-1-onium bromide (1.00 g, 1.81 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 2 h. The resulting mixture was quenched with saturated aqueous NH4Cl solution (5 mL) and then 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 eluted with PE / EA (5 / 1) to provide N-[[1-benzyl-5-(2,3-dichloro-6-methoxyphenyl)-3,6-dihydro-2H-pyridin-2-yl]methyl]carbamate tert-butyl ester (300 mg, 40% by two steps) as a pale yellow oil: against C 25 H 30 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :477,479(3:2), actual measurement 477,479(3:2); 1 H NMR (400MHz, CDCl3) δ7.45-7.38(m,2H),7.37-7.26(m,4H),6.71(d,J=8.9Hz,1H),5.70(s,1H),5.25-5.20(brs,1H ),3.97-3.80(m,2H),3.76(s,3H),3.46-2.94(m,5H),2.52(d,J=18.1Hz,1H),2.05(d,J=14.4Hz,1H),1.49(s,9H).

[0691] Step f:

[0692] PtO2 (100 mg, 0.44 mmol) was added to a solution of N-[[1-benzyl-5-(2,3-dichloro-6-methoxyphenyl)-3,6-dihydro-2H-pyridin-2-yl]methyl]carbamate (300 mg, 0.63 mmol) in AcOH (20 mL) at room temperature. The reaction mixture was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at room temperature for 16 h under a hydrogen atmosphere (1.5 atm). The reaction was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) to provide N-[[5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (180 mg, 74%) as a pale yellow solid: [C] 18 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :389,391(3:2), actual measurement 389,391(3:2); 1 H NMR (400MHz, CDCl3) δ7.31-7.27(m,1H),6.74(dd,J=8.9,3.0Hz,1H),3.88-3.78(m,3H),3.59-3.42(m,2H), 3.37-3.30(m,1H),3.16-2.88(m,2H),2.88-2.60(m,1H),2.29-2.06(m,2H),1.87-1.50(m,2H),1.47(s,9H).

[0693] Step g:

[0694] At 0 °C, chloroacetyl chloride (57.0 mg, 0.51 mmol) was added to a solution of N-[[5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (180 mg, 0.46 mmol) and TEA (94.0 mg, 0.93 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 1 h, diluted with water (30 mL), and 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 provide N-[[1-(2-chloroacetyl)-5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (250 mg, crude) as a pale yellow oil, which was used directly for the next step without purification: C 20 H 27 LCMS(ESI)[M+H] calculated using Cl3N2O4 +:465,467(1:1), actual measurement 465,467(1:1).

[0695] Step h:

[0696] NaH (17.0 mg, 0.43 mmol, 60% in oil) was added to a solution of N-[[1-(2-chloroacetyl)-5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate tert-butyl ester (100 mg, 0.22 mmol) in DMF (2 mL) under a nitrogen atmosphere at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL), diluted with water (20 mL), and extracted with EA (2 × 20 mL). The combined organic phases 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 eluted with PE / EA (3 / 1) to provide tert-butyl 7-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (160 mg, 80% total for both steps) as a colorless oil: [C] 20 H 26 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :429,431(3:2), actual measurement 429,431(3:2).

[0697] Step i:

[0698] BBr3 (0.32 mL, 1.28 mmol) was added dropwise to a solution of 7-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (160 mg, 0.37 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with MeOH (3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 5% B to 30% B over 9 min; detector: UV 220 nm; retention time 1: 9.07 min, retention time 2: 9.42 min. The enantiomer, which eluted more rapidly at 9.07 minutes, was obtained, presenting as compound 105 as a grayish-white foam. (7S,9aR)- rel --7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)(30.0 mg, 26%): against C14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :315,317(3:2), measured 315,317(3:2). A slower-eluting enantiomer was obtained at 9.42 minutes, presenting as compound 106 (() as a grayish-white foam). 7S,9aS)-rel --7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)(30.0 mg, 26%): against C 14 H 16 LCMS(ESI)[M+H] calculated using Cl2N2O2 + :315,317(3:2), actual measurement 315,317(3:2).

[0699] Example 42. Compound 26 ((7S,9aR)-rel--7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one)

[0700]

[0701] To a stirred solution of glycolic acid (15.0 mg, 0.19 mmol), EDCI (46.0 mg, 0.24 mmol), and HOBT (32.0 mg, 0.24 mmol) in DMF (2 mL), (7S,9aR)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one (30.0 mg, 0.10 mmol) and TEA (39.0 mg, 0.38 mmol) were added at room temperature. The reaction was stirred at room temperature for 1 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 43% B over 7 min; detector: UV 220 nm; retention time: 6.68 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 26 as a grayish-white solid. (7S,9aR)-rel -7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one (10.2 mg, 29%): [The text abruptly ends here, likely due to an incomplete translation or a formatting error.] 16 H 18LCMS(ESI)[M+H] calculated using Cl2N2O4 + :373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.24(d,J=8.7Hz,1H),6.76(d,J=8.8Hz,1H),4.50-4.20(m,4H),4.20-4.07(m, 1H),4.07-3.82(m,3H),3.74-3.59(m,1H),3.31-3.08(m,1H),2.36-2.22(m,1H),1.98-1.81(m,3H).

[0702] Example 43. Compound 13 ((7S,9aS)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one)

[0703]

[0704] Add to a stirred solution of glycolic acid (15.0 mg, 0.19 mmol), EDCI (46.0 mg, 0.24 mmol), and HOBT (32.0 mg, 0.24 mmol) in DMF (2 mL) at room temperature. (7S,9aS)-rel -7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one (30.0 mg, 0.10 mmol) and TEA (39.0 mg, 0.38 mmol). The reaction was stirred at room temperature for 1 h, diluted with water (20 mL), and extracted with EA (3 × 10 mL). The combined organic phases were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 40% B over 7 min; detector: UV 220 nm; retention time: 6.30 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 13 as a grayish-white solid. (7S,9aS)-rel -7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one (10.2 mg, 29%): [The text abruptly ends here, likely due to an incomplete translation or a formatting error.] 16 H 18 LCMS(ESI)[M+H] calculated using Cl2N2O4 +:373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.23(d,J=8.8Hz,1H),6.74(d,J=8.8Hz,1H),4.51-4.40(m,1H),4.38-4.06(m, 4H),4.06-3.88(m,1H),3.74-3.39(m,4H),2.66-2.52(m,1H),2.01-1.74(m,2H),1.64-1.47(m,1H).

[0705] Example 44. Compounds 109-122 were prepared in a manner similar to the examples disclosed herein and / or in a manner similar to that known in the art.

[0706]

[0707]

[0708]

[0709]

[0710]

[0711] Example 45. Compound 123 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(3-hydroxycyclobutyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0712]

[0713] Step a:

[0714] At room temperature, NaBH(OAc)3 (0.113 g, 0.53 mmol) was added to a stirred mixture of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one HBr salt (intermediate 8, Example 7) (40.0 mg, 0.13 mmol), NaOAc (43.0 mg, 0.53 mmol), and 3-oxocyclobutyl acetate (51 mg, 0.40 mmol) in DCM (4 mL). The reaction was carried out for 4 h, quenched with saturated NH4Cl aqueous solution (30 mL), and 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 provide 3-[(7aR,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]cyclobutyl acetate (0.100 g, crude) as a grayish-white solid, which was used directly in the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 19 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O4 + :413,415(3:2), actual measurement 413,415(3:2).

[0715] Step b:

[0716] A mixture of 3-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]cyclobutyl ester (80.0 mg, 0.19 mmol) and K₂CO₃ (80.0 mg, 0.58 mmol) in MeOH (2 mL) was stirred for 2 h at room temperature. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 5% B to 35% B over 7 min; detector: UV 220 nm; retention time: 6.77 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide compound 123 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(3-hydroxycyclobutyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one) (23.4 mg, 33%) as a grayish-white solid. 17 H 20 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :371,373(3:2), actual measurement 371,373(3:2); 1H NMR (400MHz, CD3OD) δ7.29(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.54-4.34(m,1H),4.27-4.15(m,1H),4.16-3.98(m,3H),3.93(d ,J=11.5Hz,1H),3.77-3.54(m,2H),3.45-3.36(m,1H),3.13-2.96(m,1H),2.87-2.54(m,2H),2.49-2.43(m,1H),2.38-2.06(m,3H).

[0717] Example 46. Compounds 124-147 were prepared in a manner similar to that described for compound 123.

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] Example 47. Compound 148 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxy-2-methylpropyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0727]

[0728] 2,2-Dimethylethylene oxide (11.0 mg, 0.15 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (intermediate 8 free base, Example 7) (30.0 mg, 0.10 mmol) in EtOH (1 mL) at room temperature under nitrogen atmosphere. The resulting solution was stirred at 80 °C for 36 h, followed by concentration under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: X Bridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (with 10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 25% B to 45% B over 7 min; detector: UV 220 nm; retention time: 7.12 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxy-2-methylpropyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one (20 mg, 53%) as a grayish-white solid. 17 H 22 LCMS(ESI)[M+H] calculated using Cl2N2O3 + :373,375(3:2), actual measurement 373,375(3:2); 1 H NMR (400MHz, CD3OD) δ7.25 (d, J=8.8Hz, 1H), 6.75 (d, J=8.9Hz, 1H), 4.38-4. 24(m,1H),4.15(t,J=11.5Hz,1H),4.06-3.92(m,1H),3.64(d,J=17.0Hz,1H ),3.52(t,J=10.7Hz,1H),3.40(dd,J=11.8,3.8Hz,1H),3.05(d,J=17.1Hz, 1H),2.57-2.40(m,2H),2.40-2.22(m,2H),2.14-2.02(m,1H),1.24(s,6H).

[0729] Example 48. Compounds 149-159 were prepared in a manner similar to that described for compound 148.

[0730]

[0731]

[0732]

[0733]

[0734]

[0735] Example 49. Compound 160 (4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one isomer 1) and compound 161 (4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one isomer 2)

[0736]

[0737] Step a:

[0738] At room temperature, tert-butyl pyrrolidine-1-carboxylate (Example 7, step c) (0.500 g, 1.34 mmol) and 4-aminopyrrolidine-2-one (0.550 g, 4.01 mmol) in a stirred solution in DCM (10 mL) were added with TEA (0.540 g, 5.34 mmol) and NaBH(OAc)3 (1.13 g, 5.34 mmol). The reaction was stirred for 12 h, monitored by LCMS, quenched with saturated aqueous NH4Cl solution (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 reversed-phase chromatography with 75% ACN in water (with 10 mM NH4HCO3) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(5-oxopyrrolidone-3-yl)amino]methyl]pyrrolidone-1-carboxylic acid tert-butyl ester (0.450 g, 73%) as an off-white solid: [C] 21 H 29 LCMS(ESI)[M+H] calculated using Cl2N3O4 +:458,460(3:2), measured 458,460(3:2); H NMR (400MHz, CD3OD) δ 7.42(d,J=8.9Hz,1H),7.00(d,J=9.0Hz,1H),4.15-3.97(m,2H),3.89(s,3H),3.85-3.53(m,3H),3.26-3.14(m,1H),3.14-3.03(m,1H),2.81-2.72(m,1H),2.72-2.56(m,1H),2.54-2.40(m,1H),2.39-2.11(m,2H),1.83-1.64(m,1H),1.51(s,9H).

[0739] Step b:

[0740] At room temperature, tert-butyl pyrrolidine-1-carboxylate (0.150 g, 0.33 mmol) and ethyl bromoacetate (0.110 g, 0.65 mmol) in a stirred solution of ACN (5 mL) were added to K₂CO₃ (90.5 mg, 0.65 mmol). The reaction was stirred at 80 °C for 2 h. The cooled solution was diluted with EA (20 mL) and water (30 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of 29% ACN in water (with 0.05% TFA) to provide (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-ethoxy-2-oxoethyl)(5-oxopyrrolidine-3-yl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.120 g, 67%) as a colorless oil: [C] 25 H 35 LCMS(ESI)[M+H] calculated using Cl2N3O6 + :544,546(3:2), actual measurement 544,546(3:2); 1H NMR (400MHz, CD3OD) δ7.45(d,J=9.0Hz,1H),7.02(d,J=9.0Hz,1H),4.66(d,J=27.0Hz,1H),4.46(t,J=8.2Hz,1H),4.40-4.29(m,2H),4.29-4.04(m,3 H),3.90(s,3H),3.85-3.57(m,3H),3.57-3.41(m,2H),3.03-2.57(m,2H), 2.51-2.28(m,2H),1.83-1.61(m,1H),1.54(s,9H),1.36(t,J=6.9Hz,3H).

[0741] Step c:

[0742] A solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-ethoxy-2-oxoethyl)(5-oxopyrrolidine-3-yl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.120 g, 0.220 mmol) and TFA (1.50 mL, 1.346 mmol) in DCM (3.00 mL) was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was dissolved in EtOH (3.00 mL) and TEA (1.00 mL) was added. The solution was stirred at 80 °C for 2 hours. The cooled solution was diluted with EA (20 mL) and water (30 mL) and extracted with more EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(5-oxopyrrolidine-3-yl)hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (0.100 g, crude) as a yellow oil, which was used directly in the next step without purification: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 18 H 21 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :398,400(3:2), actual measurement 398,400(3:2).

[0743] Step d:

[0744] BBr3 (0.330 g, 1.32 mmol) was added to a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(5-oxopyrrolidine-3-yl)hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (0.100 g, 0.25 mmol) in DCM (2.00 mL). The reaction was stirred for 1 h. The mixture was quenched with MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% to 40% over 8 min; detector: UV 254 / 220 nm; retention time: 6.28 min. The fraction containing the desired product was collected and concentrated under reduced pressure to provide 4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one (31.0 mg, 36.47% total for both steps) as a grayish-white solid: [C] 17 H 19 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :384,386(3:2), actual measurement 384,386(3:2); 1 H NMR(400MHz, DMSO-d6)δ7.36(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.24-4.10(m,1H),4.07-3.85(m,4H),3.81- 3.69(m,1H),3.63-3.57(m,2H),3.51-3.38(m,2H),2.96(t,J=11.3Hz,1H),2.65-2.54(m,2H),2.26-2.08(m,2H).

[0745] Step e:

[0746] 4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one (30.0 mg, 0.08 mmol) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (with 0.2% IPA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 50% to 50% over 22 min; detector: UV 254 / 220 nm; retention time 1: 10.99 min; retention time 2: 17.77 min. A faster eluting isomer (6 mg, 20%) of compound 160 (4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one isomer 1) was obtained as a grayish-white solid at 10.99 min. 17 H 19 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :384,386(3:2), actual measurement 384,386(3:2); 1 H NMR(400MHz,CD3OD)δ7.25(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),4.40-4.25(m,1H),4.16(dd,J=11.6,8.9Hz,1H), 3.99-3.87(m,1H),3.60(dd,J=9.9,7.4Hz,1H),3.55-3.41(m,4H),3.36-3.34(m,1H),2.99(d,J=16.5Hz,1H),2.54(d d, J = 16.8, 8.1 Hz, 1H), 2.45–2.30 (m, 2H), 2.27 (dd, J = 11.5, 10.1 Hz, 1H), 2.18–2.09 (m, 1H); The slower eluting isomer of compound 161 (4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidine-2-one isomer 2) as a grayish-white solid was obtained at 17.77 min (4.7 mg, 15.67%): [C] 17 H 19 LCMS(ESI)[M+H] calculated using Cl2N3O3 + :384,386(3:2), actual measurement 384,386(3:2); 1H NMR(400MHz,CD3OD)δ7.25(d,J=8.8Hz,1H),6.76(d,J=8.7Hz,1H),4.37-4.24 (m,1H),4.16(dd,J=11.4,8.9Hz,1H),3.96-3.84(m,1H),3.61(dd,J=9.7,7.3H z,1H),3.57-3.41(m,3H),3.38-3.35(m,1H),3.28-3.21(m,1H),3.00(d,J=16 .6Hz,1H),2.54(dd,J=16.8,8.1Hz,1H),2.44-2.22(m,3H),2.17-2.09(m,1H).

[0747] Example 50. Compounds 162-167 were prepared in a manner similar to that described for compounds 160 and 161.

[0748]

[0749]

[0750] Example 51. Compound 168 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-[5-(hydroxymethyl)pyridin-2-yl]-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0751]

[0752] Step a:

[0753] A mixture of (7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (intermediate 13, Example 11) (0.150 g, 0.44 mmol), ethyl 6-chloropyridine-3-carboxylate (0.250 g, 1.32 mmol), and Cs₂CO₃ (0.720 g, 2.20 mmol) in DMSO (1 mL) was stirred at 100 °C for 12 h. The resulting mixture was diluted with water (20 mL) and DCM (20 mL) and extracted with more DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA / PE (1 / 1) to provide ethyl 6-[(7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyridine-3-carboxylate (0.160 g, 74%) as a pale yellow oil: [C] 24H 25 LCMS(ESI)[M+H] calculated using Cl2N3O4 + :490,492(3:2), actual measurement 490,492(3:2).

[0754] Step b:

[0755] A solution of ethyl...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in Y is C(R2)2, NR1, or O; Z is OH; X1 is H or a halogen; X2 is a halogen; X3 is a halogen; Each occurrence of R1 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, heteroalkyl, cyclohexaalkyl, heteroaryl, (CR6R7) n6 OR a (CR6R7) n6 N(R a 2. (C=O)R a (CR6R7) n6 (C=O)NR a R b , Or (CR6R7) n6 - Heterocyclic rings; Each occurrence of R2 is independently of H, CN, C1-C6 alkyl, cyclohexaalkyl, or (CR6R7). n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a 2. (C=O)R a (CR6R7) n6 (C=O)NR a R b Or heteroaryl, wherein each R2 may be connected to On any one of the carbon ring atoms; R3 is H; Each occurrence of R6 and R7 is independently H; R a and R b Each occurrence of is independently H, C1-C6 alkyl, C3-C7 cycloalkyl, or heterocyclic; or R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted heterocycles; R1, R2, R a and R b The alkyl, cycloalkyl, cyclohexyl, heterocyclic, and heteroaryl groups are each independently and optionally selected independently from 1-4 C1-C6 alkyl, C3-C7 cycloalkyl, halogen, CN, OR8, -(CH2) groups, where applicable. 1-2 OR8, N(R8)2, (C=O)R8 and oxo substituents are substituted where the valence state allows; Each occurrence of R8 is independently H or C1-C6 alkyl; n1 is an integer between 0 and 1; n² is an integer between 0 and 2; n 3' It is an integer between 0 and 2; n4 is an integer between 1 and 2; and n6 is an integer between 0 and 3. The heteroalkyl group referred to therein is a straight-chain or branched alkyl group having 2 to 12 carbons in the chain, wherein one or more carbons have been replaced by heteroatoms selected from S, O and N; The cyclohexaalkyl group refers to a 3- to 10-membered saturated monocyclic ring containing at least one heteroatom selected from nitrogen, sulfur, and oxygen. The heterocycle refers to a fully saturated cyclic group of 3 to 7 membered monocyclic rings, containing 1 to 3 heteroatoms each selected from N, O, and S; and The heteroaryl group refers to a 3- to 7-membered monocyclic aromatic group having at least one heteroatom selected from nitrogen, oxygen and sulfur atoms.

2. The compound of claim 1, wherein the structural portion have or The structure.

3. The compound of claim 1, wherein the structural moiety is... have or The structure.

4. The compound of claim 1, wherein the structural portion have or The structure.

5. The compound of claim 4, wherein the structural portion have or The structure.

6. The compound of claim 1, wherein the structural portion have or The structure.

7. The compound of claim 1, wherein the structural moiety is... have or The structure.

8. The compound of claim 6, wherein the structural portion have or The structure.

9. The compound of any one of claims 1-8, wherein R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, heteroalkyl, or cyclohexaalkyl.

10. The compound of any one of claims 1-8, wherein R1 is a heteroaryl group.

11. The compound of any one of claims 1-8, wherein R1 is (C=O)R a (CR6R7) n6 OR a (CR6R7) n6 N(R a 2. (CR6R7) n6 (C=O)NR a R b Or (CR6R7) n6 - Heterocyclic rings.

12. The compound of any one of claims 1-8, wherein R1 is (C=O)R a .

13. The compound of claim 11, wherein R a and R b Each is independently H, C1-C6 alkyl, or C1-C6 alkyl substituted with 1-4 substituents OR8.

14. The compound of any one of claims 1-8, wherein R1 is selected from H, -CH3, -(CH2)2OH, -(CH2)2NH2, -CONH2, -CONHMe, -CONMe2 and -CONEt2.

15. The compound of any one of claims 1-8, wherein R1 is selected from... 。 16. The compound of any one of claims 1-8, wherein R1 is selected from... 。 17. The compound of any one of claims 1-8, wherein R2 appears at least once as H, CN, C1-C6 alkyl, cyclohexane, OR a (C=O)R a (C=O)NR a R b Or mixed aryl groups.

18. The compound of any one of claims 1-8, wherein R2 occurs at least once in (CR6R7). n6 OR a (CR6R7) n6 - Heterocyclic, (C=O)R a (C=O)OR a (CR6R7) n6 NR a (C=O)R a (CR6R7) n6 N(R a )2 or (CR6R7) n6 (C=O)NR a R b .

19. The compound of claim 1, wherein R2 appears at least once as CH3, -CH2-OH, 。 20. The compound of any one of claims 1-8, wherein R2 appears at least once. 。 21. The compound of any one of claims 1-8, wherein at least one occurrence of R2 is a cyclohexane.

22. The compound of any one of claims 1-8, wherein n1 is 0.

23. The compound of any one of claims 1-8, wherein n1 is 1.

24. The compound of any one of claims 1-8, wherein n2 is 0 or 1.

25. The compound of any one of claims 1-8, wherein n3 is 0, 1 or 2.

26. The compound of any one of claims 1-8, wherein n4 is 1.

27. The compound of any one of claims 1-8, wherein n6 is 0, 1 or 2.

28. The compound of claim 1, wherein X1 is H, F, Cl or Br.

29. The compound of claim 28, wherein X1 is H or Cl.

30. The compound of claim 1, wherein X2 is F, Cl or Br.

31. The compound of claim 30, wherein X2 is Cl.

32. The compound of any one of claims 1-8, wherein X3 is F, Cl or Br.

33. The compound of claim 32, wherein X3 is Cl.

34. The compound of any one of claims 1-8, wherein the structural moiety have , , , , or The structure.

35. The compound of any one of claims 1-8, wherein R a or R b It appears at least once independently as H, C1-C6 alkyl, C3-C7 cycloalkyl or heterocyclic.

36. The compound of claim 35, wherein R a or R b The at least one occurrence of is independently H, Me, Et, Pr, or selected from , , , , , , , , , , and The heterocycle; wherein the heterocycle is optionally converted by C1-C6 alkyl, OH, oxo, or (C=O)C 1-4 Alkyl groups are substituted where the valence state allows.

37. The compound of any one of claims 1-8, wherein R a and R b Together with the nitrogen atoms to which they are attached, they form optional substituted heterocycles containing a nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

38. The compound of claim 1, wherein the heterocycle is selected from... , , , , , , , , , , and .

39. A compound, wherein the compound is selected from the group consisting of compounds 1-62:

40. A compound, wherein the compound is selected from the group consisting of:

41. A pharmaceutical composition comprising at least one compound according to any one of claims 1-40 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

42. Use of a therapeutically effective amount of at least one compound of any one of claims 1-40 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition by blocking the Kv1.3 potassium channel in a mammalian species in which such condition is desired, wherein the condition is selected from cancer, immunological conditions, central nervous system (CNS) conditions, inflammatory conditions, gastrointestinal conditions, metabolic conditions, cardiovascular conditions, and kidney diseases.

43. The use of claim 42, wherein the immunological condition is transplant rejection or an autoimmune disease.

44. The use of claim 43, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

45. The use of claim 42, wherein the central nervous system condition is Alzheimer's disease.

46. ​​The use of claim 42, wherein the inflammatory condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neurological disease.

47. The use of claim 42, wherein the gastrointestinal disease is inflammatory bowel disease.

48. The use of claim 42, wherein the metabolic disorder is obesity or type II diabetes.

49. The use of claim 42, wherein the cardiovascular condition is ischemic stroke.

50. The use of claim 42, wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

51. The use of claim 42, wherein the condition is selected from cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin diseases, inflammatory neurological diseases, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

52. The use of claim 42, wherein the mammal species is human.

53. Use of a therapeutically effective amount of at least one compound according to any one of claims 1-40 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for blocking the Kv1.3 potassium channel in mammalian species in which this is desired.

54. The use of claim 53, wherein the mammal species is human.

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