Aryl heterobicyclic compounds as Kv1.3 potassium shaker channel blockers

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof are described, wherein the substituents are as defined herein. Pharmaceutical compositions containing the compounds and methods of using them are also described. [Formula 1] JPEG2022551199000290.jpg4349

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 911,648, filed October 7, 2019, the entire contents of which are incorporated herein by reference.

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights whatsoever.

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

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

[0005] Voltage-gated Kv1.3 potassium (K +Kv1.3 channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, regulating numerous physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels regulate membrane potential, thereby indirectly affecting calcium signaling in human effector memory T cells ("TEMs"). TEMs are mediators of several conditions, including multiple sclerosis ("MS"), type 1 diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. Upon activation, TEMs increase Kv1.3 channel expression. Among human B cells, naive and early memory B cells express low numbers of Kv1.3 channels when resting. In contrast, class-switched memory B cells express high numbers of Kv1.3 channels. Furthermore, Kv1.3 channels promote calcium homeostasis, which is necessary for T cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol., 565-569). Blockade of Kv1.3 channels in effector memory T cells suppresses activities such as calcium signaling, cytokine production (e.g., interferon-gamma, interleukin-2), and cell proliferation.

[0006] Autoimmune diseases are a family of disorders resulting from tissue damage caused by attacks from the body's own immune system. Such diseases can affect a single organ, as in MS and type 1 diabetes, or can involve multiple organs, as in rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative, using anti-inflammatory and immunosuppressive drugs that can have severe side effects. The need for more effective treatments has led to the search for drugs that can selectively inhibit the function of TEMs, which are known to be involved in the pathogenesis of autoimmune diseases. These inhibitors are thought to be able to ameliorate autoimmune disease symptoms without compromising protective immune responses. TEMs express numerous Kv1.3 channels and depend on these channels for their function. In vivo, Kv1.3 channel blockers paralyze TEMs at sites of inflammation and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the motility of naive and central memory T cells within lymph nodes. Inhibition of the function of these cells by selectively blocking Kv1.3 channels offers the potential for effective treatment of autoimmune diseases with minimal side effects.

[0007] MS is caused by autoimmune damage to the central nervous system ("CNS"). Symptoms include muscle weakness and paralysis, which severely impact the quality of life for patients. MS progresses rapidly, unpredictably, and ultimately leads to death. Kv1.3 channels are also highly expressed in autoreactive TEMs of MS patients (Wulff H., et al., 2003, J. Clin. Invest., 1703-1713; Rus H., et al., 2005, PNAS, 11094-11099). Animal models of MS have been successfully treated using blockers of Kv1.3 channels.

[0008] Therefore, the compound that is selective Kv1.3 channel blocker is a potential therapeutic agent as immunosuppressant or immune system modulator.Kv1.3 channel is also considered as a therapeutic target for treating obesity and enhancing peripheral insulin sensitivity in patients with type 2 diabetes.These compounds can also be used to prevent transplant rejection and treat immunological (for example, autoimmune) and inflammatory disorders.

[0009] Tubulointerstitial fibrosis (TIF) is a progressive connective tissue deposition in the renal parenchyma that leads to the deterioration of renal function. It is involved in the pathology of chronic kidney disease, chronic renal failure, nephritis, and glomerular inflammation, and is a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes is involved in the underlying pathology of these kidney diseases and can promote proliferation, leading to chronic inflammation and excessive stimulation of cell-mediated immunity, which are contributing factors in the progression of tubulointerstitial fibrosis. Inhibition of lymphocyte Kv1.3 channel currents suppresses renal lymphocyte proliferation and ameliorates the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm., 1-12).

[0010] Kv1.3 channels also play a role in gastroenterological disorders, including inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC can impair quality of life and lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients are associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are thought to serve as a marker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy in UC. Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNFα 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 be the result of intestinal inflammation via a T cell-driven process initiated by normally harmless bacteria, and therefore Kv1.3 channel inhibition could be used to treat Crohn's disease.

[0011] In addition to T cells, Kv1.3 channels are also expressed in microglia, where they are involved in inflammatory cytokine and nitric oxide production and microglia-mediated neuronal death. In humans, strong Kv1.3 channel expression is found in microglia in the frontal cortex of patients with Alzheimer's disease and in CD68 in multiple sclerosis brain lesions. + It has been observed in cells. It has been suggested that Kv1.3 channel blockers can preferentially target detrimental pro-inflammatory microglial function. Kv1.3 channels are expressed on activated microglia in infarcted rodent and human brains. Higher Kv1.3 channel current density is observed in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere in a mouse model of stroke (Chen YJ, et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0012] Kv1.3 channel expression is elevated in microglia in human Alzheimer's disease brains, suggesting that Kv1.3 channels are a pathologically relevant microglial target in Alzheimer's disease (Rangaraju S., et al., 2015, J. Alzheimers Dis., 797-808). Soluble AβOs enhance microglial Kv1.3 channel activity. Kv1.3 channels are required for AβO-induced microglial proinflammatory activation and neurotoxicity. Kv1.3 channel expression / activity is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of microglial Kv1.3 channels 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.

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

[0014] Kv1.3 channel expression is associated with the regulation of proliferation, apoptosis, and cell survival in multiple cell types. These processes are crucial for cancer progression. In this context, Kv1.3 channels located in the inner mitochondrial membrane can interact with the apoptosis regulator Bax (Serrano-Albarras, A., et al., 2018, Expert Opin. Ther. Targets, 101-105). Therefore, inhibitors of Kv1.3 channels can be used as anticancer drugs.

[0015] Several peptide toxins with multiple disulfide bonds derived from spiders, scorpions, and sea anemones are known to block Kv1.3 channels. A few selective and potent peptide inhibitors of Kv1.3 channels have been developed. A synthetic derivative of stichodactyla toxin ("shk") with an unnatural amino acid (shk-186) is the most advanced peptide toxin. Shk has demonstrated efficacy in preclinical models and is currently in phase I clinical trials for the treatment of psoriasis. Shk can inhibit the growth of TEMs and improve the condition in animal models of MS. Unfortunately, Shk also binds to the closely related Kvi channel subtype found in the CNS and heart. To avoid potential cardiotoxicity and neurotoxicity, selective Kv1.3 channel inhibitors are needed. Furthermore, small peptides such as shk-186 are rapidly eliminated from the body after administration, resulting in a short circulatory half-life and frequent dosing events. Therefore, there is a need for the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases. Summary of the Invention [Problem to be solved by the invention]

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

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

[0018] [ka] wherein the various substituents are defined herein. Compounds of formula I described herein are useful as potassium channel blockers having the formula: +) channels and can be used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have several clinical uses, including as pharmaceutically active agents and in methods of treating cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, renal disease, or a combination thereof.

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

[0020] [ka] (In the formula, Y is C(R2)2, NR1, or O; Z is OR a and; X1 is H, halogen, or alkyl; X2 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; X3 is H, halogen, alkyl halide, or alkyl; or X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; Each occurrence of R is independently H, alkyl, alkenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, (CR6R7) n6 OR a , (CR6R7) n6 N(R a )2, (C=O)R a , (C=O)OR a , (CR6R7) n6 (C=O)NRa R b , SO2R a or (CR6R7) n6 -heterocyclic; Each occurrence of R2 is independently H, halogen, CN, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, (CR6R7) n6 OR a , (CR6R7) n6 -Heterocycle, (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, and each R2 is

[0021] [ka] may be attached to any one of the carbon ring atoms; R3 is H, alkyl, or halogen; each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R a and R b each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle; The heterocycle contains 1 to 3 heteroatoms each selected from the group consisting of N, O, and S; X1, X2, X3, R1, R2, R3, R6, R7, R, if applicable a , and R b The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, R, OR, -(CH) 1~2 each independently optionally substituted with 1 to 4 substituents independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; each occurrence of R8 is independently H, alkyl, cycloalkyl, or a heterocycle optionally substituted with alkyl; or two R8 groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; n1 is an integer from 0 to 1; n2 is an integer from 0 to 2; n3 is an integer from 0 to 3; n4 is an integer from 1 to 2; n6 is an integer between 0 and 3. is described.

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

[0023] [ka] but,

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

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

[0026] [ka] but,

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

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

[0029] [ka] but,

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

[0031] In any one of the embodiments described herein, the structural moiety

[0032] [ka] but,

[0033] [ka] It has the following structure.

[0034] In any one of the embodiments described herein, the structural moiety

[0035] [ka] but,

[0036] [ka] It has the following structure.

[0037] In any one of the embodiments described herein, the structural moiety

[0038] [ka] but,

[0039] [ka] It has the following structure.

[0040] In any one of the embodiments described herein, the structural moiety

[0041] [ka] but,

[0042] [ka] It has the following structure.

[0043] In any one of the embodiments described herein, R1 is H, alkyl, alkenyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl.

[0044] In any one of the embodiments described herein, R1 is aryl or heteroaryl.

[0045] In any one 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 ring.

[0046] In any one of the embodiments described herein, R1 is (C=O)R a is.

[0047] In any one of the embodiments described herein, R a and R b are each independently H, alkyl, or alkyl substituted with one or more OR8.

[0048] In any one of the embodiments described herein, R8 is H or alkyl.

[0049] In any one of the embodiments described herein, R1 is selected from the group consisting of H, -CH3, -(CH2)2OH, -(CH2)2NH2, -CONH2, -CONHMe, -CONMe2, -CONEt2, SO2Me, and SO2Et.

[0050] In any one of the embodiments described herein, R1 is H,

[0051] [ka] is selected from the group consisting of:

[0052] In any one of the embodiments described herein, R1 is

[0053] [ka] is selected from the group consisting of:

[0054] In any one of the embodiments described herein, at least one occurrence of R2 is H, halogen, CN, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, OR a , N(R1)2, (C=O)R a , (C=O)NR a R b , aryl, or heteroaryl.

[0055] In any one of the embodiments described herein, at least one occurrence of R2 is (CR6R7) n6 OR a , (CR6R7) n6 -heterocycle, (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 is.

[0056] In any one of the embodiments described herein, at least one occurrence of R2 is CH3, -CH2-OH, -CH2-CH2-OH, -CH(OH)-CH3, -CH2-NH2,

[0057] [ka] is.

[0058] In any one of the embodiments described herein, at least one occurrence of R2 is heteroalkyl, cycloheteroalkyl,

[0059] [ka] is.

[0060] In any one of the embodiments described herein, n1 is 0.

[0061] In any one of the embodiments described herein, n1 is 1.

[0062] In any one of the embodiments described herein, n2 is 0 or 1.

[0063] In any one of the embodiments described herein, n3 is 0, 1, or 2.

[0064] In any one of the embodiments described herein, n4 is 1.

[0065] In any one of the embodiments described herein, n6 is 0, 1, or 2.

[0066] In any one of the embodiments described herein, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or OBu.

[0067] In any one of the embodiments described herein, Z is OH, OMe, or OEt.

[0068] In any one of the embodiments described herein, Z is OH.

[0069] In any one of the embodiments described herein, X 1 is H, halogen, Me, or Et.

[0070] In any one of the embodiments described herein, X 1 is H, F, Cl, Br, or Me.

[0071] In any one of the embodiments described herein, X 1 is H or Cl.

[0072] In any one of the embodiments described herein, X2 is H, halogen, fluorinated alkyl, or alkyl.

[0073] In any one of the embodiments described herein, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0074] In any one of the embodiments described herein, X2 is H or Cl.

[0075] In any one of the embodiments described herein, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3.

[0076] In any one of the embodiments described herein, X3 is H or Cl.

[0077] In any one of the embodiments described herein, R3 is H.

[0078] In any one of the embodiments described herein, R3 is alkyl.

[0079] In any one of the embodiments described herein, R3 is halogen.

[0080] In any one of the embodiments described herein, R3 is H, F, Cl, or Me.

[0081] In any one of the embodiments described herein, the structural moiety

[0082] [ka] but,

[0083] [ka] It has the following structure.

[0084] In any one of the embodiments described herein, the compound has the structure of Formula II' or II:

[0085] [ka] (In the formula, R 3’ are independently H, halogen, or alkyl; n5 is an integer between 0 and 3. It has.

[0086] In any one of the embodiments described herein, n5 is 0, 1, or 2.

[0087] In any one of the embodiments described herein, n5 is 0.

[0088] In any one of the embodiments described herein, R 3’ is H or alkyl.

[0089] In any one of the embodiments described herein, R 3’ is a halogen.

[0090] In any one of the embodiments described herein, Z is OH, OMe, OEt, OPr, Oi-Pr, Ot-Bu, O-iso-Bu, O-sec-Bu, or OBu.

[0091] In any one of the embodiments described herein, Z is OH, OMe, or OEt.

[0092] In any one of the embodiments described herein, Z is OH.

[0093] In any one of the embodiments described herein, R a or R b At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0094] In any one of the embodiments described herein, R a or R bat least one occurrence of independently is H, Me, Et, Pr, or

[0095] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0096] In any one of the embodiments described herein, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0097] In any one of the embodiments described herein, the heterocycle

[0098] [ka] is selected from the group consisting of:

[0099] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-62 shown in Table 4.

[0100] In any one of the embodiments described herein, the compound is selected from the group consisting of 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.

[0101] In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0102] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising the step of administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0103] In any one of the embodiments described herein, the immunological disorder is transplant rejection or an autoimmune disease.

[0104] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0105] In any one of the embodiments described herein, the central nervous system disorder is Alzheimer's disease.

[0106] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0107] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease.

[0108] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0109] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0110] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0111] In any one of the embodiments described herein, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0112] In any one of the embodiments described herein, the mammalian species is human.

[0113] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof.

[0114] In any one of the embodiments described herein, the mammalian species is human.

[0115] Any one of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein.The combination of any one of the embodiments disclosed herein with any other embodiment disclosed herein is expressly contemplated.In particular, the selection of one or more embodiments for a certain substituent can be appropriately combined with the selection of one or more specific embodiments for any other substituent.Such combinations can be made with any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION OF THE INVENTION

[0116] definition The following are definitions of terms used herein. Unless otherwise specified, the initial definition provided for a group or term herein applies to that group or term throughout the specification, whether individually or as part of another group. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0117] The terms "alkyl" and "alk" refer to straight- or branched-chain 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, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(C1-C4) alkyl" refers to straight- or branched-chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e, S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, and R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0118] The term "heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 12 carbons, and more preferably 2 to 10 carbons, in the chain, one or more of which are replaced by a heteroatom selected from the group consisting of S, O, P, and N. Exemplary heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like. The group can be a terminal group or a bridging group.

[0119] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C2-C6 alkenyl" includes ethylenyl, 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-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-1 ... "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hexa-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group having a single halogen substituent or multiple halogen substituents, such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2Re , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0120] The term "alkynyl" refers to a straight- or branched-chain 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- or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e each occurrence is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.) The exemplary substituents themselves can be optionally substituted.

[0121] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2Re , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0122] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom, preferably 1 to 3 heteroatoms, selected from the group consisting of nitrogen, sulfur, and oxygen, in at least one ring. Each ring preferably has 3 to 10 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include, but are not limited to, pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group.

[0123] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), cyano, nitro, oxo (i.e., ═O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. bC(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0124] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. When containing two or more aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, in which two adjacent aromatic rings share two carbon atoms. "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF3 or CCl3, in the latter case), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. dS(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e (each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0125] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the aryl or heteroaryl ring size of the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0126] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring, or a cyclic aromatic hydrocarbon group having one to five aromatic rings, such as phenyl, biphenyl, or naphthyl, particularly a monocyclic or bicyclic group. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl, as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably one to four substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves may be optionally substituted.

[0127] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) containing aromatic (i.e., "heteroaryl") groups, having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group can independently be saturated, or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, with the nitrogen and sulfur heteroatoms optionally being oxidized and the nitrogen heteroatom optionally being quaternized. The term "heteroarylium" refers to a heteroaryl group bearing a quaternary nitrogen atom, and thus a positive charge. A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, and the like. nyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, and the like.Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, Included are benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0128] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =0), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2Re , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R eis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0129] The term "oxo" refers to a ring that may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring.

[0130] [ka] When an oxo substituent is attached to a carbon ring atom on an aromatic group, such as an aryl or heteroaryl, the bonds on the aromatic ring can be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent is

[0131] [ka] may have the structure

[0132] [ka] Also included are the tautomeric forms thereof:

[0133] 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, iso-propylamino, cyclopropylamino, n-butylamino, t-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0134] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined herein. R and R' can be the same or different dialkylamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(t-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0135] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0136] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group disclosed herein, or any other group) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl), in the latter case, cyano, nitro, oxo (i.e., ═O), CF, OCF, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. bC(=O)R a , or NR b P(=O)2R e (In the formula, R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocyclic ring together with the N to which they are attached; R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) may or may not be substituted with one or more of the substituents described above.

[0137] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0138] The compounds of the present invention can form salts that are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise indicated. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid or a phenol, zwitterions ("internal salts") may be formed and are included in the term "salt" as used herein. Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with an equivalent amount of acid or base in a medium, such as a medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0139] Compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acids; e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. Salts include sulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0140] The compounds of the present invention that contain an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary base salts include ammonium salts, alkali metal salts, such as sodium, lithium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, and t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0141] Prodrugs and solvates of the compounds of the present invention are also contemplated herein.The term "prodrug" as used herein refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce the compounds of the present invention, or their salts and / or solvates.Solvates of the compounds of the present invention include, for example, hydrates.

[0142] The compounds of the present invention, and their salts or solvates, may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric form.

[0143] All stereoisomers of the present compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms on various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the present compounds may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), e.g., as racemates, or admixed with all other or selected stereoisomers. Chiral centers of the present invention may have the S or R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.

[0144] After preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing 90% by weight or more, e.g., 95% by weight or more, 99% by weight or more of the compound (a "substantially pure" compound), which are then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also contemplated herein as part of the present invention.

[0145] All configurational isomers of the compounds of the invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the invention encompasses both cis (Z) and trans (E) alkene isomers, as well as both cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0146] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0147] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999).

[0148] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates 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 being within the scope of the present 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 the present invention.

[0149] Isomeric mixtures containing any of a variety of isomer ratios can be utilized by the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0150] The present invention also includes isotopically labeled compounds identical to the compounds disclosed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, that contain the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., 3 H and 14 Those in which a radioactive isotope, such as 1C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes such as H can confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0151] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with an asymmetric auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0152] It is understood that the compounds described herein can be substituted with any number of substituents or functional moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, and whether the substituent is included in the formula of the invention, refers to the replacement of a hydrogen radical in a given structure with the radical of the specified substituent. When more than one position in any given structure can be substituted with more than one substituent selected from the specified group, the substituents can be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. As used herein, the term "stable" refers to compounds that preferably have sufficient stability to permit manufacture and maintain compound integrity for a period of time sufficient to be detected, preferably to be useful for the purposes detailed herein.

[0153] As used herein, the terms "cancer," and equivalently, "tumor," refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; and thyroid cancer; as well as other carcinomas and sarcomas. Cancer can be primary or metastatic. Because diseases other than cancer can be associated with mutational changes in components of the Ras signaling pathway, the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases may include neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0154] As used herein, "effective amount" refers to any amount that is necessary or sufficient to achieve or promote a desired outcome.In some instances, an effective amount is a therapeutically effective amount.A therapeutically effective amount is any amount that is necessary or sufficient to promote or achieve a desired biological response in a subject.The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific drug being administered, the size of the subject, or the severity of the disease or condition.Those skilled in the art can empirically determine the effective amount of a particular drug without undue experimentation.

[0155] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, domestic animals, and non-domestic animals.

[0156] compound Novel compounds are described as Kv1.3 potassium channel blockers. Applicants have surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, applicants have surprisingly discovered that the compounds disclosed herein selectively block Kv1.3 potassium channels and do not block hERG channels, and therefore have desirable cardiovascular safety profiles.

[0157] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof

[0158] [ka] (In the formula, Y is C(R2)2, NR1, or O; Z is OR a and; X1 is H, halogen, or alkyl; X2 is H, halogen, CN, alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; X3 is H, halogen, alkyl halide, or alkyl; or X1 and X2 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; or X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl; Each occurrence of R is independently H, alkyl, alkenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, 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; Each occurrence of R2 is independently H, halogen, CN, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, (CR6R7) n6 OR a , (CR6R7) n6 -heterocycle, (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, and each R2 is

[0159] [ka] may be attached to any one of the carbon ring atoms; R3 is H, alkyl, or halogen; each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Ra and R b each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle; The heterocycle contains 1 to 3 heteroatoms each selected from the group consisting of N, O, and S; X1, X2, X3, R1, R2, R3, R6, R7, R, if applicable a , and R b The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, R, OR, -(CH) 1~2 each independently optionally substituted with 1 to 4 substituents independently selected from the group consisting of OR, N(R), (C=O)R, (C=O)N(R), NR(C=O)R, and oxo; each occurrence of R8 is independently H, alkyl, cycloalkyl, or a heterocycle optionally substituted with alkyl; or two R8 groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; n1 is an integer from 0 to 1; n2 is an integer from 0 to 2; n3 is an integer from 0 to 3; n4 is an integer from 1 to 2; n6 is an integer between 0 and 3. is described.

[0160] In some embodiments, the structural moiety

[0161] [ka] but,

[0162] [ka] In some specific embodiments, the structural moiety

[0163] [ka] but,

[0164] [ka] It has the following structure.

[0165] In some embodiments, the structural moiety

[0166] [ka] but,

[0167] [ka] In some specific embodiments, the structural moiety

[0168] [ka] but,

[0169] [ka] It has the following structure.

[0170] In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, n2 is an integer from 0 to 2. In some embodiments, n2 is an integer from 1 to 2. In some embodiments, n2 is 0. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 1.

[0171] In some embodiments, the structural moiety

[0172] [ka] but,

[0173] [ka] In some embodiments, the structural moiety

[0174] [ka] but,

[0175] [ka] It has the following structure.

[0176] In some embodiments, the structural moiety

[0177] [ka] but,

[0178] [ka] In some embodiments, the structural moiety

[0179] [ka] but,

[0180] [ka] It has the following structure.

[0181] In some embodiments, Y is C(R2)2. In other embodiments, Y is NR1. In still other embodiments, Y is O.

[0182] In some embodiments, the structural moiety

[0183] [ka] but,

[0184] [ka] In some specific embodiments, the structural moiety

[0185] [ka] but,

[0186] [ka] In some specific embodiments, the structural moiety

[0187] [ka] but,

[0188] [ka] In some specific embodiments, the structural moiety

[0189] [ka] but,

[0190] [ka] In some specific embodiments, the structural moiety

[0191] [ka] but,

[0192] [ka] It has the following structure.

[0193] In some specific embodiments, the structural moiety

[0194] [ka] but,

[0195] [ka] In some specific embodiments, the structural moiety

[0196] [ka] but,

[0197] [ka] In some embodiments, the structural moiety

[0198] [ka] but,

[0199] [ka] In some embodiments, the structural moiety

[0200] [ka] but,

[0201] [ka] In some embodiments, the structural moiety

[0202] [ka] but,

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

[0204] In some embodiments, R 1 is H, alkyl, alkenyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl.

[0205] In some embodiments, R1 is H. In some embodiments, R1 is alkyl, such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In other embodiments, R1 is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0206] In some embodiments, R is heteroalkyl. In some specific embodiments, R is an alkyl ether, secondary or tertiary alkylamine, or alkyl sulfide, such as -CH-CH-OMe, -CH-CH-OEt, -CH-CH-OPr, -CH-CH-SMe, -CH-CH-SEt, -CH-CH-SPr, -CH-CH-NHMe, -CH-CH-NMe, -CH-CH-NEtMe, or -CH-CH-NEt. In some embodiments, R is cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane.

[0207] In some embodiments, R is aryl or heteroaryl. In some embodiments, R 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 In some embodiments, R1 is (CR6R7) n6 (C=O)NR a R b , SO2R a or (CR6R7) n6 In some specific embodiments, R is (C=O)R a In some specific embodiments, R a and R b are each independently H, alkyl, or alkyl substituted with one or more OR8. In some specific embodiments, R8 is H or alkyl.

[0208] In some embodiments, R1 is selected from the group consisting of H, -CH3, -(CH2)2OH, -(CH2)2NH2, -CONH2, -CONHMe, -CONMe2, -CONEt2, SO2Me, or SO2Et.

[0209] [ka] In yet another embodiment, R1 is selected from the group consisting of

[0210] [ka] is selected from the group consisting of:

[0211] In some embodiments, at least one occurrence of R2 is H, CN, alkyl, heteroalkyl, cycloalkyl, or cycloheteroalkyl. In some embodiments, at least one occurrence of R2 is H. In some embodiments, at least one occurrence of R2 is alkyl, such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In other embodiments, at least one occurrence of R2 is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, at least one occurrence of R2 is aryl or heteroaryl.

[0212] In some embodiments, at least one occurrence of R2 is (CR6R7) n6 OR a , (CR6R7) n6 -heterocycle, (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 embodiments, each R2 is

[0213] [ka] In some specific embodiments, at least one occurrence of R2 is -CH3, -CH2-OH, -CH2-CH2-OH, -CH(OH)-CH3, -CH2-NH2,

[0214] [ka] is.

[0215] In some embodiments, at least one occurrence of R2 is OR a In some embodiments, at least one occurrence of R is N(R). In some embodiments, at least one occurrence of R is (C=O)R. a In some embodiments, at least one occurrence of R2 is (C=O)NR a R b In some embodiments, at least one occurrence of R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, at least one occurrence of R2 is heteroalkyl or cycloheteroalkyl. In some embodiments, R2 is heteroalkyl. In some specific embodiments, R2 is an alkyl ether, secondary and tertiary alkyl amine, or 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 cycloheteroalkyl. Non-limiting examples of cycloheteroalkyl include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepane, 1,4-diazepane, 1,4-oxazepane, and 1,4-oxathiapane. In some embodiments, at least one occurrence of R2 is

[0216] [ka] is.

[0217] In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n3 is 0, 1, 2, or 3. In some embodiments, n3 is 0. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n4 is 1. In some embodiments, n4 is 2. In some embodiments, n6 is 0. In some embodiments, n6 is 1. In some embodiments, n6 is 2. In some embodiments, n6 is 3.

[0218] In some embodiments, R8 is H or alkyl. 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 containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0219] In some embodiments, 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.

[0220] In some embodiments, X1 is H, halogen, or alkyl. In any one of the embodiments described herein, X1 can be H or alkyl. In some embodiments, X1 is Me, Et, Pr, i-Pr, or Bu. In some embodiments, X1 is H or halogen. In other embodiments, X1 is alkyl. 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 H or Cl. In some embodiments, X1 is F. In some embodiments, X1 is H.

[0221] In some embodiments, X2 is H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl. In any one of the embodiments described herein, X2 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X2 is H or halogen. In other embodiments, X2 is fluorinated alkyl or alkyl. In other embodiments, X2 is cycloalkyl. In some embodiments, X2 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is H or Cl. In some embodiments, X2 is F. In some embodiments, X2 is CF3. In some embodiments, X2 is CF2Cl. In some embodiments, X2 is Cl.

[0222] In some embodiments, X3 is H, halogen, alkyl, or halogenated alkyl. In any one of the embodiments described herein, X3 can be H, halogen, fluorinated alkyl, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is fluorinated alkyl or alkyl. In some embodiments, X3 is H, F, Cl, Br, Me, CF2H, CF2Cl, or CF3. In some embodiments, X3 is H, F, or Cl. In some embodiments, X3 is F or Cl. In some embodiments, X3 is H or Cl. In some embodiments, X3 is F. In some embodiments, X3 is CF3. In some embodiments, X3 is CF2Cl. In some embodiments, X3 is Cl.

[0223] In some embodiments, the structural moiety

[0224] [ka] but,

[0225] [ka] It has the following structure.

[0226] In any one of the embodiments described herein, R3 is H, alkyl, or halogen. In some embodiments, R3 is halogen. In some embodiments, R3 is H, halogen, or alkyl. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, and sec-butyl. In some embodiments, R3 is H.

[0227] In some embodiments, the compound of formula I has the structure of formula II' or II.

[0228] [ka] (In the formula, R 3’ each occurrence of is independently H, halogen, or alkyl, n5 is an integer from 0 to 3, and other substituents are as defined herein. It has.

[0229] In some embodiments, 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.

[0230] In some embodiments, n5 is an integer from 0 to 3. In some embodiments, n5 is an integer from 1 to 3. In some embodiments, n5 is 0. In some embodiments, n5 is 1 or 2. In some embodiments, n5 is 1. In some embodiments, R 3’ is H or alkyl. In some embodiments, R 3’ is H. In some embodiments, R 3’ is alkyl. In some embodiments, R 3’ is a halogen.

[0231] In any one of the embodiments described herein, R a or R b is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. a or R b is independently H, Me, Et, Pr, or Bu. a or R b At least one occurrence of independently

[0232] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C 1~4 Optionally substituted with alkyl.

[0233] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0234] In some embodiments, the heterocycle is

[0235] [ka] is selected from the group consisting of:

[0236] In some embodiments, the compound of formula I is selected from the group consisting of compounds 1-62 shown in Table 4 below.

[0237] In some embodiments, the compound of Formula I is selected from the group consisting of 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.

[0238] [Table 1]

[0239] Preparation method The following are general synthetic schemes for preparing 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 can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Furthermore, various steps of the synthesis can be performed in an alternative sequence or order to obtain the desired compound. All documents cited herein are incorporated by reference in their entirety. For example, the following reactions are illustrative, but not limiting, of the preparation of some of the starting materials and compounds disclosed herein.

[0240] Schemes 1-8 below describe synthetic routes that can be used to synthesize compounds of the present invention, such as compounds having the structure of Formula I, or precursors thereof. Various modifications of these methods to achieve results similar to those of the present invention provided below may occur to those skilled in the art. In the following embodiments, synthetic routes are described using compounds having the structure of Formula I, or precursors thereof, as examples. The general synthetic routes described in Schemes 1-8 and the examples provided in the Examples section below illustrate methods used to prepare the compounds described herein.

[0241] Compounds I-1a and I-2, shown immediately below in Scheme 1, can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH and amine groups. Other substituents are defined herein. As shown in Scheme 1, the core of the compound of Formula I can be synthesized from an appropriately substituted bromo- or iodobenzene I-1a, which is converted to the corresponding boronic acid I-1b by, for example, metallation with n-butyllithium and reaction with a trialkyl borate, such as trimethyl borate. The ketoester I-2 is reacted with LiHMDS and a base, such as N-phenyltriflimide, to form the enol trifluoromethanesulfonate I-3. Coupling of the enol trifluoromethanesulfonate I-3 with the boronic acid I-1b in the presence of a catalyst such as 1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium(II) (Pd(dppf)Cl) affords the cyclic amine I-4. Hydrogenation of I-4 over a catalyst such as platinum oxide affords the saturated cyclic amine ester I-5a. Selective removal of the protecting group on the nitrogen of compound I-5a affords the corresponding cyclic amine ester I-5c. The protecting group of compound I-5c can then be removed, and the resulting compound with a free phenolic OH group can be optionally converted to a compound of Formula I using methods known in the art.

[0242] [ka]

[0243] Compound I-1a, shown immediately below in Scheme 2, can be prepared by any method known in the art and / or is commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, 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 2, compounds of Formula I (where n1 = 1) can be prepared by alternative routes shown therein. Iodo- or bromobenzene I-1a is coupled with pyridine boronate ester I-6 in the presence of a palladium catalyst such as Pd(dppf)Cl2 to form 4-arylpyridine ester I-8, or with cyanopyridine boronate ester I-7 to form 4-arylpyridine nitrile I-9. Hydrogenation of ester I-8 over a catalyst such as platinum oxide provides 4-arylpiperidine I-5b. The protecting group of compound I-5b can then be removed and the resulting compound with a free phenolic OH group can be optionally converted to a compound of formula I using methods known in the art.

[0244] [ka]

[0245] As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. The intermediate aminomethyl heterocycles I-12a and I-12b can be obtained by several routes, as shown immediately below in Scheme 3. For compounds of Formula I (where n1 = 1), pyridine nitrile I-9 (shown in Scheme 2) can be converted to primary amide I-10 by hydrolysis with alkaline peroxide or reduced to aminomethylpyridine I-11 with borane-tetrahydrofuran complex. Hydrogenation of the pyridine ring of I-10 or I-11 over a catalyst such as platinum oxide in the presence of an acid such as hydrochloric acid or acetic acid provides the corresponding piperidine I-13 or I-12a, respectively. Alternatively, hydrogenation of I-9 under similar conditions affords I-12a directly. In an approach applicable to all ring sizes, ester I-5c (shown in Scheme 1) is converted to primary amide I-13 by heating with ammonia in methanol in a sealed vessel. Reduction of amide I-13 with borane-methyl sulfide affords diamine I-12b. The protecting groups of compounds I-12a, I-12b, and I-13 can be optionally removed to afford compounds of formula I using methods known in the art.

[0246] [ka]

[0247] As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. Diamine I-12b can be used to prepare bicyclic amide I-17 by one of two routes shown immediately below in Scheme 4. The carboxylic acid R can be reacted with a peptide coupling reagent such as EDCI / HOBT, TBTU, or HATU to prepare the bicyclic amide I-17. a Acylation of I-12b with COH is selective on the primary amine to give I-14. Acylation of I-14 on the cyclic amine with chloroacetyl chloride gives chloroacetamide I-15, which cyclizes to form piperazinone I-16 upon treatment with a base such as cesium carbonate in a polar solvent such as DMF. Deprotection of the protecting group on the phenol with boron tribromide, for example, when the protecting group is methyl, gives I-17. Alternatively, selective protection of the primary amine of I-12b (e.g., with a Boc group) gives I-18. A similar sequence of acylation to I-19 with chloroacetyl chloride and base-mediated cyclization, followed by simultaneous deprotection of both the amine and phenol, gives I-20, which can be converted to the carboxylic acid R under standard conditions. a Acylation with CO2H can give I-17. Compound I-20 can be used to give compounds with other R4 groups on the nitrogen by standard methods.

[0248] [ka]

[0249] As shown in Scheme 5, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. Compounds of Formula I (where Y is oxygen) are synthesized as shown immediately below in Scheme 5. The cyclic amine ester I-5c (shown in Scheme 1) is reduced to the alcohol I-21 with, for example, borane-tetrahydrofuran, under heating. I-21 is coupled with the potassium salt of 2-oxiranecarboxylic acid using reagents such as HATU, TBTU, or EDC / HOBt to form the epoxyamide I-22. Treatment of the epoxide I-22 with a base such as sodium hydride in an inert solvent such as THF results in cyclization to I-23. The hydroxymethyl group of I-23 can be converted to other substituents by standard methods. Removal of the protecting group affords the free phenol.

[0250] [ka]

[0251] As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. Compounds of Formula I (where Y is N) having a ring system (e.g., 8-phenyl-octahydro-4H-pyrido[1,2-a]pyrazin-4-one (I-27) substituted at C3 with R2) can be obtained from amino alcohol I-21 by either of two routes shown immediately below in Scheme 6. Acylation of I-21 (shown in Scheme 5) with an appropriately protected amino acid using a coupling reagent such as HATU, TBTU, or EDC / HOBT provides amide I-24. Typically, the amino group is protected with Boc, but other protecting groups such as alloc, troc, or Fmoc could also be used. Oxidation of the primary alcohol to the aldehyde I-25 is carried out using the Dess-Martin reagent or Swern oxidation conditions. Removal of the amine protecting group with TFA results in cyclization to I-26, followed by reduction of the imine double bond by hydrogenation or 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 with the Dess-Martin reagent. 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 afford I-30. Removal of the Boc protecting group on the nitrogen, followed by heating with a base such as triethylamine in a solvent such as ethanol, results in cyclization to I-27. I-27 can be further modified by amine derivatization and protecting group removal by standard methods to give the free phenol, forming additional compounds of Formula I.

[0252] [ka]

[0253] As shown in Scheme 7, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH and amines. Other substituents are defined herein. Compounds of Formula I (where Y is N) having a ring system (e.g., 8-phenyl-octahydro-4H-pyrido[1,2-a]pyrazin-4-one (I-35) substituted at C1 with R2) are prepared from protected amino ester I-5a (shown in Scheme 1) by the route shown immediately below in Scheme 7. Ester I-5a is first hydrolyzed to the carboxylic acid and converted to Weinreb amide I-31 by treatment with N,O-dimethylhydroxylamine and a coupling reagent such as carbonyldiimidazole or EDC / HOBT. Reaction of I-31 with the Grignard reagent, R2MgBr, forms ketone I-32. The protecting group on the nitrogen is then selectively removed. When PG is Boc, removal of the Boc group can be achieved by using TFA. The cyclic amine is acylated with a protected amino acid, such as Boc glycine, to give the amide I-33. Removal of the Boc group with TFA and concomitant cyclization of the amine to a ketone forms the cyclic imine I-34. Reduction of the imine with sodium borohydride gives the cyclic amine I-35, which can be further modified on the amine nitrogen, for example, by acylation or alkylation using standard methods. Removal of the protecting group on the phenol to give the free phenol can be performed before or after derivatization of the amine.

[0254] [ka]

[0255] As shown in Scheme 8, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or other protecting groups known in the art suitable for use as protecting groups for OH. Other substituents are defined herein. The stereoselective synthesis of intermediate I-5d is shown immediately below in Scheme 8. Enantiomerically pure piperidone I-36 was synthesized from protected L-aspartic acid and Meldrum's acid by the method described in Org. Syn., 2008, 85, 147, and then converted to enol triflate I-37 by treatment with trifluoromethanesulfonic anhydride and base according to the procedure described in Syn. Lett. 2009, 71-74. Enol triflate I-37 is coupled with boronic acid I-1b using a palladium catalyst such as Pd(dppf)Cl to give I-39. Hydrogenation of I-17 over a catalyst such as platinum oxide affords piperidinone I-40 predominantly as the 2S,4S enantiomer, and reduction of the amide using borane methyl sulfide complex affords enantiomerically pure I-5d, which can be used in the syntheses outlined in Schemes 3, 4, 5, 6, and 7.

[0256] [ka]

[0257] The reactions described in Schemes 1-8 can be carried out in a suitable solvent. 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 at 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 cooling bath at a temperature below room temperature, such as 0, -10, -20, -30, -40, -50, -78, or -90°C. The reaction can be worked up by removing the solvent or by partitioning the organic solvent phase with one or more aqueous phases, each optionally containing NaCl, NaHCO3, or NHCl. The solvent of the organic phase can be removed by evaporation in vacuo, and the resulting residue can be purified using a silica gel column or HPLC.

[0258] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0259] In yet another aspect, the present invention provides pharmaceutical compositions comprising at least one compound selected from the group consisting of compounds of formula I described herein and a pharmaceutically acceptable carrier or diluent.

[0260] In certain embodiments, the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The composition can be administered to a subject by any suitable route of administration, including, but not limited to, oral and parenteral.

[0261] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the pharmaceutical agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as butylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations.The term "carrier" refers to a natural or synthetic organic or inorganic ingredient that combines with active ingredients to facilitate application. The components of the pharmaceutical compositions also are capable of being co-mingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0262] As noted above, certain embodiments of the pharmaceutical agent may be provided in the form of a pharmaceutically acceptable salt. 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 isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. See, e.g., Berge et al., (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.

[0263] Pharmaceutically acceptable salts of the present compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, and the like; and salts prepared from organic acids such as acetate, butyonic acid, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, isothionic acid, and the like.

[0264] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al., supra.

[0265] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0266] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0267] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0268] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0269] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato, etc. Disintegrating agents such as maize or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0270] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0271] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxybutylmethylcellulose, other polymer matrices, liposomes, and / or microspheres that provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents into the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0272] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain solubilizers and emulsifiers, such as inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isobutyl alcohol, ethyl carbonate, EA, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compound.

[0273] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0274] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0275] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0276] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0277] Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example, butane.

[0278] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the drug in a suitable medium.Absorption enhancers can also be used to increase the flux of the drug of the present invention across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0279] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0280] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents; or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0281] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections to prolong the drug's effect. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle. One strategy for depot injection involves the use of polyethylene oxide-polypropylene oxide copolymers, whose vehicles are fluid at room temperature but solidify at body temperature.

[0282] Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0283] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be given as they are (neat) or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0284] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures.The specific combination of treatments (therapeutic agents or procedures) used in combination regimen will take into account the compatibility of desired therapeutic agents and / or procedures and the desired therapeutic effect achieved.It will also be understood that the treatments used can achieve the desired effect for the same disorder (for example, the compounds of the present invention can be administered simultaneously with another anticancer drug).

[0285] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock and domestic animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0286] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, optionally accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting approval by the agency of the manufacture, use, or sale for human administration.

[0287] Administration to subjects In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of a compound selected from the group consisting of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0288] In some embodiments, the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0289] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.

[0290] In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In some embodiments, the central nervous system (CNS) disorder is Alzheimer's disease.

[0291] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0292] In some embodiments, the mammalian species is human.

[0293] In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0294] In yet another aspect, a method of blocking Kv1.3 potassium channels in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the compounds described herein are selective in blocking the Kv1.3 potassium channel with minimal or no off-target inhibitory activity against other potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel, and therefore have a desirable cardiovascular safety profile.

[0296] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular outcome. Accordingly, small molecule compositions useful according to the methods of the invention can be formulated in any manner suitable for pharmaceutical use.

[0297] The formulations of the present invention are administered in pharmaceutically acceptable solutions which may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0298] For use in treatment, an effective amount of the compound can be administered to a subject by any method that allows the compound to be taken up by appropriate target cells.The "administration" of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art.Specific administration routes include, but are not limited to, oral, transdermal (for example, via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.).Injection can be bolus or continuous infusion.

[0299] For example, pharmaceutical compositions according to the present invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or as an implant, and even rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, cochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for implantation in the skin, or dried on a sharp object for scratching into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with extended release of 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 commonly used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief overview of this method for drug delivery, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

[0300] The concentration of the compound contained in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. An effective dose is believed to be in the range of about 100 picomoles / kg to about 100 micromoles / kg.

[0301] 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. To treat a patient, different dosages may be required depending on the activity of the compound, the method of administration, the purpose of administration (i.e., preventive or therapeutic), the nature and severity of the disorder, and the age and weight of the patient. The administration of a given dosage can be carried out by both single administration in the form of individual dosage units or several smaller dosage units. Repeated doses and multiple administrations at specific daily, weekly or monthly intervals are also contemplated by the present invention.

[0302] The composition can be administered as is (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, TsOH (p-toluenesulfonic acid), tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts can also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0303] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0304] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the recipient's blood. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed, or non-mineral oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous administration, etc. can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0305] The compounds useful in the present invention may be delivered in a mixture of three or more such compounds, which may further include one or more adjuvants in addition to the combination of compounds.

[0306] A variety of administration routes are available.The specific mode selected will naturally depend on the specific compound selected, the age and general health condition of the subject, the specific condition to be treated, and the dosage required for therapeutic effectiveness.The method of the present invention can be carried out using any medically acceptable administration mode, which generally means any mode that produces an effective level of response without causing clinically unacceptable adverse effects.Preferred administration modes are discussed above.

[0307] Composition can be conveniently provided in unit dosage form, and can be prepared by any method well known in the field of pharmacy.All methods comprise the step of associating compound with carrier that constitutes one or more accessory components.Generally, composition is prepared by associating compound with liquid carrier, finely divided solid carrier, or both, uniformly and intimately, and then, if necessary, shaping product.

[0308] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems. Such systems can avoid repeated administration of the compound, increasing convenience for patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Drug-containing microcapsules of these polymers are described, for example, in U.S. Pat. No. 5,075,109. Delivery systems also include non-polymeric systems, such as lipids containing sterols, such as cholesterol, cholesterol esters, and fatty acids, or neutral lipids, e.g., mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; and partially fused implants. Specific examples include, but are not limited to, (a) erosion systems in which the agents of the invention are contained within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974, and 5,407,686. Additionally, pump-based hardware delivery systems, some of which are adapted for implantation, may be used.

[0309] Assay for efficacy of Kv1.3 potassium channel blockers In some embodiments, the compound described herein is tested for its activity against Kv1.3 potassium channel.In some embodiments, the compound described herein is tested for its Kv1.3 potassium channel electrophysiology.In some embodiments, the compound described herein is tested for its hERG electrophysiology.

[0310] equivalent The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the complete contents of this document, including the following examples, and with reference to the scientific and patent literature cited herein. It should be further understood that the contents of these cited references are incorporated herein by reference to help illustrate the prior art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. [Example]

[0311] Examples 1-7 describe various intermediates used in the synthesis of representative compounds of Formula I disclosed herein.

[0312] [Example 1] Intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) and Intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene)

[0313] [ka]

[0314] Step A: To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br (98.04 g, 613.49 mmol) dropwise under a nitrogen atmosphere at 0 °C. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched with saturated aqueous NaSO (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (100 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0315] To a crude mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (32 g, 125.04 mmol, 1 equiv.) and KCO (54.9 g, 396.87 mmol, 3 equiv.) in ACN (210 mL) was added MeI (16.5 mL, 116.05 mmol, 2 equiv.) dropwise 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 eluting with PE to give intermediate 1 (2-bromo-3,4-dichloro-1-methoxybenzene) (8.7 g, 25.7%) as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 9.0, 1.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H); and intermediate 2 (1-bromo-4,5-dichloro-2-methoxybenzene) (24.3 g, 71.77%) as a white solid: 1 H NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H). was obtained as.

[0316] [Example 2] Intermediate 3 ((2,3-Dichloro-6-methoxyphenyl)boronic acid)

[0317] [ka]

[0318] Step A: To a stirred solution of 3,4-dichlorophenol (120 g, 0.74 mol) in THF (400 mL) under nitrogen atmosphere at room temperature, NaOH (75 g, 1.88 mol) was added portionwise, followed by stirring for 30 minutes. To this, N,N-diethylcarbamoyl chloride (150 g, 1.11 mol) was added over 40 minutes, followed by stirring for 15 hours. The reaction mixture was poured into water (1.5 L) and extracted with PE (2 x 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 give 3,4-dichlorophenyl N,N-diethylcarbamate as a yellow oil (213 g, crude): LCMS (ESI) C 11 H 13 Cl2NO2[M + H] + Calculated values: 262, 264 (3 : 2), measured values: 262, 264 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.50-3.34 (m, 4H), 1.32-1.17 (m, 6H).

[0319] Step B: To a solution of DIPA (32 g, 0.32 mol) in THF (400 mL) was added n-BuLi (131 mL, 0.33 mmol) dropwise under a nitrogen atmosphere at −65° C. The resulting mixture was stirred for 1 h. To this was added a solution of 3,4-dichlorophenyl N,N-diethylcarbamate (77 g, 0.29 mol) in THF (200 mL) dropwise, followed by stirring for 1 h. To this was added a solution of I2 (82 g, 0.32 mol) in THF (200 mL) dropwise over 1 h. The resulting mixture was stirred at −65° C. for an additional 30 min. The reaction was quenched at room temperature by the addition of aqueous 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 3,4-dichlorophenyl N,N-diethylcarbamate) were similarly reacted, worked up, and then combined with the previous batch. The resulting residue was slurried in PE (500 mL) and then filtered to give 300 g of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate. The filtrate was purified by silica gel column chromatography eluting with PE / EA (50 / 1) to give an additional 75 g of pure product. 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (375 g, 83% over two steps) was obtained as an off-white solid: LCMS (ESI) C 11 H 12 Cl2INO3[M + H] + Calculated values: 388, 390 (3 : 2), measured values ​​388, 390 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.55 (q, J = 7.2 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0320] Step C: To a stirred solution of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (200 g, 0.52 mol) in EtOH (1.50 L) was added NaOH (165 g, 4.1 mol) 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 to pH = 3 with aqueous HCl (6 N). The resulting mixture was extracted with EA (3 × 1 L). The combined organic layers were washed with brine (800 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3,4-dichloro-2-iodophenol as a brown oil (202 g, crude): LCMS (ESI) C6H3Cl2IO [M - H] - Calculated values: 287, 289 (3:2), measured values: 287, 289 (3:2).

[0321] Step D: To a stirred solution of 3,4-dichloro-2-iodophenol (220 g, 0.76 mol) in DMF (700 mL) was added KCO (210 g, 1.52 mol) and MeI (119 g, 0.84 mol). The resulting mixture was stirred at room temperature for 5 hours. Another batch (100 g of 3,4-dichloro-2-iodophenol) was similarly reacted 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was slurried in PE (300 mL) and then filtered to give 128 g of the desired product. The filtrate was purified by silica gel column chromatography eluting with PE / EA (40 / 1) to give an additional 64 g of the desired product. 1,2-Dichloro-3-iodo-4-methoxybenzene (192 g, 78% over two steps) was obtained as a pale yellow solid: 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H).

[0322] Step E: To a solution of 1,2-dichloro-3-iodo-4-methoxybenzene (100 g, 0.33 mol) in THF (1.2 L) was added i-PrMgCl (182 mL, 0.36 mol) dropwise under a nitrogen atmosphere at 0 °C. The reaction mixture was then stirred at 0 °C for 1 h. B(OMe) (86 g, 0.83 mol) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature over 1 h and stirred at room temperature for another 1 h. Aqueous HSO (5%, 500 mL) was then added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with EA (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated. The residue was stirred in DCM (200 mL) and then filtered to give intermediate 3 ((2,3-dichloro-6-methoxyphenyl)boronic acid) as an off-white solid (55 g, 76%): LCMS (ESI) C 15 H 16 Cl2N2O4[M - H] - Calculated values: 219, 221 (3 : 2), measured values: 219, 221 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 5.65 (s, 2H), 3.89 (s, 3H).

[0323] [Example 3] Intermediate 4 (1-tert-butyl 2-methyl(2S)-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylate)

[0324] [ka]

[0325] Step A: To a solution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.22 mmol) in THF (15 mL) was added LiHMDS (9.87 mL, 9.87 mmol, 1 M in THF) dropwise over 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 for 1 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl (50 mL) at room temperature. 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 give intermediate 4 (1-tert-butyl 2-methyl(2S)-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylate) as a yellow oil (3 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 12 H 16 F3NO7S[M + H - 56] + Calculated value 320, measured value 320.

[0326] [Example 4] Intermediate 5 (1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanamine bis(trifluoroacetic acid))

[0327] [ka]

[0328] Step A: To a solution of Intermediate 1 (Example 1) (5.00 g, 16.51 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (3.80 g, 16.51 mmol) in 1,4-dioxane (80 mL) and HO (20 mL) was added NaCO (5.25 g, 49.53 mmol) and Pd(dppf)Cl·CHCl (0.67 g, 0.83 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give 4-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carbonitrile as an off-white solid (3.00 g, 65%): LCMS (ESI) C 13 H8Cl2N2O [M + H] + Calculated values: 279, 281 (3 : 2), measured values: 279, 281 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.80 (dd, J = 5.0, 0.9 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.46 (dd, J = 5.0, 1.7 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H).

[0329] To a stirred mixture of 4-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carbonitrile (3.00 g, 10.75 mmol) in MeOH (400 mL) and concentrated HCl (12 M, 40.00 mL) was added PtO (0.50 g, 2.16 mmol) in small portions at room temperature. The reaction mixture was degassed and stirred under a hydrogen atmosphere (50 atm) at 30 °C for 48 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN in water (+0.05% TFA) to give intermediate 5 (1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanamine bis(trifluoroacetic acid)) as an off-white solid (2.8 g, 50%): LCMS (ESI) C 13 H 18 Cl2N2O [M + H] + Calculated values: 289, 291 (3 : 2), measured values: 289, 291 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.36 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 9.0 Hz, 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, 12.8 Hz, 2H).

[0330] [Example 5] Intermediate 6 (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0331] [ka]

[0332] Step A: To a stirred mixture of 1-[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methanamine trifluoroacetic acid (Intermediate 5, Example 4) (1.00 g, 2.59 mmol) and TEA (0.75 g, 7.50 mmol) in DCM (15.00 mL) was added BocO (0.43 g, 2.00 mmol) at −50° C. under a nitrogen atmosphere. The resulting mixture was stirred at −50° C. for 1 h under a nitrogen atmosphere, then quenched with NH HO (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 Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EA (1 / 1) to give tert-butyl N-[[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate as an off-white solid (0.6 g, 62%): LCMS (ESI) C 18 H 26 Cl2N2O3[M + H] + Calculated values: 389, 401 (3:2), measured values: 389, 401 (3:2).

[0333] Step B: To a solution of tert-butyl N-[[4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (0.60 g, 1.54 mmol) and TEA (0.47 g, 4.62 mmol) in DCM (10 mL) at 0° C., chloroacetyl chloride (0.19 g, 2.00 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated to give tert-butyl N-[[1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate as a yellow oil (0.7 g, crude): LCMS (ESI) C 20 H 27 Cl3N2O4[M + H] + Calculated values: 465, 467 (1:1), measured values: 465, 467 (1:1).

[0334] Step C: To a solution of tert-butyl N-[[1-(2-chloroacetyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (0.70 g, 1.50 mmol) in DMF (10 mL) was added Cs2CO3 (0.98 g, 3.00 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate as a yellow oil (0.30 g, 46%). tert-Butyl 8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (0.30 g, 0.70 mmol) was separated by preparative chiral HPLC using 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: 30% B to 30% B in 13 min; Detector: UV254 / 210 nm; Retention times: RT1: 9.048 min; RT2: 11.244 min. The faster eluting enantiomer was obtained at 9.048 min as tert-butyl (8S,9aR)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate as a yellow oil (0.12 g, 18%): LCMS (ESI) C 20 H 26 Cl2N2O4[M + H] + Calculated values: 429, 431 (3:2), measured values: 429, 431 (3:2). The slower eluting enantiomer was obtained at 11.244 min as tert-butyl (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate as a yellow oil (0.12 g, 18%): LCMS (ESI) C 20 H 26 Cl2N2O4[M + H] + Calculated values: 429, 431 (3:2), measured values: 429, 431 (3:2). 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.32 (s, 1H), 4.92-4.80 (m, 1H), 4.27 (d, J = 18.4 Hz, 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).

[0335] Step D: To a solution of tert-butyl (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (0.12 g, 0.279 mmol) in DCM (3 mL) was added BBr (0.13 mL, 0.527 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 hours, quenched with water (1 mL), diluted with NaHCO (saturated 10 mL), and then extracted with EA (3 × 20 mL). The combined organic layers were concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mM ammonium formate), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 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 give intermediate 6 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) as an off-white solid (65.1 mg, 74%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values: 315, 317 (3:2), measured values: 315, 317 (3:2). 1 H NMR (400 MHz, methanol-d4) δ 7.20 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 8.8 Hz, 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, 5.1 Hz, 1H), 2.86-2.61 (m, 2H), 2.56-2.32 (m, 2H), 1.72-1.58 (m, 2H).

[0336] [Example 6] Intermediate 7 (1-tert-butyl 2-methyl(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate)

[0337] [ka]

[0338] Step A: To a stirred solution of 1-tert-butyl 2-methyl 4-(trifluoromethanesulfonyloxy)-2,3-dihydropyrrole-1,2-dicarboxylate (Intermediate 4, Example 3) (3.09 g, 8.23 ​​mmol), 2,3-dichloro-6-methoxyphenyl)boronic acid (Intermediate 3, Example 2) (1.40 g, 6.34 mmol), and NaCO (2.02 g, 19.06 mmol) in dioxane (15 mL) and HO (3 mL) was added Pd(dppf)Cl·CHCl (0.10 g, 0.12 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 h. The reaction 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give 1-tert-butyl 2-methyl(2S)-4-(2,3-dichloro-6-methoxyphenyl)-2,3-dihydropyrrole-1,2-dicarboxylate as a pale yellow oil (1.30 g, 51%): LCMS (ESI) C 18 H 21 Cl2NO5[M + H] + Calculated values ​​402, 404 (3:2), measured values ​​402, 404 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.48 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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 = 15.9 Hz, 9H).

[0339] Step B: A solution of 1-tert-butyl 2-methyl(2S)-4-(2,3-dichloro-6-methoxyphenyl)-2,5-dihydropyrrole-1,2-dicarboxylate (1.30 g, 3.23 mmol) and PtO (0.22 g, 0.970 mmol) in HOAc (8 mL) was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 16 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7 (1-tert-butyl 2-methyl(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate) as a pale yellow oil (1.30 g, 99%): LCMS (ESI) C 18 H 23 Cl2NO5[M + H] + Calculated values ​​404, 406 (3:2), measured values ​​404, 406 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 9.0, 1.2 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.48-4.38 (m, 1H), 4.30-4.18 (m, 1H), 3.86 (d, J = 2.2 Hz, 3H), 3.80 (d, J = 3.7 Hz, 3H), 3.71-3.57 (m, 1H), 3.35-3.29 (m, 1H), 2.70-2.41 (m, 2H), 1.47 (d, J = 14.2 Hz, 9H).

[0340] [Example 7] Intermediate 8 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide)

[0341] [ka]

[0342] Step A: To a stirred solution of 1-tert-butyl 2-methyl(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (Intermediate 7, Example 6) (6.00 g, 14.84 mmol) in THF (20 mL) under a nitrogen atmosphere at room temperature was added BH3·Me2S (2.97 mL, 29.68 mmol). The reaction was stirred at 70°C for 2 hours. The reaction was quenched with MeOH (5 mL) at 0°C, and then aqueous HCl (6N, 5 mL) was added. The resulting solution was stirred at 70°C for 1 hour. The reaction was concentrated under reduced pressure to afford [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methanol hydrochloride as a pale yellow oil (5.0 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 12 H 15 Cl2NO2[M + H] + Calculated values: 276, 278 (3:2), measured values: 276, 278 (3:2).

[0343] Step B: To a stirred solution of [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methanol hydrochloride (5.0 g, 15.99 mmol) and TEA (3.22 g, 31.82 mmol) in DCM (20 mL) was added BocO (3.80 g, 17.41 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 75% ACN in water containing 10 mmol / L NH4HCO3 to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate as an off-white solid (1.90 g, 32% over two steps): LCMS (ESI) C 17 H 23 Cl2NO4[M + H]+ Calculated values ​​376, 378 (3 : 2), measured values ​​376, 378 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 9.0 Hz, 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 = 11.2 Hz, 9H).

[0344] Step C: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.90 g, 5.050 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.57 g, 6.06 mmol) at room temperature. The reaction was stirred for 1 h and then quenched with saturated aqueous NaSO (30 mL). The mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO (3 × 30 mL) and brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate as a pale yellow oil (1.9 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 17 H 21 Cl2NO4[M + H] + Calculated values: 374, 376 (3:2), measured values: 374, 376 (3:2).

[0345] Step D: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (1.90 g, 5.08 mmol) and methyl 2-aminoacetate hydrochloride (0.96 g, 7.65 mmol) in DCM (20 mL) was added TEA (1.28 g, 12.65 mmol) and NaBH(AcO) (2.15 g, 10.14 mmol) at room temperature. The reaction was stirred for 2 hours 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 45% ACN in water (0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]pyrrolidine-1-carboxylate as a yellow foam (1.80 g, 79% overall for two steps): LCMS (ESI) C 20 H 28 Cl2N2O5[M + H] + Calculated values ​​447, 449 (3 : 2), measured values ​​447, 449 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 4.28 (s, 1H), 4.23-3.95 (m, 3H), 3.90 (d, J = 9.3 Hz, 6H), 3.87-3.71 (m, 2H), 3.41-3.35 (m, 2H), 2.49-2.32 (m, 2H), 1.53 (s, 9H).

[0346] Step E: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]pyrrolidine-1-carboxylate (1.80 g, 4.02 mmol) in DCM (15 mL) was added TFA (3 mL) at room temperature. The reaction was stirred at room temperature for 1 hour 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 to it. The reaction was stirred at 70° C. for 1 hour. The reaction 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 over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one as a yellow oil (1.10 g, 87%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values ​​315, 317 (3 : 2), measured values ​​315, 317 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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, 10.3 Hz, 1H), 2.26-2.06 (m, 2H).

[0347] Step F: To a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (1.10 g, 3.49 mmol) in DCM (10 mL) was added BBr3 (3.50 g, 13.97 mmol) dropwise at room temperature. The reaction was stirred for 2 hours 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 give intermediate 8 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one hydrobromide) as an off-white solid (1.00 g, 63%): LCMS (ESI) C 13 H 14 Cl2N2O2[M + H] + Calculated values ​​301, 303 (3:2), measured values ​​301, 303 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.29 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.44-4.28 (m, 1H), 4.28-4.18 (m, 1H), 4.18-4.05 (m, 1H), 3.98-3.84 (m, 3H), 3.71-3.55 (m, 1H), 3.19 (t, J = 11.9 Hz, 1H), 2.49 (q, J = 11.5 Hz, 1H), 2.37-2.24 (m, 1H).

[0348] [Example 8] Intermediate 9 (tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carboxylate) and Intermediate 10 (tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carboxylate)

[0349] [ka]

[0350] Step A: To a stirred solution of (3S)-4-(tert-butoxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoic acid (120 g, 415 mmol) in DCM (1.50 L) at −8 °C, EDCI (120 g, 622 mmol), DMAP (76.0 g, 622 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (60.0 g, 414 mmol) were added. The resulting mixture was stirred at −8 °C for 3 h under a nitrogen atmosphere. The resulting mixture was washed with saturated aqueous KHSO (2 × 1 L) and brine (2 × 1 L). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (3.70 L) to give a 0.1 M solution, which was refluxed for 16 h. After cooling to room temperature, the mixture was washed with saturated aqueous KHSO (2 x 1 L) and brine (2 x 1 L). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1,2-di-tert-butyl (2S)-4,6-dioxopiperidine-1,2-dicarboxylate as an off-white solid (123 g, 94%): LCMS (ESI) C 15 H 23 NO6[M + H] + Calculated value: 314, measured value 314; 1 H NMR (400 MHz, CDCl3) δ 5.12-5.03 (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).

[0351] Step B: To a solution of 1,2-di-tert-butyl (2S)-4,6-dioxopiperidine-1,2-dicarboxylate (50.0 g, 160 mmol) in DCM (500 mL) was added DIEA (83 mL, 645 mmol) dropwise at 0 °C. The resulting reaction was stirred at 0 °C for 10 minutes, and then trifluoromethylsulfonic anhydride (54.0 g, 191 mmol) was added dropwise at 0 °C. The reaction was then warmed to room temperature and stirred for an additional 2 hours. The reaction was quenched with saturated aqueous NaHCO (100 mL) at 10 °C. The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phase was washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 1,2-di-tert-butyl (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylate as a yellow solid (39.0 g, 55%): LCMS (ESI) C 16 H 22 F3NO8S [M + H] + Calculated value: 446 Found value: 346 [M + H -100] + ; 1 H NMR (300 MHz, CDCl3) δ 6.03 (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).

[0352] Step C: To a stirred mixture of 1,2-di-tert-butyl (2S)-6-oxo-4-(trifluoromethanesulfonyloxy)-2,3-dihydropyridine-1,2-dicarboxylate (39.0 g, 78.8 mmol), 2,3-dichloro-6-methoxyphenylboronic acid (20.0 g, 81.5 mmol), and NaCO (17.0 g, 163 mmol) in dioxane (400 mL) and HO (100 mL) was added Pd(dppf)Cl·CHCl (2.66 g, 3.26 mmol) at room temperature under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. The reaction was then stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give 1,2-di-tert-butyl (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylate as a pale yellow liquid (31.0 g, 72%): LCMS (ESI) C 22 H 27 Cl2NO6[M + H] + Calculated value: 472, 474 (3:2) Found value: 372, 374 [M + H -100] + (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 5.92 (d, J = 2.7 Hz, 1H), 4.95 (dd, J = 7.2, 1.8 Hz, 1H), 3.78 (s, 3H), 3.14 (d, J = 17.6 Hz, 1H), 2.90 (d, J = 18.2 Hz, 1H), 1.60 (s, 9H), 1.50 (s, 9H).

[0353] Step D: To a stirred solution of 1,2-di-tert-butyl (2S)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridine-1,2-dicarboxylate (31.0 g, 65.6 mmol) in EA (400 mL) and AcOH (100 mL) was added PtO (6.26 g, 27.6 mmol) in small portions at room temperature. The resulting mixture was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 16 hours, filtered, and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-2-carboxylate as a pale yellow liquid (20.8 g, 76%): LCMS (ESI) C 17 H 21 Cl2NO4[M + H] + Calculated value: 374, 376 (3 : 2) Measured value: 374, 376 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 4.12-3.92 (m, 2H), 3.85 (s, 3H), 3.03 (dd, J = 17.7, 11.2 Hz, 1H), 2.57-2.34 (m, 2H), 2.28-2.09 (m, 1H), 1.86-1.63 (m, 1H), 1.51 (d, J = 2.1 Hz, 9H).

[0354] Step E: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-6-oxopiperidine-2-carboxylate (20.8 g, 50.0 mmol) in THF (200 mL) was added BHMeS (14.2 mL, 187 mmol, 10 M in MeS solution) at room temperature under a nitrogen atmosphere. The reaction was stirred at 70 °C for 4 hours. The reaction was quenched with MeOH (50 mL) at 0 °C. 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 h and then concentrated under reduced pressure to give [(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 without further purification (20.0 g, crude): LCMS (ESI) C 13 H 17 Cl2NO2[M + H] + Calculated value: 290, 292 (3:2) Measured value: 290, 292 (3:2).

[0355] Step F: 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) was added BocO (17.7 mL, 81.1 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give intermediate 9 (tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carboxylate) as a pale yellow liquid (13.0 g, 43%): LCMS (ESI) C 18 H 25 Cl2NO4[M + H] +Calculated: 390, 392 (3:2) Found: 334, 336 [M + H - 56] + (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 9.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 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).

[0356] Step G: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carboxylate (1.40 g, 3.58 mmol) in DCM (10 mL) was added Dess-Martin reagent (1.80 g, 4.31 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aqueous NaSO (10 mL) and saturated aqueous NaHCO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 10 (tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carboxylate) as a yellow liquid (1.30 g, crude): LCMS (ESI) C 18 H 23 Cl2NO4[M + H - 56] + Calculated value: 332, 334 (3 : 2) Measured value: 332, 334 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 9.52 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 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 = 5.8 Hz, 9H).

[0357] [Example 9] Intermediate 11 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0358] [ka]

[0359] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carboxylate (1.30 g, 3.35 mmol) (Intermediate 10, Example 8) and methyl glycinate hydrochloride (0.640 g, 5.09 mmol) in DCM (10 mL) was added TEA (0.510 g, 5.04 mmol) and NaBH(OAc) (1.42 g, 6.70 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. The reaction 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 35% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]piperidine-1-carboxylate trifluoroacetate as a colorless liquid (1.00 g, 52%): LCMS (ESI) C21 H 30 Cl2N2O5[M + H] + Calculated values: 461, 463 (3 : 2) Measured values: 461, 463 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.20 (s, 1H), 4.12 - 3.96 (m, 2H), 3.88 (d, J = 1.2 Hz, 6H), 3.76-3.54 (m, 2H), 3.54-3.37 (m, 2H), 3.22-3.10 (m, 1H), 2.41 (d, J = 13.2 Hz, 1H), 2.00-1.87 (m, 2H), 1.69 (d, J = 13.3 Hz, 1H), 1.57 (s, 9H); 19 F NMR (376 MHz, CD3OD) δ -77.31 (s, 3F).

[0360] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-methoxy-2-oxoethyl)amino]methyl]piperidine-1-carboxylate trifluoroacetate (1.00 g, 1.74 mmol) in DCM (10 mL) at room temperature was added TFA (4 mL). The reaction was stirred at room temperature for 1 hour 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 hour 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 over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 11 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) as an off-white foam (0.550 g, crude): LCMS (ESI) C 15 H 18 Cl2N2O2[M + H] +Calculated value: 329, 331 (3:2) Measured value: 329, 331 (3:2). 1 H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 4.78 (ddd, J = 13.3, 4.4, 2.2 Hz, 1H), 3.85 (s, 3H), 3.80-3.68 (m, 1H), 3.63-3.54 (m, 1H), 3.52 (d, J = 2.0 Hz, 2H), 3.30 (d, J = 5.2 Hz, 1H), 2.86 (dd, J = 13.3, 8.4 Hz, 1H), 2.71 (td, J = 13.2, 3.0Hz, 1H), 2.41-2.23 (m, 2H), 1.72-1.62 (m, 2H).

[0361] [Example 10] Intermediate 12 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one)

[0362] [ka]

[0363] Step A: 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) at room temperature was added BBr (4.19 g, 16.7 mmol). The reaction was stirred at room temperature for 1 hour. 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 basified to pH 8 with TEA. After concentration under reduced pressure, the residue was purified by reverse-phase chromatography eluting with 36% ACN in water (+10 mM NH4HCO3) to give the crude product. Fractions containing the desired product were combined and concentrated under reduced pressure to give intermediate 12 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one) as an off-white solid (0.250 g, 47%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values: 315, 317 (3 : 2) Measured values: 315, 317 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.20 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 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, 5.1 Hz, 1H), 2.81-2.61 (m, 2H), 2.56-2.31 (m, 2H), 1.70-1.59 (m, 2H).

[0364] [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)

[0365] [ka]

[0366] Step A: 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) was added BocO (1.14 g, 5.24 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with EA (3 × 40 mL). The combined organic layer was washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate as a pale yellow solid, which was used directly in the next step without further purification (2.10 g, crude): LCMS (ESI) C 18 H 22 Cl2N2O4[M + H] + Calculated values: 401, 403 (3:2), measured values: 401, 403 (3:2).

[0367] Step B: To a stirred solution of tert-butyl (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate (2.10 g, 5.23 mmol) and K2CO3 (1.45 g, 10.5 mmol) in DMF (40 mL) was added allyl bromide (0.760 g, 6.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, diluted with water (100 mL), and then extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (5 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate as a pale yellow solid, which was used directly in the next step without further purification (2.10 g, crude): LCMS (ESI) C 21 H 26 Cl2N2O4[M + H] + Calculated values: 441, 443 (3:2), measured values: 441, 443 (3:2).

[0368] Step C: To a stirred solution of tert-butyl (7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate (2.00 g, 4.53 mmol) in DCM (20 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography eluting with 60% ACN in water (+10 mM NH4HCO3) to give intermediate 13 ((7R,8aS)-7-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one) as a pale yellow liquid (1.50 g, 66% over three steps): LCMS (ESI) C 16 H 18 Cl2N2O2[M + H] +Calculated values: 341, 343 (3 : 2), measured values ​​341, 343 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 9.0 Hz, 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, 10.2 Hz, 1H), 2.24-2.06 (m, 2H).

[0369] [Example 12] Intermediate 14 (8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-4-one)

[0370] [ka]

[0371] Step A: To a stirred solution of glycidic acid (0.668 g, 7.58 mmol) and HATU (3.17 g, 8.34 mmol) in DMF (20.0 mL) was added [(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) at room temperature. 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 layer was washed with brine (2 × 80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The reaction was purified by reverse phase chromatography eluting with 33% ACN in water (+10 mM NH4HCO3) to give [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-1-(oxirane-2-carbonyl)piperidin-2-yl]methanol as an off-white semi-solid (1.10 g, 40%): LCMS (ESI) C 16 H 19 Cl2NO4[M + 1] + Calculated values ​​360, 362 (3 : 2) Measured values ​​360, 362 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 9.0 Hz, 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).

[0372] Step B: To a stirred solution of [(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-1-(oxirane-2-carbonyl)piperidin-2-yl]methanol (1.10 g, 3.05 mmol) in THF (10.0 mL) was added t-BuOK (0.516 g, 4.61 mmol) under a nitrogen atmosphere at 0° C. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 40% ACN in water (+0.05% TFA) to give intermediate 14 ((8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-4-one) as a yellow liquid (0.450 g, 50%): LCMS (ESI) C 16 H 19 Cl2NO4[M + 1] + Calculated values ​​360, 362 (3 : 2) Measured values ​​360, 362 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.38 (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 = 6.7 Hz, 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).

[0373] [Example 13] Intermediate 15 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindolizine-5,7-dione)

[0374] [ka]

[0375] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (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) was added TEA (26.6 g, 263 mmol) dropwise at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate as an off-white solid (42.5 g, 75%): LCMS (ESI) C 24 H 29 Cl2NO6S [M + H - 100] + Calculated value: 430, 432 (3 : 2) Measured value: 430, 432 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.82 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 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 = 11.1 Hz, 1H), 2.47 (s, 3H), 2.26-2.07 (m, 1H), 1.42 (s, 9H).

[0376] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate (12.0 g, 22.6 mmol) in DMSO (20 mL) was added KCN (2.95 g, 45.3 mmol) at room temperature. The resulting solution was stirred at 80 °C for 1 h, diluted with saturated aqueous NaHCO (100 mL), and then extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA (2 / 1) to give tert-butyl (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate as an off-white solid (3.50 g, 40%): LCMS (ESI) C 18 H 22 Cl2N2O3[M + H] + Calculated values: 385, 387 (3 : 2) Measured values: 385, 387 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 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).

[0377] Step C: To a stirred solution of tert-butyl (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (9.30 g, 24.1 mmol) in concentrated HCl (20 mL) at room temperature was added AcOH (4 mL). The reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. DCM (20 mL), TEA (12.2 g, 121 mmol), and BocO (5.79 g, 26.6 mmol) were then added sequentially to the crude product. The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 65% ACN in water (+0.1% FA) to give [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]acetic acid as an off-white solid (9.00 g, 92%): LCMS (ESI) C 18 H 23 Cl2NO5 [M + H] + Calculated values: 404, 406 (3 : 2) Measured values: 404, 406 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 7.42 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 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).

[0378] Step D: To a stirred solution of [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]acetic acid (9.00 g, 22.3 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (4.81 g, 33.4 mmol) in DCM (50.0 mL) was added DMAP (4.08 g, 33.4 mmol) and EDCI (6.40 g, 33.5 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. The resulting solution was diluted with DCM (100 mL), washed with aqueous HCl (1 M, 2 × 100 mL) and brine (3 × 100 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (30 mL) and stirred at 90 °C for 1 hour. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylate as a pale yellow liquid (9.00 g, 85%): LCMS (ESI) C 22 H 29 Cl2NO6 [M + H] + Calculated value: 474, 476 (3 : 2) Measured value: 474, 476 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4.29-3.99 (m, 4H), 4.17-4.01 (m, 1H), 3.85 (s, 3H), 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 = 7.2 Hz, 3H).

[0379] Step E: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylate (9.00 g, 19.0 mmol) in DCM (40 mL) at room temperature was added TFA (10 mL). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]-3-oxobutanoate as a yellow liquid (9.00 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 17 H 21 Calculated [M + H]+ for Cl2NO4: 374, 376 (3:2) Found: 374, 376 (3:2).

[0380] Step F: To a stirred solution of ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]-3-oxobutanoate (9.00 g, 24.1 mmol) in MeOH (50 mL) was added K2CO3 (16.7 g, 120 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, 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 eluting with EA to give intermediate 15 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindolizine-5,7-dione) as a pale yellow solid (5.00 g, 80% over two steps): LCMS (ESI) C 15 H 15 Cl2NO3 [M + H] + Calculated value: 328, 330 (3 : 2) Measured value: 328, 330 (3 : 2); 1H NMR (300 MHz, CDCl3) δ 7.38 (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).

[0381] [Example 14] Intermediate 16 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one)

[0382] [ka]

[0383] Step A: To a solution of methyltriphenylphosphanium bromide (48.7 g, 136 mmol) in THF (400 mL) was added t-BuOK (136 mL, 136 mmol, 1 M in THF) dropwise under a nitrogen atmosphere at −10° C. for 30 minutes. Then, tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (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 with saturated aqueous NH4Cl (200 mL) at 0° C., 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 eluting with PE / EA (5 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidine-1-carboxylate as a colorless liquid (8.50 g, 43%): LCMS (ESI) C 18 H 23Cl2NO3[M + H - 56] + Calculated values: 316, 318 (3 : 2), measured values ​​316, 318 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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).

[0384] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidine-1-carboxylate (3.60 g, 9.67 mmol) in DCM (36 mL) at room temperature was added TFA (9 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidine as a yellow liquid (3.60 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 13 H 15 Cl2NO [M + H] + Calculated values: 272, 274 (3:2), measured values: 272, 274 (3:2).

[0385] Step C: To a stirred solution of (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidine (3.60 g, 13.2 mmol) and TEA (4.02 g, 39.7 mmol) in DMF (30 mL) was added 3-butenoic acid (1.37 g, 15.9 mmol) and diethyl cyanophosphonate (3.12 g, 17.2 mmol) 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidin-1-yl]but-3-en-1-one as a pale yellow liquid (2.60 g, 79% over two steps): LCMS (ESI) C 17 H 19 Cl2NO2[M + H] + Calculated values: 340, 342 (3 : 2), measured values ​​340, 342 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.11-5.82 (m, 2H), 5.36-5.07 (m, 4H), 4.73-4.34 (m, 1H), 4.18-3.94 (m, 2H), 3.92-3.59 (m, 4H), 3.16 (d, J = 6.6 Hz, 2H), 2.59-2.23 (m, 2H).

[0386] Step D: To a stirred mixture of 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidin-1-yl]but-3-en-1-one (2.60 g, 7.64 mmol) in DCM (26 mL) was added Grubbs second generation catalyst (0.260 g, 0.30 mmol) at room temperature. The resulting mixture was stirred at 40° C. for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give intermediate 16 ((2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one) as a brown solid (2.20 g, 74%): LCMS (ESI) C 15 H 15 Cl2NO2[M + H] + Calculated values: 312, 314 (3 : 2), measured values ​​312, 314 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 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).

[0387] [Example 15] Intermediate 17 ((2R,8aR)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,8,8a-tetrahydro-1H-indolizin-5-one)

[0388] [ka]

[0389] Step A: To a stirred mixture of (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one (Intermediate 16, Example 14) (2.20 g, 7.05 mmol) in toluene (15 mL) was added DBU (10 mL, 66.9 mmol) 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give intermediate 17 ((2R,8aR)-2-(2,3-dichloro-6-methoxyphenyl)-2,3,8,8a-tetrahydro-1H-indolizin-5-one) as an off-white solid (1.50 g, 61%): LCMS (ESI) C 15 H 15 Cl2NO2[M + H] + Calculated values: 312, 314 (3 : 2), measured values ​​312, 314 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 9.0 Hz, 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).

[0390] [Example 16] Intermediate 18 ((6R,7aR)-6-(2,3-dichloro-6-methoxyphenyl)-hexahydropyrrolidin-3-one)

[0391] [ka]

[0392] Step A: To a solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, step c) (2.00 g, 5.34 mmol) in DCM (30 mL) at room temperature was added methyl 2-(triphenyl-λ5-phosphanylidene)acetate (1.79 g, 5.34 mmol). 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 eluting with PE / EA (2 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate as an off-white solid (1.65 g, 72%): LCMS (ESI) C 20 H 25 Cl2NO5[M + Na] + Calculated values: 452, 454 (3 : 2), measured values: 452, 454 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 1H), 6.99-6.95 (m, 1H), 6.77 (d, J = 9.0 Hz, 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).

[0393] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (0.450 g, 1.05 mmol) in MeOH (6 mL) was added PtO (50.0 mg, 0.220 mmol). The mixture was degassed under reduced pressure and purged with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 4 hours. The mixture was then filtered and concentrated under reduced pressure to give tert-butyl (2R,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate as a colorless liquid (0.450 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 20 H 27 Cl2NO5[M + H] + Calculated values: 432, 434 (3 : 2), measured values: 432, 434 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.11-3.91 (m, 2H), 3.86 (s, 3H), 3.80-3.62 (m, 5H), 2.46-2.14 (m, 5H), 2.09-1.95 (m, 1H), 1.50 (d, J = 7.7 Hz, 9H).

[0394] Step C: To a solution of tert-butyl (2R,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate (0.500 g, 1.16 mmol) in DCM (5 mL) was added TFA (1.50 mL) at room temperature. The reaction was stirred at room temperature for 1 hour 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 hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 65% ACN in water (+0.05% TFA) to give intermediate 18 ((6R,7aR)-6-(2,3-dichloro-6-methoxyphenyl)-hexahydropyrrolidin-3-one) as a pale yellow solid (0.250 g, 72%): LCMS (ESI) C 14 H 15 Cl2NO2[M + H] + Calculated values: 300, 302 (3 : 2), measured values ​​300, 302 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 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).

[0395] [Example 17] Intermediate 19 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-3-oxo-hexahydropyrrolidine-2-carboxylic acid)

[0396] [ka]

[0397] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, Step c) (1.00 g, 2.67 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (0.380 g, 2.67 mmol), and ethidine (0.67 g, 2.67 mmol) in ACN (10 mL) was added L-proline (31.0 mg, 0.27 mmol) at room temperature. 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) and subsequently filtered, and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methyl]pyrrolidine-1-carboxylate as a pale yellow liquid (1.20 g, 89%): LCMS (ESI) C 23 H 29 Cl2NO7[M + H] + Calculated values: 502, 504 (3 : 2), measured values ​​502, 504 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 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).

[0398] Step B: A solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methyl]pyrrolidine-1-carboxylate (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 basified 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 reverse phase chromatography eluting with 35% ACN in water (+0.05% TFA) to give intermediate 19 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-3-oxo-hexahydropyrrolidine-2-carboxylic acid) as a pale yellow liquid (0.780 g, 95%): LCMS (ESI) C 15 H 15 Cl2NO4[M + H] + Calculated values: 344, 346 (3 : 2), measured values ​​344, 346 (3 : 2); 1 H NMR (300 MHz, CDCl3)δ 7.34 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 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).

[0399] [Example 18] Intermediate 20 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-1-(hydroxymethyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one)

[0400] [ka]

[0401] Step A: To a stirred mixture of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-ethenylpyrrolidine-1-carboxylate (Intermediate 16, Step a) (3.30 g, 8.86 mmol) in DCM (25 mL) was added m-CPBA (4.59 g, 26.6 mmol) at room temperature. After 2 h, the reaction was quenched with saturated aqueous NaSO (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO (3 × 30 mL) and brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(oxiran-2-yl)pyrrolidine-1-carboxylate as a pale yellow liquid (3.50 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 18 H 23 Cl2NO4 [M + Na] + Calculated values: 410, 412 (3:2), measured values: 410, 412 (3:2).

[0402] Step B: A mixture of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(oxiran-2-yl)pyrrolidine-1-carboxylate (3.30 g, 8.50 mmol) and TsOH (0.150 g, 0.850 mmol) in MeOH (25 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give intermediate 20 ((6R,7aS)-6-(2,3-dichloro-6-methoxyphenyl)-1-(hydroxymethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one) as a pale yellow solid (1.70 g, 57% over two steps): LCMS (ESI) C 14 H 15 Cl2NO4[M + H] +Calculated values: 332, 334 (3 : 2), measured values ​​332, 334 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 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).

[0403] Examples 19-108 describe the synthesis of representative compounds of Formula I disclosed herein.

[0404] [Example 19] Compound 1 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one)

[0405] [ka]

[0406] Step A: To a stirred solution of glycolic acid (9 mg, 0.12 mmol) in DMF (1.00 mL) was added EDCI (32 mg, 0.17 mmol) and HOBT (23 mg, 0.17 mmol) at room temperature. After 5 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 in vacuo. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD, 30 × 150 mm, 5 μm column; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 45% B in 7 min; Detector: UV 220 nm; Retention time: 6.97 min. Fractions containing the desired product were combined and concentrated under reduced pressure to give compound 1 ((8R,9aR)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) as an off-white solid (15.6 mg, 38%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values: 373, 375 (3:2), measured values: 373, 375 (3:2). 1H NMR (400 MHz, methanol-d4) δ 7.20 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.77 - 4.65 (m, 1H), 4.45 - 3.87 (m, 5H), 3.82 - 3.42 (m, (400 MHz, CD3OD) δ 7.20 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.74 (d, J = 13.3 Hz, 1H), 4.41-3.87 (m, 5H), 3.86-3.39 (m, 3H), 2.76 (td, J = 13.2, 3.0 Hz, 1H), 2.54-2.32 (m, 2H), 1.83-1.54 (m, 2H).

[0407] [Example 20] Compound 2 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyethyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0408] [ka]

[0409] Step A: 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) was added dropwise DIEA (38 mg, 0.30 mmol) at 0° C. The reaction mixture was stirred at 80° C. for 12 hours. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 40% B in 7 min; Detector: UV 254 / 220 nm; Retention time: 6.92 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 2 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyethyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one) as an off-white solid (15 mg, 41%): LCMS (ESI) C 15 H 18 Cl2N2O3[M + H] + Calculated values: 345, 347 (3 : 2), Measured values: 345, 347 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 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 = 10.6 Hz, 1H), 3.35-3.25 (m, 1H), 3.11 (d, J = 16.8 Hz, 1H), 2.85-2.67 (m, 2H), 2.53-2.33 (m, 1H), 2.22 (q, J = 11.5 Hz, 1H), 2.16-2.04 (m, 1H).

[0410] [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 The following compounds were made in a manner similar to Compound 1 (Example 19) or Compound 2 (Example 20) and / or by methods known in the art.

[0411] [Table 2-1]

[0412] [Table 2-2]

[0413] [Table 2-3]

[0414] [Table 2-4]

[0415] [Table 2-5]

[0416] [Table 2-6]

[0417] [Table 2-7]

[0418] [Table 2-8]

[0419] [Table 2-9]

[0420] [Table 2-10]

[0421] [Table 2-11]

[0422] [Table 2-12]

[0423] [Example 22] Compound 61 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxyhexahydroindolizin-5(1H)-one isomer 1) and compound 62 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxyhexahydroindolizin-5(1H)-one isomer 2)

[0424] [ka]

[0425] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (Example 7, step b) (6.6 g, 17.541 mmol, 1.00 equiv.), TsCl (3.68 g, 19.295 mmol, 1.10 equiv.), and DMAP (214 mg, 1.754 mmol, 0.10 equiv.) in DCM (60 mL) was added TEA (3.55 g, 35.081 mmol, 2.00 equiv.) at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate (6.6 g, 64%): LCMS (ESI) C 24 H 29 Cl2NO6S [M + H] + Calculated values: 530, 532 (3 : 2), measured values ​​530, 532 (3 : 2); 1 H NMR (300 MHz, chloroform-d) δ 7.82 (d, J = 8.2 Hz, 2H), 7.38-7.33 (m, 3H), 6.78 (d, J = 9.0 Hz, 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).

[0426] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate (1.0 g, 1.885 mmol, 1.00 equiv.) in DMSO (10 mL) at room temperature was added KCN (245 mg, 3.770 mmol, 2.00 equiv.). The reaction was stirred at 80 °C for 1 h. The resulting mixture was diluted with NaHCO (saturated, 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA (3:1) to give tert-butyl (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (3.4 g, 47%) as an off-white solid: LCMS (ESI) C 18 H 22 Cl2N2O3[M + H] + Calculated values: 385, 387 (3 : 2), measured values ​​385, 387 (3 : 2); 1 H NMR (400 MHz, methanol-d₄) δ 7.44 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 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).

[0427] Step C: To a stirred solution of tert-butyl (2S,4R)-2-(cyanomethyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (2 g, 5.191 mmol, 1.00 equiv) in HCl (20 mL) at room temperature was added AcOH (4 mL). The reaction was stirred at 100° C. for 1 hour. The reaction was concentrated under reduced pressure. To the resulting residue were added DCM (20 mL), TEA (2.63 g, 25.991 mmol, 5.01 equiv), and BocO (2.27 g, 10.382 mmol, 2.00 equiv) sequentially. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 65% ACN in water (+0.1% FA) to give [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]acetic acid (1.8 g, 86%) as an off-white solid: LCMS (ESI) C 18 H 23 Cl2NO5[M + H] + Calculated values: 404, 406 (3 : 2), measured values: 404, 406 (3 : 2); 1 H NMR (400 MHz, methanol-d4) δ 7.42 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 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).

[0428] Step D: To a stirred solution of [(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]acetic acid (1.1 g, 2.721 mmol, 1.00 equiv.) in DCM (10 mL) and Meldrum's acid (0.59 g, 4.081 mmol, 1.50 equiv.) at room temperature, DMAP (0.66 g, 5.442 mmol, 2.00 equiv.) and EDCI (0.78 g, 4.081 mmol, 1.50 equiv.) were added. The reaction was stirred at room temperature for 1 hour. 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 hours. TsOH (243 mg, 1.36 mmol, 0.50 equiv.) was then added. The reaction mixture was stirred at 100° C. for 16 hours. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 65% ACN in water (+0.05% TFA) to afford tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylate (1 g, 77%) as a yellow oil: LCMS (ESI) C 22 H 29 Cl2NO6[M + H] + Calculated values: 474, 476 (3 : 2), measured values: 474, 476 (3 : 2); 1 H NMR (400 MHz, 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).

[0429] Step E: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1-carboxylate (300 mg, 0.632 mmol, 1.00 equiv) in DCM (3 mL) at room temperature was added TFA (1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]-3-oxobutanoate (300 mg, crude) as a yellow oil: LCMS (ESI) C 17 H 21 Cl2NO4[M + H] + Calculated values: 374, 376 (3:2), measured values: 374, 376 (3:2).

[0430] Step F: To a stirred solution of ethyl 4-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]-3-oxobutanoate (300 mg, 0.802 mmol, 1.00 equiv) in MeOH (3 mL) was added LiOH.HO (67 mg, 1.603 mmol, 2.00 equiv) and HO (1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to afford (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindolizine-5,7-dione (90 mg, 34%) as a yellow oil: LCMS (ESI) C 15 H 15 Cl2NO3[M + H] + Calculated values: 328, 330 (3 : 2), measured values ​​328, 330 (3 : 2); 1H NMR (400 MHz, chloroform-d) δ 7.38 (dd, J = 8.9, 2.4 Hz, 1H), 6.80 (dd, J = 9.0, 3.4 Hz, 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).

[0431] Step G: To a stirred solution of (2R,8aS)-2-(2,3-dichloro-6-methoxyphenyl)-hexahydroindolizine-5,7-dione (300 mg, 0.609 mmol, 1.00 equiv) in DCM (1.00 mL) at room temperature was added BBr (0.9 mL, 10 equiv). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (2 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography eluting with 20% ACN in water (+10 mmol / L NH4HCO3) to give (2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-hexahydroindolizine-5,7-dione (180 mg, 58%) as an off-white solid: LCMS (ESI) C 14 H 13 Cl2NO3[M + H] + Calculated values: 314, 316 (3 : 2), measured values ​​314, 316 (3 : 2); 1 H NMR (400 MHz, 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).

[0432] Step H: To a stirred solution of (2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-hexahydroindolizine-5,7-dione (180 mg, 0.516 mmol, 1.00 equiv, 90%) in THF (2 mL) was added NaBH (39 mg, 1.026 mmol, 1.99 equiv) at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chiral HPLC using the following conditions (column: CHIRALPAK IE, 2 * 25 cm, 5 μm; Mobile phase A: Hex (0.1% FA), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 20B to 20B in 11 min; 220 / 254 nm. Retention times: 6.98 min and 8.68 min. The faster-eluting isomer was obtained as compound 61 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxy-hexahydro-1H-indolizin-5-one isomer 1) (10 mg, 2%) as an off-white solid: LCMS (ESI) C 14 H 15 Cl2NO3[M + H] + Calculated values: 316, 318 (3 : 2), measured values ​​316, 318 (3 : 2); 1 H NMR (400 MHz, methanol-d₄) δ 7.25 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 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).

[0433] The slower eluting isomer was obtained as compound 62 ((2R,8aS)-2-(2,3-dichloro-6-hydroxyphenyl)-7-hydroxy-hexahydro-1H-indolizin-5-one isomer 2) (45 mg, 43%) as an off-white solid: LCMS (ESI) C 14 H 15 Cl2NO3[M + H] + Calculated values: 316, 318 (3 : 2), measured values ​​316, 318 (3 : 2); 1 H NMR (400 MHz, methanol-d4) δ 7.25 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 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).

[0434] [Example 23] Compounds 63-64 were prepared in a manner analogous to the examples disclosed herein and / or methods known in the art.

[0435] [Table 3]

[0436] [Example 24] Compounds 65-78 were prepared in a manner analogous to the examples disclosed herein and / or methods known in the art.

[0437] [Table 4-1]

[0438] [Table 4-2]

[0439] [Table 4-3]

[0440] [Table 4-4]

[0441] [Table 4-5]

[0442] [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

[0443] [ka]

[0444] Step A: 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) at room temperature was added [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). The reaction was stirred for 0.5 h, and the resulting mixture was directly purified by reverse-phase chromatography eluting with 55% ACN in 0.05% aqueous TFA to afford tert-butyl (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (cis, mixture of two diastereoisomers) (0.230 g, 71%) as a pale yellow solid. LCMS (ESI) C 15 H 18 Cl2N2O3[M + H] + Calculated values: 517, 519 (3 ​​: 2) Measured values: 517, 519 (3 ​​: 2); 1 H NMR (400 MHz, CDCl3) δ 7.36-7.29 (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).

[0445] Step B: To a stirred solution of tert-butyl (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(hydroxymethyl)piperidine-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.230 g, 0.44 mmol) in DCM (1.00 mL) was added Dess-Martin periodinane (0.280 g, 0.67 mmol) at room temperature. The reaction was stirred for 1 h, quenched with aqueous NaSO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 70% ACN in 0.05% aqueous TFA to give tert-butyl (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (cis, mixture of two isomers) as a yellow oil (0.150 g, 65%). LCMS (ESI) C 24 H 32 Cl2N2O6[M + 1] + Calculated values ​​515, 517 (3 : 2) Measured values ​​515, 517 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 25.0 Hz, 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, 2H), 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).

[0446] Step C: To a stirred solution of tert-butyl (4R)-4-[4-(2,3-dichloro-6-methoxyphenyl)-2-(dihydroxymethyl)piperidine-1-carbonyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.150 g, 0.29 mmol) in DCM (2 mL) at room temperature was added TFA (0.5 mL). The reaction was stirred for 2 hours and concentrated under reduced pressure to afford 8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-1H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one (cis, mixture of two isomers) as a yellow oil (0.110 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 16 H 18 Cl2N2O3[M + 1] + Calculated values: 357, 359 (3:2) Measured values: 357, 359 (3:2).

[0447] Step D: 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, mixture of two isomers) (0.110 g, 0.31 mmol) in MeOH (2 mL) at room temperature was added PtO (20 mg). The reaction was stirred under H (1.5 atm) for 1 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 26% ACN in 0.05% aqueous TFA to give (3R)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, mixture of two isomers) as a yellow oil (80.0 mg, 72%): LCMS (ESI) C 16 H 20 Cl2N2O3[M + 1] + Calculated values: 359, 361 (3:2) Measured values: 359, 361 (3:2).

[0448] Step E: To a stirred solution of (3R)-8-(2,3-dichloro-6-methoxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, mixture of two isomers) (80.0 mg, 0.22 mmol) in DCM (2 mL) at room temperature was added BBr3 (0.560 g, 2.23 mmol). The reaction was stirred for 2 hours, quenched with MeOH (2 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 28% B to 40% B in 7 min; Detector: UV: 254 / 220 nm; Retention time: 6.30 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, mixture of two isomers) as an off-white solid (18.0 mg, 23%): LCMS (ESI) C 15 H 18 Cl2N2O3[M + 1] + Calculated values: 345, 347 (3:2) Measured values: 345, 347 (3:2). 1 H NMR (400 MHz, CD3OD) δ 7.23 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 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).

[0449] Step F: 3R)-8-(2,3-Dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one (cis, mixture of two isomers) (12 mg, 0.04 mmol) was separated by chiral preparative HPLC using the following conditions: Column: CHIRALPAK IG, 2 × 25 cm, 5 μm; Mobile phase A: Hex (+0.2% IPA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 14 min; Detector: UV 220 / 254 nm; Retention time 1: 7.51 min; Retention time 2: 11.52 min. Obtaining the faster eluting isomer at 7.51 min gave compound 57 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one) as an off-white solid (1.9 mg, 16%): LCMS (ESI) C 15 H 18 Cl2N2O3[M + H] + Calculated values: 345, 347 (3 : 2) Measured values: 345, 347 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 8.8 Hz, 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, 3.9 Hz, 1H), 3.36-3.34 (m, 1H), 2.82-2.62 (m, 2H), 2.53-2.24 (m, 2H), 1.66 (t, J = 11.9 Hz, 2H). Obtaining the slower eluting isomer at 11.52 min gave compound 36 ((3R,8S,9aR)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)-octahydropyrido[1,2-a]pyrazin-4-one) as an off-white solid (2.6 mg, 21%): LCMS (ESI) C 15 H 18 Cl2N2O3[M + H] +Calculated values: 345, 347 (3 : 2) Measured values: 345, 347 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.79-4.71 (m, 1H), 3.96 (dd, J = 11.0, 6.6 Hz, 1H), 3.83 (dd, J = 11.0, 3.8 Hz, 1H), 3.77-3.71 (m, 1H), 3.55-3.47 (m, 1H), 3.45 (dd, J = 6.6, 3.7 Hz, 1H), 3.18 (dd, J = 13.4, 5.0 Hz, 1H), 3.01 (dd, J = 13.5, 5.2 Hz, 1H), 2.71 (td, J = 13.1, 2.9 Hz, 1H), 2.62-2.58 (m, 1H), 2.53-2.39 (m, 1H), 1.60 (dt, J = 13.2, 3.4 Hz, 2H).

[0450] [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)

[0451] [ka]

[0452] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpiperidine-1-carboxylate (Intermediate 10, Example 8) (200 mg, 0.51 mmol) and methyl L-alaninate (63.0 mg, 0.620 mmol) in DCM (2 mL) was added TEA (100 mg, 1.03 mmol) and NaBH(AcO) (330 mg, 1.54 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and subsequently extracted with EA (3 × 20 mL). The combined organic phase was 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 reverse phase chromatography eluting with 45% ACN in water (0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropan-2-yl]amino]methyl)piperidine-1-carboxylate as a yellow oil (180 mg, 73%): LCMS (ESI) C 22 H 32 Cl2N2O5[M + H] + Calculated value: 475, 477 (3 : 2) Measured value: 475, 477 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.28-4.15 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.72-3.59 (m, 1H), 3.55-3.33 (m, 2H), 3.09 (d, J = 12.4 Hz, 1H), 2.40-2.25 (m, 1H), 2.01-1.83 (m, 2H), 1.64 (d, J = 7.1 Hz, 2H), 1.53 (s, 9H), 1.48 (d, J = 3.8 Hz, 3H).

[0453] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropan-2-yl]amino]methyl)piperidine-1-carboxylate (180 mg, 0.39 mmol) in DCM (2 mL) at room temperature was added TFA (1 mL). The reaction solution was stirred at room temperature for 1 h. The reactions were each quenched with saturated aqueous NaHCO3 (5 mL), diluted with water (10 mL), and extracted 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 give methyl (2S)-2-([[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]amino)propanoate as a yellow oil (0.20 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 17 H 24 Cl2N2O3[M + H] + Calculated value: 375, 377 (3:2) Measured value: 375, 377 (3:2).

[0454] Step C: To a stirred solution of methyl (2S)-2-([[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]amino)propanoate (200 mg, 0.53 mmol) in EtOH (2 mL) at room temperature was added TEA (160 mg, 1.60 mmol). The reaction solution was stirred at 80° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 55% ACN in water (+10 mM NH4HCO3) to give (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-methyl-octahydropyrido[1,2-a]pyrazin-4-one as a yellow oil (50.0 mg, 38% over two steps): LCMS (ESI) C 16 H 20 Cl2N2O2[M + H] + Calculated value: 343, 345 (3 : 2) Measured value: 343, 345 (3 : 2);1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 4.90-4.79 (m, 1H), 3.82 (s, 3H), 3.77-3.64 (m, 1H), 3.58 (q, J = 7.0 Hz, 1H), 3.45-3.37 (m, 1H), 3.21 (dd, J = 13.3, 5.1 Hz, 1H), 3.00-2.89 (m, 1H), 2.61 (td, J = 12.8, 2.8 Hz, 1H), 2.48-2.27 (m, 2H), 1.72-1.54 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H).

[0455] Step D: 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) was added (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) 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 layer was washed with brine (5 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one as a yellow oil (90 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 18 H 22 Cl2N2O4[M + H] + Calculated value: 401, 403 (3:2) Measured value: 401, 403 (3:2).

[0456] Step E: 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) was added BBr3 (0.25 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, quenched with MeOH (2 mL) at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% to 49% in 8 min; Detector: UV 254 / 220 nm; Retention time: 6.58 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 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) as an off-white solid (8.7 mg, 15% over two steps): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.21 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 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, 4.5 Hz, 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 = 7.1 Hz, 2H).

[0457] [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)

[0458] [ka]

[0459] (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 by the same method as in the previous example using methyl D-alaninate.

[0460] 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) was added BBr3 (0.25 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, quenched with MeOH (2 mL) at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% to 48% in 8 min; Detector: UV 254 / 220 nm. Retention time: 7.13 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 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) as an off-white solid (6.6 mg, 15% over two steps): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated values: 387, 389 (3 : 2) Measured values: 387, 389 (3 : 2);1 H NMR (400 MHz, CD3OD) δ 7.20 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 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 = 11.7 Hz, 1H), 2.86-2.73 (m, 1H), 2.60-2.33 (m, 2H), 1.74-1.51 (m, 3H), 1.45 (d, J = 7.1 Hz, 2H).

[0461] [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)

[0462] [ka]

[0463] Step A: To a solution of 1-tert-butyl 2-methyl(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-1,2-dicarboxylate (2.00 g, 4.78 mmol) in MeOH (20 mL) and HO (1.00 mL) was added LiOH·HO (600 mg, 14.3 mmol) 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 phase was washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)piperidine-2-carboxylic acid as a pale yellow solid (1.90 g, 89%): LCMS (ESI) C 18 H 23 Cl2NO5[M + H] + Calculated values: 404, 406 (3 : 2), measured values: 404, 406 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 8.9 Hz, 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).

[0464] Step B: 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 at room temperature for 30 minutes. To the above solution, TEA (1.03 mL, 10.19 mmol) and N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.95 mmol) were added at room temperature. The reaction was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (40 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1 / 1) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate as a pale yellow oil (400 mg, 36%): LCMS (ESI) C 20 H 28 Cl2N2O5[M + H] + Calculated values: 447, 449 (3 : 2), measured values: 447, 449 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.9 Hz, 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).

[0465] Step C: To a solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (400 mg, 0.89 mmol) in THF (4 mL) was added MeMgBr (3.58 mL, 3.58 mmol, 1 M in THF) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EA (2 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidine-1-carboxylate as a pale yellow oil (0.36 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 19 H 25 Cl2NO4[M + H] + Calculated value: 402, 404 (3:2) Measured value: 402, 404 (3:2).

[0466] Step D: To a stirred solution of tert-butyl (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidine-1-carboxylate (360 mg, 0.90 mmol) in DCM (4 mL) at room temperature, TFA (1 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]ethanone as a pale yellow oil (280 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 14 H 17 Cl2NO2[M + H] + Calculated values: 302, 304 (3 : 2) Measured values: 302, 304 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.27 (dd, J = 12.8, 3.4 Hz, 1H), 3.90-3.88 (m, 1H), 3.87 (s, 3H), 3.57-3.50 (m, 1H), 3.16 (td, J = 13.1, 3.3 Hz, 1H), 2.65-2.43 (m, 2H), 2.41-2.32 (m, 1H), 2.29 (s, 3H), 1.82 (d, J = 14.3 Hz, 1H).

[0467] Step E: 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) was added TEA (0.39 mL, 3.82 mmol) and 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]ethanone (280 mg, 0.93 mmol) at room temperature. 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 layer was washed with brine (5 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidin-1-yl]-2-oxoethyl]carbamate as a yellow oil (500 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 21 H 28 Cl2N2O5[M + H] + Calculated values: 459, 461 (3 : 2) Measured values: 459, 461 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 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).

[0468] Step F: To a solution of tert-butyl N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)piperidin-1-yl]-2-oxoethyl]carbamate (500 mg, 1.09 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was basified to pH 7 with aqueous NaHCO3. The resulting mixture was then extracted with DCM (2 x 20 mL). The combined organic phase was washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,9H,9aH-pyrido[1,2-a]pyrazin-4-one as a pale yellow oil (360 mg, crude): LCMS (ESI) C 16 H 18 Cl2N2O2[M + H] + Calculated values: 341, 343 (3 : 2), measured values ​​341, 343 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 9.0 Hz, 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, 3.0 Hz, 1H), 2.39-2.26 (m, 2H), 2.16-2.08 (m, 1H), 2.06 (t, J = 1.7 Hz, 3H), 1.64 (d, J = 13.3 Hz, 1H).

[0469] Step G: 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) was added PtO (24.0 mg, 0.11 mmol) at room temperature. The mixture was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 12 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 32% MeCN in water (+0.05% TFA) to give (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-1-methyl-octahydropyrido[1,2-a]pyrazin-4-one; trifluoroacetic acid as a pale yellow oil (300 mg, 73%): LCMS (ESI) C 16 H 20 Cl2N2O2[M + H] + Calculated values: 343, 345 (3 : 2), measured values: 343, 345 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 8.8 Hz, 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).

[0470] Step H: To a solution of methoxyacetic acid (120 mg, 1.33 mmol) in DMF (3 mL) and HATU (580 mg, 1.53 mmol) was added (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) at room temperature. 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 phase was washed with brine (4 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge 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: 25% B to 55% B in 7 min; Detector: UV 220 nm; Retention time 1: 6.35 min; Retention time 2: 6.55 min; The faster eluting enantiomer at 6.35 min was obtained as (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one isomer 1 as a pale yellow foam (80.0 mg, 25%): LCMS (ESI) C 19 H 24 Cl2N2O4[M + H] +Calculated values: 415, 417 (3 : 2), measured values: 415, 417 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 9.1 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 5.65-5.18 (m, 1H), 5.03-4.60 (m, 2H), 4.56-3.89 (m, 3H), 3.86-3.61 (m, 4H), 3.59-3.19 (m, 4H), 2.67 (t, J = 12.8 Hz, 1H), 2.44-2.17 (m, 2H), 1.62 (dd, J = 38.6, 13.0 Hz, 2H), 1.50-1.23 (m, 3H). The slower eluting enantiomer at 6.55 min was obtained as (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 (80 mg, 25%): LCMS (ESI) C 19 H 24 Cl2N2O4[M + H] + Calculated values: 415, 417 (3 : 2) Measured values: 415, 417 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.9 Hz, 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 = 12.7 Hz, 1H), 2.45-2.07 (m, 2H), 1.63 (dd, J = 54.4, 13.0 Hz, 2H), 1.39-1.16 (m, 3H).

[0471] Step I: 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) was added BBr (0.15 mL, 1.59 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with MeOH (5 mL). The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 50% B in 7 min; Detector: UV 220 nm; Retention time: 4.15 min 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. Fractions containing the desired product were collected and concentrated under reduced pressure to give 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) as an off-white solid (33.4 mg, 45%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.7 Hz, 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 = 11.2 Hz, 1H), 2.80 (td, J = 13.0, 2.9 Hz, 1H), 2.54-2.34 (m, 2H), 1.71 (dd, J = 35.1, 12.6 Hz, 1H), 1.57 (d, J = 13.3 Hz, 1H), 1.47-1.32 (m, 3H).

[0472] Fractions containing the desired product were collected and concentrated under reduced pressure to give 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 an off-white solid (41.4 mg, 56%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.21 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 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, 13.1 Hz, 2H), 1.39-1.19 (m, 3H).

[0473] [Example 29] Compound 85 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one)

[0474] [ka]

[0475] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, step c) (500 mg, 1.34 mmol) and D-alanyl ester hydrochloride (370 mg, 2.65 mmol) in DCM (5 mL) was added TEA (340 mg, 3.36 mmol) and NaBH(AcO) (570 mg, 2.69 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours, 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropan-2-yl]amino]methyl)pyrrolidine-1-carboxylate as a yellow oil (300 mg, 48%): LCMS (ESI) C 21 H 30 Cl2N2O5[M + H] + Calculated values ​​461, 463 (3 : 2) Measured values ​​461, 463 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 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 = 7.2 Hz, 3H), 1.52 (s, 9H).

[0476] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-([[(2S)-1-methoxy-1-oxopropan-2-yl]amino]methyl)pyrrolidine-1-carboxylate (300 mg, 0.65 mmol) in DCM (5 mL) at room temperature was added TFA (1 mL). The reaction was stirred at room temperature for 1 h. The resulting reaction was concentrated under reduced pressure. The residue was dissolved in EtOH (5 mL) and TEA (200 mg, 1.95 mmol) was added. The reaction 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 give (3S,7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one as a yellow oil (220 mg, 95%): LCMS (ESI) C 15 H 18 Cl2N2O2[M + H] + Calculated values ​​329, 331 (3 : 2) Measured values ​​329, 331 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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).

[0477] Step C: To a stirred solution of (3S,7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (120 mg, 0.36 mmol) in DCM (3 mL) was added BBr (550 mg, 2.20 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 12% ACN in water (+0.05% TFA) to give compound 85 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one) as a pale yellow oil (80.0 mg, 51%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values ​​315, 317 (3 : 2) Measured values ​​315, 317 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.31 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 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).

[0478] [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)

[0479] [ka]

[0480] 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) was added (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) at room temperature. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (0.5 mL) and purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 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 give compound 60 ((3S,7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one) as an off-white solid (14.5 mg, 24%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values ​​373, 375 (3 : 2) Measured values ​​373, 375 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.26 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.45-4.21 (m, 4H), 4.21-4.10 (m, 2H), 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 = 7.0 Hz, 3H).

[0481] [Example 31] Compound 87 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methylhexahydropyrrolo[1,2-a]pyrazin-4(1H)-one isomer 1) and compound 88 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methylhexahydropyrrolo[1,2-a]pyrazin-4(1H)-one isomer 2)

[0482] [ka]

[0483] Step A: To a stirred solution of 1-tert-butyl 2-methyl(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (Intermediate 7, Example 6) (2.00 g, 4.95 mmol) in MeOH (20 mL) was added LiOH·HO (620 mg, 14.84 mmol) in HO (1 mL) at room temperature. The reaction was then stirred at room temperature for 12 h, acidified to pH 3 with citric acid (30 mL), and subsequently extracted with EA (3 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL) and dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-carboxylic acid as an off-white foam (1.60 g, 83%): LCMS (ESI) C 17 H 21 Cl2NO5[M + Na] + Calculated value: 412, 414 (3 : 2) Measured value: 412, 414 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 9.0 Hz, 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).

[0484] Step B: 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) was added EDCI (1.03 g, 5.38 mmol) and HOBT (720 mg, 5.38 mmol) 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 phase was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 4) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate as a pale yellow oil (1.10 g, 71%): LCMS (ESI) C 19 H 26 Cl2N2O5[M + H] + Calculated value: 433, 435 (3 : 2) Measured value: 433, 435 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.78 (s, 1H), 4.20-4.08 (m, 1H), 4.00-3.87 (m, 1H), 3.82 (d, J = 3.4 Hz, 3H), 3.80-3.66 (m, 4H), 3.25 (s, 3H), 2.64-2.35 (m, 2H), 1.47 (d, J = 11.1 Hz, 9H).

[0485] Step C: To a solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (1.10 g, 2.54 mmol) in THF (10 mL) was added MeMgBr (7.62 mL, 7.614 mmol, 1 M solution in THF) at 0 °C. The reaction was stirred at room temperature under a nitrogen atmosphere for 1 h, quenched with saturated aqueous NH4Cl (10 mL), and subsequently extracted with EA (3 × 50 mL). The combined organic phase was washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate as a yellow oil (630 mg, 89%): LCMS (ESI) C 18 H 23 Cl2NO4[M + Na] + Calculated values: 410, 412 (3 : 2), measured values: 410, 412 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.43 (t, J = 8.7 Hz, 1H), 4.27-4.17 (m, 1H), 3.93 (t, J = 10.3 Hz, 1H), 3.87-3.68 (m, 4H), 2.60-2.45 (m, 1H), 2.40-2.28 (m, 1H), 2.22 (d, J = 5.1 Hz, 3H), 1.48 (d, J = 11.7 Hz, 9H).

[0486] Step D: To a solution of tert-butyl (2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-1-carboxylate (630 mg) in DCM (4 mL) at room temperature was added TFA (1 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated under reduced pressure to give 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]ethanone as a pale yellow oil (470 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 13 H 15 Cl2NO2[M + H] + Calculated value: 288, 290 (3:2) Measured value: 288, 290 (3:2).

[0487] Step E: 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) was added 1-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]ethanone (420 mg, 1.47 mmol) and TEA (0.6 mL, 6.05 mmol) at room temperature. The reaction was then stirred at room temperature for 1 hour, poured into water (30 mL), and subsequently extracted with EA (2 × 50 mL). The combined organic phase was 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 eluting with EA / PE (3 / 2) to give tert-butyl N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-1-yl]-2-oxoethyl]carbamate as an off-white solid (580 mg, 80% over two steps): LCMS (ESI) C 20 H 26 Cl2N2O5[M + H] + Calculated value: 445, 447 (3 : 2) Measured value: 445, 447 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 4.66 (t, J = 8.8 Hz, 1H), 4.36-4.24 (m, 1H), 4.08-3.89 (m, 3H), 3.84 (s, 3H), 3.66 (t, J = 8.8 Hz, 1H), 2.51-2.33 (m, 2H), 2.24 (s, 3H), 1.47 (d, J = 5.2 Hz, 9H).

[0488] Step F: To a solution of tert-butyl N-[2-[(2S,4R)-2-acetyl-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-1-yl]-2-oxoethyl]carbamate (580 mg, 1.31 mmol) in DCM (4 mL) at room temperature was added TFA (1 mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-3H,6H,7H,8H,8aH-pyrrolo[1,2-a]pyrazin-4-one as a pale yellow oil (660 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 15 H 16 Cl2N2O2[M + H] + Calculated value: 327, 329 (3:2) Measured value: 327, 329 (3:2).

[0489] Step G: 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) was added NaBH (150 mg, 4.05 mmol) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The resulting mixture was diluted with NH Cl (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-1-methyl-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one as a pale yellow oil (380 mg, 88% over two steps): LCMS (ESI) C 15 H 18 Cl2N2O2[M + H] + Calculated values: 329, 331 (3 : 2) Measured values: 329, 331 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.46 (dd, J = 9.0, 1.7 Hz, 1H), 7.04 (dd, J = 12.9, 8.9 Hz, 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, 4.9 Hz, 3H).

[0490] Step H: A solution of methoxyacetic acid (150 mg, 1.64 mmol) and HATU (620 mg, 1.64 mmol) in DMF (8 mL) was stirred at room temperature for 30 minutes. To the mixture was then added 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) at room temperature. The reaction was stirred at room temperature for 1 hour, diluted with water (30 mL), and extracted with EA (2 × 30 mL). The combined organic layer was washed with brine (5 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one as a pale yellow oil (350 mg, 80%), which was used directly in the next step without further purification: LCMS (ESI) C 18 H 22 Cl2N2O4[M + H] + Calculated value: 401, 403 (3:2) Measured value: 401, 403 (3:2).

[0491] Step I: 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) was added BBr3 (5 mL) slowly at 0 °C. The resulting mixture was stirred at room temperature for 50 minutes. 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 using the following conditions: Column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm, 10 nm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 23% B to 48% B in 11 min; UV: Detector 220 nm; Retention time 1: 10.05 min, Retention time 2: 10.6 min. The fractions containing the desired product at 10.05 min gave compound 87 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one isomer 1) as an off-white solid (35 mg, 12.54%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values: 373, 375 (3 : 2), measured values: 373, 375 (3 : 2); 1 H NMR (400 MHz,CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 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 = 5.2 Hz, 3H); The fractions containing the desired product at 10.60 min were combined to give compound 88 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-1-methyl-hexahydropyrrolo[1,2-a]pyrazin-4-one isomer 2) as an off-white solid (55 mg, 19.71%): LCMS (ESI) C 16 H 18Cl2N2O4[M + H] + Calculated values: 373, 375 (3 : 2), measured values: 373, 375 (3 : 2); 1 H NMR (400 MHz,CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 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, 6.7 Hz, 1H), 1.35 (d, J = 6.2 Hz, 3H).

[0492] [Example 32] Compound 18 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one)

[0493] [ka]

[0494] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, Step c) (1.90 g, 5.08 mmol) and methyl 3-aminopropanoate hydrochloride (500 mg, 1.39 mmol) in DCM (20 mL) was added TEA (430 mg, 4.25 mmol) and NaBH(AcO) (600 mg, 2.83 mmol) at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-hydroxyphenyl)-2-[[(3-methoxy-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylate as a yellow oil (300 mg, 48%): LCMS (ESI) C 21 H 30 Cl2N2O5[M + H] + Calculated values ​​461, 463 (3 : 2) Measured values ​​461, 463 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 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).

[0495] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-hydroxyphenyl)-2-[[(3-methoxy-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylate (120 mg, 0.26 mmol) in DCM (2 mL) at room temperature was added TFA (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·HO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrrolo[1,2-a][1,4]diazepin-5-one as a yellow oil (30.0 mg, 35%): LCMS (ESI) C 15 H 18 Cl2N2O2[M + H] + Calculated values ​​329, 331 (3 : 2) Measured values ​​329, 331 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 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).

[0496] Step C: To a stirred solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-octahydropyrrolo[1,2-a][1,4]diazepin-5-one (30.0 mg, 0.09 mmol) in DCM (1 mL) was added BBr3 (91.0 mg, 0.37 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 20% ACN in water (+0.05% TFA) to give (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrrolo[1,2-a][1,4]diazepin-5-one trifluoroacetate as a colorless oil (30.0 mg, 77%): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated values ​​315, 317 (3 : 2) Measured values ​​315, 317 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.55-4.42 (m, 1H), 4.05-3.96 (m, 1H), 3.80-3.70 (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).

[0497] Step D: 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) at room temperature was added (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrrolo[1,2-a][1,4]diazepin-5-one trifluoroacetic 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 using 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: 15% B to 45% B in 8 min; Detector: UV 254 / 220 nm; Retention time: 6.98 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 18 (8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one as an off-white solid (8.7 mg, 33%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values ​​373, 375 (3 : 2) Measured values ​​373, 375 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 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).

[0498] [Example 33] Compound 90 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diazepin-5-one)

[0499] [ka]

[0500] Step A: To a stirred mixture of (methoxymethyl)triphenylphosphanium chloride (770 mg, 2.23 mmol) in THF (5 mL) was added dropwise t-BuOK (2.22 mL, 2.22 mmol, 1 M in THF) under a nitrogen atmosphere at 0° C. The reaction was stirred at 0° C. for 15 min. Then, tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (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 and then diluted 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 70% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyethenyl)pyrrolidine-1-carboxylate as a yellow oil (300 mg, 59%): LCMS (ESI) C 19 H 25 Cl2NO4[M + H] + Calculated values ​​402, 404 (3:2) Measured values ​​402, 404 (3:2); 1H NMR (400 MHz, CD3OD) δ 7.47-7.39 (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).

[0501] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyethenyl)pyrrolidine-1-carboxylate (300 mg, 0.75 mmol) in acetone (5 mL) at room temperature was added TsOH·HO (71.0 mg, 0.37 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-oxoethyl)pyrrolidine-1-carboxylate as a yellow oil (300 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 18 H 23 Cl2NO4[M + H] + Calculated values ​​388, 340 (3 : 2) Measured values ​​388, 340 (3 : 2);

[0502] Step C: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (210 mg, 0.54 mmol) and methyl 2-aminoacetate hydrochloride (140 mg, 1.08 mmol) in DCM (2 mL) was added TEA (160 mg, 1.62 mmol) and NaBH(AcO) (340 mg, 1.62 mmol) at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 35% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[(2-methoxy-2-oxoethyl)amino]ethyl]pyrrolidine-1-carboxylate as a pale yellow oil (110 mg, 48% over two steps): LCMS (ESI) C 21 H 30 Cl2N2O5[M + H] + Calculated values ​​461, 463 (3 : 2) Measured values ​​461, 463 (3 : 2);

[0503] Step D: To a stirred solution of methoxyacetic acid (43.0 mg, 0.48 mmol) and HATU (180 mg, 0.48 mmol) in DMF (2 mL) at room temperature was added [2-[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]ethyl](2-methoxy-2-oxoethyl)aminyl (110 mg, 0.24 mmol) and TEA (72.0 mg, 0.72 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 40% ACN in water (+0.05% TFA) to afford tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[2-methoxy-N-(2-methoxy-2-oxoethyl)acetamido]ethyl]pyrrolidine-1-carboxylate as a pale yellow oil (50.0 mg, 39%): LCMS (ESI) C 24 H 34 Cl2N2O7[M + H] + Calculated values ​​533, 535 (3 : 2) Measured values ​​533, 535 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.1 Hz, 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).

[0504] Step E: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[2-[2-methoxy-N-(2-methoxy-2-oxoethyl)acetamido]ethyl]pyrrolidine-1-carboxylate (50.0 mg, 0.09 mmol) in DCM (2 mL) at room temperature was added TFA (1 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 HO (20.0 mg, 0.47 mmol) in water (0.5 mL) was added. The reaction was stirred at 40° C. for 1 hour. The reaction was concentrated under reduced pressure to give (N-[2-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]ethyl]-2-methoxyacetamido)acetic acid as a yellow solid (50.0 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 18 H 24 Cl2N2O5[M + H] + Calculated values: 419, 421 (3:2) Measured values: 419, 421 (3:2).

[0505] Step F: A solution of (N-[2-[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]ethyl]-2-methoxyacetamido)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 reverse-phase chromatography eluting with 35% ACN in water (+0.05% TFA) to afford (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(2-methoxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diazepin-5-one as a pale yellow oil (25.0 mg, 65% over two steps): LCMS (ESI) C 18 H 22 Cl2N2O4[M + H] + Calculated values ​​401, 403 (3:2) Measured values ​​401, 403 (3:2); 1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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).

[0506] Step G: To a stirred solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-3-(2-methoxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diazepin-5-one (25.0 mg, 0.06 mmol) in DCM (1 mL) was added BBr3 (94.0 mg, 0.37 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column 30 × 150 mm 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B in 7 min; Detector: UV 220 nm; Retention time: 6.92 min. Fractions containing the desired product were combined and concentrated under reduced pressure to give compound 90 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-3-(2-hydroxyacetyl)-hexahydro-1H-pyrrolo[1,2-d][1,4]diazepin-5-one) as an off-white solid (7.8 mg, 34%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values ​​373, 375 (3 : 2) Measured values ​​373, 375 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.25 (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).

[0507] [Example 34] Compound 91 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyloctahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one 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]diazepin-5-one isomer 2)

[0508] [ka]

[0509] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, Step c) (300 mg, 0.80 mmol) and methyl 3-amino-2-methylpropanoate (110 mg, 0.96 mmol) in DCM (4 mL) was added NaOAc (130 mg, 1.60 mmol) and NaBH(OAc) (500 mg, 2.40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aqueous NH4Cl (30 mL) and subsequently extracted with EA (3 × 20 mL). The combined organic phase was 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 reverse phase chromatography eluting with 55% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(3-methoxy-2-methyl-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylate as a pale yellow oil (400 mg, 80%): LCMS (ESI) C 22 H 32 Cl2N2O5[M + H] +Calculated value: 475, 477 (3 : 2) Measured value: 475, 477 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 4.26-4.08 (m, 1H), 3.86 (s, 3H), 3.83-3.72 (m, 4H), 3.67 (t, J = 9.6 Hz, 1H), 3.54-3.38 (m, 2H), 3.25-3.00 (m, 4H), 2.48-2.24 (m, 2H), 1.49 (d, J = 3.5 Hz, 9H), 1.38-1.29 (m, 3H).

[0510] Step B: To a stirred solution of methoxyacetic acid (110 mg, 1.26 mmol) and HATU (480 mg, 1.26 mmol) in DMF (4 mL) was added tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(3-methoxy-2-methyl-3-oxopropyl)amino]methyl]pyrrolidine-1-carboxylate (400 mg, 0.84 mmol) and TEA (250 mg, 2.52 mmol) 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 phase was washed with brine (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 60% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[2-methoxy-N-(3-methoxy-2-methyl-3-oxopropyl)acetamido]methyl]pyrrolidine-1-carboxylate as a yellow oil (300 mg, 65%): LCMS (ESI) C 25 H 36 Cl2N2O7[M + H] + Calculated value: 547, 549 (3 : 2) Measured value: 547, 549 (3 : 2); 1H NMR (400 MHz,CDCl3) δ 7.34 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.31-4.12 (m, 4H), 4.12-3.93 (m, 1H), 3.90 (d, J = 4.1 Hz, 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 = 19.1 Hz, 9H), 1.25-1.10 (m, 3H).

[0511] Step C: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[2-methoxy-N-(3-methoxy-2-methyl-3-oxopropyl)acetamido]methyl]pyrrolidine-1-carboxylate (300 mg, 0.55 mmol) in DCM (3 mL) at room temperature was added TFA (1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give methyl 3-(N-[[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)-2-methylpropanoate as a yellow oil (0.30 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 20 H 28 Cl2N2O5[M + H] + Calculated value: 447, 449 (3 : 2) Measured value: 447,449 (3 : 2).

[0512] Step D: To a stirred solution of methyl 3-(N-[[(2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)-2-methylpropanoate (300 mg, 0.67 mmol) in MeOH (3 mL) was added LiOH·HO (56.0 mg, 1.34 mmol) in HO (1 mL) at room temperature. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 30% ACN in water (+0.05% TFA) to give (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one as a yellow oil (60.0 mg, 27% over two steps): LCMS (ESI) C 19 H 24 Cl2N2O4[M + H] + Calculated values: 415, 417 (3 : 2) Measured values: 415, 417 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.41-7.35 (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).

[0513] Step E: To a stirred solution of (8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one (60.0 mg, 0.14 mmol) in DCM (1 mL) was added BBr3 (0.5 mL) at room temperature. 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 using the following conditions: Column: Xselect CSH OBD column 30 × 150 mm 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% to 40% in 8 min; Detector: UV 254 / 220 nm; Retention time 1: 8.68 min, Retention time 2: 8.98 min. The fractions containing the desired product at 8.68 min were collected and concentrated under reduced pressure to give compound 91 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one isomer 1) as an off-white solid (3.8 mg, 2%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.65-4.36 (m, 1H), 4.36-4.29 (m, 2H), 4.29-4.10 (m, 2H), 4.09-3.98 (m, 2H), 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, 6.6 Hz, 1H), 1.29 (dd, J = 18.8, 7.5 Hz, 3H). The fractions containing the desired product at 8.98 min were collected and concentrated under reduced pressure to give compound 92 ((8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-4-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one isomer 2) as an off-white solid (2 mg, 1%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.71-4.27 (m, 3H), 4.19-3.97 (m, 3H), 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 = 7.0 Hz, 3H).

[0514] [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]diazepin-5-one)

[0515] [ka]

[0516] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, step c) (400 mg, 1.07 mmol) and (3R)-3-aminobutanoic acid (170 mg, 1.60 mmol) in DCM (5 mL) at room temperature was added HOAc (0.06 mL, 1.020 mmol) and NaBH(AcO) (680 mg, 3.21 mmol). The reaction was stirred at room temperature for 1 h. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3R)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]amino)butanoic acid as a pale yellow oil (300 mg, 55%): LCMS (ESI) C 21 H 30 Cl2N2O5[M + H] + Calculated values: 461, 463 (3 : 2) Measured values: 461, 463 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.35 (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 = 11.7 Hz, 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).

[0517] Step B: To a stirred solution of methoxyacetic acid (79.0 mg, 0.88 mmol) and HATU (300 mg, 0.88 mmol) in DMF (3 mL) was added (3R)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]amino)butanoic acid (270 mg, 0.59 mmol) and TEA (0.24 mL, 2.41 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with EA (3 × 20 mL). The combined organic phase was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3R)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)butanoic acid as a pale yellow oil (220 mg, 63%): LCMS (ESI) C 24 H 34 Cl2N2O7[M + H] + Calculated value: 533, 535 (3 : 2) Measured value: 533, 535 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 20.6, 10.4 Hz, 1H), 6.77 (dd, J = 16.2, 9.2 Hz, 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).

[0518] Step C: To a stirred solution of (3R)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)butanoic acid (220 mg, 0.41 mmol) in DCM (2 mL) at room temperature was added TFA (0.50 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 48% ACN in water (+0.05% TFA) to give (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one as a pale yellow oil (140 mg, 74%): LCMS (ESI) C 19 H 24 Cl2N2O4[M + H] + Calculated value: 415, 417 (3:2) Measured value: 415, 417 (3:2).

[0519] Step D: To a stirred mixture of (3R,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one (70.0 mg, 0.17 mmol) in DCM (1 mL) was added BBr (0.25 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then quenched with MeOH (5 mL) at 0° C. and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 7.00 min; Detector: UV 220 nm; Retention time: 7.03 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 93 ((3R,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one) as an off-white solid (19.7 mg, 29%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.25 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 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 = 54.0 Hz, 1H), 1.36-1.22 (m, 3H).

[0520] [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]diazepin-5-one)

[0521] [ka]

[0522] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, step c) (400 mg, 1.07 mmol) and (3S)-3-aminobutanoic acid (170 mg, 1.60 mmol) in DCM (5 mL) at room temperature was added HOAc (0.06 mL, 1.02 mmol) and NaBH(AcO) (680 mg, 3.21 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and subsequently 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 reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]amino)butanoic acid as a pale yellow oil (220 mg, 40%): LCMS (ESI) C 21 H 30 Cl2N2O5[M + H] + Calculated values: 461, 463 (3 : 2) Measured values: 461, 463 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 4.18-4.02 (m, 2H), 3.87 (s, 3H), 3.83-3.66 (m, 2H), 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 = 6.5 Hz, 3H).

[0523] Step B: To a stirred solution of methoxyacetic acid (64.0 mg, 0.72 mmol) and HATU (280 mg, 0.72 mmol) in DMF (3 mL) was added (3S)-3-([[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]amino)butanoic acid (220 mg, 0.48 mmol) and TEA (140 mg, 1.43 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give (3S)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)butanoic acid as a pale yellow oil (140 mg, 50%): LCMS (ESI) C 24 H 34 Cl2N2O7[M + H] + Calculated value: 533, 535 (3 : 2) Measured value: 533, 535 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (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).

[0524] Step C: To a stirred solution of (3S)-3-(N-[[(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-yl]methyl]-2-methoxyacetamido)butanoic acid (140 mg, 0.26 mmol) in DCM (2 mL) at room temperature was added TFA (0.5 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one as a pale yellow oil (70.0 mg, 58%): LCMS (ESI) C 19 H 24 Cl2N2O4[M + H] + Calculated value: 415, 417 (3:2) Measured value: 415, 417 (3:2).

[0525] Step D: To a stirred mixture of (3S,8R,9aS)-8-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one (70.0 mg, 0.17 mmol) in DCM (1 mL) was added BBr3 (0.25 mL) dropwise at room temperature. The resulting mixture was stirred under nitrogen for 1 hour. 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 using 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: 20% B to 40% B in 7 min; Detector: UV 220 nm; Retention time: 7.03 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 94 ((3S,8R,9aS)-8-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-3-methyl-hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-5-one) as an off-white solid (17.7 mg, 27%): LCMS (ESI) C 17 H 20 Cl2N2O4[M + H] + Calculated value: 387, 389 (3 : 2) Measured value: 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 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).

[0526] [Example 37] Compound 55 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide)

[0527] [ka]

[0528] Step A: 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) was added isocyanatotrimethylsilane (17 mg, 0.14 mmol) at 0° C. The reaction was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 38% B in 8 min; Detector: UV 220 nm; Retention time: 6.40 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 55 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide) as an off-white solid (17.0 mg, 47%): LCMS (ESI) C 14 H 15 Cl2N3O3[M + H] + Calculated values: 344, 346 (3 : 2), measured values ​​344, 346 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.48-4.27 (m, 3H), 4.21-4.13 (m, 1H), 3.96-3.87 (m, 1H), 3.82 (d, J = 17.7 Hz, 1H), 3.59 (t, J = 11.4, 9.7 Hz, 1H), 2.88 (dd, J = 13.2, 10.5 Hz, 1H), 2.45-2.42 (m, 1H), 2.22-2.13 (m, 1H).

[0529] [Example 38] Compounds 96-97 were prepared in a similar manner to that described for compound 55.

[0530] [Table 5]

[0531] [Example 39] Compound 30 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-N,N-dimethyl-4-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide)

[0532] [ka]

[0533] Step A: 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) was added N,N-diisopropylethylamine (150 mg, 1.15 mmol) and 4-nitrophenyl chloroformate (84.0 mg, 0.42 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 1 h. The reaction was diluted with water (20 mL) and subsequently extracted with EA (3 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water (+0.05% TFA) to give 4-nitrophenyl (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate as a pale yellow solid (110 mg, 42%): LCMS (ESI) C 20 H 17 Cl2N3O6[M + H] + Calculated value: 466, 468 (3 : 2) Measured value: 466, 468 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.34 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.8 Hz, 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 = 10.4 Hz, 1H), 3.05 (dt, J = 72.4, 11.8 Hz, 1H), 2.31-2.08 (m, 2H).

[0534] Step B: To a stirred solution of 4-nitrophenyl(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylate (30.0 mg, 0.06 mmol) and dimethylamine (9 mg, 0.19 mmol) in DMF (1 mL) was added KCO (18 mg, 0.13 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The reaction was filtered, and the filtrate was purified by preparative HPLC using 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: 25% to 50% in 8 min; Detector: UV 254 / 220 nm; Retention time: 5.85 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 30 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-N,N-dimethyl-4-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide) as an off-white solid (14.0 mg, 55.53%): LCMS (ESI) C 16 H 19 Cl2N3O3[M + H] + Calculated value: 372, 374 (3 : 2) Measured value: 372, 374 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.26 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.37-4.25 (m, 1H), 4.19 (dd, J = 11.4, 9.2 Hz, 1H), 4.13-4.04 (m, 2H), 4.03-3.94 (m, 1H), 3.85 (d, J = 17.6 Hz, 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).

[0535] [Example 40] Compounds 99-104 were prepared in a similar manner to that described for compound 30.

[0536] [Table 6-1]

[0537] [Table 6-2]

[0538] [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)

[0539] [ka]

[0540] Step A: 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-dioxaborolan-2-yl)pyridine-2-carbonitrile (1.52 g, 6.60 mmol) in dioxane (20 mL) and HO (5 mL) was added NaCO (2.10 g, 19.81 mmol) and Pd(dppf)Cl·CHCl (540 mg, 0.66 mmol) at room temperature under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. The reaction was then 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give 5-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carbonitrile as a yellow solid (1.50 g, 81%): LCMS (ESI) C 13 H8Cl2N2O [M + H] + Calculated values: 279, 281 (3 : 2) Measured values: 279, 281 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.63 (dd, J = 1.9, 1.1 Hz, 1H), 7.83-7.75 (m, 2H), 7.54 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H).

[0541] Step B: To a stirred mixture of 5-(2,3-dichloro-6-methoxyphenyl)pyridine-2-carbonitrile (1.00 g, 3.58 mmol) in HCl (3.00 mL, 6 M) and MeOH (30 mL) at room temperature was added PtO (0.40 g, 1.76 mmol). The reaction mixture was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 16 hours. The reaction was filtered and concentrated under reduced pressure to give 1-[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methanamine as a pale yellow oil (1.50 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 13 H 12 Cl2N2O [M + H] + Calculated value: 283, 285 (3:2) Measured value: 283, 285 (3:2).

[0542] Step C: To a solution of 1-[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methanamine (1.50 g, 5.30 mmol) in DCM (15 mL) and TEA (1.84 mL, 18.2 mmol) was added BocO (1.16 g, 5.30 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give tert-butyl N-[[5-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methyl]carbamate as a colorless oil (0.80 g, 58% overall for two steps): LCMS (ESI) C 18 H 20 Cl2N2O3[M + H] + Calculated value: 383, 385 (3 : 2) Measured value: 383, 385 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.61 (dd, J = 8.0, 2.2 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 5.65-5.60 (brs, 1H), 4.55 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 1.51 (s, 9H).

[0543] Step D: To a solution of tert-butyl N-[[4-(2,3-dichloro-6-methoxyphenyl)pyridin-2-yl]methyl]carbamate (0.60 g, 1.57 mmol) in MeCN (15 mL) at room temperature was added benzyl bromide (1.34 g, 7.85 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction mixture was then concentrated under reduced pressure to give 1-benzyl-2-[[(tert-butoxycarbonyl)amino]methyl]-4-(2,3-dichloro-6-methoxyphenyl)pyridin-1-ium bromide as a light brown oil (1.00 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 25 H 27 BrCl2N2O3[M] + Calculated value: 473, 475 (3:2) Measured value: 473, 475 (3:2).

[0544] Step E: To a solution of 1-benzyl-2-[[(tert-butoxycarbonyl)amino]methyl]-5-(2,3-dichloro-6-methoxyphenyl)pyridin-1-ium bromide (1.00 g, 1.81 mmol) in MeOH (10 mL) was added NaBH (200 mg, 5.29 mmol) in small portions at room temperature. The reaction was stirred at room temperature for 2 h. The resulting mixture was quenched with saturated aqueous NH Cl (5 mL) and subsequently extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give tert-butyl N-[[1-benzyl-5-(2,3-dichloro-6-methoxyphenyl)-3,6-dihydro-2H-pyridin-2-yl]methyl]carbamate as a pale yellow oil (300 mg, 40% over two steps): LCMS (ESI) C 25 H 30 Cl2N2O3[M + H] + Calculated value: 477, 479 (3 : 2) Measured value: 477, 479 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.45-7.38 (m, 2H), 7.37-7.26 (m, 4H), 6.71 (d, J = 8.9 Hz, 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 = 18.1 Hz, 1H), 2.05 (d, J = 14.4 Hz, 1H), 1.49 (s, 9H).

[0545] Step F: To a solution of tert-butyl 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 was added PtO2 (100 mg, 0.44 mmol). The reaction mixture was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give tert-butyl N-[[5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate as a pale yellow solid (180 mg, 74%): LCMS (ESI) C 18 H 26 Cl2N2O3[M + H] + Calculated values: 389, 391 (3 : 2) Measured values: 389, 391 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 1H), 6.74 (dd, J = 8.9, 3.0 Hz, 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).

[0546] Step G: To a solution of tert-butyl 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) was added chloroacetyl chloride (57.0 mg, 0.51 mmol) at 0 °C. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-[[1-(2-chloroacetyl)-5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate as a pale yellow oil (250 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 20 H 27 Cl3N2O4[M + H] + Calculated value: 465, 467 (1:1) Measured value: 465, 467 (1:1).

[0547] Step H: To a solution of tert-butyl N-[[1-(2-chloroacetyl)-5-(2,3-dichloro-6-methoxyphenyl)piperidin-2-yl]methyl]carbamate (100 mg, 0.22 mmol) in DMF (2 mL) was added NaH (17.0 mg, 0.43 mmol, 60% in oil) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl (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 eluting with PE / EA (3 / 1) to give tert-butyl 7-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate as a colorless oil (160 mg, 80% over two steps): LCMS (ESI) C 20 H 26Cl2N2O4[M + H] + Calculated value: 429, 431 (3:2) Measured value: 429, 431 (3:2)

[0548] Step I: To a solution of tert-butyl 7-(2,3-dichloro-6-methoxyphenyl)-4-oxo-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (160 mg, 0.37 mmol) in DCM (2 mL) was added BBr3 (0.32 mL, 1.28 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with MeOH (3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 30% B in 9 min; Detector: UV 220 nm; Retention time 1: 9.07 min, Retention time 2: 9.42 min. The faster eluting enantiomer at 9.07 min was obtained as an off-white foam (30.0 mg, 26%), assumed to be compound 105 ((7S,9aR)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated: 315, 317 (3:2) Found: 315, 317 (3:2). The slower eluting enantiomer at 9.42 min was obtained as an off-white foam (30.0 mg, 26%), assumed to be compound 106 ((7S,9aS)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-octahydropyrido[1,2-a]pyrazin-4-one): LCMS (ESI) C 14 H 16 Cl2N2O2[M + H] + Calculated value: 315, 317 (3:2) Measured value: 315, 317 (3:2).

[0549] [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)

[0550] [ka]

[0551] 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) was added (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) 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 phase was washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 43% B in 7 min; Detector: UV 220 nm; Retention time: 6.68 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 26 ((7S,9aR)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) as an off-white solid (10.2 mg, 29%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated values: 373, 375 (3 : 2), measured values: 373, 375 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.24 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.8 Hz, 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).

[0552] [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)

[0553] [ka]

[0554] 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) was added (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) at room temperature. 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 phase was washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 7 min; Detector: UV 220 nm; Retention time: 6.30 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 13 ((7S,9aS)-rel-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxyacetyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-4-one) as an off-white solid (10.2 mg, 29%): LCMS (ESI) C 16 H 18 Cl2N2O4[M + H] + Calculated value: 373, 375 (3 : 2) Measured value: 373, 375 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.23 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 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).

[0555] [Example 44] Compounds 109-122 were prepared in a manner analogous to the examples disclosed herein and / or methods known in the art.

[0556] [Table 7-1]

[0557] [Table 7-2]

[0558] [Table 7-3]

[0559] [Example 45] Compound 123 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(3-hydroxycyclobutyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0560] [ka]

[0561] Step A: 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) was added NaBH(OAc) (0.113 g, 0.53 mmol) at room temperature. The reaction was quenched with saturated aqueous NH4Cl (30 mL) over 4 hours and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-[(7aR,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]cyclobutyl acetate as an off-white solid (0.100 g, crude), which was used directly in the next step without purification: LCMS (ESI) C 19 H 22 Cl2N2O4[M + H] + Calculated value: 413, 415 (3:2) Measured value: 413, 415 (3:2).

[0562] Step B: A mixture of 3-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]cyclobutyl acetate (80.0 mg, 0.19 mmol) and K2CO3 (80.0 mg, 0.58 mmol) in MeOH (2 mL) was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 35% B in 7 min; Detector: UV 220 nm; Retention time: 6.77 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 123 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(3-hydroxycyclobutyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one) as an off-white solid (23.4 mg, 33%). LCMS (ESI) C 17 H 20 Cl2N2O3[M + H] + Calculated values: 371, 373 (3 : 2) Measured values: 371, 373 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.29 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.54-4.34 (m, 1H), 4.27-4.15 (m, 1H), 4.16-3.98 (m, 3H), 3.93 (d, J = 11.5 Hz, 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).

[0563] [Example 46] Compounds 124-147 were prepared in a similar manner to that described for compound 123.

[0564] [Table 8-1]

[0565] [Table 8-2]

[0566] [Table 8-3]

[0567] [Table 8-4]

[0568] [Table 8-5]

[0569] [Table 8-6]

[0570] [Example 47] Compound 148 ((7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxy-2-methylpropyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one)

[0571] [ka]

[0572] To a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-4-one (free base of Intermediate 8, Example 7) (30.0 mg, 0.10 mmol) in EtOH (1 mL) was added 2,2-dimethyloxirane (11.0 mg, 0.15 mmol) at room temperature under nitrogen. The resulting solution was stirred at 80° C. for 36 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: X Bridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+ 10 mM NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 7 min; Detector: UV 220 nm; Retention time: 7.12 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-2-(2-hydroxy-2-methylpropyl)-hexahydropyrrolo[1,2-a]pyrazin-4-one as an off-white solid (20 mg, 53%). LCMS (ESI) C 17 H 22 Cl2N2O3 [M + H] + Calculated value: 373, 375 (3 : 2) Measured value: 373, 375 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.25 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.38-4.24 (m, 1H), 4.15 (t, J = 11.5 Hz, 1H), 4.06-3.92 (m, 1H), 3.64 (d, J = 17.0 Hz, 1H), 3.52 (t, J = 10.7 Hz, 1H), 3.40 (dd, J = 11.8, 3.8 Hz, 1H), 3.05 (d, J = 17.1 Hz, 1H), 2.57-2.40 (m, 2H), 2.40-2.22 (m, 2H), 2.14-2.02 (m, 1H), 1.24 (s, 6H).

[0573] [Example 48] Compounds 149-159 were prepared in a similar manner as described for compound 148.

[0574] [Table 9-1]

[0575] [Table 9-2]

[0576] [Table 9-3]

[0577] [Example 49] Compound 160 (4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidin-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]pyrrolidin-2-one isomer 2)

[0578] [ka]

[0579] Step A: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-formylpyrrolidine-1-carboxylate (Example 7, step c) (0.500 g, 1.34 mmol) and 4-aminopyrrolidin-2-one (0.550 g, 4.01 mmol) in DCM (10 mL) was added TEA (0.540 g, 5.34 mmol) and NaBH(OAc) (1.13 g, 5.34 mmol) at room temperature. The reaction was stirred for 12 hours while being monitored by LCMS, quenched with saturated aqueous NH4Cl (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 reverse phase chromatography eluting with 75% ACN in water (+10 mM NH4HCO3) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(5-oxopyrrolidin-3-yl)amino]methyl]pyrrolidine-1-carboxylate as an off-white solid (0.450 g, 73%): LCMS (ESI) C 21 H 29 Cl2N3O4[M + H] + Calculated value: 458, 460 (3 : 2) Actual value 458, 460 (3 : 2); H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.0 Hz, 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).

[0580] Step B: To a stirred solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(5-oxopyrrolidin-3-yl)amino]methyl]pyrrolidine-1-carboxylate (0.150 g, 0.33 mmol) and ethyl bromoacetate (0.110 g, 0.65 mmol) in ACN (5 mL) was added K2CO3 (90.5 mg, 0.65 mmol) at room temperature. 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 reverse phase chromatography eluting with 29% ACN in water (+0.05% TFA) to give tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-ethoxy-2-oxoethyl)(5-oxopyrrolidin-3-yl)amino]methyl]pyrrolidine-1-carboxylate as a colorless oil (0.120 g, 67%): LCMS (ESI) C 25 H 35 Cl2N3O6[M + H] + Calculated values: 544, 546 (3 : 2) Measured values: 544, 546 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.66 (d, J = 27.0 Hz, 1H), 4.46 (t, J = 8.2 Hz, 1H), 4.40-4.29 (m, 2H), 4.29-4.04 (m, 3H), 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 = 6.9 Hz, 3H).

[0581] Step C: A solution of tert-butyl (2S,4R)-4-(2,3-dichloro-6-methoxyphenyl)-2-[[(2-ethoxy-2-oxoethyl)(5-oxopyrrolidin-3-yl)amino]methyl]pyrrolidine-1-carboxylate (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 h. 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 h. The cooled solution was diluted with EA (20 mL) and water (30 mL) and extracted with additional 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 to give (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(5-oxopyrrolidin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one as a yellow oil (0.100 g, crude), which was used directly in the next step without purification: LCMS (ESI) C 18 H 21 Cl2N3O3[M + H] + Calculated value: 398, 400 (3 : 2) Measured value: 398, 400 (3 : 2).

[0582] Step D: To a stirred solution of (7R,8aS)-7-(2,3-dichloro-6-methoxyphenyl)-2-(5-oxopyrrolidin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (0.100 g, 0.25 mmol) in DCM (2.00 mL) was added BBr (0.330 g, 1.32 mmol) at room temperature. The reaction was stirred for 1 h, quenched with MeOH (5 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% to 40% in 8 min; Detector: UV 254 / 220 nm; Retention time: 6.28 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a]pyrazin-2-yl]pyrrolidin-2-one as an off-white solid (31.0 mg, 36.47% overall for two steps): LCMS (ESI) C 17 H 19 Cl2N3O3[M + H] + Calculated value: 384, 386 (3 : 2) Measured value: 384, 386 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 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 = 11.3 Hz, 1H), 2.65-2.54 (m, 2H), 2.26-2.08 (m, 2H).

[0583] Step E: 4-[(7R,8aS)-7-(2,3-dichloro-6-hydroxyphenyl)-4-oxo-hexahydropyrrolo[1,2-a...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, Y is NR １ , C(R ２ ) ２ or O; Z is OH; X １ is H, or Cl; X ２ is Cl; X ３ is Cl; R １ each occurrence independently represents H, alkyl, alkenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, (CR ６ R ７ ) ｎ６ OR ａ , (CR ６ R ７ ) ｎ６ N (R ａ ) ２ , (C=O)R ａ , (C=O)OR ａ , (CR ６ R ７ ) ｎ６ (C=O)NR ａ R ｂ , S.O. ２ R ａ or (CR ６ R ７ ) ｎ６ - is a heterocyclic ring; R ２ each occurrence independently represents H, halogen, CN, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, (CR ６ R ７ ) ｎ６ OR ａ , (CR ６ R ７ ) ｎ６ -heterocycle, (C=O)OR ａ , (CR ６ R ７ ) ｎ６ NR ａ (C=O)R ａ , (CR ６ R ７ ) ｎ６ N (R ａ ) ２ , N.R. ａ (CR ６ R ７ ) ｎ６ OR ａ , (C═O)NR ａ (CR ６ R ７ ) ｎ６ OR ａ , (C=O)R ａ , (CR ６ R ７ ) ｎ６ (C=O)NR ａ R ｂ , aryl, or heteroaryl, and each R ２ teeth 【Chemistry 2】 may be attached to any one of the carbon ring atoms of R ３ is H; R ６ and R ７ each occurrence is independently H, alkyl, cycloalkyl, aryl, or heteroaryl; R ａ and R ｂ each occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R ａ and R ｂ together with the nitrogen atom to which they are attached form a heterocyclic ring; each of said heterocycles contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S; If applicable, R １ , R ２ , R ６ , R ７ , R ａ , and R ｂ The alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, heterocycle, aryl, and heteroaryl of the formula (I) are, when valence permits, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogen, CN, R ８ , OR ８ , -(CH ２ ) １～２ OR ８ , N(R ８ ) ２ , (C=O)R ８ , (C═O)N(R ８ ) ２ , N.R. ８ (C=O)R ８ and oxo; R ８ each occurrence of R is independently H, alkyl, cycloalkyl, or a heterocycle optionally substituted with alkyl; or two R ８ groups, taken together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with alkyl and containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; n １ is an integer of 0 or 1; n ２ is an integer of 1, 0, or 2; n ３ is an integer of 0, 1, 2, or 3; n ４ is an integer of 1 or 2; and n ６ is an integer of 0, 1, 2, or 3, said heteroalkyl is selected from the group consisting of alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides; Said cycloheteroalkyl refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing in at least one ring at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen.

2. structural part 【Transformation 3】 but, (a) 【Chemistry 4】 or (b) 【Transformation 5】 or (c) 【Transformation 6】 or (d) 【Transformation 7】 or (e) 【Transformation 8】 or (f) 【Chemistry 9】 or (g) 【Chemistry 10】 having the structure 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. (a) R １ is H, alkyl, alkenyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl; (b) R １ is aryl or heteroaryl, or (c) R １ (C=O)R ａ , (C=O)OR ａ , S.O. ２ R ａ , (CR ６ R ７ ) ｎ６ OR ａ , (CR ６ R ７ ) ｎ６ N (R ａ ) ２ , (CR ６ R ７ ) ｎ６ (C=O)NR ａ R ｂ , or (CR ６ R ７ ) ｎ６ - is a heterocyclic ring, (d) R １ (C=O)R ａ Or (e) R １ is H, -CH ３ , -(CH ２ ) ２ OH, -(CH ２ ) ２ NH ２ , -CONH ２ , -CONHMe, -CONMe ２ , -CONET ２ , S.O. ２ Me, and SO ２ Et; or (f) R １ But H, 【Chemistry 11】 【Chemistry 12】 or selected from the group consisting of (g) R １ but, 【Chemistry 13】 【Chemistry 14】 selected from the group consisting of 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. (a) R ２ At least one occurrence of is H, halogen, CN, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, OR ａ , N(R １ ) ２ , (C=O)R ａ , (C═O)NR ａ R ｂ , aryl, or heteroaryl; (b) R ２ At least one occurrence of (CR ６ R ７ ) ｎ６ OR ａ , (CR ６ R ７ ) ｎ６ -heterocycle, (C=O)R ａ , (C=O)OR ａ , (CR ６ R ７ ) ｎ６ NR ａ (C=O)R ａ , (CR ６ R ７ ) ｎ６ N (R ａ ) ２ , N.R. ａ (CR ６ R ７ ) ｎ６ OR ａ , (C═O)NR ａ (CR ６ R ７ ) ｎ６ OR ａ , or (CR ６ R ７ ) ｎ６ (C=O)NR ａ R ｂ Or (c) R ２ At least one occurrence of CH ３ , -CH ２ —OH, —CH ２ -CH ２ -OH, -CH(OH)-CH ３ , -CH ２ -NH ２ , 【Chemistry 15】 【Chemistry 16】 Or (d) R ２ at least one occurrence of heteroalkyl, cycloheteroalkyl, 【Chemistry 17】 That is, The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. (a)n １ is 0, or n １ is 1, and / or (b) n ２ is 1 or 0, and / or (c) n ３ is 0, 1 or 2, and / or (d) n ４ is 1, and / or (e) n ６ 5. The compound of claim 1, wherein R is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

6. (a) Structural part [Chemistry 18] but, 【Chemistry 19】 or having the structure (b) Structural part 【Chemistry 20】 but, 【Chemistry 21】 having the structure 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R ａ or R ｂ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

8. R ａ or R ｂ at least one occurrence of is independently H, Me, Et, Pr, or 【Chemistry 22】 wherein said heterocycle, when valences permit, is selected from the group consisting of alkyl, OH, oxo, or (C═O)C １～４ 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl.

9. R ａ and R ｂ are taken together with the nitrogen atom to which they are attached to form a heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, or a pharmaceutically acceptable salt thereof.

10. The heterocycle 【Chemistry 23】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. The compound 【Chemistry 24】 2. The compound of claim 1, wherein:

12. The compound 【Chemistry 25】 2. The compound of claim 1, wherein:

13. The compound 【Chemistry 26】 2. The compound of claim 1, wherein:

14. The compound 【Chemistry 27】 2. The compound of claim 1, wherein:

15. The compound 【Chemistry 28】 2. The compound of claim 1, wherein:

16. The compound 【Chemistry 29】 2. The compound of claim 1, wherein:

17. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following: (a) A group consisting of the following compounds: 【Chemistry 30-1】 【Chemistry 30-2】 【Transformation 30-3】 【Transformation 30-4】 、 (b) A group consisting of the following compounds: 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【Chemistry 31-6】 【Chemistry 31-7】 【Chemistry 31-8】 【Chemistry 31-9】 【Chemistry 31-10】 【Chemistry 31-11】 【Chemistry 31-12】 【Chemistry 31-13】 【Chemistry 31-14】 。

18. 18. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

19. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in a method of treating a condition in a mammalian species in need thereof, comprising: the method comprises the step of administering to the mammalian species a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a renal disease; Optionally, said condition is: (a) an immunological disorder that is transplant rejection or an autoimmune disease, wherein said autoimmune disease is optionally rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes; (b) a central nervous system disorder that is Alzheimer's disease; (c) an inflammatory disorder that is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy; (d) a gastroenterological disorder that is inflammatory bowel disease; (e) a metabolic disorder that is obesity or type II diabetes; (f) a cardiovascular disorder that is an ischemic stroke; (g) kidney disease that is chronic kidney disease, nephritis, or chronic renal failure; or (h) is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof; and optionally said mammalian species is human. Pharmaceutical compositions.

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