Arylmethylene heterocyclic compounds as KV1.3 potassium shake channel blockers

Description

[0001] 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.FIELD OF THE INVENTION

[0002] The invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers.BACKGROUND

[0003] Voltage-gated Kv1.3 potassium (K +< ) channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues and regulate a large number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kv1.3 channels can regulate membrane potential and thereby indirectly influence calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions, including multiple sclerosis, Type I diabetes mellitus, psoriasis, spondylitis, parodontitis, and rheumatoid arthritis. Upon activation, effector-memory T cells increase expression of the Kv1.3 channel. Amongst human B cells, naive and early memory B cells express small numbers of Kv1.3 channels when they are quiescent. In contrast, class-switched memory B cells express high numbers of Kv1.3 channels. Furthermore, the Kv1.3 channel promotes the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol., 565-569). Blockade of Kv1.3 channels in effector memory T cells suppresses activities like calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.

[0004] Autoimmune Disease is a family of disorders resulting from tissue damage caused by attack from the body's own immune system. Such diseases may affect a single organ, as in multiple sclerosis and Type I diabetes mellitus, or may involve multiple organs as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative, with anti-inflammatory and immunosuppressive drugs, which can have severe side effects. A need for more effective therapies has led to search for drugs that can selectively inhibit the function of effector memory T cells, known to be involved in the etiology of autoimmune diseases. These inhibitors are thought to be able to ameliorate autoimmune diseases symptoms without compromising the protective immune response. Effector memory T cells (TEMs) express high numbers of the Kv1.3 channel and depend on these channels for their function. In vivo, Kv1.3 channel blockers paralyze TEMs at the sites of inflammation and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the motility within lymph nodes of naive and central memory T cells. Suppressing the function of these cells by selectively blocking the Kv1.3 channel offers the potential for effective therapy of autoimmune diseases with minimal side effects.

[0005] Multiple Sclerosis (MS) is caused by autoimmune damage to the Central Nervous System (CNS). Symptoms include muscle weakness and paralysis, which severely affect quality of life for patients. MS progresses rapidly and unpredictably and eventually leads to death. The Kv1.3 channel is also highly expressed in auto-reactive effector memory T cells from MS patients (Wulff H., et al., 2003, J. Clin. Invest., 1703-1713; Rus H., et al., 2005, PNAS, 11094-11099). Animal models of multiple sclerosis have been successfully treated using blockers of the Kv1.3 channel.

[0006] Compounds which are selective Kv1.3 channel blockers are thus potential therapeutic agents as immunosuppressants or immune system modulators. The Kv1.3 channel is also considered as a therapeutic target for the treatment of obesity and for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus. These compounds can also be utilized in the prevention of graft rejection, and the treatment of immunological (e.g., autoimmune) and inflammatory disorders.

[0007] Tubulointerstitial fibrosis is a progressive connective tissue deposition on the kidney parenchyma, leading to renal function deterioration and is involved in the pathology of chronic kidney disease, chronic renal failure, nephritis, and inflammation in glomeruli and is a common cause of end-stage renal failure. Overexpression of Kv1.3 channels in lymphocytes can promote their proliferation leading to chronic inflammation and overstimulation of cellular immunity, which are involved in the underlying pathology of these renal diseases and are contributing factors in the progression of tubulointerstitial fibrosis. Inhibition of the lymphocyte Kv1.3 channel currents suppress proliferation of kidney lymphocytes and ameliorate the progression of renal fibrosis (Kazama I., et al., 2015, Mediators Inflamm., 1-12).

[0008] Kv1.3 channels also play a role in gastroenterological disorders including inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease. Ulcerative colitis is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. Ulcerative colitis can impair quality of life and can lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8 positive T-cells in the inflamed mucosa of UC patients have been associated with production of pro-inflammatory compounds in active UC. Kv1.3 channels are thought to serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy in UC. Present treatment regimens for UC, including corticosteroids, salicylates, and anti-TNF-α reagents, are insufficient for many patients (Hansen L.K., et al., 2014, J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD which may affect any part of the gastrointestinal tract. Crohn's disease is thought to be the result of intestinal inflammation due to a T-cell-driven process initiated by normally safe bacteria. Thus, Kv1.3 channel inhibition can be utilized in treating the Crohn's disease.

[0009] In addition to T cells, Kv1.3 channels are also expressed in microglia, where the channel is involved in inflammatory cytokine and nitric oxide production and in microglia-mediated neuronal killing. In humans, strong Kv1.3 channel expression has been found in microglia in the frontal cortex of patients with Alzheimer's disease and on CD68 +< cells in multiple sclerosis brain lesions. It has been suggested that Kv1.3 channel blockers might be able to preferentially target detrimental proinflammatory microglia functions. Kv1.3 channels are expressed on activated microglia in infarcted rodent and human brain. Higher Kv1.3 channel current densities are observed in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of a mouse model of stroke (Chen Y.J., et al., 2017, Ann. Clin. Transl. Neurol., 147-161).

[0010] Expression of Kv1.3 channels is elevated in microglia of human Alzheimer's disease brains, suggesting that Kv1.3 channel is a pathologically relevant microglial target in Alzheimer's disease (Rangaraju S., et al., 2015, J. Alzheimers Dis., 797-808). Soluble AβO enhances microglial Kv1.3 channel activity. Kv1.3 channels are required for AβO-induced microglial pro-inflammatory 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. Thus, Kv1.3 channel may be a therapeutic target for Alzheimer's disease.

[0011] Kv1.3 channel blockers could be also useful for ameliorating pathology in cardiovascular disorders such as ischemic stroke, where activated microglia significantly contributes to the secondary expansion of the infarct.

[0012] Kv1.3 channel expression is associated with the control of proliferation in multiple cell types, apoptosis, and cell survival. 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). Thus, inhibitors of Kv1.3 channels may be used as anticancer agents.

[0013] A number of peptide toxins with multiple disulfide bonds from spiders, scorpions, and anemones are known to block Kv1.3 channels. A few selective, potent peptide inhibitors of the Kv1.3 channel 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 a phase I clinical trial for treatment of psoriasis. Shk can suppress proliferation of TEM cells resulting in improved condition in animal models of multiple sclerosis. Unfortunately, Shk also binds to the closely-related Kvi channel subtype found in CNS and heart. There is a need for Kv1.3 channel-selective inhibitors to avoid potential cardio- and neuro-toxicity. Additionally, small peptides like shk-186 are rapidly cleared from the body after administration, resulting in short circulating half-lives, frequent administration events. Thus, there is a need for the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases.

[0014] Thus, there remains a need for development of novel Kv1.3 channel blockers as pharmaceutical agents. WO 2006 / 042150 A1 describes diaminoalkane aspartic protease inhibitors allegedly useful in the treatment or amelioration of diseases associated with elevated levels of aspartic protease activity. WO 2007 / 117482 A2 describes renin inhibitors allegedly useful in the treatment or amelioration of diseases associated with aspartic protease activity. WO 2006 / 029182 A2. UTO Y ET AL: "Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 1, 1 January 2010, pages 341-345 describes benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors and identifies 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its alleged plasma triglyceride-lowering effects in Zucker fatty rats. WO 2020 / 035424 A1 describes heterocyclic compounds as monoacylglycerol lipase inhibitors. MEANWELL N A ET AL: "N-benzylated benzimidazol-2-one derivatives: activators of large-conductance Ca2+ dependent K+ channels", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 14, 1996, pages 1641-1646 describes a series of N-benzylated benzimidazol-2-one derivatives and their alleged use as potassium channel modulators.SUMMARY OF THE INVENTION

[0015] In one aspect, compounds useful as potassium channel blockers having a structure of Formula I, are described, where the various substituents are defined herein. The compounds of Formula I described herein can block Kv1.3 potassium (K +< ) channels and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. 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 a number of clinical applications, including as pharmaceutically active agents and methods for treating cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, a kidney disease or a combination thereof. For clarity, all references herein to methods of treatment utilizing a particular compound or composition are to be interpreted as references to the compound or composition for use in that method of treatment.

[0016] In one aspect of the presently claimed invention, a compound of Formula I or a pharmaceutically acceptable salt thereof is described, wherein: the structural moiety has the structure of each of which is substituted by R 3 ; R 3 is H, halogen, or alkyl; R 1 and R 2 are each independently H, alkyl, (CR 6 R 7 ) n4 OR a , (CR 6 R 7 ) n4 NR a R b , (CR 6 R 7 ) n4 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) n4 CONR a R b , wherein at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) n4 NR a R b , (CR 6 R 7 ) n4 OR a , (CR 6 R 7 ) n4 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) n4 CONR a R b ; or alternatively R 1 , R 2 and the carbon atom they are connected to taken together form a 3-5 membered carbocycle; R 4 is (CR 6 R 7 ) n4 (C=O)R c , (C=O)(CR 6 R 7 ) n4 R c , (CR 6 R 7 ) n4 OR c , (CR 6 R 7 ) n4 COOR c , (CR 6 R 7 ) n4 NR c (C=O)R d , (C=O)(CR 6 R 7 ) n4 OR c , (CR 6 R 7 ) n4 SO 2 R c , optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted -cycloalkyl-alkyl; each occurrence of R 5 is independently H, alkyl, cycloalkyl, or oxo; or two R 5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle; or two R 5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons; each occurrence of R 6 and R 7 are independently H, alkyl, or cycloalkyl; each occurrence of R a and R b are independently H, alkyl, cycycloalkyl, saturated heterocycle, aryl, or heteroaryl; or alternatively R a and R b together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of R c and R d are independently H, alkyl, alkyl substituted by 1-4 substituents each of which is independently halogen, OR 8 or N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl; or alternatively R c and R d together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of R 8 is independently H, alkyl, or an optionally substituted heterocycle; or alternatively the two R 8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; R 9 is H, alkyl, halogen, or (CR 6 R 7 ) n4 OR b ; the alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R a , R b , R c , and R d , where applicable, are optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)C 1-4 alkyl, (C=O)N(R 8 ) 2 , and oxo where valence permits; each occurrence of n 1 is independently an integer from 0-3 where valence permits; each occurrence of n 2 and n 3 is independently an integer that is 1, 2 or 0; and each occurrence of n 4 is independently an integer from 0-3.

[0017] In any one of the embodiments described herein, each occurrence of n 2 and n 3 is independently an integer from 0-1.

[0018] In any one of the embodiments described herein, the structural motif has the structure of

[0019] In any one of the embodiments described herein, the structural motif has the structure of

[0020] In any one of the embodiments described herein, the structural motif has the structure of

[0021] In any one of the embodiments described herein, at least one occurrence of R 1 and R 2 is H or alkyl.

[0022] In any one of the embodiments described herein, at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) n4 OR a , (CR 6 R 7 ) n4 NR a R b , (CR 6 R 7 ) n4 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) n4 CONR a R b .

[0023] In any one of the embodiments described herein, at least one occurrence of R 1 and R 2 is OR a or NR a R b .

[0024] In any one of the embodiments described herein, R 1 , R 2 , and the carbon atom they are connected to taken together form a 3-5 membered carbocycle.

[0025] In any one of the embodiments described herein, R 1 and R 2 are each independently H, Me, OH, CH 2 OH, NH 2 , NHMe, NMe 2 , CH 2 NH 2 , CONH 2 , CONHMe 2 , CONMe 2 , NH(C=O)Me, NMe(C=O)Me, or

[0026] In any one of the embodiments described herein, R 4 is (CR 6 R 7 ) n4 OR c , (CR 6 R 7 ) n4 COR c , (C=O)(CR 6 R 7 ) n4 R c , (CR 6 R 7 ) n4 COOR c , (CR 6 R 7 ) n4 NR c (C=O)R d , (C=O)(CR 6 R 7 ) n4 OR c or (CR 6 R 7 ) n4 SO 2 R c .

[0027] In any one of the embodiments described herein, R 4 is (CR 6 R 7 ) 2 OR c , (C=O)R c , (C=O)(CR 6 R 7 ) 1-2 R c , COOR c , (CR 6 R 7 ) 1-2 NR c (C=O)R d , (C=O)(CR 6 R 7 ) 1-2 OR c or SO 2 R c .

[0028] In any one of the embodiments described herein, R 4 is (CH 2 ) 2 OH, (CH 2 ) 2 OMe, (C=O)H, (C=O)Me, (C=O)CH 2 OH, (C=O)CH 2 OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)CH(OH)CH 2 OH, (C=O)CH(OMe)CH 2 OH, (C=O)CH(OH)CH 2 OMe (C=O)OMe, SO 2 Me, SO 2 Et, SO 2 CH 2 OH or SO 2 CH 2 OMe.

[0029] In any one of the embodiments described herein, R 4 is (C=O)R c , (C=O)(CR 6 R 7 ) 1-2 R c , (C=O)(CR 6 R 7 ) 1-2 OR c , or SO 2 R c ; and where R c is selected from the group consisting of H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR 8 and N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, and optionally substituted -cycloalkyl-alkyl.

[0030] In any one of the embodiments described herein, R c or R d is H, Me, Et,

[0031] In any one of the embodiments described herein, R c or R d is a heterocycle selected from the group consisting of where the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0032] In any one of the embodiments described herein, R c is cycloalkyl, spiroalkyl, or bicycloalkyl each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0033] In any one of the embodiments described herein, R c is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0034] In any one of the embodiments described herein, R 4 is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted -cycloalkyl-alkyl.

[0035] In any one of the embodiments described herein, R 4 is a heterocycle selected from the group consisting of where the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0036] In any one of the embodiments described herein, R 4 is cycloalkyl optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0037] In any one of the embodiments described herein, R 4 is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0038] In any one of the embodiments described herein, R 4 is or a tautomer thereof.

[0039] In any one of the embodiments described herein, at least one occurrence of R 5 is H, alkyl or cycloalkyl.

[0040] In any one of the embodiments described herein, at least one occurrence of R 5 is oxo.

[0041] In any one of the embodiments described herein, two R 5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons.

[0042] In any one of the embodiments described herein, two R 5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle.

[0043] In any one of the embodiments described herein, at least one of R a and R b is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0044] In any one of the embodiments described herein, R a and R b together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0045] In any one of the embodiments described herein, each occurrence of R 6 and R 7 are independently H or alkyl.

[0046] In any one of the embodiments described herein, R 9 is H, alkyl, or halogen.

[0047] In any one of the embodiments described herein, R 9 is (CR 6 R 7 ) n4 OR b .

[0048] In any one of the embodiments described herein, R 9 is H, F, or OH.

[0049] In any one of the embodiments described herein, R 3 is H or alkyl.

[0050] In any one of the embodiments described herein, R 3 is halogen.

[0051] In any one of the embodiments described herein, at least one occurrence of R 8 is H, alkyl, or optionally substituted heterocycle.

[0052] In any one of the embodiments described herein, R 8 is H, Me, Et, Pr, Bu, or a heterocycle selected from the group consisting of and where the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0053] In any one of the embodiments described herein, the two R 8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0054] In any one of the embodiments described herein, n 1 is 0, 1, 2, or 3.

[0055] In any one of the embodiments described herein, n 4 is 0, 1, or 2.

[0056] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR 8 and N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl.

[0057] In any one of the embodiments described herein, R c and R d together with the nitrogen atom that they are connected to form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0058] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently H, Me, Et,

[0059] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently a heterocycle selected from the group consisting of where the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0060] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently cycloalkyl, spiroalkyl, or bicycloalkyl each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0061] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0062] In any one of the embodiments described herein, the compound is a specific compound as set out in the appended set of claims or a pharmaceutically acceptable salt thereof.

[0063] In another aspect of the presently claimed invention, a pharmaceutical composition is described, including 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.

[0064] In yet another aspect of the presently claimed invention, there is described a compound according to any one of the embodiments described herein or a pharmaceutically-acceptable salt thereof for use as a medicament. In yet another aspect of the presently claimed invention, there is described a compound according to any one of the embodiments described herein or a pharmaceutically-acceptable salt thereof for use in a method of treating a condition in a mammalian species in need thereof, the method including administering to the mammalian species a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, where the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.

[0065] In any one of the embodiments described herein, the condition is an immunological disorder that is transplant rejection or an autoimmune disease.

[0066] In any one of the embodiments described herein, the condition is an immunological disorder that is an autoimmune disease that is is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or Type I diabetes mellitus.

[0067] In any one of the embodiments described herein, the condition is a Central Nerve System (CNS) disorder that is Alzheimer's disease.

[0068] In any one of the embodiments described herein, the condition is an inflammatory disorder that is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy.

[0069] In any one of the embodiments described herein, the condition is a gastroenterological disorder that is an inflammatory bowel disease.

[0070] In any one of the embodiments described herein, the condition is a metabolic disorder that is obesity or Type II diabetes mellitus.

[0071] In any one of the embodiments described herein, the condition is a cardiovascular disorder that is an ischemic stroke.

[0072] In any one of the embodiments described herein, the condition is a kidney disease that is chronic kidney disease, nephritis, or chronic renal failure.

[0073] 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 mellitus, Alzheimer's disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, Crohn's disease, ulcerative colitis, obesity, Type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof.

[0074] In any one of the embodiments described herein, the mammalian species is human.

[0075] Any one of the embodiments disclosed herein may be properly combined with any other embodiment disclosed herein. The combination of any one of the embodiments disclosed herein with any other embodiments disclosed herein is expressly contemplated. Specifically, the selection of one or more embodiments for one substituent group can be properly combined with the selection of one or more particular embodiments for any other substituent group. Such combination can be made in any one or more embodiments of the application described herein or any formula described herein.DETAILED DESCRIPTION OF THE INVENTION Definitions

[0076] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0077] The terms "alkyl" and "alk" refer to a straight or branched chain alkane (hydrocarbon) radical containing from 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 "(C 1- C 4 )alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of 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.

[0078] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C 2 -C 6 alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group 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 bearing a single halogen substituent or multiple halogen substituents such as CF 3 or CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR d R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0079] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. The term "C 2 -C 6 alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 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, 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR d R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0080] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. "C 3 -C 7 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3) , cyano, nitro, oxo (i.e., =O), CF 3 , OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0081] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0082] The term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings wherein two adjacent aromatic rings have two carbon atoms in common. "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0083] 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 numbers of the ring atoms in the heteroaryl and / or aryl rings are used to specify the sizes of the aryl or heteroaryl ring in the substituents. 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 similarly specified.

[0084] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined hereinabove. The term "substituted carbocycle" refers to carbocycle or carbocyclic groups 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, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0085] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., "heteroaryl") cyclic groups (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group may independently be saturated, or partially or fully unsaturated. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of 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, 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 and 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, 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-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0086] "Substituted heterocycle" and "substituted heterocyclic" (such as "substituted heteroaryl") refer to heterocycle or heterocyclic groups 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0087] The term "oxo" refers to substituent group, which may be attached to a carbon ring atom on a carbocycle or heterocycle. When an oxo substituent group is attached to a carbon ring atom on an aromatic group, e.g., aryl or heteroaryl, the bonds on the aromatic ring may be re-arranged to satisfy the valence requirement. For instance, a pyridine with a 2-oxo substituent group may have the structure of which also includes its tautomeric form of

[0088] The term "alkylamino" refers to a group having the structure -NHR', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0089] The term "dialkylamino" refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined herein. R and R' may be the same or different in a dialkyamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structure include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-triazinolyl, and tetrazolyl.

[0090] The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine.

[0091] The term "substituted" refers to the embodiments in which a molecule, molecular moiety or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, where valence permits, preferably 1 to 6 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, in the latter case, groups such as CF 3 or an alkyl group bearing CCl 3 ), cyano, nitro, oxo (i.e., =O), CF 3 , OCF 3 , alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted. The term "optionally substituted" refers to the embodiments in which a molecule, molecular moiety or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with aforementioned one or more substituents.

[0092] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0093] The compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the present invention may be formed, for example, by reacting a compound described herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0094] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0095] The compounds of the present invention which contain an acidic moiety, such but not limited to a phenol or carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. 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 sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0096] Compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, 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 the compound includes the tautomeric forms thereof.

[0097] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The 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. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0098] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to greater than 95%, equal to or greater than 99% of the compounds ("substantially pure" compounds), which is 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.

[0099] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0100] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0101] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999).

[0102] 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, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0103] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0104] The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 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, respectively. Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example, those into which radioactive isotopes such as 3< H and 14< C are 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. Further, substitution with heavier isotopes such as deuterium, i.e., 2< H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0105] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are 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, and subsequent recovery of the pure enantiomers.

[0106] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. 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 in the treatment, for example, of proliferative disorders. The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0107] 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. The cancer can be a malignant or non-malignant cancer. 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 neoplasms; leukemias; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas. Cancers can be primary or metastatic. Diseases other than cancers may be associated with mutational alternation of component of Ras signaling pathways and the compound disclosed herein may be used to treat these non-cancer diseases. Such non-cancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; Cardio-facio-cutaneous syndrome; Hereditary gingival fibromatosis type 1; Autoimmune lymphoproliferative syndrome; and capillary malformation-arterovenous malformation.

[0108] As used herein, "effective amount" refers to any amount that is necessary or sufficient for achieving or promoting 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 for promoting or achieving a desired biological response in a subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.

[0109] As used herein, the term "subject" refers to a vertebrate animal. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.Compounds

[0110] Novel compounds as Kv1.3 potassium channel blockers are described. Applicants have surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel-inhibiting properties. Additionally, Applicants have surprisingly discovered that the compounds disclosed herein selectively block the Kv1.3 potassium channel and do not block the hERG channel and thus have desirable cardiovascular safety profiles.

[0111] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof is described, wherein the structural moiety has the structure of each of which is substituted by R 3 ; R 3 is H, halogen, or alkyl; R 1 and R 2 are each independently H, alkyl, (CR 6 R 7 ) n4 OR a , (CR 6 R 7 ) n4 NR a R b , (CR 6 R 7 ) n4 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) n4 CONR a R b , wherein at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) n4 NR a R b , (CR 6 R 7 ) n4 OR a , (CR 6 R 7 ) n4 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) n4 CONR a R b ; or alternatively R 1 , R 2 and the carbon atom they are connected to taken together form a 3-5 membered carbocycle; R 4 is (CR 6 R 7 ) n4 (C=O)R c , (C=O)(CR 6 R 7 ) n4 R c , (CR 6 R 7 ) n4 OR c , (CR 6 R 7 ) n4 COOR c , (CR 6 R 7 ) n4 NR c (C=O)R d , (C=O)(CR 6 R 7 ) n4 OR c , (CR 6 R 7 ) n4 SO 2 R c , optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted -cycloalkyl-alkyl; each occurrence of R 5 is independently H, alkyl, cycloalkyl, or oxo; or two R 5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle; or two R 5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons; each occurrence of R 6 and R 7 are independently H, alkyl, or cycloalkyl; each occurrence of R a and R b are independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or alternatively R a and R b together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of R c and R d are independently H, alkyl, alkyl substituted by 1-4 substituents each of which is independently halogen, OR 8 or N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl; or alternatively R c and R d together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of R 8 is independently H, alkyl, or an optionally substituted heterocycle; or alternatively the two R 8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; R 9 is H, alkyl, halogen, or (CR 6 R 7 ) n4 OR b ; the alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted by 1-4 substituents each independent selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)C 1-4 alkyl, (C=O)N(R 8 ) 2 , and oxo where valence permits; each occurrence of n 1 is independently an integer from 0-3 where valence permits; each occurrence of n 2 and n 3 is independently an integer from 0-2; and each occurrence of n 4 is independently an integer from 0-3.

[0112] In some embodiments, each occurrence of n 2 and n 3 is independently an integer from 0-2. In some embodiments, n 2 and n 3 are each 0. In other embodiments, n 2 and n 3 are each 1. In still other embodiments, n 2 and n 3 are each 2. In some embodiments, n 2 and n 3 are 0 and 1, respectively. In some embodiments, n 2 and n 3 are 0 and 2, respectively. In some embodiments, n 2 and n 3 are 1 and 2, respectively.

[0113] In some embodiments, the structural motif has the structure of where the various substituents are defined herein. In some embodiments, the structural motif has the structure of wherein the various substituents are defined herein. In some embodiments, the structural motif has the structure of wherein the various substituents are defined herein.

[0114] In any one of embodiments described herein, each occurrence of R a and R b may be independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. In some embodiments, at least one of R a and R b is independently H, alkyl, or cycloalkyl. In other embodiments, at least one of R a and R b is independently saturated heterocycle, aryl, or heteroaryl. In other embodiments, R a and R b together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0115] In some embodiments, R 1 and R 2 are each H or alkyl. In some embodiments, R 1 and R 2 are both H. In some embodiments, at least one of R 1 and R 2 is alkyl, such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl or sec-butyl. In some embodiments, R 1 and R 2 are H and alkyl respectively.

[0116] In some embodiments, at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) n4 OR a or (CR 6 R 7 ) n4 NR a R b . In some embodiments, at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) 0-2 NR a R b . Non-limiting examples of NR a R b include NH 2 , NHMe, NMe 2 , NHEt, NMeEt, NEt 2 , NHPr, NMePr, NEtPr, NH(iso-Pr), and N(iso-Pr) 2 . In some embodiments, at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) 0-2 OR a . Non-limiting examples of OR a include OH, OMe, OEt, OPr, O-iso-Pr, OBu, O-tert-Bu, and O-sec-Bu. In some embodiments, at least one occurrence of R 1 and R 2 is OR a or NR a R b .

[0117] In some embodiments, at least one occurrence of R 1 and R 2 is (CR 6 R 7 ) 0-2 NR a (C=O)R b , (CR 6 R 7 ) n4 NR a SO 2 R b , or (CR 6 R 7 ) 0-2 CONR a R b . Non-limiting examples of NR a (C=O)R b include NH(C=O)Me, NMe(C=O)Me, NH(C=O)Et, NMe(C=O)Et, NEt(C=O)Et, NH(C=O)Pr, NMe(C=O)Pr, NEt(C=O)Pr, NH(C=O)(iso-Pr), NMe(C=O)(iso-Pr), and NEt(C=O)(iso-Pr). Non-limiting examples of CONR a R b include (C=O)NH 2 , (C=O)NHMe, (C=O)NMe 2 , (C=O)NHEt, (C=O)NMeEt, (C=O)NEt 2 , (C=O)NHPr, (C=O)NMePr, (C=O)NEtPr, (C=O)NH(iso-Pr), and (C=O)N(iso-Pr) 2 .

[0118] In other embodiments, R 1 , R 2 , and the carbon atom they are connected to taken together form a 3-5 membered carbocycle. In some specific embodiments, R 1 , R 2 and the carbon atom they are connected to taken together form cyclopropyl, cyclobutyl or cyclopentyl.

[0119] In some embodiments, R 1 and R 2 are each independently H, Me, OH, CH 2 OH, NH 2 , NHMe, NMe 2 , CH 2 NH 2 , CONH 2 , CONHMe 2 , CONMe 2 , NH(C=O)Me, NMe(C=O)Me,

[0120] In some specific embodiments, n 4 is 0. In other specific embodiments, n 4 is 1 or 2. In some specific embodiments, R 4 is (CR 6 R 7 ) 2 OR c , (C=O)R c , (C=O)(CR 6 R 7 ) 1-2 R c , COOR c , (CR 6 R 7 ) 1-2 NR c (C=O)R d , (C=O)(CR 6 R 7 ) 1-2 OR c or SO 2 R c . In some specific embodiments, CR 6 R 7 is CH 2 , CHMe, CMe 2 , CHEt, or CEt 2 . In some specific embodiments, R 4 is (CH 2 ) 2 OH, (CH 2 ) 2 OMe, (C=O)H, (C=O)Me, (C=O)CH 2 OH, (C=O)CH 2 OMe, (C=O)CH(OH)CH 2 OH, (C=O)CH(OMe)CH 2 OH, (C=O)CH(OH)CH 2 OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)OMe, SO 2 Me, SO 2 Et, SO 2 CH 2 OH or SO 2 CH 2 OMe. In other embodiments, R 4 is (C=O)CH(OH)CH 2 OH, (C=O)CH(OMe)CH 2 OH, or (C=O)CH(OH)CH 2 OMe.

[0121] In other embodiments, R 4 is (C=O)R c , (C=O)(CR 6 R 7 ) 1-2 R c , (C=O)(CR 6 R 7 ) 1-2 OR c , or SO 2 R c ; and wherein R c is selected from the group consisting of H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR 8 and N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, and optionally substituted -cycloalkyl-alkyl.

[0122] In some embodiments, R c or R d is H, Me, Et, or

[0123] In some embodiments, R c is a heterocycle selected from the group consisting of wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0124] In some embodiments, R c is cycloalkyl, spiroalkyl, or bicycloalkyl each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits. In other embodiments, R c is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0125] In still other embodiments, R 4 is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted -cycloalkyl-alkyl. In some specific embodiments, R 4 is a heterocycle selected from the group consisting of wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0126] In still other embodiments, R 4 is cycloalkyl optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits. In other embodiments, R 4 is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, - (CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0127] In some embodiments, R 8 is H or alkyl. In other embodiments, R 8 is optionally substituted heterocycle. In still other embodiments, the two R 8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0128] In some specific embodiments, R 4 is or a tautomer thereof.

[0129] In some embodiments, R 5 is H, alkyl, or cycloalkyl. In some specific embodiments, R 5 is H. In other specific embodiments, R 5 is Me, Et, Pr, iso-Pr, Bu, iso-Bu, sec-Bu, or tert-Bu. In other specific embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other specific embodiments, R 5 is oxo.

[0130] In other embodiments, two R 5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle. In still other embodiments, two R 5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons.

[0131] In some embodiments, each occurrence of R 6 and R 7 are independently H or alkyl. In some specific embodiments, CR 6 R 7 is CH 2 , CHMe, CMe 2 , CHEt, or CEt 2 . In some specific embodiments, CR 6 R 7 is CH 2 .

[0132] In some embodiments, R 9 is H, alkyl, or halogen. In other embodiments, R 9 is (CR 6 R 7 ) n4 OR b . In some specific embodiments, R 9 is H, F, or OH.

[0133] In any one of the embodiments described herein, R 3 is H, halogen, or alkyl. In some embodiments, R 3 is H. In other embodiments, R 3 is alkyl such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl or sec-butyl. In still other embodiments, R 3 is F, Cl or Br.

[0134] In any one of the embodiments described herein, at least one occurrence of R 8 is H, alkyl, or optionally substituted heterocycle. In some embodiments, R 8 is H, Me, Et, Pr, Bu, or a heterocycle selected from the group consisting of and wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0135] In other embodiments, the two R 8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0136] In some embodiments, n 1 is 0 or 1. In some embodiments, n 4 is 0, 1, or 2. In some embodiments, n 4 is 0 or 1. In some specific embodiments, n 4 is 0.

[0137] In any one of the embodiments described herein, at least one occurrence of R c or R d is independently H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR 8 and N(R 8 ) 2 , alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl.

[0138] In some embodiments, R c and R d together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0139] In some specific embodiments, at least one occurrence of R c or R d is independently H, Me, Et,

[0140] In some specific embodiments, at least one occurrence of R c or R d is independently a heterocycle selected from the group consisting of and wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH 2 , oxo, or (C=O)C 1-4 alkyl where valence permits.

[0141] In some specific embodiments, at least one occurrence of R c or R d is independently cycloalkyl, spiroalkyl, or bicycloalkyl each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0142] In some specific embodiments, at least one occurrence of R c or R d is independently each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, - (CH 2 ) 0-2 OR 8 , N(R 8 ) 2 , (C=O)N(R 8 ) 2 , and oxo where valence permits.

[0143] In some embodiments, the compound of Formula I is a specific compound as set out in the appended set of claims or a pharamaceutically acceptable salt thereof.Abbreviations

[0144] ACNAcetonitrile 9-BBN9-Borabicyclo[3.3.1]nonane BOPBenzotriazol-1-yloxytris(diethylamino)phosphonium hexafluorophospahte BOPClBis(2-oxo-3-oxazolidinyl)phosphinic chloride CDICarbonyldiimidazole DASTDiethylaminosulfur trifluoride DCE1,2-Dichloroethane DCMDichloromethane DEADDiethyl azodicarboxylate DIBAL-H or DIBALDiisobutylaluminum hydride DIPEA or DIEADiisopropylethylamine DMAP4-Dimethylaminopyridine DMFDimethyl formamide DMSODimethyl sulfoxide EAEthyl acetate EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATUN-[(dimethylamino)(3H-1,2,3-triazolelo(4,4-b)pyridin-3-yloxy)methylene]-N-methylmethaneaminium hexafluorophosphate HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBT or HOBt1-Hydroxybenzotriazole LDALithium diisopropylamide NBSN-bromosuccinimide NCSN-chlorosuccinimide NISN-iodosuccinimide NMPN-Methylpyrrolidone PCCPyridinium chlorochromate PDCPyridinium dichromate PEPetroleum ether PyBOP1H-Benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate SEM[2-(Trimethylsilyl)ethoxy]methyl acetal TEATriethylamine TEMPO2,2,6,6-Tetramethyl-1-piperidinyloxy TFA or TFAATrifluoroacetic acid THFTetrahydrofuran TMSTrimethylsilyl TsOHp-Toluenesulfonic acid Methods of Preparation

[0145] Following are general synthetic schemes for manufacturing compounds of the presently claimed invention and structurally related compounds. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture the compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). The following reactions are illustrations but not limitations of the preparation of some of the starting materials and compounds disclosed herein. For avoidance of doubt, to the extent the reactions are directed to compounds other than those defined in the appended set of claims they are provided herein for reference purposes only.

[0146] Schemes 1-9 below describe synthetic routes which may be used for the synthesis of compounds, e.g., compounds having a structure of Formula I or precursors thereof. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results. In the embodiments below, the synthetic route is described using compounds I-4, I-6, I-4a, I-6a, I-7, I-7b, I-10, I-10a, and I-13 as examples. Other compounds of Formula I can be prepared by using methods similar to those described in Schemes 1-9 or using methods known in the art. The general synthetic route described in Schemes 1-9 and examples described in the Example section below illustrate methods used for the preparation of the compounds described herein.

[0147] As shown in Scheme 1, compound I-4 can be prepared from compound I-1a or I-1b.

[0148] Compound I-1a, I-1b, I-2a, I-2b, and I-2c can be prepared by any method known in the art. As shown in Scheme 1, "Br / I" refers to a Br or I substituent and PG refers to a protecting group. Non-limiting examples of the protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 1, step i, the intermediate ketone I-3 can be synthesized by Friedel-Crafts reaction of a protected phenol I-1a with a suitably protected acid chloride I-2a in the presence of a Lewis acid. Non-limiting examples of the Lewis acid include aluminum III chloride. Alternatively, aryl bromide or iodide I-1b is converted to the corresponding Grignard reagent, e.g., by treatment with isopropyl magnesium chloride (R is isopropyl), or to the corresponding aryl lithium reagent by treatment with butyl lithium (Step ii). The resulting organometallic reagent reacts with the Weinreb amide I-2b to form ketone I-3. Ketone I-3 can be reduced using a suitable reducing agent to afford alcohol I-4 (Step v). Non-limiting examples of suitable reducing agents include NaBH 4 . Still alternatively, aryl bromide or iodide I-1b is converted to the corresponding Grignard reagent, e.g., by treatment with isopropyl magnesium chloride (R is isopropyl), or to the corresponding aryl lithium reagent by treatment with butyl lithium and the resulting organometallic reagent reacts with aldehyde I-2c to give benzylic alcohol I-4 (Step vi). Benzylic alcohol I-4 can be oxidized to ketone I-3 using a oxidation agent, e.g., Dess-Martin periodinane. The protecting groups in compound I-4 can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0149] As shown in Scheme 2, compound I-6 can be prepared from compound I-1b, I-2d or I-3.

[0150] Compounds I-1b and I-2d can be prepared by any method known in the art. Compound I-3 can be prepared by the method shown in Scheme 1. As shown in Scheme 2, "Br / I" refers to a Br or I substituent and PG refers to a protecting group. Non-limiting examples of the protecting group include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 2, step i, compounds having Formula I where R 1 includes an amino group (e.g., compound I-6) can be obtained from ketone I-3 by forming the sulfinyl imine I-5 by heating ketone I-3 with an alkyl sulfinimide for example t-butyl sulfinimide (i.e., R is alkyl such as t-butyl) in the presence of a Lewis acid (e.g., titanium tetraethoxide). Reduction of the sulfinyl imine I-5 with reducing agent, e.g., sodium borohydride or diisobutyl aluminum hydride (DIBAL), gives the sulfinimide I-6 (Step ii). The single enantiomer of compound I-6 can be prepared by methods known in the art. Alternatively, as shown in Step iii, compound I-6 can be synthesized by forming the Grignard or organolithium reagent from I-1b and reacting the formed Grignard or organolithium reagent with sulfinyl imine I-2d (prepared from I-2c in Scheme 1 using method known in the art) to give I-6 directly. The protecting groups in compound I-6 can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0151] As shown in Scheme 3, compounds I-3a, I-4a, and I-6a can be prepared from compounds I-1d and I-2b, I-1d and I-2c, and I-1d and I-2d, respectively.

[0152] Compounds I-1d, I-2b, I-2c, and I-2d can be prepared by any method known in the art. As shown in Scheme 3, PG refers to a protecting group. Non-limiting examples of the protecting group include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 3, Step i, ii, or iii, a suitably protected phenol such as the diethyl carbamate I-1d can be activated by lithiation ortho to the carbamate and reacted with a Weinreb amide I-2b (Step i), aldehyde I-2c (Step ii) or a sulfinyl imine I-2d (Step iii) as shown in Scheme 3. The protecting groups in compounds I-4a and I-6a can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art. Ketone I-3a can be reduced using a suitable reducing agent (e.g., NaBH 4 ) to afford the corresponding alcohol (not shown). The resulting alcohol's protecting groups can then be selectively removed and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0153] As shown in Scheme 4, compounds I-4, I-3", and I-7 can be prepared from compound I-3.

[0154] Compound I-3 can be prepared by the method shown in Scheme 1. As shown in Scheme 4, PG refers to a protecting group. Non-limiting examples of the protecting group include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 4, for compounds where R 1 = R 2 = H (e.g., compound I-7), ketone I-3 is reduced to alcohol I-4 with a reducing agent (e.g., sodium borohydride; Step i). Alcohol I-4 is then reduced with a silane such as triethyl silane in the presence of a Lewis acid such as boron trifluoride etherate or an acid such as trifluoroacetic acid to afford compound I-7 (Step ii). Where the nitrogen-protecting group is Boc, the nitrogen-protecting group is removed under these conditions to give the benzyl cyclic amine I-7. For compounds where R 1 is alkyl, ketone I-3 is treated with the appropriate alkyl-Grignard reagent (e.g., R 1 MeBr) to afford alcohol I-3' (Step iii). As shown in Scheme 4, Step iv, the alcohol I-3' can be reduced with triethyl silane using procedure similar to those used in Step ii to remove the OH group to afford compound I-3'' (where the nitrogen-protecting group is Boc, the nitrogen-protecting group is removed under these conditions). The protecting groups in compounds I-3'' and I-7 can then be selectively removed, and the resulting compound's free phenol OH group can optionally be converted to a compound of Formula I using methods known in the art.

[0155] As shown in Scheme 5, compound I-7b can be prepared from compound I-8 and I-9.

[0156] Compounds I-8, 1-9a, and I-9 can be prepared by any method known in the art. As shown in Scheme 5, PG refers to a protecting group. Non-limiting examples of the protecting group include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 5, another route to prepare a compound where R 1 = R 2 = H and n 2 = n 3 = 1 is reacting a benzyl bromide I-8 with a pyridine boronic acid or boronate ester I-9 (R is H or alkyl) with a palladium catalyst for example tetrakis triphenylphoshine palladium to give benzyl pyridine I-10 (Step i). Reduction of the pyridine I-10 by a reducing agent (e.g., hydrogen over platinum oxide in the presence of acid (e.g., HCl)) gives benzyl piperidine I-7b. Alternatively, a vinyl boronate I-9a can be used following similar steps (Steps iii and iv) to afford compound I-7b. A base such as Na 2 CO 3 can be used in Steps I and iii. The protecting group in compound I-7b can then be selectively removed, and the resulting compound with free NH and phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0157] As shown in Scheme 6, compound I-7 can be prepared from compound I-1b and I-11.

[0158] Compounds I-11 and I-1b can be prepared by any method known in the art. As shown in Scheme 6, PG refers to a protecting group. Non-limiting examples of the protecting group include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 6, another route to a compound where R 1 = R 2 = H is hydroboration of an exocyclic alkenyl cyclic amine I-8 and coupling of the resulting boronate with a bromo or iodo phenol I-1b using a palladium catalyst (e.g., Pd(dppf)Cl 2 ). The protecting groups in compound I-7 can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0159] As shown in Scheme 7, compound I-7 can be also prepared from compound I-1b and I-12.

[0160] Compounds I-12 and I-1b can be prepared by any method known in the art. As shown in Scheme 7, PG refers to a protecting group. Non-limiting examples of the protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 7, another route to a compound where R 1 = R 2 = H is photoredox reaction of bromophenol I-1b and a bromomethyl cyclic amine I-12 using tris trimethylsilyl silane, a combination of iridium and nickel catalyst (e.g., Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 and NiCl 2 , respectively) under irradiation with blue LED light. The protecting groups in compound I-7 can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0161] As shown in Scheme 8, compound I-13 can be prepared from compound I-8 and I-2d.

[0162] Compounds I-8 and I-2d can be prepared by the method known in the art. As shown in Scheme 8, PG refers to a protecting group. Non-limiting examples of the protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl group, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as protecting groups for OH or NH 2 . Other substituents are defined herein. As shown in Scheme 8, compounds with a substituent R 9 can be obtained by reacting a cyclic amine I-2d containing an electron withdrawing group (EWG) such as an ester or a nitrile with a benzyl bromide I-8 in the presence of a base such as sodium hexamethyldisilazide to give compound I-13. Any suitable base may be used in this reaction. The ester or nitrile group (or other electro-withdrawing group) in compound I-13 can be converted to a range of R 9 groups as defined herein by methods known in the art. The protecting groups in the resulting compounds with the desirable R 9 groups can then be selectively removed, and the resulting compound with free NH and / or phenol OH groups can optionally be converted to a compound of Formula I using methods known in the art.

[0163] Compounds of Formula I having other R 1 and R 2 substituents can be synthesized from ketone I-3 by, for example, reductive amination, Wittig reaction followed by cyclopropanation or hydroboration, or from alcohol I-4 by conversion to the corresponding bromide and displacement the bromide with a nucleophile.

[0164] As shown in Scheme 9, compounds where R 1 is NH 2 , n 2 =1 and n 3 =1 (e.g., compounds I-16 and 1-17) can be prepared from compound I-1e and 1-14.

[0165] Compounds I-14 and I-1e can be prepared by any method known in the art. As shown in Scheme 9, a three-component reaction of phenol I-1e, pyridine aldehyde I-14 and acetamide is carried out by optionally heating all three components with aluminum trichloride without solvent to provide acetamide I-15. Hydrogenation over platinum oxide reduces the pyridine to piperidine I-16, and acid hydrolysis gives amine I-17.

[0166] The reactions described in Schemes 1-9 can be carried out in a suitable solvent. Suitable solvents include, but are not limited to, acetonitrile, methanol, ethanol, dichloromethane, DMF, THF, MTBE, or toluene. The reactions described in Schemes 1-9 may be conducted under inert atmosphere, e.g., under nitrogen or argon, or the reaction may be carried out in a sealed tube. The reaction mixture may be heated in a microwave or heated to an elevated temperature. Suitable elevated temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 °C or higher or the refluxing / boiling temperature of the solvent used. The reaction mixture may alternatively be cooled in a cold bath at a temperature lower than room temperature, e.g., 0, -10, -20, -30, -40, -50, -78, or -90 °C. The reaction may be worked up by removing the solvent or partitioning of the organic solvent phase with one or more aqueous phases each optionally containing NaCl, NaHCO 3 , or NH 4 Cl. The solvent in the organic phase can be removed by reduced vacuum evaporation and the resulting residue may be purified using a silica gel column or HPLC.Pharmaceutical Compositions

[0167] This invention also provides a pharmaceutical composition comprising at least one of the compounds of the presently claimed invention as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0168] In certain embodiments, the composition is in the form of a hydrate, solvate or pharmaceutically acceptable salt. The composition can be administered to the subject by any suitable route of administration, including, without limitation, oral and parenteral.

[0169] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. 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 which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being comingled 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 efficiency.

[0170] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically-acceptable salt", in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its 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, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0171] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0172] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).

[0173] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0174] 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 being treated, the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0175] 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.

[0176] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0177] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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 starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0178] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets, may be, made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0179] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0180] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl-β-cyclodextrin, may be used to solubilize compounds.

[0181] 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.

[0182] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar--agar and tragacanth, and mixtures thereof.

[0183] Dosage forms for the 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 which may be required.

[0184] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0185] Powders and sprays can contain, in addition to a compound of this 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, such as propane and butane.

[0186] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the proper medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0187] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0188] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0189] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polypropylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.

[0190] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.

[0191] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0192] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another therapeutic agent). Non-limiting examples of another therapeutic agent including biological and small molecule anticancer agent, immunomodulator, immunosuppressant, antiinflammatory agent, anti-arthritis agent, corticosteroid, antidiarrheal agent, anticoagulation agent, and antithrombotic agent.

[0193] The compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds may be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), race horses, birds, lizards, and any other organism, which can tolerate the compounds.

[0194] 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 is herein described. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.Administration to a Subject

[0195] In yet another aspect, the present invention provides a compound of the invention, or a pharmaceutically-acceptable salt thereof for use as a medicament. In another aspect, the presently claimed invention provides a compound of the presently claimed invention, or a pharmaceutically-acceptable salt thereof for use in a method for treating a condition in a mammalian species in need thereof, the method comprising 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 nerve system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.

[0196] 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 neoplasms, leukemias, lymphomas, liver cancer, lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcomas, skin cancer, testicular cancer, and thyroid cancer.

[0197] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0198] 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 mellitus). In some embodiments, the Central Nerve System (CNS) disorder is Alzheimer's disease.

[0199] In some embodiments, the metabolic disorder is obesity or Type II diabetes mellitus. In some embodiments, the cardiovascular disorder is an ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0200] In some embodiments, the mammalian species is human.

[0201] 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 mellitus, Alzheimer's disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, inflammatory bowel disease, obesity, Type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof.

[0202] A method of blocking Kv1.3 potassium channel in a mammalian species in need thereof is described herein, including administering to the mammalian species a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the compounds described herein is selective in blocking the Kv 1.3 potassium channels with minimal or no off-target inhibition activities against other potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles.

[0204] Some aspects of the invention involve an effective amount of a composition to a subject to be administered to achieve a specific outcome. The small molecule compositions useful according to the disclosed methods thus can be formulated in any manner suitable for pharmaceutical use.

[0205] The formulations of the invention are to be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0206] For use in therapy, an effective amount of the compound can be administered to a subject by any mode allowing the compound to be taken up by the appropriate target cells. "Administering" the pharmaceutical composition of the present invention can be accomplished by any means known to the skilled artisan. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.). An injection can be in a bolus or a continuous infusion.

[0207] For example the pharmaceutical compositions according to the invention are often to be administered by intravenous, intramuscular, or other parenteral means. They can also be to be administered by intranasal application, inhalation, topically, orally, or as implants, and even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer R (1990) Science 249:1527-33.

[0208] The concentration of compounds included in compositions used in the disclosed methods can range from about 1 nM to about 100 µM. Effective doses are believed to range from about 10 picomole / kg to about 100 micromole / kg.

[0209] The pharmaceutical compositions are preferably prepared and to be administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. Solid dose units are tablets, capsules, powders, and suppositories. For treatment of a patient, depending on activity of the compound, manner of administration, purpose of the administration (i.e., prophylactic or therapeutic), nature and severity of the disorder, age and body weight of the patient, different doses may be necessary. The administration of a given dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units. Repeated and multiple administration of doses at specific intervals of days, weeks, or months apart are also contemplated by the invention.

[0210] The compositions can be to be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0211] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0212] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents are water, Ringer's solution, phosphate buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0213] The compounds useful in the invention can be to be delivered in mixtures of more than two such compounds. A mixture can further include one or more adjuvants in addition to the combination of compounds.

[0214] A variety of administration routes is available. The particular mode selected will depend, of course, upon the particular compound selected, the age and general health status of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy. The methods, generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above.

[0215] The compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0216] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compounds, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which an agent of the invention is contained in a form within a matrix such as those described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos. 3,854,480, 5,133,974 and 5,407,686. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation.Assays for Effectiveness of Kv1.3 potassium channel blockers

[0217] In some embodiments, the compounds as described herein are tested for their activities against Kv1.3 potassium channel. In some embodiments, the compounds as described herein are tested for their Kv1.3 potassium channel electrophysiology. In some embodiments, the compounds as described herein are tested for their hERG electrophysiology.

[0218] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments.EXAMPLES

[0219] Examples 1-76 describe various intermediates used in the syntheses of representative compounds of Formula I disclosed herein.Example 1. Intermediate 1 (1-(4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl)ethanone)

[0220] Step a:

[0221] To a stirred solution of 1-acetylpiperidine-4-carboxylic acid (2.00 g, 11.68 mmol) in DCE (20 mL) was added SOCl 2 (10 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was allowed to warm to room temperature. After stirring for additional 1.5 h at room temperature, the resulting solution was concentrated under reduced pressure to afford crude 1-acetylpiperidine-4-carbonyl chloride, which was used in the next step without further purification.Step b:

[0222] To a solution of 1-acetylpiperidine-4-carbonyl chloride (0.39 g, 2.03 mmol) in DCE (20 mL) was added 1,2-dichloro-4-methoxybenzene (0.30 g, 1.69 mmol) at room temperature under nitrogen atmosphere. After stirring for 5 min, anhydrous AlCl 3 (0.49 g, 3.73 mmol) was added in portions at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to 50 °C and stirred for 2 h under nitrogen atmosphere. After cooling to 0 °C, the resulting mixture was quenched with ice water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford the crude product as a dark yellow solid. The crude product was purified by Prep-HPLC with following conditions: Column: Sunfire Prep C18 OBD Column, 10 µm, 19 x 250 mm; Mobile Phase A: water (plus 0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 56% B to 64% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 6.98 min. The fractions containing desired product were collected and concentrated under reduced pressure to afford 1-(4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl)ethanone as an off-white solid (85.6 mg, 16%): LCMS (ESI) calc'd for C 14 H 15 Cl 2 NO 3 [M + H] +< : 316, 318 (3 : 2), found 316, 318 (3 : 2); 1< H NMR (300 MHz, DMSO-d 6 ) δ 11.65 (s, 1H), 7.94 (s, 1H), 7.22 (s, 1H), 4.31 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.69-3.54 (m, 1H), 3.21-3.03 (m, 1H), 2.75-2.58 (m, 1H), 1.96 (s, 3H), 1.86-1.71 (m, 2H), 1.53-1.18 (m, 2H).Example 2. Intermediate 2 ((4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl)methanone)

[0223] Step a:

[0224] A mixture of 1-[4-[(4,5-dichloro-2-hydroxyphenyl)carbonyl]piperidin-1-yl]ethan-1-one (0.15 g, 0.48 mmol) in aq. HCl (6 N, 15 mL) was stirred for 4 h at 105 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column 19 x 250 mm, 10 µm; Mobile Phase A: water with 10 mmol / L NH 4 HCO 3 , Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 60% B in 9 min; Detector: UV 254 / 210 nm; Retention time: 8.5 min. The fractions containing desired product were collected and concentrated under reduced pressure to afford (4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl)methanone as a yellow solid (23.5 mg, 18%): LCMS (ESI) calc'd for C 12 H 13 Cl 2 NO 2 [M + H] +< : 274, 276 (3 : 2), found 274, 276 (3 : 2); 1< H NMR (300 MHz, DMSO-d 6 ) δ 7.85 (br, 1H), 7.57 (s, 1H), 6.67 (s, 1H), 3.96-3.76 (m, 1H).3.12 (d, J = 12.0 Hz, 2H), 2.83-2.62 (m, 2H), 1.81 (d, J = 13.1 Hz, 2H), 1.57-1.34 (m, 2H).Example 3. Intermediate 3 (tert-butyl 4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate trifluoroacetic acid)

[0225] Step a:

[0226] To a stirred solution of tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)piperidine-1-carboxylate (1.00 g, 2.68 mmol) in DMF (10 mL) were added K 2 CO 3 (0.74 g, 5.36 mmol) and CH 3 I (0.75 g, 5.36 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) at room temperature and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford tert-butyl 4-(4,5-dichloro-2-methoxybenzoyl)piperidine-1-carboxylate as a light yellow solid (0.85 g, 83%): LCMS (ESI) calc'd for C 18 H 23 Cl 2 NO 4 [M + H] +< : 388, 390 (3 : 2), found 388, 390 (3 : 2);Step b:

[0227] To a stirred solution of tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine-1-carboxylate (1.70 g, 4.38 mmol) in THF (20 mL) was added NaBH 4 (0.25 g, 6.58 mmol) in portions at 0 °C. After stirring for additional 1.5 h, the reaction mixture was quenched with saturated aq. NH 4 Cl (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (30 / 1) to afford tert-butyl 4-((4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl)cyclohexane-1-carboxylate as an off-white solid (1.40 g, 82%): LCMS (ESI) calc'd for C 18 H 25 Cl 2 NO 4 [M + H] +< : 390, 392 (3 : 2), found 390, 392 (3 : 2); 1< H NMR (300 MHz, DMSO-d 6 ) δ 7.41 (s, 1H), 7.19 (s, 1H), 5..22 (d, J = 5.0 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 4.25 (d, J = 5.8 Hz, 1H), 3.99 (d, J = 5.8 Hz, 1H), 3.76 (s, 3H), 2.91-2.74 (m, 2H), 1.84-1.71 (m, 2H), 1.35 (s, 9H), 1.32-1.01 (m, 3H).Step c:

[0228] To a stirred solution of tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]piperidine-1-carboxylate (2.50 g, 6.41 mmol) in DCM (18 mL) was added PBr 3 (3.50 g, 12.81 mmol) dropwise at 0 °C. After stirring for additional 1 h, the reaction solution was quenched with saturated aq. NaHCO 3 (30 mL) at 0 °C and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford crude 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine, which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 13 H 16 BrCl 2 NO [M + H] +< : 352, 354, 356 (2 : 3 : 1), found 352, 354, 356 (2 : 3 : 1).Step d:

[0229] To a stirred solution of 4-[bromo(4,5-dichloro-2-methoxyphenyl)methyl]piperidine (2.00 g, 5.66 mmol) and Et 3 N (0.90 g, 8.50 mmol) in DCM (20 mL) was added a solution of Boc 2 O (1.90 g, 8.50 mmol) in DCM (5 mL) dropwise at 0 °C. After stirring for additional 1 h at 0 °C, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford tert-butyl 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate as a yellow oil (0.30 g, 12% overall two steps): LCMS (ESI) calc'd for C 18 H 24 BrCl 2 NO 3 [M + 1 - 56] +< : 396, 398, 400 (2 : 3 : 1), found 396, 398, 400 (2 : 3 : 1); 1< H NMR (300 MHz, CDCl 3 ) δ 7.50 (s, 1H), 6.95 (s, 1H), 5.15 (d, J = 9.4 Hz, 1H), 4.18 (d, J = 13.5 Hz, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.85 (s, 3H), 2.81-2.54 (m, 2H), 2.27-2.02 (m, 2H), 1.48 (s, 9H), 1.32-0.97 (m, 3H).Step e:

[0230] To a stirred solution of tert-butyl 4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate (0.26 g, 0.58 mmol) in DMF (5 mL) was added NaN 3 (0.11 g, 1.74 mmol) at room temperature. The reaction mixture was allowed to warm to 100 °C and stirred for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with water (2 x 15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to a quarter of the volume. The residue was used in the next step directly without further purification: LCMS (ESI) calc'd for C 18 H 24 Cl 2 N 4 O 3 [M + H] +< : 415, 417 (3 : 2), found 415, 417 (3 : 2).Step f:

[0231] To a stirred solution of tert-butyl 4-[azido(4,5-dichloro-2-methoxyphenyl)methyl]piperidine-1-carboxylate (0.20 g, 0.48 mmol) and PPh 3 (0.25 g, 0.96 mmol) in THF (2 mL) was added NH 3 ·H 2 O (1 mL, 28% in H 2 O) dropwise at room temperature. The reaction solution was stirred for 16 h at room temperature. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 30% ACN in water (plus 0.05% TFA) to afford tert-butyl 4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidine-1-carboxylate trifluoroacetic acid as a yellow oil (0.10 g, 45% overall two steps): LCMS (ESI) calc'd for C 18 H 26 Cl 2 N 2 O 3 [M + H] +< : 389, 391 (3 : 2), found 389, 391 (3 : 2); 1< H NMR (300 MHz, CD 3 OD) δ 7.46 (s, 1H), 7.29 (s, 1H), 4.21-4.09 (m, 2H), 4.05-3.93 (m, 1H), 3.86 (s, 3H), 2.82-2.53 (m, 1H), 2.20-2.06 (m, 2H), 1.95-1.83 (m, 1H), 1.40 (s, 9H), 1.32-0.97 (m, 3H).Example 4. Intermediate 4 (1-(4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)ethanone)

[0232] Step a:

[0233] To a stirred solution of 1-[4-(4,5-dichloro-2-hydroxybenzoyl)piperidin-1-yl]ethan-1-one (1.00 g, 3.16 mmol) in DMF (10 mL) were added K 2 CO 3 (0.87 g, 6.33 mmol) and CH 3 I (0.90 g, 6.33 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) at room temperature and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford 1-[4-(4,5-dichloro-2-methoxybenzoyl)piperidin-1-yl]ethan-1-one as a light yellow solid (1.00 g, 95%): LCMS (ESI) calc'd for C 15 H 17 Cl 2 NO 3 [M + H] +< : 330, 332 (3 : 2), found 330, 332 (3 : 2).Step b:

[0234] To a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidin-1-yl]ethan-1-one (0.70 g, 2.12 mmol) in MeOH (5 mL) was added NaBH 4 (0.12 g, 3.18 mmol) in portions at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated aq. NH 4 Cl (30 mL) at 0 °C and extracted with EA (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to afford 1-(4-((4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl)piperidin-1-yl)ethanone as a yellow oil (0.46 g, 66%): LCMS (ESI) calc'd for C 15 H 19 Cl 2 NO 3 [M + H] +< : 332, 334 (3 : 2), found 332, 334 (3 : 2).Step c:

[0235] To a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]piperidin-1-yl]ethan-1-one (0.46 g, 1.38 mmol) in DCM (5 mL) was added PBr 3 (0.75 g, 2.77 mmol) dropwise at 0 °C. After stirring for 1 h at 0 °C, the reaction solution was quenched with water (30 mL) at 0 °C and extracted with EA (4 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford 1-(4-(bromo(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)ethanone as a yellow oil (50 mg, 10%): LCMS (ESI) calc'd for C 15 H 18 BrCl 2 NO 2 [M + H] +< : 394, 396, 398 (2 : 3 : 1), found 394, 396, 398 (2 : 3 : 1); 1< H NMR (300 MHz, CD 3 OD) δ 7.57 (s, 1H), 7.15 (s, 1H), 5.14 (dd, J = 9.5, 2.4 Hz, 1H), 3.99-3.90 (m, 1H), 3.85 (s, 3H), 3.84-3.80 (m, 1H), 3.18-2.91 (m, 1H), 2.69-2.45 (m, 1H), 2.38-2.17 (m, 2H), 2.05 (d, J = 15.0 Hz, 3H), 1.43-1.15 (m, 3H).Step d:

[0236] To a solution of 1-(4-(bromo(4,5-dichloro-2-hydroxyphenyl)methyl)piperidin-1-yl)ethanone (50 mg, 0.13 mmol) in DMF (3 mL) was added NaN 3 (26 mg, 0.40 mmol) at room temperature. The reaction mixture was allowed to warm to 100 °C and stirred for 8 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 25 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to a quarter of volume. The residue was used in the next step directly without further purification: LCMS (ESI) calc'd for C 15 H 18 Cl 2 N 4 O 2 [M + H] +< : 357, 359 (3 : 2), found 357, 359 (3 : 2).Step e:

[0237] To a solution of 1-[4-[azido(4,5-dichloro-2-methoxyphenyl)methyl]piperidin-1-yl]ethan-1-one (0.10 g, 0.28 mmol) in THF (4 mL) were added PPh 3 (0.15 g, 0.56 mmol) and NH 3 ·H 2 O (1 mL, 28% in H 2 O) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted 29% ACN in water (plus 0.05% TFA) to afford 1-(4-(amino(4,5-dichloro-2-methoxyphenyl)methyl)piperidin-1-yl)ethanone as a light yellow solid (30 mg, 71% overall two steps): LCMS (ESI) calc'd for C 15 H 20 Cl 2 N 2 O 2 [M + H] +< : 331, 333 (3 : 2), found 331, 333 (3 : 2); 1< H NMR (300 MHz, CD 3 OD) δ 7.47 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 4.60-4.40 (m, 1H), 3.99-3.82 (m, 2H), 3.81 (s, 3H), 3.17-2.89 (m, 1H), 2.66-2.44 (m, 1H), 2.15-1.78 (m, 5H), 1.43-1.03 (m, 3H).Example 5. Intermediate 5 (N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0238] Step a:

[0239] To a stirred solution of (4,5-dichloro-2-hydroxyphenyl)(piperidin-4-yl)methanone (17 g, 62.27 mmol) and Et 3 N (31.44 g, 0.31 mol) in DCM (150 mL) was added Boc 2 O (14.90 g, 68.21 mmol) in portions at 0 °C. The reaction solution was allowed to warm to room temperature and stirred for 4 h at room temperature. The resulting solution was quenched with water (300 mL) at room temperature and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 17 H 21 Cl 2 NO 4 [M + H] +< : 374, 376 (3 : 2), found 374, 376 (3 : 2).Step b:

[0240] To a stirred mixture of tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)piperidine-1-carboxylate (crude) and K 2 CO 3 (33.20 g, 0.24 mmol) in DMF (200 mL) was added allyl bromide (14.48 g, 0.12 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was allowed to warm to 40 °C and stirred for 12 h. The resulting mixture was diluted with water (500 mL) and extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate as a light yellow solid (15.40 g, 64% overall two steps): LCMS (ESI) calc'd for C 20 H 25 Cl 2 NO 4 [M + H] +< : 414, 416 (3 : 2), found 414, 416 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.69 (s, 1H), 7.07 (s, 1H), 6.16-6.00 (m, 1H), 5.55-5.36 (m, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.18-4.08 (m, 2H), 3.41-3.32 (m, 1H), 2.94-2.74 (m, 2H), 1.93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.54 (s, 9H).Step c:

[0241] To a stirred mixture of tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]piperidine-1-carboxylate (8.80 g, 21.24 mmol) and Ti(OEt) 4 (21.51 g, 94.30 mmol) in THF (50 mL) was added 2-methylpropane-2-sulfinamide (3.86 g, 31.85 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was allowed to warm to 70 °C and stirred for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water (200 mL) at room temperature. The solid was formed and filtered. The filtrate was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to crude tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate. The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 24 H 34 Cl 2 N 2 O 4 S [M + H] +< : 517, 519 (3 : 2), found 517, 519 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.16 (s, 1H), 6.95 (s, 1H), 6.05-5.95 (m, 1H), 5.43-5.26 (m, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4.25-4.00 (m, 2H), 2.86-2.52 (m, 3H), 1.91-1.54 (m, 4H), 1.45 (s, 9H), 1.21 (s, 9H).Step d:

[0242] To a solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate (crude) in MeOH (80 mL) was added NaBH 4 (1.21 g, 31.86 mmol) in portions at 0 °C under nitrogen atmosphere. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water (150 mL) at 0 °C and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 45% ACN in water (plus 0.05% TFA) to afford tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate as a yellow oil (6.58 g, 60% overall two steps): LCMS (ESI) calc'd for C 24 H 36 Cl 2 N 2 O 4 S [M + H] +< : 519, 521 (3 : 2), found 519, 521 (3 : 2); 1< H NMR (300 MHz, CD 3 OD) δ 7.51 (s, 1H), 7.15 (s, 1H), 6.19-6.03 (m, 1H), 5.52-5.29 (m, 2H), 4.67-4.58 (m, 2H), 4.30 (d, J = 9.1 Hz, 1H), 4.04 (dd, J = 35.2, 13.5 Hz, 2H), 2.84-2.50 (m, 2H), 2.14-1.87 (m, 2H), 1.46 (s, 9H), 1.30-1.05 (m, 3H), 1.23 (s, 9H).Step e:

[0243] To a stirred solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (6.58 g, 12.68 mmol) in DCM (100 mL) was added TFA (20 mL) dropwise at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (200 mL). The pH value of the reaction system was adjusted to 9 with saturated aq. NaHCO 3 at 0 °C. The aqueous layer was extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 35% ACN in water (plus 0.05% TFA) to afford N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide as a light yellow oil (4.24 g, 80%): LCMS (ESI) calc'd for C 19 H 28 Cl 2 N 2 O 2 S [M + H] +< : 419, 421 (3 : 2), found 419, 421 (3 : 2); 1< H NMR (300 MHz, DMSO-d 6 + D 2 O) δ 7.50 (s, 1H), 7.19 (s, 1H), 6.06-5.92 (m, 1H), 5.42-5.18 (m, 2H), 4.63-4.48 (d, J = 4.8 Hz, 2H), 4.47-4.34 (d, J = 8.7 Hz, 1H), 3.38-3.14 (m, 2H), 2.84-2.65 (m, 2H), 2.20-2.05 (m, 1H), 1.96-1.82 (m, 1H), 1.42-1.18 (m, 3H), 0.97 (s, 9H).Example 6. Intermediate 6 ((S)-N-((R)-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method A

[0244] Step a:

[0245] To a stirred solution of tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)piperidine-1-carboxylate (5.16 g, 12.45 mmol) and Ti(OEt) 4 (8.52 g, 37.36 mmol) in THF (50 mL) was added (S)-2-methylpropane-2-sulfinamide (1.67 g, 13.70 mmol) at room temperature under nitrogen atmosphere. The reaction solution was allowed to warm to 70 °C and stirred for 36 h. After cooling to room temperature, the resulting solution was quenched with water (300 mL) at room temperature. The solid was formed and filtered. The filtrate was extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was dried in a vacuum oven to afford (S)-tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate as a light yellow solid (6.00 g, 93%): LCMS (ESI) calc'd for C 24 H 34 Cl 2 N 2 O 4 S [M + H] +< : 517, 519 (3 : 2), found 517, 519 (3 : 2); 1< H NMR (300 MHz, CDCl 3 ) δ 7.28 (s, 1H), 6.97 (s, 1H), 6.06-5.94 (m, 1H), 5.46-5.26 (m, 2H), 4.58 (d, J = 5.7 Hz, 2H), 4.23-4.01 (m, 2H), 3.81-3.62 (m, 1H), 2.84-2.57 (m, 2H), 1.93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.46 (s, 9H), 1.22 (s, 9H).Step b:

[0246] To a solution of (S)-tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate (1.50 g, 2.90 mmol) in toluene (10 mL) was added DIBAL-H (4.35 mL, 4.35 mmol, 1 M in toluene) dropwise over 30 min at -65 °C under nitrogen atmosphere. After the addition, the reaction solution was stirred for 3 h at -65 °C under nitrogen atmosphere. The resulting solution was quenched with water (20 mL) at -65 °C, and then diluted with saturated aq. potassium sodium tartrate (200 mL). The aqueous layers were extracted with EA (3 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 45% ACN in water (plus 0.05% TFA) to afford tert-butyl 4-((R)-(2-(allyloxy)-4,5-dichlorophenyl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate as a yellow oil (0.78 g, 52%): LCMS (ESI) calc'd for C 24 H 36 Cl 2 N 2 O 4 S [M + H] +< : 519, 521 (3 : 2), found 519, 521 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.23 (s, 1H), 6.96 (s, 1H), 6.10-5.92 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.50-4.37 (m, 1H), 4.28-4.04 (m, 2H), 3.84-3.64 (m, 1H), 2.71-2.49 (m, 2H), 2.01-1.81 (m, 2H), 1.47 (s, 9H), 1.49-1.22 (m, 3H), 1.17 (s, 9H).Step c:

[0247] To a stirred solution of tert-butyl 4-((R)-(2-(allyloxy)-4,5-dichlorophenyl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (16.00 g, 30.80 mmol) in DCM (120 mL) was added TFA (30 mL) dropwise at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (200 mL). The pH value of the reaction system was adjusted to 8 with saturated aq. NaHCO 3 at 0 °C. The aqueous layer was extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 35% ACN in water with 10 mmol / L NH 4 HCO 3 to afford (S)-N-((R)-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide as a yellow oil (7.00 g, 46%): LCMS (ESI) calc'd for C 19 H 28 Cl 2 N 2 O 2 S [M + H] +< : 419, 421 (3 : 2), found 419, 421 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49-4.37 (m, 1H), 4.88-3.95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H).Intermediate 6 ((S)-N-((R)-(2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide), Method B

[0248] Step a:

[0249] To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br 2 (98.04 g, 613.49 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with saturated aq. Na 2 S 2 O 3 (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo-4,5-dichlorophenol as a yellow oil. The crude product was used in the next step directly without further purification: 1< H NMR (400 MHz, CDCl 3 ) δ 7.57 (s, 1H), 7.15 (s, 1H).Step b:

[0250] To a stirred solution of 2-bromo-4,5-dichlorophenol (50.00 g, 206.71 mmol) and K 2 CO 3 (57.14 g, 413.41 mmol) in DMF (500 mL) was added 3-bromoprop-1-ene (37.51 g, 310.06 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 40 °C under nitrogen atmosphere. The resulting mixture was diluted with water (1.5 L) and extracted with EA (3 x 0.5 L). The combined organic layers were washed with brine (4 x 0.5 L), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene as a light yellow oil (40.00 g, 61%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 6.98 (s, 1H), 6.12-6.06 (m, 1H), 5.60-5.29 (m, 2H), 4.69-4.57 (m, 2H).Step c:

[0251] To a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (30.00 g, 106.39 mmol) in THF (800 mL) was added i-PrMgCl-LiCl (125 mL, 159.59 mmol, 1.3 M in THF) dropwise over 30 min at -15 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 0.5 h at -15 °C under nitrogen atmosphere. To resulting solution was added the tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (33.67 g, 106.39 mmol) at -15 °C under nitrogen atmosphere. After addition, the reaction mixture was stirred for 2 h at -15 °C. The reaction was quenched with saturated aq. NH 4 Cl (100 mL) at -15 °C and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2) to afford tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate as an off-white solid (34.00 g, 58%): LCMS (ESI) calc'd for C 24 H 36 Cl 2 N 2 O 4 S [M + H] +< : 519, 521 (3 : 2), found 519, 521 (3 : 2); 1< H NMR (400 MHz, CD 3 OD) δ 7.44 (s, 1H), 7.17 (s, 1H), 6.18-6.03 (m, 1H), 5.49-5.31 (m, 2H), 4.62 (d, J = 5.2 Hz, 2H), 4.52 (d, J = 8.8 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.01 (d, J = 13.4 Hz, 1H), 2.70 (d, J = 35.8 Hz, 2H), 2.12 (d, J = 13.6 Hz, 1H), 2.01-1.88 (m, 1H), 1.46 (s, 9H), 1.36-1.19 (m, 3H), 1.13 (d, J = 1.4 Hz, 9H).Step d:

[0252] To a stirred mixture of tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (5.70 g, 10.97 mmol) in DCM (40 mL) was added TFA (10 mL) dropwise at room temperature. The reaction solution was stirred for 1 h at room temperature. The mixture was neutralized to pH 9 with saturated aq. NaHCO 3 at 0 °C. The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography, eluted with the 40% ACN in water with 10 mmol / L NH 4 HCO 3 to afford (S)-N-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a yellow solid (3.50 g, 68%): LCMS (ESI) calc'd for C 19 H 28 Cl 2 N 2 O 2 S [M + H] +< : 419, 421 (3 : 2), found 419, 421 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49-4.37 (m, 1H), 4.88-3.95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H).Example 7. (which is a reference example) Intermediate 7 (N-((2-hydroxynaphthalen-1-yl)(pyridin-4-yl)methyl)acetamide)

[0253] Step a:

[0254] To a stirred mixture of naphthalen-2-ol (3.50 g, 24.28 mmol), acetamide (1.72 g, 29.13 mmol) and pyridine-4-carbaldehyde (2.60 g, 24.28 mmol) was added AlCl 3 (0.49 g, 3.64 mmol) in several portions at 110 °C under nitrogen atmosphere. The reaction mixture was stirred for 8 h at 110 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (60 mL). The aqueous layers were extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (8 / 1) to afford N-[(2-hydroxynaphthalen-1-yl)(pyridin-4-yl)methyl]acetamide as a yellow green solid (1.00 g, 14%): LCMS (ESI) calc'd for C 18 H 16 N 2 O 2 [M + H] +< : 293, found 293; 1< H NMR (400 MHz, CD 3 OD) δ 8.39 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.87 (t, J = 9.0 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.29-7.24 (m, 3H), 7.21 (d, J = 8.6 Hz, 1H), 2.10 (s, 3H).Example 8. Intermediate 8 (N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide trifluoroacetic acid)

[0255] Step a:

[0256] To a stirred solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (0.50 g, 0.96 mmol) in 1,4-dioxane (5 mL) was added aq. HCl (6 N, 0.5 mL) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was neutralized to pH 7 with saturated aq. NaHCO 3 , and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 60% ACN in water with 20 mmol / L NH 4 HCO 3 to afford tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(amino)methyl)piperidine-1-carboxylate as a brown oil (0.40 g, 90%): LCMS (ESI) calc'd for C 20 H 28 Cl 2 N 2 O 3 [M + H] +< : 415, 417 (3 : 2), found 415, 417 (3 : 2).Step b:

[0257] To a stirred solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(amino)methyl)piperidine-1-carboxylate (0.11 g, 0.27 mmol) and Et 3 N (54 mg, 0.53 mmol) in DCM (3 mL) was added TFAA (61 mg, 0.29 mmol) dropwise at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was diluted with DCM (50 mL). The solution was washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After the filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate as a yellow solid (0.13 g, 95%): LCMS (ESI) calc'd for C 22 H 27 Cl 2 F 3 N 2 O 4 [M + H] +< : 511, 513 (3 : 2), found 511, 513 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.11-5.99 (m, 1H), 5.47-5.38 (m, 2H), 4.78 (t, J = 12.0 Hz, 1H), 4.86-4.57 (m, 2H), 4.31-3.93 (m, 2H), 2.75-2.48 (m, 2H), 2.01-1.91 (m, 1H), 1.83-1.72 (m, 1H), 1.46 (s, 9H), 1.49-1.22 (m, 3H).Step c:

[0258] To a solution of tert-butyl 4-((2-(allyloxy)-4,5-dichlorophenyl)(2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (0.13 g, 0.25 mmol) in DCM (3 mL) was added TFA (3 mL) dropwise at room temperature. The reaction solution was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to afford N-((2-(allyloxy)-4,5-dichlorophenyl)(piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide trifluoroacetic acid as a yellow solid (0.10 g, 90%): LCMS (ESI) calc'd for C 17 H 19 Cl 2 F 3 N 2 O 2 [M + H] +< : 411, 413 (3 : 2), found 411, 413 (3 : 2).Example 9. Intermediate 9 (1-(allyloxy)-2-bromo-3,4,5-trichlorobenzene)

[0259] Step a:

[0260] To a stirred solution of (3,4,5-trichlorophenyl)boronic acid (5.00 g, 22.20 mol) in THF (15 mL) were added H 2 O 2 (1.51 g, 44.39 mmol, 30%) and NaOH (1.78 g, 44.39 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated aq. Na 2 SO 3 (10 mL) at room temperature. The mixture was acidified to pH 3 with aq. HCl (1 N). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford 3,4,5-trichlorophenol as a light yellow solid (4.30 g, 95%): 1< H NMR (300 MHz, CDCl 3 ) δ 6.92 (s, 2H).Step b:

[0261] To a stirred solution of 3,4,5-trichlorophenol (4.60 g, 23.30 mol) in AcOH (20 mL) was added Br 2 (3.70 g, 23.15 mol) dropwise at room temperature under argon atmosphere. After stirring for 6 h, the reaction was quenched with saturated aq. Na 2 SO 3 (80 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (3 x 80 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 2-bromo-3,4,5-trichlorophenol as an off-white solid (2.40 g, 37%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 7.15 (s, 1H).Step c:

[0262] To a stirred solution of 2-bromo-3,4,5-trichlorophenol (2.40 g, 8.69 mmol) and K 2 CO 3 (2.40 g, 17.37 mmol) in DMF (15 mL) was added allyl bromide (1.26 g, 10.42 mmol) at room temperature. The reaction was allowed to warm to 50 °C and stirred for 1 h. The reaction mixture was diluted with EA (80 mL) and water (80 mL), and then extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (6 x 80 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 2-bromo-3,4,5-trichloro-1-(prop-2-en-1-yloxy)benzene as a light yellow oil (1.80 g, 66%).Example 10. Intermediate 10 ((S)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate)

[0263] Step a:

[0264] To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (50.00 g, 0.23 mol) and (S)-2-methylpropane-2-sulfinamide (43.00 g, 0.35 mmol) in THF (300 mL) was added Ti(OEt) 4 (187.00 g, 0.82 mol) dropwise at room temperature under nitrogen atmosphere. The reaction solution was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting solution was quenched with saturated aq. NH 4 Cl (200 mL) at room temperature and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate as an off-white solid (67 g, 81%): LCMS (ESI) calc'd for C 15 H 28 N 2 O 3 S [M + H] +< : 317, found 317; 1< H NMR (300 MHz, CDCl 3 ) δ 8.01 (d, J = 3.9 Hz, 1H), 4.09 (d, J = 13.4 Hz, 2H), 2.97-2.82 (m, 2H), 2.62 (m, 1H), 1.90 (dd, J = 13.4, 3.6 Hz, 2H), 1.71-1.43 (m, 2H), 1.47 (s, 9H), 1.20 (s, 9H).Example 11. Intermediate 11 (tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate)

[0265] Step a:

[0266] To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (20.00 g, 93.90 mmol) and 2-methylpropane-2-sulfinamide (17.00 g, 0.14 mol) in THF (300 mL) was added Ti(OEt) 4 (50.00 g, 0.18 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction solution was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting solution was quenched with saturated aq. NH 4 Cl (200 mL) at room temperature and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate as a light yellow solid (24.00 g, 80%): LCMS (ESI) calc'd for C 15 H 28 N 2 O 3 S [M + H] +< : 317, found 317.Example 12. Intermediate 12 ((S)-N-((1-((R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide)

[0267] Step a:

[0268] To a stirred solution tert-butyl 4-formylpiperidine-1-carboxylate (9.00 g, 42.20 mmol) in DCM (60 mL) was added TFA (30 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was dried under reduced pressure. The crude product was used in the next step without further purification: LCMS (ESI) calc'd for C 6 H 11 NO [M + H] +< : 114, found 114.Step b:

[0269] To a stirred solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (8.37 g, 57.27 mmol) and HATU (21.77 g, 57.26 mmol) in DMF (150 mL) were added piperidine-4-carbaldehyde (5.40 g, 47.72 mmol) and Et 3 N (72.43 g, 0.72 mol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (100 mL) at room temperature and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification: LCMS (ESI) calc'd for C 12 H 19 NO 4 [M + H] +< : 242, found 242.Step c:

[0270] To a stirred solution of 1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidine-4-carbaldehyde (4.30 g, 17.82 mmol) and (S)-2-methylpropane-2-sulfinamide (3.24 g, 26.73 mmol) in THF (40 mL) was added Ti(OEt) 4 (12.20 g, 53.48 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 3) to afford (S)-N-((1-((R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide as a light yellow oil (4.37 g, 71%): LCMS (ESI) calc'd for C 16 H 28 N 2 O 4 S [M + H] +< : 345, found 345. 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J = 3.9 Hz, 1H), 4.91-4.77 (m, 1H), 4.36-4.12 (m, 2H), 4.11-3.94 (m, 1H), 3.16 (dt, J = 25.1, 12.4 Hz, 1H), 2.91-2.73 (m, 2H), 1.90 (d, J = 14.6 Hz, 2H), 1.56-1.40 (m, 1H), 1.39-1.25 (m, 8H), 1.11 (d, J = 1.3 Hz, 9H).Example 13. Intermediate 13 (2,2-dimethyl-1,3-dioxolane-4-carboxylic acid)

[0271] Step a:

[0272] To a stirred mixture of KOH (2.10 g, 37.42 mmol) in H 2 O (9 mL) and EtOH (18 mL) was added methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (3.00 g, 18.73 mmol) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature. The mixture was acidified to pH 4 with 10% aq. H 3 PO 4 . The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a colorless oil (1.80 g, 65%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.81 (s, 1H), 4.58-4.50 (m, 1H), 4.17 (t, J = 7.9 Hz, 1H), 4.05-3.89 (m, 1H), 1.37 (s, 3H), 1.30 (s, 3H).Example 14. Intermediate 14 ((R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid)

[0273] Step a:

[0274] To a stirred solution of KOH (3.50 g, 62.38 mmol) in H 2 O (5 mL) and EtOH (10 mL) was added methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (5.00 g, 31.22 mmol) in portions at room temperature. The reaction mixture was stirred for additional 2 h at room temperature. The resulting mixture was diluted with H 2 O (10 mL) and acidified to pH 3 with 10% aq. H 3 PO 4 . The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a light yellow oil (3.00 g, 66%): LCMS (ESI) calc'd for C 6 H 10 O 4 [M - H] +< : 145, found 145; 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.80 (br, 1H), 4.59-4.50 (m, 1H), 4.27-4.10 (m, 1H), 4.00-3.91 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H).Example 15. Intermediate 15 (1,2-dichloro-3-iodo-4-methoxybenzene)

[0275] Step a:

[0276] To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol), DMAP (74.95 g, 613.50 mmol) and Et 3 N (62.08 g, 613.50 mmol) in DCM (500 mL) was added diethylcarbamoyl chloride (62.39 g, 460.12 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40 / 1) to afford 3,4-dichlorophenyl N,N-diethylcarbamate as a yellow oil (72.00 g, 80%): LCMS (ESI) calc'd for C 11 H 13 Cl 2 NO 2 [M + H] +< : 262, 264 (3 : 2), found 262, 264 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.42 (dq, J = 14.2, 7.2 Hz, 4H), 1.24 (dt, J = 14.8, 7.2 Hz, 6H).Step b:

[0277] To a solution of diethylpropyl amine (DIPA, 42.46 g, 419.64 mmol) in THF (400 mL) was added n-BuLi (29.32 g, 457.79 mmol, 2.5 M in hexane) dropwise in 0.5 h at -78 °C under nitrogen atmosphere. After stirring for 20 min at -78 °C, to resulting solution was added a solution of 3,4-dichlorophenyl N,N-diethylcarbamate (100.00 g, 381.49 mmol) in THF (100 mL) dropwise over 20 min at -78 °C. After addition, the resulting mixture was stirred for additional 0.5 h at -78 °C under nitrogen atmosphere. To the above mixture was added a solution of I 2 (101.67 g, 400.56 mmol) in THF (50 mL) dropwise over 0.5 h at -78 °C. The resulting mixture was stirred for additional 2 h at -78 °C. The resulting mixture was quenched with saturated aq. Na 2 SO 3 (300 mL) at -78 °C and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40 / 1) to afford 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate as an off-white solid (117.00 g, 79%): LCMS (ESI) calc'd for C 11 H 12 Cl 2 INO 2 [M + H] +< : 388, 390 (3 : 2), found 388, 390 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 3.55 (q, J = 7.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).Step c:

[0278] To a stirred solution of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (65.80 g, 169.58 mmol) in MeOH (100 mL) was added a solution of NaOH (67.82 g, 1695.75 mmol) in H 2 O (200 mL) at 0 °C. The resulting mixture was allowed to warm to 50 °C and stirred for 10 h. The pH value of the solution was adjusted to 6~7 with aq. HCl (1 N). The reaction was diluted with water (400 mL) at room temperature and extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40 / 1) to afford 3,4-dichloro-2-iodophenol as a yellow oil (47.00 g, 96%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.09 (s, 1H).Step d:

[0279] To a stirred solution of 3,4-dichloro-2-iodophenol (100.00 g, 346.15 mmol) in DMF (300 mL) were added CH 3 I (73.70 g, 519.23 mmol) and K 2 CO 3 (95.68 g, 692.31 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 h at room temperature under nitrogen atmosphere. The reaction was diluted with water (500 mL) at room temperature and extracted with EA (3 x 600 mL). The combined organic layers were washed with brine (3 x 1000 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 1,2-dichloro-3-iodo-4-methoxybenzene as an off-white solid (88.00 g, 84%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H).Example 16. Intermediate 16 (1-(allyloxy)-3,4-dichloro-2-iodobenzene)

[0280] Step a:

[0281] To a stirred solution of 3,4-dichloro-2-iodophenol (25.00 g, 86.54 mmol) and K 2 CO 3 (35.88 g, 259.61 mmol) in DMF (100 mL) was added 3-bromoprop-1-ene (15.70 g, 129.81 mmol) dropwise at room temperature. The resulting mixture was allowed to warm to 40 °C and stirred for 4 h under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford 1,2-dichloro-3-iodo-4-(prop-2-en-1-yloxy)benzene as a yellow solid (16.00 g, 50%): 1< H NMR (400 MHz, CD 3 OD) δ 7.49 (d, J = 8.9 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.17-6.00 (m, 1H), 5.54 (dt, J = 17.3, 1.7 Hz, 1H), 5.31 (dt, J = 10.7, 1.7 Hz, 1H), 4.65 (dd, J = 4.0, 2.3 Hz, 2H).Example 17. Intermediate 17 (tert-butyl 4-(1-(4,5-dichloro-2-methoxyphenyl)vinyl)piperidine-1-carboxylate)

[0282] Step a:

[0283] To a stirred solution of methyltriphenylphosphonium bromide (1.10 g, 3.09 mmol) in THF (15 mL) was added NaH (0.12 g, 3.09 mmol, 60% in the mineral oil) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred 15 min. Then the solution of tert-butyl 4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidine-1-carboxylate (0.80 g, 2.06 mmol) in THF (3 mL) was added. The reaction mixture was stirred at room temperature for additional 2 h under nitrogen atmosphere. The resulting mixture was quenched with saturated aq. NH 4 Cl (40 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)ethenyl]piperidine-1-carboxylate as a light yellow oil (0.50 g, 63%): LCMS (ESI) calc'd for C 19 H 25 Cl 2 NO 3 [M + H] +< : 386, 388 (3 : 2), found 386, 388 (3 : 2); 1< H NMR (400 MHz, CD 3 OD) δ 7.18 (s, 1H), 7.14 (s, 1H), 5.18 (s, 1H), 4.99 (s, 1H), 4.17-4.07 (m, 2H), 3.82 (s, 3H), 2.83-2.70 (s, 2H), 2.64-2.52 (m, 1H), 1.81-1.70 (m, 2H), 1.50-1.37 (s, 9H), 1.35-1.21 (m, 2H).Example 18. Intermediate 18 ((S)-N-((R)-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0284] Step a:

[0285] To a solution of 5-bromo-1,2-dichloro-3-fluorobenzene (4.00 g, 16.40 mmol) in THF (50 mL) was added i-PrMgCl·LiCl (25 mL, 32.80 mmol, 1.3 M in THF) dropwise for 30 min at -65 °C under nitrogen atmosphere. After stirring for additional 30 min, a solution of B(OMe) 3 (2.56 g, 24.60 mmol) in THF (10 mL) was added dropwise at -65 °C. After the addition, the reaction mixture was stirred for 30 min at -65 °C under nitrogen atmosphere. The resulting mixture was quenched with water (100 mL) at -65 °C and extracted with EA (2 x 300 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 50% ACN in water with 10 mmol / L NH 4 HCO 3 to afford (3,4-dichloro-5-fluorophenyl)boronic acid as a yellow solid (0.36 g, 94%): LCMS (ESI) calc'd for C 6 H 4 BCl 2 FO 2 [M - H] +< : 207, 209 (3 : 2), found 207, 209 (3 : 2); 1< H NMR (400 MHz, CD 3 OD) δ 7.66 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H).Step b:

[0286] To a stirred mixture of (3,4-dichloro-5-fluorophenyl)boronic acid (3.60 g, 18.66 mmol) and KOH (4.19 g, 74.71 mmol, 4.00 equiv) in MeOH (20 mL) was added H 2 O 2 (2.54 g, 74.71 mmol, 30% in water) dropwise at room temperature under air atmosphere. The reaction mixture was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was quenched with saturated aq. NaHSO 3 (100 mL) at room temperature, and then a solution was acidified to pH 4 with citric acid. The resulting mixture was extracted with EA (2 x 400 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford 3,4-dichloro-5-fluorophenol as a yellow solid (2.65 g, 70%): 1< H NMR (400 MHz, CDCl 3 ) 6.83 (s, 1H), 6.64 (dd, J = 9.8, 2.8 Hz, 1H), 5.64 (s, 1H).Step c:

[0287] To a stirred solution of 3,4-dichloro-5-fluorophenol (2.60 g, 14.36 mmol), Et 3 N (4.36 g, 43.09 mmol) and DMAP (3.51 g, 28.73 mmol) in DCM (20 mL) was added diethylcarbamoyl-chloride (2.33 g, 17.24 mmol) dropwise at room temperature under nitrogen atmosphere. After stirring for 2 h at room temperature under nitrogen atmosphere, the reaction solution was quenched with water (130 mL) at room temperature and extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford 3,4-dichloro-5-fluorophenyl N,N-diethylcarbamate as an off-white solid (3.20 g, 70%): LCMS (ESI) calc'd for C 11 H 12 Cl 2 FNO 2 [M + H] +< : 280, 282 (3 : 2), found 280, 282 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.15 (s, 1H), 7.00 (dd, J = 9.3, 2.6 Hz, 1H), 3.49-3.32 (m, 4H), 1.31-1.15 (m, 6H).Step d:

[0288] To a solution of 3,4-dichloro-5-fluorophenyl N,N-diethylcarbamate (0.50 g, 1.79 mmol) in THF (10 mL) was added LDA (1.34 mL, 2.68 mmol, 2 M in THF) over 10 min at -65 °C under nitrogen atmosphere. After addition, the reaction solution was stirred for 30 min at -65 °C, and then a solution of (S)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate (0.85 g, 2.68 mmol) in THF (5 mL) was added dropwise over 10 min at -65 °C under nitrogen atmosphere. After stirring for additional 1 h at -65 °C under nitrogen atmosphere, the resulting mixture was quenched with water (30 mL) at -65 °C and extracted with EA (2 x 70 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford crude tert-butyl 4-((R)-(3,4-dichloro-6-((diethylcarbamoyl)oxy)-2-fluorophenyl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate. The crude product was used in next step without further purification: LCMS (ESI) calc'd for C 26 H 40 Cl 2 FN 3 O 5 S [M + H] +< : 596, 598 (3 : 2), found 596, 598 (3 : 2).Step e:

[0289] To a solution of tert-butyl 4-((R)-(3,4-dichloro-6-((diethylcarbamoyl)oxy)-2-fluorophenyl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidine-1-carboxylate (crude) in MeOH (20 mL) was added NaOH (0.45 g, 11.32 mmol) in portions at room temperature. The resulting mixture was allowed to warm to 50 °C and stirred for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) at room temperature and acidified to pH 4 with citric acid. The resulting solution was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 60% ACN in water (plus 0.05% TFA) to afford tert-butyl 4-[(S)-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)([[(R)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate as a yellow solid (0.60 g, 68% overall two steps): LCMS (ESI) calc'd for C 21 H 31 Cl 2 FN 2 O 4 S [M + H] +< : 497, 499 (3 : 2), found 497, 499 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 6.89 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 8.2 Hz, 1H), 4.27-3.92 (m, 2H), 2.80-2.51 (m, 2H), 2.09-1.98 (m, 2H), 1.54-1.46 (m, 3H), 1.45 (s, 9H), 1.20 (s, 9H).Step f:

[0290] To a solution of tert-butyl 4-[(S)-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)([[(R)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (crude) in DCM (10 mL) was added TFA (2 mL) dropwise at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was adjusted to pH 8 with saturated aq. NaHCO 3 and extracted with EA (2 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford crude (R)-N-[(S)-(3,4-dichloro-2-fluoro-6-hydroxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a light yellow oil (0.40 g, 83%). The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 16 H 23 Cl 2 FN 2 O 2 S [M + H] +< : 397, 399 (3 : 2), found 397, 399 (3 : 2); 1< H NMR (400 MHz, CD 3 OD) δ 6.76 (s, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.52-3.40 (m, 1H), 3.30-3.20 (m, 1H), 3.03-2.80 (m, 2H), 2.55-2.40 (m, 1H), 2.38-2.22 (m, 1H), 1.59-1.37 (m, 3H), 1.10 (s, 9H).Example 19. Intermediate 19 (lithio (2R)-1-methyl-S-oxopyrrolidine-2-carboxylate)

[0291] Step a:

[0292] To a stirred solution of ethyl (2R)-5-oxopyrrolidine-2-carboxylate (0.50 g, 3.18 mmol) in THF (4 mL) was added NaH (0.25 g, 6.36 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0 °C. Then MeI (0.90 g, 6.36 mmol) was added into the mixture. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction was quenched with water (3 mL) at 0 °C. The resulting mixture was diluted with DCM (30 mL) and water (30 mL), and then the aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford ethyl (2R)-1-methyl-5-oxopyrrolidine-2-carboxylate as a light yellow oil (0.22 g, 40%): LCMS (ESI) calc'd for C 8 H 13 NO 3 [M + H] +< : 172 found 172; 1< H NMR (400 MHz, CDCl 3 ) δ 4.26 (q, J = 8.6, 7.9 Hz, 2H), 4.18-4.08 (m, 1H), 2.89 (s, 3H), 2.58-2.29 (m, 3H), 2.16-2.05 (m, 1H), 1.44-1.30 (m, 3H).Step b:

[0293] To a stirred solution of ethyl (2R)-1-methyl-5-oxopyrrolidine-2-carboxylate (0.15 g, 0.95 mmol) in MeOH (2 mL) was added a solution of LiOH·H 2 O (48 mg, 1.15 mmol) in H 2 O (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The resulting solution was concentrated under reduced pressure to afford lithio (2R)-1-methyl-5-oxopyrrolidine-2-carboxylate as an off-white solid (0.15 g, crude), which was used in next step directly without further purification: LCMS (ESI) calc'd for C 6 H 9 NO 3 [M + H] +< : 144, found 144.Example 20. (which is a reference example) Intermediate 20 (1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene)

[0294] Step a:

[0295] To a stirred mixture of 4-chloro-3-iodophenol (3.00 g, 11.79 mmol) and K 2 CO 3 (3.26 g, 23.59 mmol) in DMF (30 mL) was added CH 3 I (2.51 g, 17.69 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EA (50 mL) and water (100 mL). The aqueous solution was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (6 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 1-chloro-2-iodo-4-methylbenzene as a colorless oil (2.90 g, 92%): 1< H NMR (400 MHz, CD 3 OD) δ 7.47-7.41 (m, 1H), 7.41-7.33 (m, 1H), 6.99-6.90 (m, 1H), 3.78 (s, 3H).Step b:

[0296] To a stirred solution of 1-chloro-2-iodo-4-methoxybenzene (1.00 g, 3.73 mmol) in THF (5 mL) was added n-BuLi (2.2 mL, 5.59 mmol, 2.5 M solution in hexane) dropwise at -78 °C under nitrogen atmosphere. The solution was stirred for 30 min at -78 °C under nitrogen atmosphere. Then cyclobutanone (0.39 g, 5.59 mmol) was added into the solution. The resulting solution was stirred for 1 h at -78 °C under nitrogen atmosphere. The reaction was quenched with saturated aq. NH 4 Cl (3 mL). The resulting mixture was diluted with EA (30 mL) and water (30 mL), and then the aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to afford 1-(2-chloro-5-methoxyphenyl)cyclobutan-1-ol as a light yellow oil (0.56 g, 71%): 1< H NMR (400 MHz, CD 3 OD) δ 7.28 (dd, J = 8.7, 1.5 Hz, 1H), 6.96 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.7, 2.2 Hz, 1H), 3.81 (s, 3H), 2.75-2.63 (m, 2H), 2.50-2.37 (m, 2H), 2.23-2.12 (m, 1H), 1.78-1.66 (m, 1H).Step c:

[0297] To a stirred solution of 1-(2-chloro-5-methoxyphenyl)cyclobutan-1-ol (0.56 g, 2.63 mmol) and Et 3 SiH (0.61 mg, 5.27 mmol) in DCM (3 mL) was added BF 3 ·Et 2 O (0.75 g, 5.27 mmol) at room temperature under nitrogen atmosphere. The solution was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 1-chloro-2-cyclobutyl-4-methoxybenzene as a colorless oil (0.49 g, 95%): 1< H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.74 (dd, J = 8.7, 3.0 Hz, 1H), 3.81 (s, 3H), 3.79-3.72 (m, 1H), 2.47-2.33 (m, 2H), 2.19-1.97 (m, 3H), 1.92-1.81 (m, 1H).Step d:

[0298] To a stirred solution of 1-chloro-2-cyclobutyl-4-methoxybenzene (0.48 g, 2.44 mmol) in HOAc (5 mL) was added Br 2 (0.43 g, 2.69 mmol) dropwise at room temperature. The solution was stirred at room temperature for 1 h. The reaction was quenched with saturated aq. Na 2 SO 3 (2 mL), and diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene as a colorless liquid (0.60 g, 72%): 1< H NMR (400 MHz, CD 3 OD) δ 7.48 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 3.83-3.71 (m, 1H), 2.51-2.34 (m, 2H), 2.24-2.02 (m, 3H), 1.94-1.80 (m, 1H).Example 21. (which is a reference example) Intermediate 21 (1-bromo-5-chloro-4-fluoro-2-(prop-2-en-1-yloxy)benzene)

[0299] Step a:

[0300] To a stirred solution of 4-chloro-3-fluorophenol (2.00 g, 13.65 mmol) in DCM (15 mL) was added Br 2 (2.62 g, 16.40 mmol) at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with saturated aq. Na 2 SO 3 (30 mL) at room temperature. The aqueous layers were extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo-4-chloro-5-fluorophenol as a light yellow oil (3.40 g, crude), which was used in the next step directly without further purification: 1< H NMR (400 MHz, CD 3 OD) δ 7.58 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 10.5 Hz, 1H).Step b:

[0301] To a stirred mixture of 2-bromo-4-chloro-5-fluorophenol (3.40 g, 15.08 mmol) and K 2 CO 3 (4.17 g, 30.17 mmol) in DMF (30 mL) was added 3-bromoprop-1-ene (2.74 g, 22.65 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20 / 1) to afford 1-bromo-5-chloro-4-fluoro-2-(prop-2-en-1-yloxy)benzene as a colorless oil (2.40 g, 60%): 1< H NMR (400 MHz, CD 3 OD) δ 7.68 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 11.0 Hz, 1H), 6.14-6.02 (m, 1H), 5.50 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.6 Hz, 1H), 4.65 (d, J = 4.3 Hz, 2H).Example 22. Intermediate 22 (tert-butyl 8-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.2.1]octane-3-carboxylate)

[0302] Step a:

[0303] To a stirred solution of methyl 3-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (0.50 g, 2.43 mmol) and Et 3 N (0.98 g, 9.72 mmol) in DCM (6 mL) was added Boc 2 O (0.80 g, 3.65 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was diluted with EA (20 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure to afford 3-tert-butyl 8-methyl 3-azabicyclo[3.2.1]octane-3,8-dicarboxylate as a yellow oil (0.65 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 14 H 23 NO 4 [M + H - 15] +< : 255, found 255; 1< H NMR (400 MHz, CDCl 3 ) δ 3.90 (d, J = 60.4 Hz, 1H), 3.79-3.60 (m, 4H), 3.17 (d, J = 41.4 Hz, 1H), 2.97-2.77 (m, 1H), 2.69-2.41 (m, 3H), 1.85-1.61 (m, 4H), 1.47 (d, J = 3.7 Hz, 9H).Step b:

[0304] To a stirred solution of 3-tert-butyl 8-methyl 3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (0.65 g, 2.41 mmol) in MeOH (5 mL) was added a solution of NaOH (0.19 g, 4.83 mmol) in water (2 mL) at room temperature. The reaction was stirred at 40 °C for 1 h. After cooling to room temperature, the resulting solution was diluted with EA (20 mL) and water (30 mL). The aqueous solution was acidified with citric acid to pH 3, and then extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure to afford 3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid as a yellow oil (0.70 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 13 H 21 NO 4 [M + H -56] +< : 200, found 200; 1< H NMR (400 MHz, CD 3 OD) δ 3.88 (d, J = 12.5 Hz, 1H), 3.68 (d, J = 13.1 Hz, 1H), 3.32-3.13 (m, 1H), 3.05-2.75 (m, 3H), 2.73-2.36 (m, 2H), 1.89-1.74 (m, 2H), 1.64-1.55 (m, 1H), 1.47 (s, 9H).Step c:

[0305] To a stirred solution of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (0.70 g, 2.74 mmol), HOBt (0.56 g, 4.11 mmol) and EDCI (0.79 g, 4.11 mmol) in DMF (6 mL) were added N,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et 3 N (0.55 g, 5.48 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford tert-butyl 8-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.2.1]octane-3-carboxylate as a light yellow oil (0.43 g, 53%): LCMS (ESI) calc'd for C 15 H 26 N 2 O 4 [M + H - 56] +< : 243, found 243; 1< H NMR (400 MHz, CDCl 3 ) δ 3.91 (d, J = 47.8 Hz, 1H), 3.73 (d, J = 10.9 Hz, 3H), 3.69-3.39 (m, 2H), 3.21 (d, J = 12.8 Hz, 3H), 3.03-2.84 (m, 1H), 2.74 (d, J = 17.2 Hz, 1H), 2.55-2.33 (m, 3H), 2.03-1.88 (m, 1H), 1.84-1.57 (m, 2H), 1.47 (d, J = 7.2 Hz, 9H).Example 23. (which is a reference example) Intermediate 23 ((S)-N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane-2-sulfinamide)

[0306] Step a:

[0307] To a stirred mixture of 3-bromo-4-chlorophenol (5.00 g, 24.10 mmol) and K 2 CO 3 (9.99 g, 72.31 mmol) in THF (50 mL) was added MeI (10.26 g, 72.31 mmol) dropwise at 40 °C. The reaction mixture was stirred for 16 h at 40 °C. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 2-bromo-1-chloro-4-methoxybenzene as a colorless oil (4.50 g, 84%): 1< H NMR (400 MHz, CD 3 OD) δ 7.41 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.93 (dd, J = 8.9, 2.9 Hz, 1H), 3.81 (s, 3H).Step b:

[0308] To a stirred solution of 2-bromo-1-chloro-4-methoxybenzene (2.00 g, 9.03 mmol) in DCM (20 mL) was added AgOTf (2.55 g, 9.93 mmol) at room temperature. After addition, I 2 (2.52 g, 9.93 mmol) was added to the reaction and the mixture was stirred for 3 h at room temperature. The reaction was quenched with saturated aq. Na 2 SO 3 (50 mL) at room temperature and extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-bromo-2-chloro-4-iodo-5-methoxybenzene as an off-white solid (2.50 g, 80%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.84 (s, 1H), 7.04 (s, 1H), 3.89 (s, 3H).Step c:

[0309] To a solution of 1-bromo-2-chloro-4-iodo-5-methoxybenzene (10.00 g, 28.79 mmol) in THF (20 mL) was dropwise added n-BuLi (11.5 mL, 28.75 mmol, 2.5 M in hexane) at -90 °C over 10 min under nitrogen atmosphere. The solution was stirred for 30 min at same temperature. The solution of tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (9.10 g, 28.79 mmol) in THF (10 mL) was quickly added to above solution at -90 °C (the reaction temperature was increased from -90 to - 70 °C). After the addition, the reaction was stirred for additional 1.5 h at -75 °C. The reaction was quenched by saturated aq. NH 4 Cl (20 mL), and then diluted with water (100 mL). The aqueous phase was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 60% ACN in water with 10 mmol / L NH 4 HCO 4 to afford tert-butyl 4-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate as an off-white solid (12.40 g, 80%): LCMS (ESI) calc'd for C 22 H 34 BrClN 2 O 4 S [M + H] +< : 537, 539 (2 : 3 : 1), found 537, 539 (2 : 3 : 1); 1< H NMR (400 MHz, CD 3 OD) δ 7.43 (s, 1H), 7.30 (s, 1H), 4.44 (d, J = 8.9 Hz, 1H), 4.16 (d, J = 13.4 Hz, 1H), 4.01 (d, J = 13.1 Hz, 1H), 3.85 (s, 3H), 2.84-2.57 (m, 2H), 2.17-2.05 (m, 1H), 2.02-1.84 (m, 1H), 1.545 (s, 9H), 1.30-1.08 (m, 3H), 1.13 (s, 9H).Step d:

[0310] To a stirred solution of tert-butyl 4-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (6.00 g, 11.19 mmol) in DCM (60 mL) was added TFA (10 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at room temperature. The reaction was neutralized with saturated aq. NaHCO 3 (50 mL) at room temperature. The aqueous layers were extracted with DCM (3 x 200 mL). The combined organic layers were concentrated under reduced pressure to afford (S)-N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a yellow oil (4.60 g, crude). The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 17 H 26 BrClN 2 O 2 S [M + H] +< : 437, 439 (2 : 3: 1), found 437, 439 (2 : 3: 1); 1< H NMR (400 MHz, CD 3 OD) δ 7.45 (s, 1H), 7.35 (s, 1H), 4.50 (d, J = 9.1 Hz, 1H), 3.90 (s, 3H), 3.47 (d, J = 12.8 Hz, 1H), 3.30-3.25 (m, 1H), 3.01-2.80 (m, 2H), 2.42-2.33 (m, 1H), 2.19-2.06 (m, 1H), 1.57-1.28 (m, 3H), 1.14 (s, 9H).Step e:

[0311] To a stirred solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (1.70 g, 11.63 mmol) and HATU (4.43 g, 11.65 mmol) in DMF (10 mL) were added (S)-N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)(piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (3.40 g, 7.76 mmol) and Et 3 N (2.36 g, 23.29 mmol) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was quenched with water (60 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 70% ACN in water with 10 mmol / L NH 4 HCO 3 to afford (S)-N-[(R)-(4-bromo-5-chloro-2-methoxyphenyl)([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane-2-sulfinamide as an off-white solid (3.80 g, 86%): LCMS (ESI) calc'd for C 23 H 34 BrClN 2 O 5 S [M + H] +< : 565, 567 (2 : 3: 1), found 565, 567 (2 : 3: 1); 1< H NMR (400 MHz, CD 3 OD) δ 7.43 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 5.48-5.32 (dd, J = 33.5, 7.5 Hz, 1H), 4.59-4.37 (m, 2H), 4.20-4.10 (m, 1H), 4.32-4.18 (m, 2H), 3.88 (d, J = 2.2 Hz, 3H), 3.20-2.90 (m, 1H), 2.73-2.56 (m, 1H), 2.25-2.06 (m, 2H), 1.48-1.33 (m, 8H), 1.17-1.09 (m, 10H).Example 24. (which is a reference example) Intermediate 24 ((S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane-2-sulfinamide)

[0312] Step a:

[0313] To a stirred solution of 1-bromo-2-chloro-4-iodo-5-methoxybenzene (47.00 g, 135.30 mmol) in DCM (470 mL) was added BBr 3 (101.00 g, 405.90 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred for 20 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (500 mL) at 0 °C and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 5-bromo-4-chloro-2-iodophenol as a light yellow solid (45.50 g, 95%), which was used in next step without further purification.Step b:

[0314] To a stirred solution of 5-bromo-4-chloro-2-iodophenol (45.20 g, 141.59 mmol) in DMF (100 mL) were added K 2 CO 3 (39.14 g, 283.18 mmol) and allyl bromide (29.12 g, 240.70 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzene as a colorless oil (28.50 g, 54%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 1.0 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 6.12-5.98 (m, 1H), 5.53 (dq, J = 17.2, 1.6 Hz, 1H), 5.37 (dq, J = 10.7, 1.4 Hz, 1H), 4.59 (dq, J = 4.6, 1.5 Hz, 2H).Step c:

[0315] To a stirred solution of 1-bromo-2-chloro-4-iodo-5-(prop-2-en-1-yloxy)benzene (10.00 g, 26.78 mmol) in THF (250 mL) was added n-BuLi (10.71 mL, 26.78 mmol, 2.5 M in hexane) dropwise to -100 °C under nitrogen atmosphere. After stirring for 30 min at -100 °C under nitrogen atmosphere, a solution of tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (8.47 g, 26.7 mmol) in THF (40 mL) was added dropwise to the above mixture at -100 °C. The resulting mixture was stirred for additional 1 h at -100 °C. The reaction was quenched with saturated aq. NH 4 Cl (200 mL) at -100 °C. The aqueous layer was extracted with EA (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 70% ACN in water (plus 0.05% TFA) to afford tert-butyl 4-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate as a light yellow oil (10.00 g, 60%): LCMS (ESI) calc'd for C 24 H 36 BrClN 2 O 4 S [M + H] +< : 563, 565 (2 : 3 : 1), found 563, 565 (2 : 3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 7.22 (s, 1H), 7.12 (s, 1H), 6.11-5.96 (m, 1H), 5.48-5.30 (m, 2H), 4.61-4.55 (m, 2H), 4.46 (s, 1H), 4.24-4.02 (m, 2H), 2.74-2.47 (m, 2H), 2.03-1.77 (m, 2H), 1.46 (s, 9H), 1.40-1.11 (m, 3H), 1.18 (s, 9H).Step d:

[0316] To a stirred solution of tert-butyl 4-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (5.60 g, 9.96 mol) in DCM (50 mL) was added TFA (10 mL) dropwise at room temperature. The reaction solution was stirred for 0.5 h at room temperature. The reaction was neutralized with saturated aq. NaHCO 3 at room temperature. The aqueous layer was extracted with EA (3 x 100 mL). The combined organic layers were concentrated under reduced pressure to afford (S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a light yellow semi-solid (5.30 g, crude). The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 19 H 28 BrClN 2 O 2 S [M + H] +< : 463, 465 (2 : 3 : 1), found 463, 465 (2 : 3: 1); 1< H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.13 (s, 1H), 6.08-5.98 (m, 1H), 5.46-5.34 (m, 2H), 4.62-4.51 (m, 2H), 4.45-4.36 (s, 1H), 4.25-4.18 (m, 1H), 3.49-3.34 (dd, J = 32.3, 12.9 Hz, 2H), 2.90-2.73 (m, 2H), 2.26-1.97 (m, 2H), 1.80-1.52 (m, 3H), 1.18 - 1.09 (s, 9H).Step e:

[0317] To a stirred solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2.50 g, 17.13 mmol) and HATU (6.52 g, 17.13 mmol) in DMF (30 mL) were added (S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide (5.30 g, 11.42 mmol) and Et 3 N (3.47 g, 34.27 mmol) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was quenched with water (60 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 70% ACN in water with 10 mmol / L NH 4 HCO 3 to afford (S)-N-[(R)-[4-bromo-5-chloro-2-(prop-2-en-1-yloxy)phenyl]([1-[(4R)-2,2-dimethyl-1,3-dioxolane-4-carbonyl]piperidin-4-yl])methyl]-2-methylpropane-2-sulfinamide as an off-white solid (3.80 g, 54%): LCMS (ESI) calc'd for C 25 H 36 BrClN 2 O 5 S [M + H] +< : 591, 593 (2 : 3 : 1), found 591, 593 (2 : 3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 7.24 (d, J = 22.6 Hz, 1H), 7.12 (s, 1H), 6.07-5.97 (m, 1H), 5.46-5.30 (m, 2H), 4.68-4.58 (m, 2H), 4.60-4.50 (m, 3H), 4.49-4.33 (m, 1H), 4.21-4.01 (m, 2H), 3.92-3.88 (m, 1H) 3.09-2.82 (m, 1H), 2.56 (t, J = 12.7 Hz, 1H), 2.19-1.96 (m, 2H), 1.57-1.25 (m, 9H), 1.17 (d, J = 11.7 Hz, 9H).Example 25. Intermediate 25 ((S)-N-((R)-(2-(allyloxy)-5-chloro-4-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0318] Step a:

[0319] To a stirred solution of 2-bromo-5-methylphenol (42.00 g, 224.56 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (500 mL) was added NCS (31.00 g, 235.78 mmol) in portions at room temperature under air atmosphere. The reaction solution was allowed to warm to 50 °C and stirred for 16 h under air atmosphere. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50 / 1) to afford 2-bromo-4-chloro-5-methylphenol as a light yellow solid (47.00 g, 90%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.45 (s, 1H), 6.93 (d, J = 0.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 3H).Step b:

[0320] To a stirred mixture of 2-bromo-4-chloro-5-methylphenol (31.00 g, 0.14 mol) and K 2 CO 3 (39.00 g, 0.28 mol) in DMF (300 mL) was added allyl bromide (29.00 g, 0.24 mol) dropwise at room temperature under air atmosphere. The reaction mixture was stirred for 16 h at 40 °C under air atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (6 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100 / 1) to afford 1-bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene as a colorless oil (24.50 g, 66%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 1H), 6.77 (s, 1H), 6.12-6.02 (m, 1H), 5.50 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.63-4.56 (m, 2H), 2.34 (s, 3H).Step c:

[0321] To a stirred solution of 1-bromo-5-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene (29.00 g, 0.12 mol) in THF (900 mL) was added n-BuLi (48 mL, 0.12 mol, 2.5 M in hexane) dropwise at -90 °C under nitrogen atmosphere. After stirring for 40 min at -90 °C under nitrogen atmosphere, a solution of tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (35.57 g, 0.12 mol) in THF (80 mL) was added dropwise to a stirred solution over 20 min at -90 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at -90 °C under nitrogen atmosphere. The reaction was quenched with saturated aq. NH 4 Cl (100 mL) at -90 °C. The reaction solution was concentrated under reduced pressure to remove THF. The aqueous layer was extracted with EA (3 x 600 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 4-[(R)-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate as a light yellow oil (25.40 g, 44%): LCMS (ESI) calc'd for C 25 H 39 ClN 2 O 4 S [M + H] +< : 499, 501 (3 : 1), found 499, 501 (3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 7.09 (s, 1H), 6.74 (s, 1H), 6.10-5.93 (m, 1H), 5.47-5.26 (m, 2H), 4.61-4.50 (m, 2H), 4.41-4.28 (m, 1H), 4.21-4.04 (m, 2H), 3.95-3.73 (m, 1H), 2.82-2.47 (m, 2H), 2.41 (s, 3H), 2.10-1.96 (m, 1H), 1.93-1.75 (m, 1H), 1.47 (s, 9H), 1.37-1.21 (m, 3H), 1.12 (s, 9H).Step d:

[0322] To a stirred solution of tert-butyl 4-[(R)-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (48.00 g, 95.77 mmol) in DCM (380 mL) was added TFA (96 mL) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The mixture was basified to pH 8 with saturated aq. NaHCO 3 . The resulting mixture was extracted with EA (3 x 1 L). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (S)-N-[(R)-[5-chloro-4-methyl-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a light yellow oil (33.10 g, 88%): LCMS (ESI) calc'd for C 20 H 31 ClN 2 O 2 S [M + 1] +< : 399, 401 (3 : 1), found 399, 401 (3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 7.10 (s, 1H), 6.75 (s, 1H), 6.08-5.93 (m, 1H), 5.44-5.21 (m, 2H), 4.60-4.47 (m, 2H), 4.34-4.22 (m, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.34 (d, J = 13.0 Hz, 1H), 2.88-2.72 (m, 2H), 2.34 (s, 3H), 2.12 (d, J = 10.5 Hz, 2H), 1.69-1.51 (m, 3H), 1.10 (s, 9H).Example 26. Intermediate 26 (N-[(1-acetylpiperidin-4-yl)(4,5-dichloro-2-methoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide)

[0323] Step a:

[0324] To a stirred solution of 1-[4-[(4,5-dichloro-2-methoxyphenyl)carbonyl]piperidin-1-yl]ethan-1-one (0.30 g, 0.91 mmol) and Ti(OEt) 4 (0.41 g, 1.82 mmol) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (0.22 g, 1.82 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 70 °C under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with saturated aq. NH 4 Cl (50 mL) at room temperature and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford N-[(1-acetylpiperidin-4-yl)(4,5-dichloro-2-methoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide as a light yellow oil (0.27 g, 68%): LCMS (ESI) calc'd for C 19 H 26 Cl 2 N 2 O 3 S [M + H] +< : 433, 435 (3 : 2), found 433, 435 (3 : 2).Example 27. Intermediate 27 ((2R,3S)-3-(benzoyloxy)oxolane-2-carboxylic acid)

[0325] Step a:

[0326] To a solution of (4R,5S)-5-(hydroxymethyl)oxolane-2,4-diol (15.00 g, 111.83 mmol) in MeOH (130 mL) was added H 2 SO 4 (1.49 mL, 27.95 mmol, 97%) in MeOH (20 mL) at 0 °C. The reaction was stirred for 16 h at 0 °C to room temperature. The mixture was neutralized to pH 7 with saturated aq. NaHCO 3 . The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 4) to afford (2S,3R)-2-(hydroxymethyl)-5-methoxyoxolan-3-ol as a light yellow oil (15.00 g, 91%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 4.64 (t, J = 3.3 Hz, 1H), 4.52 (d, J = 5.5 Hz, 1H), 4.48-4.44 (m, 1H), 3.80-3.73 (m, 1H), 3.57-3.52 (m, 2H), 3.52-3.46 (m, 1H), 3.24-3.22 (m, 3H), 1.87-1.80 (m, 1H), 1.53 (dt, J = 12.8, 4.0 Hz, 1H).Step b:

[0327] A solution of (2S,3R)-2-(hydroxymethyl)-5-methoxyoxolan-3-ol (5.00 g, 33.75 mmol) and bis(trimethylsilyl)trifluoroacetamide (17.37 g, 67.48 mmol) in ACN (5 mL) was stirred for 5 h at 80 °C. After cooling to room temperature, Et 3 SiH (19.62 g, 168.74 mmol) and TMSOTf (37.50 g, 168.72 mmol) were added to the above mixture in portions over 15 min at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The reaction was quenched with water (30 mL) at 0 °C and neutralized to pH 7 with saturated aq. NaHCO 3 . The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford (2S, 3R)-2-(hydroxymethyl)oxolan-3-ol as a light yellow semi-solid (1.40 g, 35%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 4.93-4.77 (m, 1H), 4.71-4.54 (m, 1H), 3.82-3.67 (m, 2H), 3.57 (td, J = 5.3, 2.9 Hz, 1H), 3.40-3.33 (m, 1H), 1.98-1.85 (m, 1H), 1.74-1.63 (m, 1H).Step c:

[0328] To a stirred solution of (2S,3R)-2-(hydroxymethyl)oxolan-3-ol (1.30 g, 11.01 mmol) and imidazole (0.76 g, 11.12 mmol) in DMF (8 mL) was added TBDMSCl (1.66 g, 11.01 mmol) dropwise at room temperature. The resulting solution was stirred for 0.5 h at room temperature. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford (2S,3R)-2-[[(tertbutyldimethylsilyl)oxy]methyl]oxolan-3-ol as a colorless oil (1.54 g, 60%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 4.88 (d, J = 4.2 Hz, 1H), 4.08-3.99 (m, 1H), 3.82-3.68 (m, 2H), 3.62-3.55 (m, 1H), 3.55-3.44 (m, 2H), 2.01-1.85 (m, 1H), 1.78-1.63 (m, 1H), 0.87 (s, 9H), 0.04 (d, J = 2.5 Hz, 6H).Step d:

[0329] To a stirred solution of (2S,3R)-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxolan-3-ol (0.82 g, 3.53 mmol) and benzoic acid (0.56 g, 4.59 mmol) in THF (8 mL) were added Ph 3 P (1.85 g, 7.05 mmol) and DEAD (1.23 g, 7.06 mmol) at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford (2S,3S)-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxolan-3-yl benzoate as a colorless oil (1.00 g, 84%): 1< H NMR (400 MHz, CDCl 3 ) δ 8.06 (dt, J = 8.2, 1.1 Hz, 2H), 7.66-7.55 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 5.72-5.59 (m, 1H), 4.20-4.01 (m, 1H), 4.01-3.81 (m, 1H), 3.96 (td, J = 8.7, 4.8 Hz, 1H), 3.91 (dd, J = 6.3, 2.0 Hz, 2H), 2.48-2.32 (m, 1H), 2.20-2.08 (m, 1H), 0.85 (s, 9H), 0.05--0.05 (m, 6H).Step e:

[0330] To a stirred solution of (2S,3S)-2-[[(tert-butyldimethylsilyl)oxy]methyl]oxolan-3-yl benzoate (0.50 g, 1.49 mmol) in THF (3 mL) and HOAc (0.1 mL) was added TBAF (2.97 mL, 2.970 mmol, 1 M in THF) at room temperature. The reaction was stirred room temperature for 3 h. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was purified by silica gel column chromatography, eluted with PE / EA (1 / 4) to afford (2S,3S)-2-(hydroxymethyl)oxolan-3-yl benzoate as a colorless oil (0.30 g, 91%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.96-7.91 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 5.51-5.46 (m, 1H), 3.97-3.86 (m, 2H), 3.81-3.72 (m, 1H), 3.65-3.57 (m, 2H), 2.40-2.29 (m, 1H), 2.02-1.93 (m, 1H).Step f:

[0331] To a stirred solution of (2S,3S)-2-(hydroxymethyl)oxolan-3-yl benzoate (0.34 g, 1.53 mmol) and (acetyloxy)(phenyl)-lambda3-iodanyl acetate (0.74 g, 2.30 mmol) in ACN (3 mL) and water (3 mL) was added TEMPO (48 mg, 0.31 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The resulting mixture was quenched with saturated aq. Na 2 SO 3 (10 mL) and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford (2R,3S)-3-(benzoyloxy)oxolane-2-carboxylic acid as a colorless oil (0.20 g, 55%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.07-7.81 (m, 2H), 7.68 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.3 Hz, 2H), 5.93-5.64 (m, 1H), 4.69-4.51 (m, 1H), 4.17-3.84 (m, 2H), 2.38-2.23 (m, 1H), 2.20-2.02 (m, 1H).Example 28. Intermediate 28 (lithio 4-methyl-5-oxomorpholine-2-carboxylate)

[0332] Step a:

[0333] To a stirred mixture of isoserine (50.00 g, 475.77 mmol) in MeOH (300 mL) was added SOCl 2 (41. mL, 570.97 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford methyl 3-amino-2-hydroxypropanoate as an off-white solid (50.00 g, 71%): LCMS (ESI) calc'd for C 4 H 9 NO 3 [M + H] +< : 120, found 120; 1< H NMR (400 MHz, CD 3 OD) δ 4.50 (dd, J = 8.2, 4.0 Hz, 1H), 3.82 (s, 3H), 3.36-3.30 (m, 1H), (dd, J = 13.0, 8.3 Hz, 1H).Step b:

[0334] To a stirred solution of methyl 3-amino-2-hydroxypropanoate (22.50 g, 188.89 mmol) and Et 3 N (57.34 g, 566.66 mmol) in DCM (300 mL) was added chloroacetyl chloride (21.33 g, 188.89 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2) to afford methyl 3-(2-chloroacetamido)-2-hydroxypropanoate as a yellow solid (13.00 g, 35%): LCMS (ESI) calc'd for C 6 H 10 ClNO 4 [M + H] +< : 196, 198 (3 : 1), found 196, 198 (3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 6.97 (s, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.08 (s, 2H), 3.84 (s, 3H), 3.79-3.62 (m, 2H), 3.26 (s, 1H).Step c:

[0335] To a stirred solution of methyl 3-(2-chloroacetamido)-2-hydroxypropanoate (5.00 g, 25.56 mmol) in THF (300 mL) was added t-BuOK (5.74 g, 51.15 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. After starting material was consumed completely, MeI (4.35 g, 30.65 mmol) was added into the reaction. The mixture was stirred at room temperature for additional 2 h. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford methyl 4-methyl-5-oxomorpholine-2-carboxylate as a light yellow semi-solid (0.90 g, 20%): LCMS (ESI) calc'd for C 7 H 11 NO 4 [M + H] +< : 174, found 174; 1< H NMR (400 MHz, CD 3 OD) δ 4.61 (dd, J = 7.5, 4.8 Hz, 1H), 4.30 (d, J = 16.5 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.78 (s, 3H), 3.63 (dd, J = 6.2, 4.1 Hz, 2H), 2.98 (s, 3H).Step d:

[0336] To a stirred solution of methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.15 g, 0.87 mmol) in MeOH (3 mL) was added a solution of LiOH·H 2 O (73 mg, 1.73 mmol) in water (1 mL) at room temperature. The reaction solution was stirred at 40 °C for 1 h. The reaction was concentrated under reduced pressure to afford lithio 4-methyl-5-oxomorpholine-2-carboxylate as an off-white solid (0.14 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 6 H 9 NO 4 [M + H] +< : 160, found 160.Example 29. Intermediate 29 (tert-butyl 3-[methoxy(methyl)carbamoyl]-8-azabicyclo[3.2.1]octane-8-carboxylate)

[0337] Step a:

[0338] To a stirred solution of methyl 8-azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 5.91 mmol) and Et 3 N (1.20 g, 11.86 mol) in DCM (10 mL) was added Boc 2 O (1.60 g, 7.33 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was diluted with EA (50 mL) and water (50 mL). The isolated aqueous solution was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 8-tert-butyl 3-methyl 8-azabicyclo[3.2.1]octane-3,8-dicarboxylate as a light yellow oil (1.30 g, 99%): LCMS (ESI) calc'd for C 14 H 23 NO 4 [M + H -15] +< : 255, found 255.Step b:

[0339] To a stirred solution of 8-tert-butyl 3-methyl 8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1.30 g, 4.83 mol) in MeOH (5 mL) was added a solution of NaOH (0.39 g, 9.65 mol) in H 2 O (0.5 mL) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 20 mL). The combined aqueous layers were acidified with citric acid to pH 3 and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 , After filtration, the filtrate was concentrated under reduced pressure to afford (8-[(tert-butoxy)carbonyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid) as a light yellow oil (1.20 g, 97%): LCMS (ESI) calc'd for C 13 H 21 NO 4 [M + Na] +< : 278, found 278; 1< H NMR (300 MHz, CDCl 3 ) δ 4.40-4.21 (m, 2H), 2.94-2.79 (m, 1H), 2.06-1.98 (m, 2H), 1.98-1.84 (m, 2H), 1.84-1.73 (m, 2H), 1.73-1.59 (m, 2H), 1.49 (s, 9H).Step c:

[0340] To a stirred solution of 8-[(tert-butoxy)carbonyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1.20 g, 4.70 mmol) and Et 3 N (0.95 g, 9.40 mmol) in DCM (10 mL) were added CDI (0.91g, 5.64 mmol) and N,O-methoxy(methyl)amine hydrochloride (0.69 g, 7.05 mmol) at room temperature. The reaction was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 3-[methoxy(methyl)carbamoyl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a light yellow oil (1.10 g, 69% overall three steps): LCMS (ESI) calc'd for C 15 H 26 N 2 O 4 [M + H - 56] +< : 243, found 243; 1< H NMR (400 MHz, CDCl 3 ) δ 4.40-4.23 (m, 1H), 3.82-3.76 (m, 1H), 3.76-3.71 (m, 3H), 3.35-3.21 (m, 1H), 3.19 (d, J = 2.6 Hz, 3H), 2.18-1.93 (m, 4H), 1.81-1.56 (m, 4H), 1.56-1.44 (m, 9H).Example 30. Intermediate 30 (tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate)

[0341] Step a:

[0342] To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 mL) were added Et 3 N (1.20 g, 11.93 mmol) and N,O-methoxy(methyl)amine hydrochloride (0.90 g, 14.91 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 h. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a light yellow oil (2.10 g, 78%): LCMS (ESI) calc'd for C 11 H 20 N 2 O 4 [M + H - 56] +< : 189, found 189; 1< H NMR (300 MHz, CD 3 OD) δ 4.14-3.99 (m, 4H), 3.89-3.76 (m, 1H), 3.72 (s, 3H), 3.22 (s, 3H), 1.46 (s, 9H).Example 31. Intermediate 31 (tert-butyl 4-fluoro-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate)

[0343] Step a:

[0344] To a stirred solution of 1-[(tert-butoxy)carbonyl]-4-fluoropiperidine-4-carboxylic acid (2.00 g, 8.09 mmol) and CDI (2.60 g, 16.18 mmol) in DCM (10 mL) were added Et 3 N (2.50 g, 24.27 mmol) and N,O-methoxy(methyl)amine hydrochloride (1.00 g, 16.18 mmol) at room temperature. The reaction solution was stirred at room temperature for 16 h at room temperature. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to afford tert-butyl 4-fluoro-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate as a colorless oil (1.50 g, 57%): LCMS (ESI) calc'd for C 13 H 23 FN 2 O 4 [M + H - 56] +< : 235, found 235; 1< H NMR (400 MHz, CDCl 3 ) δ 4.01 (d, J = 13.5 Hz, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.21-3.01 (m, 1H), 2.06 (dd, J = 19.6, 10.9 Hz, 5H), 1.49 (s, 9H).Example 32. Intermediate 32 (litho 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate)

[0345] Step a:

[0346] To a stirred solution of ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.64 mmol) and Et 3 N (0.19 g, 1.91 mmol) in DMF (1 mL) was added Boc 2 O (0.17 g, 0.76 mmol) at room temperature. The resulting solution was stirred for 12 h at room temperature. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 55% ACN in water with 10 mmoL / L NH 4 HCO 3 to afford ethyl 5-[[(tert-butoxy)carbonyl]amino]-1,3,4-oxadiazole-2-carboxylate as a light yellow oil (0.10 g, 55%): LCMS (ESI) calc'd for C 10 H 15 N 3 O 5 [M + H - 56] +< : 202, found 202; 1< H NMR (400 MHz, DMSO-d 6 ) δ 4.38 (q, J = 7.1 Hz, 2H), 1.46 (d, J = 3.1 Hz, 9H), 1.32 (t, J = 7.1 Hz, 3H).Step b:

[0347] To a stirred solution of ethyl 5-[[(tert-butoxy)carbonyl]amino]-1,3,4-oxadiazole-2-carboxylate (0.16 g, 0.62 mmol) in MeOH (2 mL) was added a solution of LiOH·H 2 O (78 mg, 1.87 mmol) in water in MeOH (3 mL) a solution of LiOH·H 2 O (48 mg, 1.15 mmol) in H 2 O (2 mL) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford litho 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate as an off-white solid (0.16 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 8 H 11 N 3 O 5 [M + H] +< : 230, found 230; 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 2.50 (s, 9H).Example 33. Intermediate 33 (3-iodo-1-(triphenylmethyl)-1H-pyrazole)

[0348] Step a:

[0349] To a stirred solution of 3-iodo-1H-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) were added TrtCl (0.86 g, 3.09 mmol) and Et 3 N (0.52 g, 5.16 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (12 / 1) to afford 3-iodo-1-(triphenylmethyl)-1H-pyrazole as an off-white solid (0.60 g, 48%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.19-7.10 (m, 15H), 6.42 (d, J = 2.5 Hz, 2H).Example 34. Intermediate 34 (4-iodo-1-(triphenylmethyl)-1H-pyrazole)

[0350] Step a:

[0351] To a stirred solution of 4-iodo-1H-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) were added TrtCl (0.86 g, 3.09 mmol) and Et 3 N (0.52 g, 5.16 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford 4-iodo-1-(triphenylmethyl)-1H-pyrazole as an off-white solid (0.80 g, 64%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.75 (s, 1H), 7.45 (s, 1H), 7.40-7.35 (m, 9H), 7.07-7.00 (m, 6H).Example 35. Intermediate 35 (lithio (S)-3-methoxy-2-(trityloxy)propanoate)

[0352] Step a:

[0353] To a stirred solution of methyl (2S)-oxirane-2-carboxylate (2.00 g, 19.59 mmol) in MeOH (15 mL) was added Mg(OSO 2 CF 3 ) 2 (3.15 g, 9.80 mmol) at room temperature. The resulting mixture was stirred for 16 h at 40 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford methyl (2S)-2-hydroxy-3-methoxypropanoate as a light yellow oil (1.50 g, 46%): LCMS (ESI) calc'd for C 5 H 10 O 4 [M + H] +< : 135, found 135; 1< H NMR (400 MHz, CDCl 3 ) δ 4.34 (t, J = 3.4 Hz, 1H), 3.83 (s, 3H), 3.75-3.65 (m, 2H), 3.41 (s, 3H), 2.65 (brs, 1H).Step b:

[0354] To a stirred solution of methyl (2S)-2-hydroxy-3-methoxypropanoate (0.70 g, 5.22 mmol) and DMAP (64 mg, 0.52 mmol) in pyridine (8 mL) was added TrtCl (1.60 g, 5.74 mmol) at room temperature. The resulting solution was allowed to warm to 80 °C and stirred for 24 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford methyl (2S)-3-methoxy-2-(triphenylmethoxy)propanoate as an off-white solid (0.80 g, 33%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.45-7.19 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10.6, 5.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H).Step c:

[0355] To a stirred solution of methyl (2S)-3-methoxy-2-(triphenylmethoxy)propanoate (0.80 g, 2.13 mmol) in MeOH (8 mL) was added a solution of LiOH·H 2 O (0.45 g, 10.63 mmol) in water (3 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford lithio (S)-3-methoxy-2-(trityloxy)propanoate (0.80 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 23 H 22 O 4 [M + Na] +< : 385, found 385.Example 36. Intermediate 36 (lithium 1-oxo-1,2-dihydroisoquinoline-4-carboxylate)

[0356] Step a:

[0357] To a stirred solution of methyl 1-oxo-2H-isoquinoline-4-carboxylate (0.20 g, 1.00 mmol) in MeOH (2 mL) was added was added a solution of LiOH·H 2 O (84 mg, 2.00 mmol) in water (3 mL) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford lithium 1-oxo-1,2-dihydroisoquinoline-4-carboxylate (0.20 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 10 H 7 NO 3 [M - H] +< : 188, found 188.Example 37. Intermediate 37 (lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate)

[0358] Step a:

[0359] To a stirred solution of methyl 5-ethynyl-6-oxo-1H-pyridine-3-carboxylate (0.18 g, 1.00 mmol) in MeOH (2 mL) was added was added a solution of LiOH·H 2 O (84 mg, 2.00 mmol) in water (3 mL) at room temperature. The resulting mixture was stirred for 0.5 h at 40 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to afford lithium 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate (0.20 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 7 H 4 N 2 O 3 [M - H] +< : 163, found 163.Example 38. Intermediate 38 (N-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide)

[0360] Step a:

[0361] To a stirred solution of tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate(0.50 g, 0.96 mmol) in 1,4-dioxane (8 mL) was added aq. HCl (4 N, 2 mL) at room temperature. The reaction solution was stirred at room temperature for 20 min. The reaction solution was adjusted pH to 8 with saturated aq. Na 2 CO 3 at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(R)-amino[4,5-dichloro-2-(prop-2-en-1-yloxy)phenylmethyl]piperidine-1-carboxylate as a yellow oil (0.40 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 20 H 28 Cl 2 N 2 O 3 [M + H] +< : 415, 417 (3 : 2), found 415, 417 (3 : 2).Step b:

[0362] To a stirred solution of tert-butyl 4-[(R)-amino[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl]methyl]piperidine-1-carboxylate (0.40 g, 0.96 mmol) and Et 3 N (0.29 g, 2.89 mmol) in DCM (5 mL) was added TFAA (0.24 g, 1.16 mmol) at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with DCM (50 mL) and water (30 mL). The aqueous solution was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylate as a yellow oil (0.40 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 22 H 27 Cl 2 F 3 N 2 O 4 [M + Na] +< : 533, 535 (3 : 2), found 533, 535 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.12-5.98 (m, 1H), 5.48-5.39 (m, 2H), 4.77 (t, J = 9.7 Hz, 1H), 4.69-4.56 (m, 2H), 4.10 (d, J = 16.0 Hz, 2H), 2.75-2.48 (m, 2H), 2.08-1.97 (m, 1H), 1.78 (d, J = 13.3 Hz, 1H), 1.45 (s, 9H), 1.31-1.20 (m, 3H).Step c:

[0363] To a stirred solution of tert-butyl 4-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](2,2,2-trifluoroacetamido)methyl]piperidine-1-carboxylate (0.40 g, 0.78 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 50% ACN in water with 10 mmol / L NH 4 HCO 3 to afford N-[(R)-[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide as a light yellow solid (0.30 g, 76% overall three steps): LCMS (ESI) calc'd for C 17 H 19 Cl 2 F 3 N 2 O 2 [M + H] +< : 411, 413 (3 : 2), found 411, 413 (3 : 2).Example 39. Intermediate 39 (lithio 2-(oxetan-3-yloxy)acetate)

[0364] Step a:

[0365] To a stirred mixture of NaH (12.65 g, 316.16 mmol, 60%) in THF (300 mL) was added oxetan-3-ol (19.52 g, 263.47 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred at room temperature for 0.5 h under nitrogen atmosphere. To the above mixture was added ethyl 2-bromoacetate (44.00 g, 263.47 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for additional 2 h at room temperature. The resulting mixture was quenched with water (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (30 x 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford ethyl 2-(oxetan-3-yloxy)acetate as a colorless oil (25.00 g, 59%): 1< H NMR (400 MHz, CDCl 3 ) δ 4.79-4.72 (m, 2H), 4.72-4.67 (m, 2H), 4.67-4.59 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H).Step b:

[0366] To a stirred solution of ethyl 2-(oxetan-3-yloxy)acetate (1.00 g, 6.24 mmol) in THF (2 mL) and MeOH (2 mL) was added LiOH·H 2 O (0.29 g, 6.89 mmol) at 0 °C. The reaction solution was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure to afford lithio 2-(oxetan-3-yloxy)acetate as an off-white solid (0.70 g, crude), which was used in the next step directly without further purification: 1< H NMR (400 MHz, D 2 O) δ 4.77-4.74 (m, 1H), 4.71-4.68 (m, 2H), 4.59-4.53 (m, 2H), 3.79 (s, 2H).Example 40. Intermediate 40 (lithio (R)-3-methoxy-2-(trityloxy)propanoate)

[0367] Step a:

[0368] To a stirred solution of methyl (2R)-oxirane-2-carboxylate (1.00 g, 9.80 mmol) in MeOH (10 mL) was added Mg(OSO 2 CF 3 ) 2 (1.58 g, 4.90 mmol) at room temperature. The resulting mixture was stirred for 16 h at 40 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford methyl (2R)-2-hydroxy-3-methoxypropanoate as a light yellow oil (0.90 g, 55%): LCMS (ESI) calc'd for C 5 H 10 O 4 [M + H] +< : 135, found 135; 1< H NMR (400 MHz, CDCl 3 ) δ 4.33 (t, J = 3.7 Hz, 1H), 3.83 (d, J = 1.5 Hz, 3H), 3.76-3.65 (m, 2H), 3.41 (d, J = 1.5 Hz, 3H), 2.91-2.39 (brs, 1H).Step b:

[0369] To a stirred solution of methyl (2R)-2-hydroxy-3-methoxypropanoate (0.50 g, 3.73 mmol) and DMAP (46 mg, 0.37 mmol) in pyridine (4 mL) was added TrtCl (1.14 g, 4.10 mmol) at room temperature. The resulting solution was stirred for 24 h at 80 °C. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford methyl (2R)-3-methoxy-2-(triphenylmethoxy)propanoate as an off-white solid (0.60 g, 34%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.49-7.09 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10.6, 5.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H).Step c:

[0370] To a stirred solution of methyl (2R)-3-methoxy-2-(triphenylmethoxy)propanoate (0.60 g, 1.59 mmol) in MeOH (6 mL) was added a solution of LiOH-H 2 O (0.33 g, 7.97 mmol) in water (2 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford lithio (R)-3-methoxy-2-(trityloxy)propanoate (0.80 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 23 H 22 O 4 [M + Na] -< : 385, found 385.Example 41. Intermediate 41 (tert-butyl (1R,5S,6R)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate)

[0371] Step a:

[0372] To a stirred solution of (1R,5S,6R)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (0.50 g, 2.20 mmol), HOBt (0.45 g, 3.30 mmol) and EDCI (0.63 g, 3.30 mmol) in DMF (6 mL) were added N,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et 3 N (0.45 g, 4.40 mmol) at room temperature. The reaction solution was stirred at room temperature for 2 h. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 70% ACN in water (plus 0.05% TFA) to afford tert-butyl (1R,5S,6R)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate a light yellow oil (0.30 g, 45%): LCMS (ESI) calc'd for C 13 H 22 N 2 O 4 [M + H - 56] +< : 215, found 215; 1< H NMR (400 MHz, CDCl 3 ) δ 3.76 (s, 3H), 3.72-3.64 (m, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.52-3.41 (m, 3H), 3.22 (s, 3H), 2.15-2.04 (m, 1H), 2.02-1.93 (m, 1H), 1.47 (s, 9H).Example 42. Intermediate 42 (tert-butyl 4-[methoxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylate)

[0373] Step a:

[0374] To a stirred solution of 2-methylpyridine-4-carboxylic acid (2.00 g, 14.58 mmol) in MeOH (10 mL) was added PtO 2 (0.40 g, 1.75 mmol) and HCl (6 N, 1 mL) at room temperature. The reaction was degassed for three times under hydrogen and stirred at 30 °C for 16 h under H 2 (50 atm). The reaction was filtered and the filtrate was concentrated under reduced pressure to afford methyl 2-methylpiperidine-4-carboxylate as a light yellow oil (2.00 g, 96%), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 8 H 15 NO 2 [M + H] +< : 158, found 158; 1< H NMR (400 MHz, CD 3 OD) δ 3.51-3.43 (m, 1H), 3.37 (s, 3H), 3.31-3.24 (m, 1H), 3.12-3.02 (m, 1H), 2.77 (tt, J = 12.4, 3.8 Hz, 1H), 2.30-2.16 (m, 2H), 1.77 (qd, J = 13.8, 4.3 Hz, 1H), 1.63-1.49 (m, 1H), 1.37 (d, J = 6.5 Hz, 3H).Step b:

[0375] To a stirred mixture of methyl 2-methylpiperidine-4-carboxylate (2.00 g, 12.72 mmol) and Et 3 N (2.57 g, 25.40 mmol) in DCM (10 mL) was added Boc 2 O (4.16 g, 19.06 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 1-tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate as a light yellow oil (3.3 g, crude), which was used in the next step directly without further purification. LCMS (ESI) calc'd for C 13 H 23 NO 4 [M + H - 56] +< : 202 found 202; 1< H NMR (400 MHz, CDCl 3 ) δ 4.28-4.09 (m, 1H), 3.91-3.76 (m, 1H), 3.72 (s, 3H), 3.11 (td, J = 13.1, 4.1 Hz, 1H), 2.76-2.51 (m, 1H), 2.10-1.86 (m, 3H), 1.85-1.69 (m, 1H), 1.47 (s, 9H), 1.09 (d, J = 6.5 Hz, 3H).Step c:

[0376] To a stirred solution of 1-tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate (3.30 g, 12.82 mmol) in MeOH (10 mL) was added a solution of NaOH (1.03 g, 25.75 mmol) in water (2 mL) at room temperature. The reaction solution was stirred at 40 °C for 1 h. The reaction was diluted with water (50 mL). The aqueous solution was acidified with citric acid to pH 3, and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 23% ACN in water (plus 0.05% TFA) to afford 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-4-carboxylic acid as a light yellow semi-solid (2.20 g, 71%): LCMS (ESI) calc'd for C 12 H 21 NO 4 [M + H -56] +< : 188, found 188.Step d:

[0377] To a stirred solution of 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-4-carboxylic acid (1.80 g, 7.40 mmol), HOBt (1.50 g, 11.10 mmol) and EDCI (1.80 g, 11.10 mmol) in DCM (10 mL) were added N,O-dimethylhydroxylamine hydrochloride (1.08 g, 11.10 mmol) and Et 3 N (1.50 g, 14.80 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL). The aqueous solution was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford tert-butyl 4-[methoxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylate as a light yellow oil (1.50 g, 71%): LCMS (ESI) calc'd for C 14 H 26 N 2 O 4 [M + H] +< : 287 found 287; 1< H NMR (400 MHz, CDCl 3 ) δ 4.04-3.92 (m, 1H), 3.89-3.81 (m, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 3.20-3.10 (m, 1H), 2.88 (d, J = 10.4 Hz, 1H), 2.01-1.90 (m, 1H), 1.90-1.76 (m, 2H), 1.73-1.60 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.4 Hz, 3H).Example 43. Intermediate 43a (tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate containing cis isomer, racemic); Intermediate 43b (tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate containing trans isomer, racemic)

[0378] Step a:

[0379] To a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (2.76 g, 9.78 mmol) in THF (10 mL) was added i-PrMgCl (4.86 mL, 9.72 mmol, 2 M solution in THF) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min. Then tert-butyl 4-[methoxy(methyl)carbamoyl]-2-methylpiperidine-1-carboxylate (1.40 g, 4.89 mmol) was added into the reaction. The reaction mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The resulting mixture was quenched with saturated aq. NH 4 Cl (5 mL) and diluted with water (30 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate as a light yellow semi-solid (0.50 g, 24%): LCMS (ESI) calc'd for C 21 H 27 Cl 2 NO 4 [M + H -56] +< : 372, 374 (3 : 2), found 372, 374 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J = 10.3 Hz, 1H), 7.07 (s, 1H), 6.17-5.98 (m, 1H), 5.56-5.28 (m, 2H), 4.69-4.59 (m, 2H), 4.23-4.02 (m, 1H), 3.93-3.78 (m, 1H), 3.56-3.39 (m, 1H), 3.17-3.02 (m, 1H), 2.06-1.81 (m, 1H), 1.81-1.57 (m, 2H), 1.57-1.43 (m, 10H), 1.09 (d, J = 6.6 Hz, 3H). And tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)-2-methylpiperidine-1-carboxylate as a light yellow oil (1.00 g, 53%): LCMS (ESI) calc'd for C 18 H 23 Cl 2 NO 4 [M + H - 56] +< : 332, 334 (3 : 2), found 332, 334 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 12.30 (s, 1H), 7.79 (s, 1H), 7.17 (s, 1H), 4.21-4.02 (m, 1H), 3.96 (dd, J = 14.0, 6.9 Hz, 1H), 3.50-3.37 (m, 1H), 3.25-3.06 (m, 1H), 2.08-1.96 (m, 2H), 1.96-1.81 (m, 1H), 1.81-1.67 (m, 1H), 1.53 (s, 9H), 1.20 (d, J = 6.4 Hz, 3H).

[0380] To a stirred mixture of tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)-2-methylpiperidine-1-carboxylate (1.00 g, 2.56 mmol) and K 2 CO 3 (0.71 g, 5.15 mmol) in DMF (5 mL) was added 3-bromoprop-1-ene (0.47 g, 3.86 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EA (30 mL) and water (30 mL) and the aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate as a light yellow oil (1.00 g, 90%). The total amount of tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate was 1.50 g (72%).Step b:

[0381] tert-Butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate (1.50 g, 3.51 mmol) was separated under SFC with following condtions: Column: CHIRALPAK IF, 2 x 25 cm, 5 µm; Mobile Phase A: CO 2 : 75%, Mobile Phase B: MeOH: 25%; Flow rate: 40 mL / min; Detector: UV: 220 / 254 nm; Retention time: RT 1 : 3.29 min; RT 2 : 3.85 min.

[0382] The first peak at 3.29 min was obtained from which tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate containing two cis enantiomers was isolated as a light yellow semi-solid (0.50 g, 45%): LCMS (ESI) calc'd for C 21 H 27 Cl 2 NO 4 [M + H -56] +< : 372, 374 (3 : 2), found 372, 374 (3 : 2); and the second peak at 3.85 min was obtained from which tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-2-methylpiperidine-1-carboxylate containing two trans enantiomers was isoalted as a light yellow semi-solid (0.40 g, 36%): LCMS (ESI) calc'd for C 21 H 27 Cl 2 NO 4 [M + H -56] +< : 372, 374 (3 : 2), found 372, 374 (3 : 2).Example 44. Intermediate 44 ((2,3-dichloro-6-methoxyphenyl)(piperidin-4-yl)methanol trifluoroacetic acid)

[0383] Step a:

[0384] To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br 2 (98.04 g, 613.49 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with saturated aq. Na 2 S 2 O 3 (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 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 in the next step directly without further purification.Step b:

[0385] To a crude mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (32 g, 125.04 mmol, 1 equiv) and K 2 CO 3 (54.9 g, 396.87 mmol, 3 equiv) in MeCN (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, eluted with PE to afford 2-bromo-3,4-dichloro-1-methoxybenzene (8.7 g, 25.7%) as a white solid: 1< H NMR (300 MHz, CDCl 3 ) δ 7.40 (dd, J = 9.0, 1.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H), and 1-bromo-4,5-dichloro-2-methoxybenzene (24.3 g, 71.77%) as a white solid: 1< H NMR (300 MHz, CDCl 3 ) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H).Step c:

[0386] To a solution of 2-bromo-3,4-dichloro-1-methoxybenzene (0.80 g, 3.13 mmol) in THF (8 mL) was added i-PrMgCl (2.0 mL, 19.76 mmol, 2 M in THF) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred at 0 °C for 0.5 h. Then a solution of tert-butyl 4-formylpiperidine-1-carboxylate (0.67 g, 3.13 mmol) in THF (2 mL) was added dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for additional 0.5 h, the reaction mixture was allowed to warm to room temperature and stirred for additional 0.5 h under nitrogen atmosphere. The reaction was quenched with saturated aq. NH 4 Cl (40 mL) and extracted with EA (2 x 40 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluted with PE / EA (3 / 2) to afford tert-butyl 4-[(2,3-dichloro-6-methoxyphenyl)(hydroxy) methyl] piperidine-1-carboxylate as an off-white foam (1.00 g, 82%): LCMS (ESI) calc'd for C 18 H 25 Cl 2 NO 4 [M + Na] +< : 412, 414 (3 : 2), found 412, 414 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.38 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.98 (d, J = 8.9 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.07 (d, J = 13.5 Hz, 1H), 3.92 (s, 3H), 2.70 (td, J = 12.9, 2.8 Hz, 1H), 2.59 (td, J = 12.8, 3.0 Hz, 1H), 2.17-1.97 (m, 2H), 1.48 (s, 9H), 1.42-1.24 (m, 3H).Step d:

[0387] To a solution of tert-butyl 4-[(2,3-dichloro-6-methoxyphenyl)(hydroxy) methyl] piperidine-1-carboxylate (0.50 g, 1.28 mmol) in DCM (5 mL) was added TFA (2 mL) at room temperature. The reaction solution was stirred at room temperature for 1 h and concentrated to afford (2,3-dichloro-6-methoxyphenyl)(piperidin-4-yl) methanol trifluoroacetic acid as a colorless oil (0.60 g, crude): LCMS (ESI) calc'd for C 13 H 17 Cl 2 NO 2 [M + H] +< : 290, 292 (3 : 2), found 290, 292 (3 : 2).Example 45. (which is a reference example) Intermediate 45 ((S)-N-((R)-(2-(allyloxy)-4-chloro-5-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0388] Step a:

[0389] To a stirred solution of 3-chloro-4-methylphenol (0.50 g, 3.51 mmol) in HOAc (5 mL) was added Br 2 (0.56 g, 3.51 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction solution was stirred at room temperature for 3 h. The reaction solution was quenched with saturated aq. Na 2 SO 3 (50 mL) and extracted with EA (2 x 30 mL). The combined organic layers were washed with saturated aq. NaHCO 3 (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluted with PE / EA (5 / 1) to afford 2-bromo-5-chloro-4-methylphenol as an off-white solid (0.70 g, 90%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.33 (s, 1H), 7.06 (s, 1H), 5.46 (s, 1H), 2.30 (s, 3H).Step b:

[0390] To a stirred mixture of 2-bromo-5-chloro-4-methylphenol (0.70 g, 3.16 mmol) and K 2 CO 3 (0.87 g, 6.32 mmol) in DMF (5 mL) was added 3-bromoprop-1-ene (0.50 g, 4.11 mmol) at room temperature. The reaction mixture was allowed to warm to 40 °C and stirred for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (2 x 15 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-bromo-4-chloro-5-methyl-2-(prop-2-en-1-yloxy)benzene as an off-white solid (0.45 g, 54%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.42 (s, 1H), 6.90 (s, 1H), 6.12-6.02 (m, 1H), 5.58-5.40 (m, 1H), 5.40-5.30 (m, 1H), 4.59 (dt, J = 5.0, 1.6 Hz, 2H), 2.30 (s, 3H).Step c:

[0391] To a stirred solution of 1-bromo-4-chloro-5-methyl-2-(prop-2-en-1-yloxy)benzene (0.43 g, 1.64 mmol) in THF (4 mL) was added n-BuLi (0.76 mL, 1.90 mmol, 2.5 M in hexane) dropwise at -65 °C under nitrogen atmosphere. After stirring for 30 min, a solution of tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (0.40 g, 1.26 mmol) in THF (2 mL) was added dropwise at -65 °C under nitrogen atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for additional 1 h. The reaction was quenched with saturated aq. NH 4 Cl (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 5) to afford tert-butyl 4-((R)-(2-(allyloxy)-4-chloro-5-methylphenyl)(((S)-tert-butylsulfinyl)amino)methyl)piperidine-1-carboxylate as a light yellow oil (0.18 g, 30%): LCMS (ESI) calc'd for C 25 H 39 ClN 2 O 4 S [M + H] +< : 499, 501 (3 : 1), found 499, 501 (3 : 1); 1< H NMR (400 MHz, CDCl 3 ) δ 6.96 (s, 1H), 6.87 (s, 1H), 6.09-5.99 (m, 1H), 5.50-5.27 (m, 2H), 4.61-4.45 (m, 2H), 4.42-3.82 (m, 4H), 2.66-2.57 (m, 2H), 2.29 (s, 3H), 1.92-1.91 (m, 1H), 1.66 (s, 3H), 1.45 (s, 9H), 1.13 (s, 9H).Step d:

[0392] To a stirred solution of tert-butyl 4-((R)-(2-(allyloxy)-4-chloro-5-methylphenyl)(((S)-tert-butylsulfinyl)amino)methyl)piperidine-1-carboxylate (0.18 g, 0.38 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was neutralized with saturated aq. NaHCO 3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (S)-N-((R)-(2-(allyloxy)-4-chloro-5-methylphenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide as a light yellow oil (0.10 g, 70%): LCMS (ESI) calc'd for C 20 H 31 ClN 2 O 2 S [M + H] +< : 399, 401 (3 : 1), found 399, 401 (3 : 1).Example 46. (which is a reference example) Intermediate 46 (1-bromo-4,5-dichloro-3-fluoro-2-(prop-2-en-1-yloxy)benzene)

[0393] Step a:

[0394] To a solution of 3-chloro-2-fluorophenol (1.50 g, 10.23 mmol) in MeCN (60 mL) and TFA (1.00 mL) was added NCS (1.37 g, 10.24 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford 3,4-dichloro-2-fluorophenol as an off-white solid (1.60 g, 86%): 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.64 (s, 1H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1H).Step b:

[0395] To a stirred solution of 3,4-dichloro-2-fluorophenol (1.60 g, 8.84 mmol) in AcOH (20 mL) was added Br 2 (1.55 g, 9.72 mmol) dropwise at room temperature. The reaction solution was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL). Then the reaction mixture was extracted with EA (2 x 50 mL). The organic phase were washed with saturated aq. Na 2 SO 3 (2 x 50 mL), saturated aq. NaHCO 3 (2 x 50 mL) and brine (2 x 50 mL). Then solution was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluted with PE / EA (5 / 1) to afford 6-bromo-3,4-dichloro-2-fluorophenol as off-white solid (1.80 g, 78%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J = 2.3 Hz, 1H).Step c:

[0396] To a stirred mixture of 6-bromo-3,4-dichloro-2-fluorophenol (1.80 g, 6.97 mmol) and K 2 CO 3 (2.00 g, 14.47 mmol) in DMF (20 mL) was added 3-bromoprop-1-ene (1.26 g, 10.39 mmol) at room temperature. Then the reaction was stirred at 40 °C for 3 h. The reaction mixture was diluted with water (80 mL) and extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-bromo-4,5-dichloro-3-fluoro-2-(prop-2-en-1-yloxy)benzene as a colorless liquid (1.70 g, 82%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 2.3 Hz, 1H), 6.18-6.03 (m, 1H), 5.47-5.37 (m, 1H), 5.32 (dd, J = 10.2, 1.5 Hz, 1H), 4.70-4.60 (m, 2H); 19< F NMR (376 MHz, CDCl 3 ) δ -121.32.Example 47. Intermediate 47 (lithio (R)-2-methoxy-3-(trityloxy)propanoate)

[0397] Step a:

[0398] To a stirred solution of methyl (2R)-2,3-dihydroxypropanoate (0.50 g, 4.16 mmol) and (chlorodiphenylmethyl)benzene (3.50 g, 12.5 mmol) in DCM (4 mL) were added DMAP (30 mg, 0.25 mmol) and Et 3 N (1.26 g, 12.5 mmol) in portions at room temperature. The resulting mixture was stirred for 72 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 25 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8 / 1) to afford methyl (2R)-2-methoxy-3-(triphenylmethoxy)propanoate as an off-white solid (0.10 g, 6%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.37-7.29 (m, 15H), 4.31 (t, J = 3.5 Hz, 1H), 3.91 (dd, J = 14.0, 3.6 Hz, 2H), 3.87 (s, 3H).Step b:

[0399] To a stirred solution of methyl (2R)-2-hydroxy-3-(triphenylmethoxy)propanoate (0.50 g, 1.38 mmol) and CH 3 I (1 mL) in Et 2 O (5 mL) was added Ag 2 O (0.96 g, 4.14 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford methyl (2R)-2-methoxy-3-(triphenylmethoxy)propanoate as an off-white solid (0.40 g, 77%): LCMS (ESI) calc'd for C 24 H 24 O 4 [M + Na] +< : 399, found 399; 1< H NMR (400 MHz, CDCl 3 ) δ 7.39-7.21 (m, 15H), 4.00-3.90 (m, 2H), 3.82 (s, 3H), 3.87-3.76 (m, 1H), 3.53 (s, 3H).Step c:

[0400] To a stirred mixture of methyl (2R)-2-methoxy-3-(triphenylmethoxy)propanoate (50 mg, 0.13 mmol) in MeOH (2 mL) was added a solution of LiOH·H 2 O (9 mg, 0.4 mmol) in H 2 O (1 mL) at room temperature. The resulting mixture was stirred for 16 h at room temperature and concentrated under reduced pressure to afford lithio (2R)-2-methoxy-3-(triphenylmethoxy)propanoate (50 mg, crude). The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 23 H 22 O 4 [M + Na] +< : 385, found 385.Example 48. Intermediate 48 (lithio (2S)-2-methoxy-3-(triphenylmethoxy)propanoate)

[0401] Step a:

[0402] To a stirred solution of methyl (2S)-2,3-dihydroxypropanoate (1.00 g, 8.32 mmol) and (chlorodiphenylmethyl)benzene (2.50 g, 9.16 mmol) in DCM (10 mL) were added Et 3 N (1.26 g, 12.5 mmol) and DMAP (61 mg, 0.50 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford methyl (2S)-2-hydroxy-3-(triphenylmethoxy)propanoate as an off-white solid (1.00 g, 33%): 1< H NMR (400 MHz, CDCl 3 ) δ 7.49-7.39 (m, 5H), 7.33 (dt, J = 6.9, 1.5 Hz, 5H), 7.33-7.22 (m, 5H), 4.32-4.27 (m, 1H), 3.80 (s, 3H), 3.54-3.45 (m, 1H), 3.38 (dd, J = 9.4, 3.4 Hz, 1H).Step b:

[0403] To a stirred solution of methyl (2S)-2-hydroxy-3-(triphenylmethoxy)propanoate (0.50 g, 1.38 mmol) and CH 3 I (1 mL) in Et 2 O (5 mL) was added Ag 2 O (0.96 g, 4.14 mmol) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 25 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford methyl (2S)-2-methoxy-3-(triphenylmethoxy)propanoate as an off-white solid (0.40 g, 77%): LCMS (ESI) calc'd for C 24 H 24 O 4 [M + Na] +< : 399, found 399; 1< H NMR (400 MHz, CDCl 3 ) δ 7.49-7.42 (m, 6H), 7.36-7.25 (m, 6H), 7.29-7.21 (m, 3H), 3.97 (dd, J = 5.4, 4.0 Hz, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 3.45-3.36 (m, 2H).Step c:

[0404] To a stirred solution of methyl (2S)-2-methoxy-3-(triphenylmethoxy)propanoate (0.20 g, 0.53 mmol) in MeOH (3 mL) was added LiOH·H 2 O (38 mg, 1.59 mmol) in H 2 O (1 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford lithio (2S)-2-methoxy-3-(triphenylmethoxy)propanoate as an off-white solid (0.10 g, crude). The crude product was used in the next step directly without further purification: LCMS (ESI) calc'd for C 23 H 22 O 4 [M + Na] +< : 385, found 385.Example 49. Intermediate 49 (tert-butyl 4-(1-(4,5-dichloro-2-methoxyphenyl)-2-oxoethyl)piperidine-1-carboxylate)

[0405] Step a:

[0406] To a stirred mixture of (methoxymethyl)triphenylphosphanium chloride (12.36 g, 36.06 mmol) in THF (60 mL) was added n-BuLi (10.30 mL, 25.75 mmol, 2.5 M in hexane) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at - 78 °C under nitrogen atmosphere. To the above mixture was added a solution of tert-butyl 4-(4,5-dichloro-2-methoxybenzoyl)piperidine-1-carboxylate (2.00 g, 5.15 mmol) in THF (5 mL) dropwise over 5 min at -78 °C. The resulting mixture was stirred for additional 2 h at -78 °C. The reaction was quenched with saturated aq. NH 4 Cl (80 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-methoxyethenyl]piperidine-1-carboxylate as a light yellow oil (1.60 g, 59%): LCMS (ESI) calc'd for C 20 H 27 Cl 2 NO 4 [M + H] +< : 416, 418 (3 : 2), found 416, 418 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.09 (d, J = 1.3 Hz, 1H), 6.91 (s, 1H), 5.87 (d, J = 1.3 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 2.74-2.58 (m, 4H), 1.71-1.53 (m, 5H), 1.46 (d, J = 1.3 Hz, 9H).Step b:

[0407] To a stirred solution of tert-butyl 4-[(E)-1-(4,5-dichloro-2-methoxyphenyl)-2-methoxyethenyl]piperidine-1-carboxylate (1.80 g, 4.32 mmol) in 1,4-dioxane (10 mL) was added aq. HCl (6 N, 10 mL) dropwise at 0 °C. Then the resulting mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification: LCMS (ESI) calc'd for C 14 H 17 Cl 2 NO 2 [M + H] +< : 302, 304 (3 : 2), found 302, 304 (3 : 2)Step c:

[0408] To a stirred mixture of 2-(4,5-dichloro-2-methoxyphenyl)-2-(piperidin-4-yl)acetaldehyde (1.50 g, 4.96 mmol) in THF (15 mL) and saturated aq. NaHCO 3 (20 mL) was added Boc 2 O (1.62 g, 7.445 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[1-(4,5-dichloro-2-methoxyphenyl)-2-oxoethyl]piperidine-1-carboxylate as a light yellow oil (1.30 g, 65%): LCMS (ESI) calc'd for C 19 H 25 Cl 2 NO 4 [M + H] +< : 402, 404 (3 : 2), found 402, 404 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 9.68 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.67 (dd, J = 8.9, 1.7 Hz, 1H), 2.82-2.71 (m, 1H), 2.66 (t, J = 12.6 Hz, 1H), 2.36-2.21 (m, 1H), 1.89 (dt, J = 13.3, 2.9 Hz, 1H), 1.67 (s, 1H), 1.45 (s, 9H), 1.41 (s, 1H), 1.26-1.16 (m, 1H), 1.10-0.95 (m, 1H).Example 50. Intermediate 50 (tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)amino]methyl]-2,2-dimethylpiperidine-1-carboxylate)

[0409] Step a:

[0410] To a solution of (methoxymethyl) triphenylphosphanium chloride (1508 mg, 4.40 mmol) in THF (7 mL) was added n-BuLi (2.5 mL, 38.46 mmol, 2.5 M in hexane) dropwise at - 10 °C under nitrogen atmosphere. The solution was stirred at 0 °C for 1 h. Then a solution of tert-butyl 2, 2-dimethyl-4-oxopiperidine-1-carboxylate (1 g, 4.40 mmol) in THF (5 mL) was added dropwise at -20 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 15 h. The reaction mixture was quenched with saturated aq. NH 4 Cl (30 mL) and extracted with EA (2 x 20 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 4 (methoxymethylidene)-2,2-dimethylpiperidine-1-carboxylate as a colorless oil (0.80 g, 71%): LCMS (ESI) calc'd for C 14 H 25 NO 3 [M + H] +< : 256, found 256; 1< H NMR (300 MHz, Methanol) δ 5.97 (d, J = 24.0 Hz, 1H), 3.62-3.45 (m, 5H), 2.37-2.27 (m, 2H), 2.26-2.20 (m, 1H), 2.18 (s, 1H), 1.46 (d, J = 1.7 Hz, 9H), 1.38 (d, J = 2.7 Hz, 6H).Step b:

[0411] To a solution of tert-butyl 4-(methoxymethylidene)-2,2-dimethylpiperidine-1-carboxylate (0.80 g, 3.13 mmol) in THF (10 mL) was added aq. HCl (4 N, 5 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. Then the reaction mixture was basified to pH 9 with saturated aq. NaHCO 3 , then Boc 2 O (821 mg, 3.76 mmol) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EA (2 x 15 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford tert-butyl 4-formyl-2,2-dimethylpiperidine-1-carboxylate as colorless oil (360 mg, 48%): LCMS (ESI) calc'd for C 13 H 23 NO 3 [M + H] +< : 242, found 242.Step c':

[0412] To a stirred solution of 2-bromo-4,5-dichlorophenol (31.00 g, 128.15 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (32.00 g, 192.23 mmol) in DCM (100 mL) was added DIEA (49.70 g, 384.46 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with water (200 mL). The resulting mixture was extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50 / 1) to afford [2-(2-bromo-4,5-dichlorophenoxymethoxy)ethyl]trimethylsilane (44.00 g, 83%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.46 (s, 1H), 5.39 (s, 2H), 3.74 (t, J = 6.0 Hz, 2H), 0.79 (t, J = 6.0 Hz, 2H), -0.05 (s, 9H).Step c:

[0413] To a solution of [2-(2-bromo-4,5-dichlorophenoxymethoxy) ethyl] trimethylsilane (product of Step c') (0.69 g, 1.86 mol) in THF (7 mL) was added dropwise i-PrMgCl (0.2 mL, 1.61 mmol, 2 M in THF) at -10 °C under nitrogen atmosphere. Then reaction mixture was stirred at -10 °C for 0.5 h under nitrogen atmosphere. A solution of tert-butyl 4-formyl-2, 2-dimethylpiperidine-1-carboxylate (300 mg, 1.24 mmol) in THF (3 mL) was added dropwise to resulting solution at -10 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 h under nitrogen atmosphere. The resulting mixture was quenched with saturated aq. NH 4 Cl (40 mL). The resulting mixture was extracted with EA (3 x 10 mL). The organic phases were combined, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9 / 1) to afford tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)(hydroxy)methyl]-2,2-dimethylpiperidine-1-carboxylate as a colorless oil (0.20 g, 30%): LCMS (ESI) calc'd for C 25 H 41 Cl 2 NO 5 Si [M + H] +< : 534, 536 (3 : 2), found 534, 536 (3 : 2); 1< H NMR (300 MHz, CDCl 3 ) δ 7.67 (s, 1H), 7.41 (s, 1H), 5.30 (s, 2H), 3.83-3.72 (m, 2H), 3.71-3.50 (m, 2H), 3.46-3.28 (m, 1H), 1.97-1.89 (m, 1H), 1.84-1.73 (m, 2H), 1.71-1.65 (m, 1H), 1.52 (d, J = 4.0 Hz, 6H), 1.49 (s, 9H), 1.40 (s, 2H), 0.04 (s, 9H).Step d:

[0414] To a solution of tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)(hydroxy)methyl]-2,2-dimethylpiperidine-1-carboxylate (0.18 g, 0.34 mmol) in DCM (8 mL) was added Dess-Martin reagent (0.14 g, 0.34 mmol) in three portions at room temperature. Then the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aq. Na 2 SO 3 , and then extracted with DCM (2 x 10 mL). The organic phase was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)carbonyl]-2,2-dimethylpiperidine-1-carboxylate as a colorless oil (0.16 g, crude): LCMS (ESI) calc'd for C 25 H 39 Cl 2 NO 5 Si [M + H] +< : 532, 534 (3 : 2), found 532, 534 (3 : 2).Step e:

[0415] To a solution of tert-butyl 4-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]benzoyl)-2,2-dimethylpiperidine-1-carboxylate (0.16 g, crude) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (44 mg, 360 mmol) and Ti(OEt) 4 (0.90 g, 3.95 mmol) in one portion at room temperature. The reaction mixture was stirred at 70 °C for 15 h under nitrogen atmosphere. The reaction mixture was quenched with water (50 mL). The solid was formed and filtered. The filtrate was extracted with EA (2 x 40 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)imino]methyl]-2,2-dimethylpiperidine-1-carboxylate as a colorless oil (0.20 g, crude): LCMS (ESI) calc'd for C 29 H 48 Cl 2 N 2 O 5 SSi [M + Na] +< : 657, 659 (3 : 2), found 657, 659 (3 : 2).Step f:

[0416] To a solution of tert-butyl 4-[(1E)-(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)[(2-methylpropane-2-sulfinyl)imino]methyl]-2,2-dimethylpiperidine-1-carboxylate (0.20 g, 0.31 mmol) in MeOH (5 mL) was added NaBH 4 (58 mg, 1.54 mmol) in 5 portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction mixture was quenched with saturated aq. NH 4 Cl (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified with Prep-TLC, eluted with PE / EA (1 / 1) to afford tert-butyl 4-[(4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methoxy] phenyl)[(2-methylpropane-2-sulfinyl)amino]methyl]-2,2-dimethylpiperidine-1-carboxylate as a colorless oil (75 mg, 37%): LCMS (ESI) calc'd for C 29 H 50 Cl 2 N 2 O 5 SSi [M + Na] +< : 659, 661 (3 : 2), found 659, 661 (3 : 2).Example 51. Intermediate 51 ((S)-N-((R)-(6-(allyloxy)-2,3-dichlorophenyl)(piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide)

[0417] Step a:

[0418] To a stirred solution of 1,2-dichloro-3-iodo-4-(prop-2-en-1-yloxy)benzene (1.25 g, 3.80 mmol) in THF (10 mL) was added n-BuLi (1.2 mL, 3.80 mmol, 2.5 M in hexane) at -65 °C under nitrogen atmosphere. After stirring for 30 min at -65 °C under nitrogen atmosphere, a solution of tert-butyl 4-[[(S)-2-methylpropane-2-sulfinyl]imino]methyl]piperidine-1-carboxylate (0.80 g, 2.53 mmol) in THF (5 mL) was added dropwise at -65 °C under nitrogen atmosphere. After addition, the reaction mixture was stirred for additional 1 h at -65 °C under nitrogen atmosphere. The reaction was quenched with water (40 mL) at -65 °C and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7 / 1) to afford tert-butyl 4-((R)-(6-(allyloxy)-2,3-dichlorophenyl)(((S)-tert-butylsulfinyl)amino)methyl)piperidine-1-carboxylate as a light yellow oil (0.80 g, 57%): LCMS (ESI) calc'd for C 24 H 36 Cl 2 N 2 O 4 S [M + H] +< : 519, 521 (3 : 2), found 519, 521 (3 : 2); 1< H NMR (400 MHz, CDCL 3 ) δ 7.34 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 9.0, 4.9 Hz, 1H), 6.11-5.94 (m, 1H), 5.49-5.28 (m, 2H), 4.79 (t, J = 9.7 Hz, 1H), 4.68-4.50 (m, 3H), 4.36-3.91 (m, 3H), 2.77-2.47 (m, 2H), 2.40-2.29 (m, 1H), 2.18-2.02 (m, 1H), 1.46 (s, 9H), 1.34-1.22 (m, 1H), 1.04 (s, 9H).Step b:

[0419] To a stirred solution of tert-butyl 4-[(R)-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]([[(S)-2-methylpropane-2-sulfinyl]amino])methyl]piperidine-1-carboxylate (0.80 g, 1.54 mmol) in DCM (6 mL) was added TFA (1.5 mL) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (6 mL) and was neutralized to pH 8 with saturated aq. NaHCO 3 . The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (S)-N-[(R)-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2-methylpropane-2-sulfinamide as a light yellow oil (0.60 g, 74%): LCMS (ESI) calc'd for C 19 H 28 Cl 2 N 2 O 2 S [M + H] +< : 419, 421 (3 : 2), found 419, 421 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.36-7.31 (m, 1H), 6.81-6.76 (m, 1H), 6.11-5.95 (m, 1H), 5.49-5.34 (m, 2H), 4.81 (t, J = 10.0 Hz, 1H), 4.67-4.50 (m, 3H), 3.26 (d, J = 12.5 Hz, 1H), 3.08 (d, J = 12.4 Hz, 1H), 2.68-2.36 (m, 5H), 2.13 (t, J = 10.7 Hz, 1H), 1.04 (s, 9H).Example 52. Intermediate 52 (lithio 4-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylate)

[0420] Step a:

[0421] To a stirred mixture of 5-oxo-4H-pyrazine-2-carboxylic acid (3.00 g, 21.41 mmol) and K 2 CO 3 (14.8 g, 1.07 mol) in DMF (30 mL) was added CH 3 I (15.2 g, 1.08 mol) at room temperature. The resulting mixture was stirred for 16 h at 40 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EA (5 x 60 mL). The combined organic layers were washed with brine (5 x 80 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-methyl-5-oxopyrazine-2-carboxylate as a dark brown solid (2.50 g, 69%): LCMS (ESI) calc'd for C 7 H 8 N 2 O 3 [M + H] +< : 169, found 169; 1< H NMR (400 MHz, CD 3 OD) δ 8.48 (s, 1H), 8.02 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H).Step b:

[0422] To a stirred mixture of methyl 4-methyl-5-oxopyrazine-2-carboxylate (0.60 g, 3.57 mmol) in MeOH (7 mL) was added a solution of LiOH (0.26 g, 10.71 mmol) in H 2 O (1 mL) at room temperature. After stirring for 20 h at room temperature, the resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI) calc'd for C 6 H 6 N 2 O 3 [M + H] +< : 155, found 155.Example 53. Intermediate 53 (1-bromo-4-methyl-2-(prop-2-en-1-yloxy)benzene)

[0423] Step a:

[0424] To a stirred solution of 2-bromo-5-methylphenol (2.00 g, 10.69 mmol) in DMF (20 mL) were added K 2 CO 3 (2.96 g, 21.41 mmol) and 3-bromoprop-1-ene (1.94 g, 16.04 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford 1-bromo-4-methyl-2-(prop-2-en-1-yloxy)benzene as a light yellow oil (1.29 g, 53%): 1< H NMR (400 MHz, CD 3 OD) δ 7.38 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.69 (dd, J = 7.9, 2.0 Hz, 1H), 6.16-6.02 (m, 1H), 5.40-5.30 (m, 1H), 5.28-5.20 (m, 1H), 4.60 (d, J = 5.0 Hz, 2H), 2.32 (s, 3H).Example 54. Intermediate 54 (tert-butyl 4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylate)

[0425] Step a:

[0426] To a stirred mixture of 3-methylpyridine-4-carboxylic acid (2.00 g, 14.58 mmol) and HCl (6 N, 3 mL) in MeOH (15 mL) was added PtO 2 (0.33 g, 1.46 mmol) at room temperature. The resulting mixture was stirred for 12 h at 50 °C under H 2 (50 atm) atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford methyl 3-methylpiperidine-4-carboxylate HCl as a yellow oil (2.30 g, 90%): LCMS (ESI) calc'd for C 8 H 15 NO 2 [M + H] +< : 158, found 158; 1< H NMR (400 MHz, DMSO-d 6 ) δ 3.86-3.69 (m, 2H), 3.64 (s, 3H), 3.15-2.90 (m, 2H), 2.83 (q, J = 5.7 Hz, 1H), 2.35-2.23 (m, 1H), 1.91-1.81 (m, 2H), 0.93 (d, J = 7.2 Hz, 3H).Step b:

[0427] To a stirred solution of methyl 3-methylpiperidine-4-carboxylate (2.30 g, 14.63 mmol) and Et 3 N (2.96 g, 29.26 mmol) in THF (15 mL) and MeOH (30 mL) was added Boc 2 O (4.79 g, 21.95 mmol) at room temperature. The reaction solution was stirred for 2 h at room temperature. The resulting mixture was diluted with EA (50 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 20% ACN in water (plus 0.05% TFA) to afford 1-tert-butyl 4-methyl 3-methylpiperidine-1,4-dicarboxylate as a yellow oil (2.90 g, 77% overall two steps): LCMS (ESI) calc'd for C 13 H 23 NO 4 [M + H - 15] +< : 243, found 243; 1< H NMR (400 MHz, CDCl 3 ) δ 4.02 (s, 1H), 3.80 (dd, J = 13.3, 1.5 Hz, 1H), 3.70 (s, 3H), 3.31-2.81 (m, 2H), 2.62 (dt, J = 10.5, 4.3 Hz, 1H), 2.27-2.15 (m, 1H), 1.92-1.77 (m, 1H), 1.75-1.58 (m, 1H), 1.47 (s, 9H), 0.90 (dd, J = 6.8, 2.5 Hz, 3H).Step c:

[0428] To a stirred solution of 1-tert-butyl 4-methyl 3-methylpiperidine-1,4-dicarboxylate (2.70 g, 10.49 mmol) in MeOH (20 mL) was added a solution of NaOH (0.83 g, 20.98 mmol) in H 2 O (4 mL) at room temperature. The reaction mixture was stirred for 12 h at room temperature and was acidified to pH 3 with citric acid. The mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 1-[(tert-butoxy)carbonyl]-3-methylpiperidine-4-carboxylic acid as a yellow oil (1.30 g, 63%): LCMS (ESI) calc'd for C 12 H 21 NO 4 [M +Na] +< : 266, found 266; 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.24 (s, 1H), 3.88 (s, 1H), 3.70 (dd, J = 13.1, 3.6 Hz, 1H), 3.09-2.65 (m, 2H), 2.56 (dt, J = 10.0, 4.5 Hz, 1H), 2.19-2.08 (m, 1H), 1.65-1.49 (m, 2H), 1.39 (s, 9H), 0.80 (d, J = 6.9 Hz, 3H).Step d:

[0429] To a stirred mixture of 1-[(tert-butoxy)carbonyl]-3-methylpiperidine-4-carboxylic acid (1.10 g, 4.52 mmol) and HOBt (0.91 g, 6.78 mmol) in DMF (10 mL) were added EDCI (1.30 g, 6.78 mmol), Et 3 N (0.55 g, 5.43 mmol) and N,O-methoxy(methyl)amine (0.30 g, 4.97 mmol) at room temperature. The reaction solution was stirred for 12 h at room temperature. The resulting solution was quenched with water (50 mL) at room temperature and extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford tert-butyl 4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylate as a colorless oil (1.00 g, 77%): LCMS (ESI) calc'd for C 14 H 26 N 2 O 4 [M + H - 56] +< : 231 found 231; 1< H NMR (400 MHz, CDCl 3 ) δ 4.17-3.89 (m, 2H), 3.86-3.76 (m, 1H), 3.73 (s, 3H), 3.29-3.13 (m, 4H), 3.13-2.94 (m, 2H), 2.24-2.09 (m, 1H), 2.06-1.87 (m, 1H), 1.48 (s, 9H), 0.93 (d, J = 7.0 Hz, 3H).Example 55. Intermediate 55 (tert-butyl (3S,4S)-rel-4-(2-(prop-2-en-1-yloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylate; tert-butyl (3R,4S)-rel-4-(2-(prop-2-en-1-yloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylate)

[0430] Step a:

[0431] To a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (2.12 g, 7.68 mmol) in THF (10 mL) was added i-PrMgCl (3.84 mL, 7.68 mmol, 2 M solution in THF) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min. Then a solution of tert-butyl 4-[methoxy(methyl)carbamoyl]-3-methylpiperidine-1-carboxylate (1.10 g, 3.84 mmol) in THF (8 mL) was added dropwise into the solution. After addition, the resulting solution was stirred at 0 °C for additional 1 h. The reaction was quenched with saturated aq. NH 4 Cl (5 mL). The reaction mixture was diluted with EA (30 mL) and water (30 mL), and then the aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford a mixture of tert-butyl 4-(2-(allyloxy)-4,5-dichlorobenzoyl)-3-methylpiperidine-1-carboxylate and tert-butyl 4-(4,5-dichloro-2-hydroxybenzoyl)-3-methylpiperidine-1-carboxylate. The residue was dissolved in DMF (10 mL) and K 2 CO 3 (0.88 g, 6.37 mmol) and allyl bromide (0.77 g, 6.37 mmol) was added at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford tert-butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-3-methylpiperidine-1-carboxylate containing two cis enantiomers as a light yellow oil (0.90 g, 55%): LCMS (ESI) calc'd for C 21 H 27 Cl 2 NO 4 [M + H - 56] +< 372, 374 (3 : 2), found 372, 374 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.67 (s, 1H), 7.06 (s, 1H), 6.15-5.97 (m, 1H), 5.52-5.38 (m, 2H), 4.69-4.54 (m, 2H), 4.25-4.03 (m, 1H), 4.01-3.86 (m, 1H), 3.68-3.52 (m, 1H), 3.12-2.94 (m, 1H), 2.91-2.76 (m, 1H), 2.24-2.10 (m, 1H), 2.01-1.84 (m, 1H), 1.76-1.55 (m, 1H), 1.55-1.39 (m, 9H), 0.85 (d, J = 6.5 Hz, 3H).

[0432] tert-Butyl 4-[4,5-dichloro-2-(prop-2-en-1-yloxy)benzoyl]-3-methylpiperidine-1-carboxylate) containing two trans enantiomers was isolated as a light yellow oil (0.12 g, 7%): LCMS (ESI) calc'd for C 21 H 27 Cl 2 NO 4 [M + Na] +< : 450, 452 (3 : 2), found 450, 452 (3 : 2); 1< H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 7.07 (s, 1H), 6.11-5.93 (m, 1H), 5.44 (q, J = 11.2 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.19-4.10 (m, 1H), 3.92 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 13.1 Hz, 1H), 2.87-2.78 (m, 1H), 2.23-2.08 (m, 1H), 1.97-1.82 (m, 1H), 1.76-1.58 (m, 1H), 1.56-1.32 (m, 9H), 0.82-0.75 (m, 3H).Example 56. Intermediate 56 ((2S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid)

[0433] Step a:

[0434] A stirred solution of tert-butyl (2S)-5-oxopyrrolidine-2-carboxylate (0.50 g, 2.70 mmol) in THF (5 mL) was added NaH (0.22 g, 5.40 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C under nitrogen atmosphere. To the above mixture was added MeI (1.15 g, 8.10 mmol) dropwise at 0°C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (40 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 50% ACN in water (plus 0.05% TFA) to afford tert-butyl (2S)-1-methyl-5-oxopyrrolidine-2-carboxylate as a light yellow oil (0.34 g, 63%): LCMS (ESI) calc'd for C 10 H 17 NO 3 [2M + H] +< : 399, found 399; 1< H NMR (400 MHz, CDCl 3 ) δ 4.09-3.92 (m, 1H), 2.87 (s, 3H), 2.57-2.43 (m, 1H), 2.43-2.24 (m, 2H), 2.13-1.98 (m, 1H), 1.50 (s, 9H).Step b:

[0435] To a stirred solution of tert-butyl (2S)-1-methyl-5-oxopyrrolidine-2-carboxylate (50 mg, 0.25 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The reaction solution was stirred for 2 h at room temperature. The resulting solution was concentrated under reduced pressure to afford (2S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid as a yellow oil (64 mg, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 6 H 9 NO 3 [M + H] +< : 144, found 144; 1< H NMR (400 MHz, CDCl 3 ) δ 4.35-4.12 (m, 1H), 2.96 (s, 3H), 2.75-2.36 (m, 3H), 2.31-2.10 (m, 1H).Example 57. (which is a reference example) Intermediate 57 (bromo-5-chloro-4-ethyl-2-(prop-2-en-1-yloxy)benzene)

[0436] Step a:

[0437] To a stirred solution of 4-chloro-3-ethylphenol (3.00 g, 19.15 mmol) in DCM (20 mL) was added Br 2 (3.67 g, 22.96 mmol) dropwise at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with saturated aq. Na 2 SO 3 (20 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo-4-chloro-5-ethylphenol as a colorless oil (4.50 g, crude), which was used in the next step directly without further purification: 1< H NMR (400 MHz, CD 3 OD) δ 7.42 (s, 1H), 6.83 (s, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H).Step b:

[0438] To a stirred solution of 2-bromo-4-chloro-5-ethylphenol (4.50 g, 19.10 mmol) and K 2 CO 3 (5.28 g, 38.20 mmol) in DMF (40 mL) was added 3-bromoprop-1-ene (3.47 g, 28.68 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (6 x 30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford 1-bromo-5-chloro-4-ethyl-2-(prop-2-en-1-yloxy)benzene as a colorless oil (2.40 g, 45% overall two steps); 1< H NMR (400 MHz, CD 3 OD) δ 7.52 (s, 1H), 6.96 (s, 1H), 6.16-5.91 (m, 1H), 5.53-5.38 (m, 1H), 5.35-5.21 (m, 1H), 4.73-4.48 (m, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H).Example 58. Intermediate 58 (tert-butyl 5-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.1]heptane-2-carboxylate)

[0439] Step a:

[0440] To a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.2.1]heptane-5-carboxylic acid (0.50 g, 2.07 mmol) in DCM (5 mL) were added EDCI (0.60 g, 3.11 mmol) and HOBt (0.42 g, 3.11 mmol) at room temperature. After stirring for 10 min at room temperature, to the above mixture were added N,O-methoxy(methyl)amine hydrochloride (0.30 g, 3.11 mmol) and Et 3 N (0.63 g, 6.22 mmol) at room temperature. After stirring for 5 h at room temperature, the resulting solution was diluted with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 40% ACN in water (plus 0.05% TFA) to afford tert-butyl 5-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.1]heptane-2-carboxylate as a yellow oil (0.31g, 52%): LCMS (ESI) calc'd for C 14 H 24 N 2 O 4 [M + H - 56] +< : 229, found 229; 1< H NMR (400 MHz, CDCl 3 ) δ 4.25 (s, 1H), 3.73 (s, 3H), 3.29 (dd, J = 9.9, 3.4 Hz, 1H), 3.22 (s, 3H), 3.17-2.98 (m, 1H), 2.98-2.81 (m, 1H), 2.75-2.67 (m, 1H), 2.03-1.84 (m, 2H), 1.81 (d, J = 10.1 Hz, 1H), 1.62 (d, J = 10.1 Hz, 1H), 1.49 (s, 9H).Example 59. Intermediate 59 (lithio 2-methyl-6-oxo-1H-pyridine-3-carboxylate)

[0441] Step a:

[0442] To a stirred solution of ethyl 2-methyl-6-oxo-1H-pyridine-3-carboxylate (0.10 g, 0.55 mmol) in MeOH (1 mL) was added a solution of LiOH·H 2 O (46 mg, 1.10 mmol) in water (0.5 mL) at room temperature. The resulting mixture was stirred for 1 h at 40 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to afford lithio 2-methyl-6-oxo-1H-pyridine-3-carboxylate as an off-white solid (0.15 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 7 H 7 NO 3 [M + H] +< : 154, found 154.Example 60. Intermediate 60 (lithio 1-[2-(oxan-2-yloxy)ethyl]-6-oxopyridine-3-carboxylate)

[0443] Step a:

[0444] To a stirred solution of methyl 6-oxo-1H-pyridine-3-carboxylate (0.50 g, 3.26 mmol) in DMF (5 mL) was added NaH (0.26 g, 6.53 mmol, 60% in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 10 min. Then 2-(2-chloroethoxy)oxane (1.61 g, 9.79 mmol) and NaI (97 mg, 0.65 mmol) were added into the mixture. After addition, the reaction mixture was allowed to warm to 70 °C and stirred for 5 h. After cooling to room temperature, the resulting mixture was quenched with water (30 mL) at 0 °C and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (6 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford methyl 1-[2-(oxan-2-yloxy)ethyl]-6-oxopyridine-3-carboxylate as a yellow oil (0.50 g, 54%): LCMS (ESI) calc'd for C 14 H 19 NO 5 [M + H] +< : 282 found 282; 1< H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 8.18 (dt, J = 8.8, 2.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.81-4.49 (m, 3H), 4.17-3.93 (m, 1H), 3.93-3.77 (m, 4H), 3.68-3.45 (m, 2H), 1.95-1.46 (m, 6H).Step b:

[0445] To a stirred solution of methyl 1-[2-(oxan-2-yloxy)ethyl]-6-oxopyridine-3-carboxylate (0.20 g, 0.711 mmol) in MeOH (5 mL) was added a solution of LiOH·H 2 O (59 mg, 1.42 mmol) in water (0.5 mL) at room temperature. The resulting mixture was stirred for 1 h at 40 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to afford lithio 1-[2-(oxan-2-yloxy)ethyl]-6-oxopyridine-3-carboxylate (0.16 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 13 H 17 NO 5 [M + Na] +< : 290, found 290.Example 61. Intermediate 61 (lithio 3-[(tert-butoxycarbonyl)amino]-2-[[(tert-butoxycarbonyl)amino]methyl]propanoate)

[0446] Step a:

[0447] To a stirred solution of methyl 3-amino-2-(aminomethyl)propanoate dihydrochloride (0.50 g, 2.44 mmol) and Et 3 N (0.74 g, 7.31 mmol) in DCM (5 mL) was added Boc 2 O (1.17 g, 5.36 mmol) at room temperature. The reaction solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford methyl 3-[(tert-butoxycarbonyl)amino]-2-[[(tert-butoxycarbonyl)amino]methyl]propanoate as a yellow oil (1.00 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 15 H 28 N 2 O 6 [M + H] +< : 333, found 333; 1< H NMR (400 MHz, CDCl 3 ) δ 3.73 (s, 3H), 3.62-3.51 (m, 2H), 3.23 (dt, J = 13.6, 5.7 Hz, 2H), 2.80-2.64 (m, 1H), 1.55 (s, 9H), 1.46 (s, 9H).Step b:

[0448] To a stirred solution of methyl 3-[(tert-butoxycarbonyl)amino]-2-[[(tert-butoxycarbonyl)amino]methyl]propanoate (1.00 g, 3.00 mmol) in MeOH (10 mL) was added a solution of LiOH·H 2 O (0.25 g, 6.01 mmol) in water (1 mL) at room temperature. The resulting mixture was stirred for 1 h at 40 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to afford lithio 3-[(tert-butoxycarbonyl)amino]-2-[[(tert-butoxycarbonyl)amino]methyl]propanoate as an off-white solid (1.00 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc'd for C 14 H 26 N 2 O 6 [M + H] +< : 319, found 319.Example 62. Intermediate 62 (1-acetylpyrrolidine-3-carboxylic acid)

[0449] Step a:

[0450] To a mixture of 1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (4.20 g, 19.51 mmol) and K 2 CO 3 (5.40 g, 39.07 mmol) in DMF (10 mL) was added (bromomethyl)benzene (5.00 g, 29.23 mmol) at room temperature. The resulting mixture was allowed to warm to 50 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford 3-benzyl 1-tert-butyl pyrrolidine-1,3-dicarboxylate as a light yellow oil (2.77 g, 47%): LCMS (ESI) calc'd for C 17 H 23 NO 4 [M + Na] +< : 328, found 328; 1< H NMR (300 MHz, CD 3 OD) δ 7.42-7.28 (m, 5H), 5.15 (s, 2H), 3.58-3.50 (m, 2H), 3.45-3.34 (m, 2H), 3.25-3.08 (m, 1H), 2.24-2.04 (m, 2H), 1.45 (s, 9H).Step b:

[0451] To a stirred solution of 3-benzyl 1-tert-butyl pyrrolidine-1,3-dicarboxylate (2.77 g, 8.84 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure to afford benzyl pyrrolidine-3-carboxylate as a light yellow oil (1.81 g, crude), which was used in next step directly without further purification: LCMS (ESI) calc'd for C 12 H 15 NO 2 [M + H] +< : 206, found 206.Step c:

[0452] To a stirred solution of benzyl pyrrolidine-3-carboxylate (1.81 g, 8.82 mmol) and Et 3 N (2.70 g, 26.46 mmol) in DMF (20 mL) was added acetic anhydride (1.40 g, 13.23 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was diluted with water (40 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford benzyl 1-acetylpyrrolidine-3-carboxylate as a light yellow oil (1.60 g, 71% overall two steps): LCMS (ESI) calc'd for C 14 H 17 NO 3 [M + H] +< : 248, found 248; 1< H NMR (400 MHz, CD 3 OD) δ 7.46-7.28 (m, 5H), 5.18 (d, J = 4.0 Hz, 2H), 3.75 (d, J = 6.9 Hz, 1H), 3.67 (d, J = 6.9 Hz, 1H), 3.63-3.54 (m, 1H), 3.54-3.40 (m, 1H), 3.32-3.18 (m, 1H), 2.34-2.10 (m, 2H), 2.05 (d, J = 3.5 Hz, 3H).Step d:

[0453] A mixture of benzyl 1-acetylpyrrolidine-3-carboxylate (1.60 g, 6.47 mmol) and Pd / C (0.16 g, 1.50 mmol) in MeOH (15 mL) was stirred for 1 h at room temperature under hydrogen (1.5 atm). The resulting mixture was filtered, a...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the structural moiety has the structure of each of which is substituted by R3; R3 is H, halogen, or alkyl; R1 and R2 are each independently H, alkyl, (CR6R7)n4ORa, (CR6R7)n4NRaRb, (CR6R7)n4NRa(C=O)Rb, (CR6R7)n4NRaSO2Rb, or (CR6R7)n4CONRaRb, wherein at least one occurrence of R1 and R2 is (CR6R7)n4NRaRb, (CR6R7)n4ORa, (CR6R7)n4NRa(C=O)Rb, (CR6R7)n4NRaSO2Rb, or (CR6R7)n4CONRaRb; or alternatively R1, R2 and the carbon atom they are connected to taken together form a 3-5 membered carbocycle; R4 is (CR6R7)n4(C=O)Rc, (C=O)(CR6R7)n4Rc, (CR6R7)n4ORc, (CR6R7)n4COORc, (CR6R7)n4NRc(C=O)Rd, (C=O)(CR6R7)n4ORc, (CR6R7)n4SO2Rc, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted -cycloalkyl-alkyl; each occurrence of R5 is independently H, alkyl, cycloalkyl, or oxo; or two R5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle; or two R5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons; each occurrence of R6 and R7 are independently H, alkyl, or cycloalkyl; each occurrence of Ra and Rb are independently H, alkyl, cycycloalkyl, saturated heterocycle, aryl, or heteroaryl; or alternatively Ra and Rb together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of Rc and Rd are independently H, alkyl, alkyl substituted by 1-4 substituents each of which is independently halogen, OR8 or N(R8)2, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl; or alternatively Rc and Rd together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; each occurrence of R8 is independently H, alkyl, or an optionally substituted heterocycle; or alternatively the two R8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; R9 is H, alkyl, halogen, or (CR6R7)n4ORb; the alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl in R1, R2, R3, R4, R5, R6, R7, R9, Ra, Rb, Rc, and Rd, where applicable, are optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, -(CH2)0-2OR8, N(R8)2, (C=O)C1-4alkyl, (C=O)N(R8)2, and oxo where valence permits; each occurrence of n1 is independently an integer from 0-3 where valence permits; each occurrence of n2 and n3 is independently an integer that is 1, 2 or 0; and each occurrence of n4 is independently an integer from 0-3.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein: (a) each occurrence of n2 and n3 is independently an integer from 0-1; or (b) the structural motif has the structure of or (c) the structural motif has the structure of 3. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the structural motif has the structure of 4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein at least one occurrence of R1 and R2 is (CR6R7)n4ORa, (CR6R7)n4NRaRb, (CR6R7)n4NRa(C=O)Rb, (CR6R7)n4NRaSO2Rb, or (CR6R7)n4CONRaRb.

5. The compound or pharmaceutically acceptable salt thereof of claim 4, wherein at least one occurrence of R1 and R2 is ORa or NRaRb.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein R1, R2, and the carbon atom they are connected to taken together form a 3-5 membered carbocycle.

7. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein R4 is (CR6R7)n4ORc, (CR6R7)n4CORc, (C=O)(CR6R7)n4Rc, (CR6R7)n4COORc, (CR6R7)n4NRc(C=O)Rd, (C=O)(CR6R7)n4ORc, or (CR6R7)n4SO2Rc.

8. The compound or pharmaceutically acceptable salt thereof of claim 7, wherein R4 is (CR6R7)2ORc, (C=O)Rc, (C=O)(CR6R7)1-2Rc, COORc, (CR6R7)1-2NRc(C=O)Rd, (C=O)(CR6R7)1-2ORc, or SO2Rc.

9. The compound or pharmaceutically acceptable salt thereof of claim 8, wherein R4 is (CH2)2OH, (CH2)2OMe, (C=O)H, (C=O)Me, (C=O)CH2OH, (C=O)CH2OMe, (C=O)Et, (C=O)Ph, (C=O)isopropyl, (C=O)CH2NH2, (C=O)CH2NHMe, (C=O)CH(OH)CH2OH, (C=O)CH(OMe)CH2OH, (C=O)CH(OH)CH2OMe, (C=O)OMe, SO2Me, SO2Et, SO2CH2OH, or SO2CH2OMe.

10. The compound or pharmaceutically acceptable salt thereof of claim 8, wherein R4 is (C=O)Rc, (C=O)(CR6R7)1-2Rc, (C=O)(CR6R7)1-2ORc, or SO2Rc; and wherein Rc is selected from the group consisting of H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR8 and N(R8)2, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, and optionally substituted - cycloalkyl-alkyl.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein R4 is (CR6R7)2ORc, (C=O)Rc, (C=O)(CR6R7)1-2Rc, COORc, (CR6R7)1-2NRc(C=O)Rd, (C=O)(CR6R7)1-2ORc, or SO2Rc, and: (a) Rc or Rd is H, Me, Et, or (b) Rc or Rd is a heterocycle selected from the group consisting of wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C1-4alkyl where valence permits; or (c) Rc is cycloalkyl, spiroalkyl, or bicycloalkyl each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, - (CH2)0-2OR8, N(R8)2, (C=O)N(R8)2, and oxo where valence permits; or (d) Rc is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH2)0-2OR8, N(R8)2, (C=O)N(R8)2, and oxo where valence permits.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein: (a) R4 is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted -cycloalkyl-alkyl; or (b) R4 is a heterocycle selected from the group consisting of wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C1-4alkyl where valence permits; or (c) R4 is cycloalkyl optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH2)0-2OR8, N(R8)2, (C=O)N(R8)2, and oxo where valence permits; or (d) R4 is each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, halogen, CN, -(CH2)0-2OR8, N(R8)2, (C=O)N(R8)2, and oxo where valence permits.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein R4 is or a tautomer thereof.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein: (a) at least one occurrence of R5 is H, alkyl or cycloalkyl; or (b) at least one occurrence of R5 is oxo; or (c) two R5 groups are connected to different carbon atoms on the ring and taken together form a bond or an alkyl chain containing 1-3 carbons; or (d) two R5 groups taken together with the carbon atom(s) that they are connected to form a 3-7 membered optionally substituted saturated carbocycle.

15. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein: (a) at least one of Ra and Rb is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or (b) Ra and Rb together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

16. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein: (a) each occurrence of R6 and R7 are independently H or alkyl; and / or (b) R9 is (i) H, alkyl, or halogen, or (ii) (CR6R7)n4ORb; or (iii) H, F, or OH.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein R3 is H or alkyl.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein R3 is halogen.

19. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein: (a) at least one occurrence of R8 is H, alkyl, or optionally substituted heterocycle, optionally wherein R8 is H, Me, Et, Pr, Bu, or a heterocycle selected from the group consisting wherein the heterocycle is optionally substituted by one or more cyano, cycloalkyl, fluorinated alkyl, fluorinated cycloalkyl, halogen, OH, NH2, oxo, or (C=O)C1-4alkyl where valence permits; or (b) the two R8 groups together with the nitrogen atom that they are connected to form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

20. The compound or pharmaceutically acceptable salt thereof of any one of claim 1-6, wherein: (a) at least one occurrence of Rc or Rd is independently H, alkyl, alkyl substituted by 1-4 substituents each independently selected from the group consisting of halogen, OR8 and N(R8)2, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -alkyl-aryl, optionally substituted -alkyl-heteroaryl, optionally substituted -alkyl-heterocycle, optionally substituted -alkyl-cycloalkyl, or optionally substituted -cycloalkyl-alkyl; or (b) at least one occurrence of Rc or Rd is independently H, Me, Et, or 21. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof 22. A pharmaceutical composition comprising at least one compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

23. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-21 for use as a medicament.

24. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-21 for use in a method of treating a condition in a mammalian species in need thereof, the method comprising 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 Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease; optionally wherein the condition is: (a) an immunological disorder that is transplant rejection or an autoimmune disease, wherein the autoimmune disease is optionally rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or Type I diabetes mellitus; or (b) a Central Nerve System (CNS) disorder that is Alzheimer's disease; (c) an inflammatory disorder that is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy; (d) an gastroenterological disorder that is an inflammatory bowel disease; or (e) a metabolic disorder that is obesity or Type II diabetes mellitus; or (f) a cardiovascular disorder that is an ischemic stroke; or (g) a kidney disease that is chronic kidney disease, nephritis, or chronic renal failure; or (h) selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Type I diabetes mellitus, Alzheimer's disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, Crohn's disease, ulcerative colitis, obesity, Type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof; and optionally wherein the mammalian species is human.