Aryl methylene aromatic compounds as Kv1.3 potassium shaker channel blockers

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof are described, wherein the substituents are as defined herein. Pharmaceutical compositions containing the compounds and methods of using them are also described. [Formula 1] TIFF2022552445000164.tif4140

Description

Technical Field

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 911,653, filed Oct. 7, 2019, the entire content of which is incorporated herein by reference.

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

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

[0004] Field of the Invention The present invention generally relates to the field of pharmacy. More specifically, the present invention relates to compounds and compositions useful as medicaments as potassium channel blockers.

Background Art

[0005] Background Voltage-gated Kv1.3 potassium (K +)The channel is expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and regulates a number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. The Kv1.3 channel regulates the membrane potential and can thereby indirectly affect calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions including multiple sclerosis, type I diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. When activated, effector memory T cells increase the expression of the Kv1.3 channel. Among human B cells, naive and early memory B cells express a small number of Kv1.3 channels when in a quiescent state. In contrast, class-switched memory B cells express a large number of Kv1.3 channels. Furthermore, the Kv1.3 channel promotes 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 the Kv1.3 channel in effector memory T cells suppresses activities such as calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.

[0006] Autoimmune diseases are a family of disorders resulting from tissue damage caused by attacks from the body's own immune system. Such diseases can affect a single organ, such as multiple sclerosis and type I diabetes, or can involve multiple organs, as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatments are generally palliative and use anti-inflammatory and immunosuppressive drugs, which can have severe side effects. The need for more effective treatments has led to the search for drugs that can selectively inhibit the function of effector memory T cells, which are known to be involved in the etiology of autoimmune diseases. These inhibitors are thought to be able to improve autoimmune disease symptoms without impairing the defensive immune response. Effector memory T cells (TEM) express a large number of Kv1.3 channels and depend on these channels for their function. In vivo, Kv1.3 channel blockers paralyze TEM at the site of inflammation and prevent their reactivation in inflamed tissue. Kv1.3 channel blockers do not affect the motility of naive and central memory T cells within lymph nodes. Inhibition of the function of these cells by selectively blocking the Kv1.3 channel offers the possibility of effective treatment of autoimmune diseases with minimal side effects.

[0007] Multiple sclerosis (MS) is caused by autoimmune damage to the central nervous system (CNS). Symptoms include muscle weakness and paralysis, which have a profound impact on the quality of life for patients. MS progresses rapidly and unexpectedly and ultimately leads to death. The Kv1.3 channel is also highly expressed in autoreactive effector memory T cells of 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.

[0008] Accordingly, compounds that are selective Kv1.3 channel blockers are potential therapeutic agents as immunosuppressive drugs or immune system modulators. The Kv1.3 channel is also considered a therapeutic target for treating obesity and enhancing peripheral insulin sensitivity in patients with type 2 diabetes. These compounds can also be used for preventing graft rejection and treating immunological (e.g., autoimmune) and inflammatory disorders.

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

[0010] The Kv1.3 channel also plays 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 compromise quality of life and lead to life-threatening complications. High levels of the Kv1.3 channel in CD4 and CD8 positive T cells in the inflamed mucosa of UC patients are associated with the production of pro-inflammatory compounds in active UC. The Kv1.3 channel is thought to serve as a marker of disease activity, and pharmacological blockade could constitute a novel immunosuppressive strategy in UC. Current treatment regimens for UC, including corticosteroids, salicylates, and anti-TNFα reagents, are inadequate for many patients (Hansen L.K., et al., 2014, J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the gastrointestinal tract. Crohn's disease is thought to result from intestinal inflammation by a T cell-driven process initiated by normally harmless bacteria. Thus, Kv1.3 channel inhibition can be utilized in the treatment of Crohn's disease.

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

[0012] The expression of the Kv1.3 channel is increased in microglia of the human Alzheimer's disease brain, suggesting that the 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. The Kv1.3 channel is required for AβO-induced pro-inflammatory activation and neurotoxicity of microglia. Kv1.3 channel expression / activity is upregulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brains. Pharmacological targeting of the microglial Kv1.3 channel can affect hippocampal synaptic plasticity and reduce amyloid deposition in APP / PS1 mice. Therefore, the Kv1.3 channel can be a therapeutic target for Alzheimer's disease.

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

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

[0015] Several peptide toxins with multiple disulfide bonds from spiders, scorpions, and sea anemones are known to block the Kv1.3 channel. A few selective and potent peptide inhibitors of the Kv1.3 channel have been developed. The synthetic derivative of stichodactyla toxin (shk) with a non-natural 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 the treatment of psoriasis. Shk can suppress the proliferation of TEM cells and bring about improvement in animal models of multiple sclerosis. Unfortunately, Shk also binds to closely related Kvi channel subtypes found in the CNS and heart. To avoid potential cardiotoxicity and neurotoxicity, Kv1.3 channel-selective inhibitors are needed. Furthermore, small peptides such as shk-186 are rapidly eliminated from the body after administration, resulting in a short circulation half-life and frequent dosing events. Therefore, the development of long-acting, selective Kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases is needed.

[0016] Therefore, the development of novel Kv1.3 channel blockers as pharmaceuticals is still needed. Summary of the Invention Means for Solving the Problems

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

[0018] [Chem.] (wherein the various substituents are as defined herein) Compounds useful as potassium channel blockers having are described. The compounds of Formula I described herein block the Kv1.3 potassium (K + +) channels and can be used for the treatment of various conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions described herein and methods of using these compositions are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and treatment methods have several clinical uses as pharmaceutical active agents and include methods for treating cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, metabolic disorders, cardiovascular disorders, kidney diseases, or combinations thereof.

[0019] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof

[0020] [Chem.] (wherein A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NR a SO2R9, (CR6R7) n3 NR a (C=O)(CR6R7) n3 OR b , (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, (CR6R7) n3 (C=O)NR a (C=O)R9, (CR6R7) n3 (C=O)NR aSO2R9,

[0021] [Chemical] or a heteroaryl containing N and optionally substituted by 1 to 5 R5; Z is OR a , NR a R b , or NR b (C=O)R a ; Each occurrence of X1, X2, and X3 is independently H, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, or halogenated cycloalkyl; or X2 and X3 and the carbon atom to which they are attached together form an optionally substituted 5- or 6-membered aryl; R1 and R2 are each independently H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, (CR6R7) n3 OR a , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 CONR a R b ; Each occurrence of R3 is independently H, halogen, or alkyl; Each occurrence of R4 is independently CN, (CR6R7) n3 OR a , (CR6R7) n3 COOR a , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 (C=O)NR a R b , (CR6R7) n3 NR a(C=O)NR a R b 、(CR6R7) n3 SO2NR a R b 、 or an optionally substituted heterocyclic ring containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; Each occurrence of R5 is independently H, halogen, alkyl, cycloalkyl, an optionally substituted saturated heterocyclic ring, an optionally substituted aryl, an optionally substituted heteroaryl, CN, CF3, OCF3, oxo, OR a 、(CR6R7) n3 OR a 、(C=O)R b 、(C=O)OR b 、SO2R a 、(C=O)(CR6R7) n3 OR b 、(C=O)(CR6R7) n3 NR a R b 、(CR6R7) n3 NR a R b 、(CR6R7) n3 NR a SO2R b 、(CR6R7) n3 NR a (C=O)R b 、(CR6R7) n3 NR a (C=O)NR a R b 、 or (CR6R7) n3 (C=O)NR a R b ; Alternatively, two R5 groups together with the carbon or nitrogen atom to which they are attached form a 3- to 7-membered optionally substituted saturated or aromatic carbocyclic or heterocyclic ring; Each occurrence of R6 and R7 is independently H, alkyl, cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R a and R bEach occurrence of is independently H, alkyl, alkenyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; When applicable, the alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl of R1, R2, R3, R4, R5, R6, R7, R9, R a , and R b are each independently optionally substituted by 1 to 4 substituents each selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0~2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, and oxo, when the valence permits; Each occurrence of R8 is independently H, alkyl, or an optionally substituted heterocycle; or two R8 groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; Each occurrence of R9 is independently H, alkyl, cycloalkyl, -(CH2) 1~2 OR8, or an optionally substituted heterocycle containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S, the heterocycle being optionally substituted by 1 to 3 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, OR8, -(CH2) 0~2 OR8, -(C=O)(CH2) 0~2 OR8, N(R8)2, (C=O)(CH2) 0~2 N(R8)2, and oxo, when the valence permits; n1 is an integer from 1 to 3 when the valence permits; n2 is an integer from 0 to 3 when the valence permits; each occurrence of n3 is independently an integer from 0 to 4) is described.

[0022] In any one of the embodiments described herein, A is

[0023]

Chemical formula

[0024] In any one of the embodiments described herein, A is a heteroaryl containing N and optionally substituted by 1 to 5 R5s.

[0025] In any one of the embodiments described herein, A is

[0026]

Chemical formula

[0027] In any one of the embodiments described herein, A is

[0028]

Chemical formula

[0029] In any one of the embodiments described herein, A is

[0030]

Chemical formula

[0031] In any one of the embodiments described herein, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NR a (C=O)(CR6R7) n3 OR b , (CR6R7) n3 NR a SO2R9, (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, (CR6R7) n3 (C=O)NR a (C=O)R9, or (CR6R7) n3 (C=O)NR a SO2R9.

[0032] In any one of the embodiments described herein, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NR a SO2R9, (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, (CR6R7) n3 (C=O)NR a (C=O)R9, or (CR6R7) n3 (C=O)NR a SO2R9.

[0033] In any one of the embodiments described herein, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NRa (C=O)R9, (CR6R7) n3 NR a SO2R9, (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, or (CR6R7) n3 (C=O)NR a (C=O)R9.

[0034] In any one of the embodiments described herein, A is -(CH2) 0~2 NR a C=O(CH2) 1~2 OR b , -(CH2) 0~2 NR a (C=O)R9, or -(CH2) 0~2 (C=O)NR a R9.

[0035] In any one of the embodiments described herein, R9 is -CH2OH, -CH2CH2OH,

[0036] [Chemical formula] .

[0037] In any one of the embodiments described herein, the compound has the structure of formula Ia

[0038] [Chemical formula] (wherein, each occurrence of R1 is independently H, NH2, OH, alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl; each occurrence of W is independently absent, CH2, C=O, or CH2C=O; R 10 and R 11 are each independently H, alkyl, -(CH2) 0~2OR8, (C=O)R9, SO2R9, aryl, heteroaryl, a heterocyclic ring; or R 10 and R 11 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S) has.

[0039] In any one of the embodiments described herein, R 10 and R 11 are each independently, -CH2OH, -CH2CH2OH,

[0040]

Chemical formula

[0041] In any one of the embodiments described herein, R1 and R2 are each independently H or alkyl.

[0042] In any one of the embodiments described herein, R1 and R2 are each independently H, alkyl, OR a , or NR a R b is.

[0043] In any one of the embodiments described herein, R1 and R2 are each independently H, (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 CONR a R b is.

[0044] In any one of the embodiments described herein, R1 and R2 are each independently H, Me, OH, CH2OH, NH2, CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, or NMe(CO)Me.

[0045] In any one of the embodiments described herein, R1 and R2 are each independently H, Me, OH,

[0046]

Chemical formula

[0047] In any one of the embodiments described herein, at least one occurrence of R4 is independently CN, (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 (C=O)NR a R b .

[0048] In any one of the embodiments described herein, at least one occurrence of R4 is CN, NH2, CH2NH2, CH2CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, NMe(CO)Me, CH2CONH2, CH2CONHMe2, CH2CONMe2, CH2NH(CO)Me, or CH2NMe(CO)Me.

[0049] In any one of the embodiments described herein, at least one occurrence of R4 is CH2NH2,

[0050]

Chemical formula

[0051] In any one of the embodiments described herein, at least one occurrence of R4 is an optionally substituted heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S.

[0052] In any one of the embodiments described herein, at least one occurrence of R4 is

[0053]

Chemical formula

[0054] In any one of the embodiments described herein, at least one occurrence of R5 is H, halogen, alkyl, cycloalkyl, an optionally substituted saturated heterocyclic ring, an optionally substituted aryl, an optionally substituted heteroaryl, CN, CF3, OCF3, OR a , (CR6R7) n3 OR a , (C=O)R b , (C=O)OR b , or SO2R a .

[0055] In any one of the embodiments described herein, at least one occurrence of R5 is (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3NR a (C=O)NR a R b 、 or (CR6R7) n3 (C=O)NR a R b is.

[0056] In any one of the embodiments described herein, at least one occurrence of R5 is H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2.

[0057] In any one of the embodiments described herein, at least one occurrence of R5 is an optionally substituted heterocyclic ring containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S.

[0058] In any one of the embodiments described herein, at least one occurrence of R5 is

[0059]

Chemical formula

[0060] In any one of the embodiments described herein, two R5 groups together with the carbon atom to which they are attached form a 3- to 7-membered optionally substituted carbocyclic or heterocyclic ring.

[0061] In any one of the embodiments described herein, each occurrence of R6 and R7 is independently H or alkyl.

[0062] In any one of the embodiments described herein, Z is OR a or NR a R b is.

[0063] In any one of the embodiments described in this specification, Z is OR a is.

[0064] In any one of the embodiments described in this specification, Z is OH, OMe, NH2, NHMe, or NMe2.

[0065] In any one of the embodiments described in this specification, Z is OH.

[0066] In any one of the embodiments described in this specification, X1 is H or halogen.

[0067] In any one of the embodiments described in this specification, X1 is alkyl fluoride, alkyl, or cycloalkyl.

[0068] In any one of the embodiments described in this specification, X1 is H, Cl, Br, Me, or CF3.

[0069] In any one of the embodiments described in this specification, X1 is H or Cl.

[0070] In any one of the embodiments described in this specification, X2 is H or halogen.

[0071] In any one of the embodiments described in this specification, X2 is alkyl fluoride, alkyl, or cycloalkyl.

[0072] In any one of the embodiments described in this specification, X2 is H, Cl, Br, Me, or CF3.

[0073] In any one of the embodiments described in this specification, X2 is H or Cl.

[0074] In any one of the embodiments described in this specification, X3 is H or halogen.

[0075] In any one of the embodiments described in this specification, X3 is an alkyl fluoride, alkyl, or cycloalkyl.

[0076] In any one of the embodiments described in this specification, X3 is H, Cl, Br, Me, or CF3.

[0077] In any one of the embodiments described in this specification, X3 is H or Cl.

[0078] In any one of the embodiments described in this specification, the structural moiety

[0079]

Chemical formula

[0080]

Chemical formula

[0081] In any one of the embodiments described in this specification, the structural moiety

[0082]

Chemical formula

[0083]

Chemical formula

[0084] In any one of the embodiments described in this specification, the compound has the structure of Formula II

[0085]

Chemical formula

[0086]

Chem.

[0087] In any one of the embodiments described herein, R3 is H or alkyl.

[0088] In any one of the embodiments described herein, R3 is halogen.

[0089] In any one of the embodiments described herein, n1 is 1, 2, or 3.

[0090] In any one of the embodiments described herein, n2 is 0, 1, 2, or 3.

[0091] In any one of the embodiments described herein, each occurrence of n3 is independently 0, 1, or 2.

[0092] In any one of the embodiments described herein, n5 is 0, 1, or 2.

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

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

[0095] [Chemical formula] (In the formula, the heterocyclic ring is alkyl, OH, oxo, or (C=O)C when the valence allows 1~4 optionally substituted by alkyl). It is a heterocyclic ring selected from the group consisting of.

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

[0097] In any one of the embodiments described herein, the compound is selected from the group consisting of Compounds 1 to 75 shown in Table 6.

[0098] In any one of the embodiments described herein, the compound is selected from the group consisting of Compounds 76 to 98 shown in Table 7.

[0099] In another aspect, a pharmaceutical composition is described that comprises a compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0100] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, the method comprising administering to the mammalian species a therapeutically effective amount of a compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0101] In any one of the embodiments described herein, the immunological disorder is graft rejection or an autoimmune disease.

[0102] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

[0103] In any one of the embodiments described herein, the central nervous system (CNS) disorder is Alzheimer's disease.

[0104] In any one of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy.

[0105] In any one of the embodiments described herein, the gastrointestinal disorder is inflammatory bowel disease.

[0106] In any one of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

[0107] In any one of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

[0108] In any one of the embodiments described herein, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0109] In any one of the embodiments described herein, the condition is selected from the group consisting of cancer, graft rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

[0110] In any one of the embodiments described herein, the mammalian species is human.

[0111] In yet another aspect, there is provided a method of blocking the Kv1.3 potassium channel in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of a compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof.

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

[0113] Any one of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein. Combinations of any one of the embodiments disclosed herein with any other embodiment disclosed herein are expressly contemplated. Specifically, the selection of one or more embodiments for a particular substituent can be appropriately combined with the selection of one or more specific embodiments for any other substituent. Such combinations can be made in any one or more embodiments of the applications described herein, or in any of the formulas described herein.

Best Mode for Carrying Out the Invention

[0114] Detailed Description of the Invention Definitions The following are definitions of terms used herein. Unless otherwise indicated, the first definition provided for a group or term herein applies to that group or term throughout this specification, individually or as part of another group. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0115] The terms "alkyl" and "alk" refer to straight-chain or branched-chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(C1-C4)alkyl" refers to straight-chain or branched-chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted at any available bond with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NRb C(=O)OR e 、NR d C(=O)NR b R c 、NR d S(=O)2NR b R c 、NR d P(=O)2NR b R c 、NR b C(=O)R a 、 or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In some embodiments, the groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl themselves may be optionally substituted.

[0116] The term "heteroalkyl" refers to a straight or branched chain alkyl group, preferably having 2 to 12 carbons, more preferably 2 to 10 carbons in the chain, one or more of which are replaced by heteroatoms selected from the group consisting of S, O, P and N. Exemplary heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, etc. This group may be a terminal group or a bridging group.

[0117] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term "C2-C6 alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-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 at any available bond with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group having a single halogen substituent or multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d, C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). The exemplary substituents themselves may be optionally substituted.

[0118] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, etc. "Substituted alkynyl" refers to an alkynyl group substituted at any available bond with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b , C(=O)OR e , NR d , C(=O)NRb R c 、 NR d S(=O)2NR b R c 、 NR d P(=O)2NR b R c 、 NR b C(=O)R a 、 or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of which is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted.

[0119] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted at any available attachment point with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2Re , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b , C(=O)OR e , NR d , C(=O)NR b R c , NR d , S(=O)2NR b R c , NR d , P(=O)2NR b R c , NR b , C(=O)R a , or NR b , P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; R eEach occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents include spiro or fused cyclic substituents, especially spiro cycloalkyl, spiro cycloalkenyl, spiro heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents themselves may be optionally substituted.

[0120] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted at any available attachment point with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a 、SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e 、NR b R c 、NR b S(=O)2R e 、NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d, C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents include spiro bonds or fused cyclic substituents, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycles (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycles, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves may be optionally substituted.

[0121] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, such as phenyl, biphenyl or naphthyl, particularly a monocyclic or bicyclic group. When containing two or more aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be linked at a single point (e.g., biphenyl) or can be fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings in which two adjacent aromatic rings have two common carbon atoms. "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available bonding point. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b , S(=O)2R e , NR b , P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b , C(=O)OR e , NR d , C(=O)NR b R c , NR dS(=O)2NR b R c 、NR d P(=O)2NR b R c 、NR b C(=O)R a 、 or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves may be optionally substituted.

[0122] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and / or aryl ring is used to specify the size of the aryl or heteroaryl ring of the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0123] The term "carbocycle" or "carbon cycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings such as phenyl, biphenyl or naphthyl, particularly a monocyclic or bicyclic group. The term "carbocycle" includes cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available bond with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl. Exemplary substituents also include a spiro bond or a fused cyclic substituent at any available bond, particularly spirocycloalkyl, spirocycloalkenyl, spiro heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, and the cycloalkyl, cycloalkenyl, heterocyclic and aryl substituents themselves may optionally be substituted.

[0124] The terms "heterocyclic ring" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) containing at least one heteroatom in at least one carbon atom-containing ring and including aromatic (i.e., "heteroaryl"). Each ring of a heterocyclic group can independently be saturated, or partially or fully unsaturated. Each ring of a heterocyclic group containing a heteroatom can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and the nitrogen and sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group having a quaternary nitrogen atom and thus a positive charge.) A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom 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-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, etc.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, dihydrobenz[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, etc.), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl, etc.), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidryl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0125] "Substituted heterocycle" and "substituted heterocyclic" (such as "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available bonding point. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or multiple halogen substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a 、SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e 、NR b R c 、NR b S(=O)2Re 、 NR b P(=O)2R e 、 S(=O)2NR b R c 、 P(=O)2NR b R c 、 C(=O)OR d 、 C(=O)R a 、 C(=O)NR b R c 、 OC(=O)R a 、 OC(=O)NR b R c 、 NR b C(=O)OR e 、 NR d C(=O)NR b R c 、 NR d S(=O)2NR b R c 、 NR d P(=O)2NR b R c 、 NR b C(=O)R a 、 or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b 、 R c and R d each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are attached optionally form a heterocycle; R eEach occurrence of independently is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl). Exemplary substituents may themselves be optionally substituted. Exemplary substituents include spiro bonds or fused cyclic substituents at any available bond point, especially spiro-bonded cycloalkyl, spiro-bonded cycloalkenyl, spiro-bonded heterocyclic (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic, or fused aryl, and the above cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents may themselves be optionally substituted.

[0126] The term "oxo" can be bonded to a carbocyclic atom on a carbocyclic or heterocyclic ring,

[0127]

Chem.

[0128]

Chem.

[0129]

Chem.

[0130] 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.

[0131] The term "dialkylamino" refers to a group having the structure -NRR' (wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined herein). R and R' may be the same or different even if the dialkylamino moiety is the same. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(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 structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0132] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0133] The term "substituted" refers to embodiments in which a molecule, molecular moiety or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aryl group or any other group disclosed herein) is substituted at any available bond point, where valency permits, with one or more substituents, preferably 1 to 6 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., in the latter case, a single halogen substituent or polyhalo substituents forming a group such as an alkyl group having CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, OR a 、SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e 、NR b R c 、NR b S(=O)2R e 、NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c 、NR b C(=O)OR e 、NR d C(=O)NR b R c 、NR d S(=O)2NR b R c 、NR d P(=O)2NR b R c 、NR bC(=O)R a 、 or NR b P(=O)2R e (wherein each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d each occurrence is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or alternatively said R b and R c together with the N to which they are attached optionally form a heterocycle; each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl). In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl themselves may optionally be substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with one or more of the above substituents.

[0134] Unless otherwise indicated, any heteroatom having an unsatisfied valence is considered to have sufficient hydrogen atoms to satisfy the valence.

[0135] The compounds of the present invention can likewise form salts that are within the scope of the present invention. References to the compounds of the present invention are understood to include references to their salts, unless otherwise indicated. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Further, when the compounds of the present invention contain both a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, zwitterions ("inner salts") can be formed and are included within the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, but other salts are also useful, for example, in isolation or purification steps that may be used during preparation. The salts of the compounds of the present invention can be formed, for example, by reacting the compounds described herein with an acid or base in an equivalent amount in a medium such as a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0136] However, the compounds of the present invention containing a basic moiety such as an amine or a pyridine or imidazole ring can form salts with various organic and inorganic acids. Exemplary acid addition salts include acetates (formed by acetic acid or trihaloacetic acids such as trifluoroacetic acid, etc.), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed by sulfuric acid, etc.), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, etc.

[0137] Not limited thereto, the compounds of the present invention containing acidic moieties such as phenol or carboxylic acid can form salts with various 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, organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed by N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, salts with t-butylamine, and salts with amino acids such as arginine and lysine. The basic nitrogen-containing group can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (e.g., benzyl and phenethyl bromide).

[0138] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, undergoes chemical conversion by a metabolic or chemical process to yield a compound of the present invention, or a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0139] The compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes its tautomeric forms.

[0140] All stereoisomers of the compounds of the present invention, including enantiomeric and diastereomeric forms (e.g., those that may exist due to chiral carbons on various substituents), are contemplated within the scope of the present invention. The individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specific activity), for example, as a racemate, or admixed with all other or other selected stereoisomers. The chiral centers of the present invention may have the S configuration or the R configuration as defined by the 1974 Recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

[0141] After preparation, the compounds of the present invention are isolated and purified to obtain a composition containing, preferably, 90% by weight or more, for example, 95% by weight or more, 99% by weight or more of the compound (a "substantially pure" compound), and 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.

[0142] All conformational isomers of the compounds of the present invention in admixture or in pure or substantially pure form are contemplated. The definition of the compounds of the present invention includes both cis (Z) alkene isomers and trans (E) alkene isomers, as well as both cis and trans isomers of cyclic hydrocarbons or heterocyclic rings.

[0143] Throughout this specification, the groups and their substituents may be selected to provide stable moieties and compounds.

[0144] The definitions of specific functional groups and chemical terms are described in more detail herein. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0145] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. It is intended that all such isomers and mixtures thereof be included in the present invention.

[0146] Isomer mixtures containing any of various isomer ratios can be utilized according to the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. One of ordinary skill in the art will readily understand that similar ratios are contemplated for more complex isomer mixtures.

[0147] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein, but differ in that one or more atoms are replaced by atoms 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 the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, containing the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, 3 H and 14 C, etc., incorporating radioactive isotopes 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 due to ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium, i.e., 2 H, etc., can result in certain therapeutic advantages due to greater metabolic stability, such as an increase in in vivo half-life or a decrease in dosage requirements, and can therefore be preferred in some situations. Isotopically labeled compounds can generally be prepared by substituting readily available non-isotopically labeled reagents with isotopically labeled reagents and performing the procedures disclosed in the following schemes and / or examples.

[0148] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivation with an asymmetric auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with a suitable optically active acid or base, and subsequently the diastereomers thus formed are resolved by fractional crystallization or chromatographic means well known in the art, and then the pure enantiomer is recovered.

[0149] It will be understood that the compounds 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 whether the substituent is included in the formula of the present invention or not, refers to the replacement of a hydrogen group in a given structure by a group of the designated substituent. If two or more positions in any given structure may be substituted with two or more substituents selected from the designated groups, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Further, the present invention is not intended to be limited in any way by the acceptable substituents of organic compounds. Combinations of substituents and variable elements contemplated by the present invention preferably result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. The term "stable" as used herein preferably refers to a compound having sufficient stability to allow for manufacture and maintaining the integrity of the compound for a period sufficient for detection, preferably for a period useful for the purposes detailed herein.

[0150] As used herein, the terms "cancer" and, equivalently, "tumor" refer to a state in which cells that are abnormally replicating of host origin are present in a detectable amount in a subject. The cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. The cancer can be primary or metastatic. Diseases other than cancer can be associated with mutational changes in components of the Ras signaling pathway, and thus the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancer diseases can include neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardio-facial-skin syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0151] As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or facilitate a desired outcome. In some examples, the effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular use can vary depending on factors such 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 undue experimentation.

[0152] As used herein, the term "subject" refers to a vertebrate. 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 including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, pets, and non-domesticated animals.

[0153] Compound Novel compounds as Kv1.3 potassium channel blockers are described. The applicants have surprisingly discovered that the compounds disclosed herein exhibit potent Kv1.3 potassium channel inhibitory properties. Furthermore, the 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 a desirable cardiovascular safety profile.

[0154] In one aspect, a compound of formula I or a pharmaceutically acceptable salt thereof

[0155]

Chemical formula

[0156]

Chem.

[0157] In some embodiments, where applicable, R1, R2, R3, R4, R5, R6, R7, R9, R a , and R b alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl of are, when the valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR8, -(CH2) 0~2 OR8, N(R8)2, (C=O)R8, (C=O)N(R8)2, and oxo are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of. In some embodiments, at least one of the substituents is alkyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl. In some embodiments, at least one of the substituents is halogen, CN, OR8, or -(CH2) 0~2 OR8. In some embodiments, at least one of the substituents is N(R8)2, (C=O)R8, (C=O)N(R8)2, or oxo.

[0158] In some embodiments, n1 is an integer from 1 to 3. In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 1.

[0159] In some embodiments, n2 is an integer from 0 to 3. In some embodiments, n2 is an integer from 1 to 3. In some embodiments, n2 is 0. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 1.

[0160] In some embodiments, n3 is an integer from 0 to 4. In some embodiments, n3 is an integer from 1 to 3. In some embodiments, n3 is 0. In some embodiments, n3 is 1 or 2. In some embodiments, n3 is 1.

[0161] In some embodiments, A is

[0162]

Chemical formula

[0163]

Chemical formula

[0164] In some embodiments, A is

[0165]

Chemical formula

[0166]

Chemical formula

[0167] In any one of the embodiments described in this specification, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NR a (C=O)(CR6R7) n3 OR b , (CR6R7) n3 NR a SO2R9, (CR6R7) n3 SO2NR a R9, (CR6R7) n3 CONR a R b , (CR6R7) n3 (C=O)NR a (C=O)R9, or (CR6R7) n3 (C=O)NR a SO2R9.

[0168] In any one of the embodiments described in this specification, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NR a SO2R9, (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, (CR6R7) n3 (C=O)NR a (C=O)R9, or (CR6R7) n3 (C=O)NR a SO2R9.

[0169] In any one of the embodiments described in this specification, A is (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R9, (CR6R7) n3 NRa SO2R9, (CR6R7) n3 CONR a R9, (CR6R7) n3 SO2NR a R9, or (CR6R7) n3 (C=O)NR a (C=O)R9. In any one of the embodiments described herein, A is -(CH2) 0~2 NR a C=O(CH2) 1~2 OR b , -(CH2) 0~2 NR a C=OR9, or -(CH2) 0~2 (C=O)NR a R9.

[0170] In any one of the embodiments described herein, R9 is -CH2OH, -CH2CH2OH,

[0171]

Chemical formula

[0172] In any one of the embodiments described herein, the compound has the structure of formula Ia

[0173]

Chemical formula

[0174] In any one of the embodiments described herein, R 10 and R 11 are each independently, -CH2OH, -CH2CH2OH,

[0175]

Chemical formula

[0176] In some embodiments, n5 is an integer from 0 to 3. In some embodiments, n5 is an integer from 1 to 3. In some embodiments, n5 is 0. In some embodiments, n5 is 1 or 2. In some embodiments, n5 is 1.

[0177] In some embodiments, R1 and R2 are each H or alkyl. In some embodiments, R1 and R2 are both H. In some embodiments, R1 and R2 are alkyl such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In some embodiments, R1 and R2 are each H and alkyl.

[0178] In some embodiments, at least one occurrence of R1 and R2 is (CR6R7) n3 OR a or (CR6R7) n3 NR a R b is. In some embodiments, R1 and R2 are OR a , or NR a R b is. In some embodiments, at least one occurrence of R1 and R2 is NR a R b, for example, NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, NHPr, NMePr, NEtPr, NH(i-Pr), N(i-Pr)2, NHBu, or N(Bu)2. In some embodiments, at least one occurrence of R1 and R2 is OR b , for example, OH, OMe, OEt, OPr, O-i-Pr, OBu, O-tert-Bu, or O-sec-Bu.

[0179] In some embodiments, R1 and R2 are each independently H, (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 CONR a R b . In some specific embodiments, R1 and R2 are each independently H, Me, OH, CH2OH, NH2, CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, or NMe(CO)Me. In other embodiments, R1 and R2 are each independently H, Me, OH,

[0180]

Chemical formula

[0181] In some embodiments, at least one occurrence of R4 is independently CN, (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , or (CR6R7) n3 (C=O)NR a R bis. In some specific embodiments, R4 is CN, NH2, CH2NH2, CH2CH2NH2, CONH2, CONHMe2, CONMe2, NH(CO)Me, NMe(CO)Me, CH2CONH2, CH2CONHMe2, CH2CONMe2, CH2NH(CO)Me, or CH2NMe(CO)Me. In other specific embodiments, at least one occurrence of R4 is CH2NH2,

[0182]

Chemical formula

[0183]

Chemical formula

[0184] In some embodiments, at least one occurrence of R5 is H, halogen, alkyl, cycloalkyl, an optionally substituted saturated heterocyclic ring, an optionally substituted aryl, an optionally substituted heteroaryl, CN, CF3, OCF3, OR a , (CR6R7) n3 OR a , (C=O)R b , (C=O)OR b , or SO2R a . In other embodiments, at least one occurrence of R5 is (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a Rb , (CR6R7) n3 NR a SO2R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 NR a (C=O)NR a R b 、 or (CR6R7) n3 (C=O)NR a R b is.

[0185] In some specific embodiments, at least one occurrence of R5 is H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2. In some specific embodiments, R5 is H, halogen, alkyl, cycloalkyl, CN, CF3, OR a , (CR6R7) n3 OR a , (C=O)OR b , (C=O)(CR6R7) n3 OR b , (C=O)(CR6R7) n3 NR a R b , (CR6R7) n3 NR a R b , (CR6R7) n3 NR a (C=O)R b , (CR6R7) n3 SO2NR a R b , (CR6R7) n3 SO2R a , oxo, or (CR6R7) n3 (C=O)NR a R b is. In some specific embodiments, R5 is H, halogen, alkyl, OR a , NR a R bor oxo. In other specific embodiments, R5 is H, F, Cl, Br, Me, Et, Pr, iso-Pr, Bu, iso-Bu, sec-Bu, or tert-Bu. In other specific embodiments, R5 is OH, NH2, NHMe, NMe2, NHEt, NMeEt, NEt2, or oxo. In still other specific embodiments, at least one occurrence of R5 is H, halogen, alkyl, OH, NH2, CN, CF3, OCF3, CONH2, CONHMe2, or CONMe2.

[0186] In other embodiments, at least one occurrence of R5 is an optionally substituted heterocyclic ring containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, at least one occurrence of R5 is

[0187]

Chemical formula

[0188] In other embodiments, two R5 groups together with the carbon atom to which they are attached form a 3- to 7-membered optionally substituted saturated or aromatic carbocyclic or heterocyclic ring.

[0189] In some embodiments, each occurrence of R6 and R7 is independently H or alkyl. In some specific embodiments, CR6R7 is CH2, CHMe, CMe2, CHEt, or CEt2. In some specific embodiments, CR6R7 is CH2. In some embodiments, at least one of R6 and R7 is a substituted aryl or an optionally substituted heteroaryl.

[0190] In some embodiments, R8 is H or alkyl. In other embodiments, R8 is an optionally substituted heterocyclic ring. In still other embodiments, two R8 groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0191] In any one of the embodiments described herein, Z is OR a , NR a R b , or NR b (C=O)R a may be. In some embodiments, Z is OR a . In some embodiments, Z is OH, OMe, NH2, NHMe, or NMe2. In some embodiments, Z is OH.

[0192] In any one of the embodiments described herein, X1 may be H, halogen, alkyl fluoride, or alkyl. In some embodiments, X1 is H or halogen. In other embodiments, X1 is alkyl fluoride or alkyl. In other embodiments, X1 is cycloalkyl. In some embodiments, X1 is H, F, Cl, Br, Me, CF3, or CF2Cl. In some embodiments, X1 is H, F, or Cl. In some embodiments, X1 is F or Cl. In some embodiments, X1 is H or Cl. In some embodiments, X1 is F.

[0193] In any one of the embodiments described herein, X2 may be H, halogen, alkyl fluoride, or alkyl. In some embodiments, X2 is H or halogen. In other embodiments, X2 is alkyl fluoride or alkyl. In other embodiments, X2 is cycloalkyl. In some embodiments, X2 is H, F, Cl, Br, Me, CF3, or CF2Cl. In some embodiments, X2 is H, F, or Cl. In some embodiments, X2 is F or Cl. In some embodiments, X2 is H or Cl. In some embodiments, X2 is F.

[0194] In any one of the embodiments described herein, X3 is H, F, Cl, Br, alkyl fluoride, or alkyl. In some embodiments, X3 is H or halogen. In other embodiments, X3 is alkyl fluoride or alkyl. In other embodiments, X3 is cycloalkyl. In some embodiments, X3 is H, F, Cl, or CF3. In some embodiments, X3 is H or Cl. In some embodiments, X3 is F or Cl.

[0195] In some embodiments, the structural moiety

[0196]

Chemical formula

[0197]

Chemical formula

[0198] In any one of the embodiments described herein, the structural moiety

[0199]

Chemical formula

[0200] [Chemistry] has the structure of.

[0201] In some embodiments, X2 and X3 and the carbon atoms to which they are attached together form an optionally substituted 5- or 6-membered aryl.

[0202] In some embodiments, the compound of formula I has the structure of formula II

[0203] [Chemistry] (wherein, each occurrence of A is independently

[0204] [Chemistry] or contains N and is a heteroaryl optionally substituted by 1-5 R5s; R 3’ each occurrence of which is independently H, halogen, or alkyl; and n6 is independently an integer from 0 to 6) has.

[0205] In some embodiments, at least one occurrence of R 3’ is H or alkyl. Non-limiting examples of alkyl include Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In other embodiments, at least one occurrence of R 3’ is halogen.

[0206] In some embodiments, n6 is 0. In some embodiments, n6 is 1. In some embodiments, n6 is 2. In some embodiments, n6 is 3. In some embodiments, n6 is 4.

[0207] In any one of the embodiments described herein, R3 is H, halogen, or alkyl. In some embodiments, R3 is H. In other embodiments, R3 is alkyl such as Me, Et, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl. In still other embodiments, R3 is F, Cl, or Br.

[0208] In any one of the embodiments described herein, R a or R b each occurrence of which is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0209] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each independently selected from the group consisting of N, O, and S.

[0210] In some specific embodiments, at least one occurrence of R a or R b is independently H, Me, Et, Pr, or

[0211]

Chemical Formula

[0212] In some embodiments, the compound of Formula I is selected from the group consisting of Compounds 1 to 75 shown in Table 6 below.

[0213] In any one of the embodiments described herein, the compound is selected from the group consisting of Compounds 76 to 98 shown in Table 7 below.

[0214]

Table 1

[0215] Preparation method The following are general synthetic schemes for producing the compounds of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that those skilled in the art may use to produce the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Further, the various steps of the synthesis can be carried out in alternative sequences or orders to obtain the desired compounds. All documents cited herein are hereby incorporated by reference in their entirety. For example, the following reactions are illustrative, but not limiting, of the preparation of some of the starting materials and compounds disclosed herein.

[0216] The following Schemes 1-5 describe synthetic routes that can be used to synthesize the compounds of the present invention, such as compounds having the structure of Formula I or their precursors. Various modifications to these methods to achieve results similar to those of the present invention given below can be envisioned by those skilled in the art. In the following embodiments, the synthetic route is described using, by way of example, a compound having the structure of Formula I or its precursor. The general synthetic routes described in Schemes 1-5 and the examples described in the Examples section below illustrate the methods used for the preparation of the compounds described herein.

[0217] The compounds I-1 and I-2 shown in Scheme 1 can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 1, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or another protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. As shown in Scheme 1, the compounds disclosed herein in which Z contains oxygen and R1 and R2 are both H can be prepared by the Suzuki reaction of benzyl bromide I-1 with an aryl or heteroaryl boronic acid I-2. This reaction may be catalyzed by a catalyst, such as 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium, in the presence of a base, such as sodium carbonate. Suitable solvents such as water and dioxane can be used. Alternatively, instead of boronic acid I-2, the corresponding pinacol boronic acid ester of I-2 may be used. The Suzuki reaction yields compound I-3a. The protecting group of compound I-3a can then be removed, and the resulting compound having a free phenolic OH group can be optionally converted to a compound of formula I using methods known in the art.

[0218] [Chemical formula]

[0219] The compounds I-4, I-5, I-7 and I-11 shown in Scheme 2 can be prepared by any method known in the art and / or are commercially available. As shown in Scheme 2, PG refers to a protecting group. Non-limiting examples of protecting groups include Me, allyl, Ac, Boc, other alkoxycarbonyl groups, dialkylaminocarbonyl, or any other protecting group known in the art suitable for use as a protecting group for OH. Other substituents are defined herein. As shown in Scheme 2, the compounds disclosed herein in which Z contains oxygen and R1 contains O or N can be prepared by the methods described herein. Bromobenzene I-4 is treated with either n-butyllithium to form the corresponding organolithium reagent or a Grignard reagent such as isopropylmagnesium bromide to form an aryl Grignard reagent. The resulting organometallic reagent can react with an aryl or heteroaryl aldehyde I-5 to form an alcohol I-6a or with Weinreb amide I-7 to form a ketone I-8a. I-8a can also be obtained from I-6a by oxidation with an oxidizing agent such as Dess-Martin reagent. Compounds in which R1 contains nitrogen can be obtained by reacting ketone I-8a with a Lewis acid such as t-butylsulfinyl imide and titanium tetraethoxide to form a sulfinyl imide I-9, which can then be reduced to sulfinyl imide I-10a with a reducing agent such as sodium borohydride or DIBAL. Alternatively, the organometallic reagent formed from I-4 as described above can react with sulfinyl imide I-11 obtained from aldehyde I-5 using methods known in the art to directly obtain I-10a. Removal of the sulfinyl group with HCl in a solvent such as dioxane provides the corresponding primary amine, which can be further modified by methods known in the art. The protecting groups in compounds I-6a and I-10a can then be removed, and the resulting compounds having a free phenolic OH group can be optionally converted to compounds of formula I using methods known in the art.

[0220] [Chemistry]

[0221] The compounds I-5 and I-12 shown in Scheme 3 can be prepared by any method known in the art and / or are commercially available. The substituents in Scheme 3 are defined herein. Scheme 3 shows a direct route for synthesizing the compounds disclosed herein where R1 contains N. The three-component reaction of phenol I-12, aromatic aldehyde I-14 and acetamide is carried out by heating all three components with aluminum trichloride without using a solvent to obtain acetamide I-10b. In the case of the compounds disclosed herein where R3 is H, a mixture of positional isomers may be obtained, which can be separated by chromatography or other methods known in the art. Hydrolysis of the acetamide with hydrochloric acid provides amine I-10c.

[0222] [Chemistry]

[0223] The compounds I-5 and I-13 shown in Scheme 4 can be prepared by any method known in the art and / or are commercially available. The substituents in Scheme 4 are defined herein. An alternative method for activating the benzene ring starts from diethylcarbamate I-13 (Scheme 4). Ortholithiation of I-13 with a base such as LDA in a solvent such as THF, followed by reaction with an aryl or heteroaryl aldehyde I-5, affords the alcohol I-6b. The alcohol I-6b can be converted to I-3b by reduction with a Lewis acid such as triethylsilane and BF3 etherate. Oxidation of I-6b to the ketone I-8b using an oxidizing agent such as Dess-Martin reagent or MnO2 provides a route to compounds where R1 is alkyl, aryl or heteroaryl. Reaction of I-8b with a lithium reagent or Grignard affords the alcohol I-14, which can then be reduced to I-16 using triethylsilane and BF3-Et2O. The alkyl group at R1 can also be introduced by a Wittig reaction of I-8b using a phospholane (e.g., R1PPh3) or a phosphonium salt and a base such as potassium t-butoxide. Hydrogenation of the resulting alkene I-15 over platinum oxide in a solvent such as methanol affords I-16.

[0224] [Chemical formula]

[0225] The substituents in Scheme 5 are defined herein. Compounds in which Z contains nitrogen can be prepared from the corresponding phenols as shown in Scheme 5. Phenol ketone I-8c can be obtained by deprotection of either I-8a or I-8b, which is converted to trifluoromethanesulfonate I-17 using triflic anhydride and pyridazine in a solvent such as DCM. Heating I-17 with an amine such as 4-methoxybenzylamine in dioxane gives the PMB-protected amine I-18. Removal of the PMB group using TFA gives amine I-19. The ketone group in I-19 can be reduced to a hydroxyl group using methods known in the art to obtain the compound of formula I.

[0226] [Chemical formula]

[0227] The reactions described in Schemes 1-5 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 1-5 can be carried out under an inert atmosphere, for example under nitrogen or argon, or the reaction can be carried out in a sealed tube. The reaction mixture can be heated with microwaves or to a high temperature. Suitable high temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 °C or higher or the reflux / boiling temperature of the solvent used. Alternatively, the reaction mixture can be cooled in a cooling bath at a temperature below room temperature, for example 0, -10, -20, -30, -40, -50, -78 or -90 °C. The reaction product can be worked up by removing the solvent or by partitioning the organic solvent phase with one or more aqueous phases optionally containing NaCl, NaHCO3 or NH4Cl respectively. The solvent in the organic phase can be removed by evaporation under reduced pressure and the residue obtained can be purified using silica gel column or HPLC.

[0228] Pharmaceutical composition The present invention also provides a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0229] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of at least one compound of formula I described herein and a pharmaceutically acceptable carrier or diluent.

[0230] In certain embodiments, the composition is in the form of a hydrate, solvate or pharmaceutically acceptable salt. The composition can be administered to a subject by any suitable route of administration including, but not limited to, oral and parenteral.

[0231] As used herein, the term "pharmaceutically acceptable carrier" 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 pharmaceutical from one organ or part of the body to another organ or part 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 that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed 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 used in pharmaceutical formulations. The term "carrier" denotes a natural or synthetic, organic or inorganic component that facilitates administration when combined with the active ingredient. The components of the pharmaceutical composition can also be mixed with the compounds of the present invention and with each other in such a way that there is no interaction that substantially impairs the desired pharmaceutical effectiveness.

[0232] As shown above, certain embodiments of the present pharmaceutical may be provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" in this context refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in their free base form with appropriate organic or inorganic acids and isolating the salts thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate, etc. (See, for example, Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0233] Pharmaceutically acceptable salts of the present compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, etc.; and salts prepared from organic acids such as acetate, butyonic salt, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, isothionic salt, etc.

[0234] In other cases, the compounds of the invention can contain one or more acidic functional groups and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the 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, ammonia, or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, among others. Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example, Berge et al., supra).

[0235] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants can also be present in the composition.

[0236] The formulations of the invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, intravaginal and / or parenteral administration. The formulations can conveniently be provided in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of the total composition.

[0237] The methods for preparing these formulations or compositions involve the step of associating the compounds of the present invention with a carrier and optionally one or more accessory components. Generally, the formulations are prepared by uniformly and intimately associating the compounds of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0238] Formulations of the present invention suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (flavor-based, usually using sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or water-in-oil or oil-in-water liquid emulsions, or elixirs or syrups, or troches (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention can also be administered as boluses, pastilles or pastes.

[0239] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; dissolution retardants such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as, for example, cetyl alcohol, glyceryl monostearate and polyethylene oxide - polybutylene oxide copolymers; absorbents such as kaolin and bentonite clays; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of the same kind can also be used as fillers in soft and hard - filled gelatin capsules using excipients such as lactose or milk sugar, and high - molecular - weight polyethylene glycols, etc.

[0240] Tablets can be prepared by compression or molding, optionally using one or more accessory ingredients. Compressed tablets can be prepared using binders (such as gelatin or hydroxybutyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or cross - linked sodium carboxymethyl cellulose), surface - active or dispersing agents. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0241] Tablets of the pharmaceutical composition of the present invention, as well as other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or may be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide delayed or controlled release of the active ingredient therein using various proportions of hydroxybutylmethylcellulose, other polymer matrices, liposomes and / or microspheres, for example, to provide a desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in certain parts of the digestive tract, optionally in a delayed manner. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, including one or more of the above excipients.

[0242] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain solubilizing and emulsifying agents commonly used in the art, such as, for example, water or other solvents as inert diluents, ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. Furthermore, cyclodextrins, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compound.

[0243] In addition to the inert diluent, the oral composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, fragrances and preservatives.

[0244] The suspension can contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0245] Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compounds can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

[0246] Ointments, pastes, creams and gels can contain, in addition to the active compound of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0247] Powders and sprays can contain, in addition to the compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0248] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the pharmaceutical in a suitable medium. Absorption enhancers can also be used to increase the flow of the pharmaceutical of the present invention across the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0249] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of the present invention.

[0250] The pharmaceutical compositions of the present invention suitable for parenteral administration may comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0251] In some cases, it is desirable to delay the absorption of a drug from a subcutaneous or intramuscular injection in order to prolong its effect. This can be achieved by the use of a liquid suspension of a poorly water-soluble crystalline or amorphous material. In that case, the absorption rate of the drug depends on its dissolution rate, which can depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms is achieved by dissolving or suspending the drug in an oily vehicle. One strategy for depot injections involves the use of polyethylene oxide - polypropylene oxide copolymers where the vehicle is fluid at room temperature but solidifies at body temperature.

[0252] The depot form for injection is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of drug to polymer and the nature of the specific polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0253] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be given alone or in combination with a pharmaceutically acceptable carrier containing, for example, from 0.1% to 99.5% (more preferably from 0.5% to 90%) of the active ingredient as a pharmaceutical composition.

[0254] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutic agents or procedures) for use in a combination regimen takes into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (e.g., the compounds of the present invention can be administered simultaneously with another anti - cancer agent).

[0255] The compounds of the present invention can be administered by intravenous, intramuscular, intraperitoneal, subcutaneous, topical, oral, or other acceptable means. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, domestic and farm animals), racehorses, birds, lizards, and any other organism that can tolerate the compounds.

[0256] The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the pharmaceutical composition of the present invention. Optionally associated with such containers may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, which notice reflects approval by the agency for manufacture, use or sale for human administration.

[0257] Administration to a subject In yet another aspect, the present invention is a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a compound selected from the group consisting of a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases.

[0258] In some embodiments, the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

[0259] In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy. In some embodiments, the gastrointestinal disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis.

[0260] In some embodiments, the immunological disorder is graft rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In some embodiments, the central nervous system (CNS) disorder is Alzheimer's disease.

[0261] In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal insufficiency.

[0262] In some embodiments, the mammalian species is human.

[0263] In some embodiments, the condition is selected from the group consisting of cancer, graft rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathies, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal insufficiency, and combinations thereof.

[0264] In yet another aspect, there is described a method of blocking the Kv1.3 potassium channel in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the compounds described herein are selective in blocking the Kv1.3 potassium channel with minimal or no off-target inhibitory activity against other potassium channels or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel and thus have a desirable cardiovascular safety profile.

[0266] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a particular outcome. Accordingly, the small molecule compositions useful by the methods of the invention can be formulated by any method suitable for pharmaceutical use.

[0267] The formulations of the invention are administered in a pharmaceutically acceptable solution that may routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0268] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that enables the compound to be taken up by the appropriate target cells. "Administration" of the pharmaceutical compositions of the present invention can be achieved by any means known to those skilled in the art. 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, rectal, vaginal, etc.). The injection can be a bolus or a continuous infusion.

[0269] For example, pharmaceutical compositions according to the present invention are often administered by intravenous, intramuscular, or other parenteral means. They can also be administered by intranasal application, by inhalation, topically, orally, or as an implant, and even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline aqueous solutions for injection or inhalation, microencapsulated, encochleated, coated on fine gold particles, contained in liposomes, atomized, an aerosol, pellets for implantation into the skin, or dried on sharp objects for scratching the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with long-term release of the active compound, in the preparation of which excipients and additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents or solubilizing agents are conventionally used as described above. The pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief overview of the method for drug delivery, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

[0270] The concentration of the compound contained in the composition used in the method of the present invention can be in the range of about 1 nM to about 100 μM. The effective dose is considered to be in the range of about 100 picomoles / kg to about 100 micromoles / kg.

[0271] The pharmaceutical composition is preferably prepared and administered in dosage units. The liquid dosage unit is a vial or an ampoule for injection or other parenteral administration. The solid dosage units are tablets, capsules, powders and suppositories. Different doses may be required depending on the activity of the compound, the method of administration, the purpose of administration (i.e., prophylactic or therapeutic), the nature and severity of the disorder, the age and weight of the patient. Administration of a given dose can be effected both by a single administration in the form of an individual dosage unit or as several smaller dosage units. Repeated and multiple administrations at specific daily, weekly or monthly intervals are also contemplated by the present invention.

[0272] The composition can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, but pharmaceutically unacceptable salts can conveniently be used to prepare their pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts can also be prepared as alkali metal or alkaline earth salts such as sodium, potassium or calcium salts of carboxylic acid groups.

[0273] Suitable buffers include acetic acid and salts (1 - 2% w / v); citric acid and salts (1 - 3% w / v); boric acid and salts (0.5 - 2.5% w / v); and phosphoric acid and salts (0.8 - 2% w / v). Suitable preservatives include benzalkonium chloride (0.003 - 0.03% w / v); chlorobutanol (0.3 - 0.9% w / v); parabens (0.01 - 0.25% w / v) and thimerosal (0.004 - 0.02% w / v).

[0274] Compositions suitable for parenteral administration advantageously include sterile aqueous preparations that can be isotonic with the recipient's blood. Among the acceptable vehicles and solvents are water, Ringer's solution, phosphate buffered saline and isotonic sodium chloride solution. In addition, sterile, non - volatile oils have conventionally been used as solvents or suspending media. For this purpose, any bland, non - volatile mineral or non - mineral oil containing synthetic mono - or diglycerides can be used. Further, fatty acids such as oleic acid have found use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous administration, etc. can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0275] The compounds useful in the present invention can be delivered as mixtures of three or more such compounds. The mixtures can further include one or more adjuvants in addition to the combination of compounds.

[0276] A variety of administration routes are available. The particular mode selected will, of course, depend on the particular compound selected, the age and general health of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy. The methods of the present invention can generally be carried out using any medically acceptable mode of administration, meaning any mode that produces a therapeutically effective level of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above.

[0277] The composition can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of associating the compound with a carrier that constitutes one or more accessory ingredients. Generally, the composition is prepared by uniformly and intimately associating the compound with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0278] Other delivery systems may include time-release, delayed-release or sustained-release delivery systems. Such systems can avoid repeated administration of the compound and increase convenience for the subject and the physician. Many types of release delivery systems are available and are known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactone, polyesteramides, polyorthoesters, polyhydroxybutyrate, and polyanhydrides. Microcapsules of the polymers containing the drug are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include non-polymeric systems such as lipids containing sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di- and tri-glycerides; hydrogel release systems; elastomeric 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) erosion systems in which the agent of the present invention is contained in matrix form, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189 and 5,736,152, and (b) diffusion systems in which the active ingredient penetrates at a controlled rate from the polymer, such as those described in U.S. Patent Nos. 3,854,480, 5,133,974 and 5,407,686. Further, a pump-based hardware delivery system, some of which is adapted for implantation, can be used.

[0279] Assay for the effectiveness of Kv1.3 potassium channel blockers In some embodiments, the compounds described herein are tested for their activity against the Kv1.3 potassium channel. In some embodiments, the compounds described herein are tested for their Kv1.3 potassium channel electrophysiology. In some embodiments, the compounds described herein are tested for their hERG electrophysiology.

[0280] Equivalents The following representative examples are intended to assist in illustrating the invention and are not intended to limit, nor should they be construed as limiting, the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof will become apparent to those skilled in the art from the complete contents of this document, including the following examples, in addition to those shown and described herein, and from the scientific and patent literature cited herein. It should be further understood that the contents of these cited references are incorporated herein by reference to assist in exemplifying the prior art. The following examples contain important additional information, illustrations, and guidance that may be adapted to the practice of the invention in its various embodiments and their equivalents.

Examples

[0281] Examples 1-5 describe various intermediates used in the synthesis of representative compounds of Formula I disclosed herein.

[0282] [Example 1] Intermediate 1 (1-(Bromomethyl)-4,5-dichloro-2-methoxybenzene)

[0283]

Chemical formula

[0284] Step a: To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol) in methanesulfonic acid (35 mL) was added hexamethylenetetramine (47.50 g, 337.40 mmol) at room temperature. The reaction solution was stirred at 110 °C for 30 minutes. The reaction solution was cooled to room temperature and quenched with water (500 mL). The resulting solution was extracted with DCM (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / DCM (10 / 1) to afford 4,5-dichloro-2-hydroxybenzaldehyde as a yellow solid (13.50 g, 23%): 1 H NMR (300 MHz, CDCl3) δ 10.96 (s, 1H), 9.84 (d, J = 0.7 Hz, 1H), 7.64 (s, 1H), 7.15 (s, 1H).

[0285] Step b: To a stirred solution of 4,5-dichloro-2-hydroxybenzaldehyde (10.00 g, 52.35 mmol) and K2CO3 (21.70 g, 157.06 mmol) in DMF (100 mL) was added CH3I (11.10 g, 78.53 mmol) at room temperature. The resulting mixture was stirred at 30 °C for 2 hours. The reaction was diluted with water (500 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to afford 4,5-dichloro-2-methoxybenzaldehyde as an off-white solid (10.30 g, 96%): 1 H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H).

[0286] Step c: A solution of 4,5-dichloro-2-methoxybenzaldehyde (5.00 g, 24.39 mmol) in EtOH (40 mL) and THF (5 mL) was added with NaBH4 (1.80 g, 48.88 mmol) at room temperature. After stirring at room temperature for 1 hour, the resulting solution was quenched with water (1 mL) at room temperature and diluted with a co-solvent of EA (80 mL) and water (100 mL). The isolated aqueous layer was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (4,5-dichloro-2-methoxyphenyl)methanol as a pale yellow solid (5.0 g, crude), which was used in the next step without further purification.

[0287] Step d: To a stirred solution of (4,5-dichloro-2-methoxyphenyl)methanol (5.00 g, 24.15 mmol) in CH2Cl2 (40 mL) was added PBr3 (13.10 g, 48.30 mmol) at room temperature. After stirring at room temperature for 1 hour, the resulting solution was quenched with water (80 mL). The aqueous layer was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to obtain Intermediate 1 (1-(bromomethyl)-4,5-dichloro-2-methoxybenzene) as a pale yellow oil (5.00 g, 69%): 1 H NMR (300 MHz, CDCl3) δ 7.37 (s, 1H), 6.93 (s, 1H), 4.42 (s, 2H), 3.86 (s, 3H).

[0288] [Example 2] Intermediate 2 (3,4-dichlorophenyl N,N-diethylcarbamate)

[0289] [Chemical formula]

[0290] Step a: To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol), DMAP (74.95 g, 613.50 mmol) and Et3N (62.08 g, 613.50 mmol) in DCM (500 mL), diethylcarbamoyl chloride (62.39 g, 460.12 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (40 / 1) to give intermediate 2 (3,4-dichlorophenyl N,N-diethylcarbamate) as a yellow oil (72.00 g, 80%): LCMS (ESI) C 11 H 13 Cl2NO2[M + H] + Calculated: 262, 264 (3:2), found 262, 264 (3:2); 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.42 (dq, J = 14.2, 7.2 Hz, 4H), 1.24 (dt, J = 14.8, 7.2 Hz, 6H).

[0291] [Example 3] Intermediate 3 (2-bromo-3,4-dichloro-1-(prop-2-en-1-yloxy)benzene)

[0292] [Chemical formula]

[0293] Step a: To a stirred solution of 3,4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) at 0 °C under a nitrogen atmosphere, Br2 (98.04 g, 613.49 mmol) was added dropwise. The reaction solution was stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous Na2S2O3 (500 mL) at 0 °C. The resulting mixture was extracted with EA (6 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol as a yellow oil. The crude product was used directly in the next step without further purification.

[0294] Step b: To a stirred solution of a mixture of 2-bromo-4,5-dichlorophenol and 2-bromo-3,4-dichlorophenol (50.00 g, 206.71 mmol) and K2CO3 (57.14 g, 413.41 mmol) in DMF (500 mL) at room temperature under a nitrogen atmosphere, 3-bromoprop-1-ene (37.51 g, 310.06 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 16 h under a nitrogen atmosphere. The resulting mixture was diluted with water (1.5 L) and extracted with EA (3 × 0.5 L). The combined organic layers were washed with brine (4 × 0.5 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give Intermediate 3 (2-bromo-3,4-dichloro-1-(prop-2-en-1-yloxy)benzene) as a pale yellow oil (4.00 g, 6%): 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.13 - 6.00 (m, 1H), 5.50 (d, J = 17.3 Hz, 1H), 5.36 (d, J = 10.6 Hz, 1H), 4.63 (d, J = 4.2 Hz, 1H).

[0295] [Example 4] Intermediate 4 (1,2 - dichloro - 3 - iodo - 4 - methoxybenzene)

[0296]

Chemical formula

[0297] Step a: To a stirred solution of 3,4 - dichlorophenol (50.00 g, 306.75 mmol), DMAP (74.95 g, 613.50 mmol) and Et3N (62.08 g, 613.50 mmol) in DCM (500 mL) under a nitrogen atmosphere at room temperature was added dropwise diethylcarbamoyl chloride (62.39 g, 460.12 mmol). The reaction mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (40 / 1) to give 3,4 - dichlorophenyl N,N - diethylcarbamate as a yellow oil (72.00 g, 80%): LCMS (ESI) C 11 H 13 Cl2NO2[M + H] + Calculated: 262, 264 (3 : 2), Found 262, 264 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.42 (dq, J = 14.2, 7.2 Hz, 4H), 1.24 (dt, J = 14.8, 7.2 Hz, 6H).

[0298] Step b: To a solution of DIPA (42.46 g, 419.64 mmol) in THF (400 mL), n-BuLi (29.32 g, 457.79 mmol, 2.5 M in hexane) was added dropwise at -78 °C under a nitrogen atmosphere for 0.5 h. After stirring at -78 °C for 20 min, a solution of 3,4-dichlorophenyl N,N-diethylcarbamate (100.00 g, 381.49 mmol) in THF (100 mL) was added dropwise to the resulting solution at -78 °C over 20 min. After the addition, the resulting mixture was stirred at -78 °C for an additional 0.5 h under a nitrogen atmosphere. To the above mixture, a solution of I₂ (101.67 g, 400.56 mmol) in THF (50 mL) was added dropwise at -78 °C over 0.5 h. The resulting mixture was stirred at -78 °C for an additional 2 h. The resulting mixture was quenched with a saturated aqueous Na₂SO₃ solution (300 mL) at -78 °C and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (40 / 1) to give 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate as an off-white solid (117.00 g, 79%): LCMS (ESI) C 11 H 12 Cl₂INO₂ [M + H] + Calculated for: 388, 390 (3 : 2), found 388, 390 (3 : 2); 1 H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 3.55 (q, J = 7.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0299] Step c: To a stirred solution of 3,4-dichloro-2-iodophenyl N,N-diethylcarbamate (65.80 g, 169.58 mmol) in MeOH (100 mL) at 0 °C was added a solution of NaOH (67.82 g, 1695.75 mmol) in H2O (200 mL). The resulting mixture was warmed to 50 °C and stirred for 10 h. The pH value of the solution was adjusted to 6 - 7 with aqueous HCl solution (1 N). The reaction mixture was diluted with water (400 mL) at room temperature and extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (40 / 1) to afford 3,4-dichloro-2-iodophenol as a yellow oil (47.00 g, 96%): 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.09 (s, 1H).

[0300] Step d: To a stirred solution of 3,4-dichloro-2-iodophenol (100.00 g, 346.15 mmol) in DMF (300 mL) at room temperature under a nitrogen atmosphere were added CH3I (73.70 g, 519.23 mmol) and K2CO3 (95.68 g, 692.31 mmol). The resulting mixture was stirred at room temperature for 5 h under a nitrogen atmosphere. The reaction mixture was diluted with water (500 mL) at room temperature and extracted with EA (3 × 600 mL). The combined organic layers were washed with brine (3 × 1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20 / 1) to afford Intermediate 4 (1,2-dichloro-3-iodo-4-methoxybenzene) as an off-white solid (88.00 g, 84%): 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H).

[0301] [Example 5] Intermediate 5 (1,2-Dichloro-3-iodo-4-(prop-2-en-1-yloxy)benzene)

[0302] [Chemical formula]

[0303] Step a: To a stirred solution of 3,4-dichloro-2-iodophenol (25.00 g, 86.54 mmol) and K2CO3 (35.88 g, 259.61 mmol) in DMF (100 mL) at room temperature was added dropwise 3-bromoprop-1-ene (15.70 g, 129.81 mmol). The resulting mixture was warmed to 40 °C and stirred for 4 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give Intermediate 5 (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, CD3OD) δ 7.49 (d, J = 8.9 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.17 - 6.00 (m, 1H), 5.54 (dt, J = 17.3, 1.7 Hz, 1H), 5.31 (dt, J = 10.7, 1.7 Hz, 1H), 4.65 (dd, J = 4.0, 2.3 Hz, 2H).

[0304] [Example 6] Intermediate 6 ((1S)-1-[2,3-Dichloro-6-(methoxymethoxy)phenyl]ethanamine)

[0305] [Chemical formula]

[0306] Step a: To a stirred mixture of 3,4-dichlorophenol (100 g, 0.61 mol) and K2CO3 (254 g, 1.84 mol) in DMF (1 L) was added dropwise MOM-Cl (61.2 g, 0.92 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, diluted with water (1 L), and extracted with EA (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (100 / 1) to give 1,2-dichloro-4-(methoxymethoxy)benzene as a colorless oil (118 g, 93%): 1 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.9, 2.8 Hz, 1H), 5.16 (s, 2H), 3.49 (s, 3H).

[0307] Step b: To a stirred solution of 1,2-dichloro-4-(methoxymethoxy)benzene (30.0 g, 0.14 mol) in THF (400 mL) was added dropwise n-BuLi (58.0 mL, 0.14 mol, 2.5 M in hexane) over 30 min at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 h, then DMF (21.2 g, 0.29 mol) was added dropwise over 20 min. The resulting solution was stirred at -78 °C for a further 1 h, quenched with saturated aqueous NH4Cl solution (500 mL) at 0 °C, and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (12 / 1) to give 2,3-dichloro-6-(methoxymethoxy)benzaldehyde as an off-white solid (26.5 g, 78%): 11H NMR (300 MHz, CDCl3) δ 10.49 (s, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.16 (d, J = 9.1 Hz, 1H), 5.29 (s, 2H), 3.53 (s, 3H).

[0308] Step c: To a stirred solution of 2,3-dichloro-6-(methoxymethoxy)benzaldehyde (5.00 g, 21.3 mmol) and (R)-2-methylpropan-2-sulfinamide (3.87 g, 31.9 mmol) in THF (30 mL), Ti(OEt)4 (14.6 g, 63.8 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 h, quenched with saturated aqueous NaHCO3 (50 mL), and filtered. The filtrate was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give (R)-N-[[2,3-dichloro-6-(methoxymethoxy)phenyl]methylidene]-2-methylpropan-2-sulfinamide as a pale yellow oil (5.60 g, 70%): LCMS (ESI) C 13 H 17 Cl2NO3S [M + H] + calculated: 338, 338 (3 : 2) found 338, 338 (3 : 2); 1 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 5.24 (s, 2H), 3.49 (s, 3H), 1.33 (s, 9H).

[0309] Step d: To a stirred solution of (R)-N-[(1E)-[2,3-dichloro-6-(methoxymethoxy)phenyl]methylidene]-2-methylpropane-2-sulfinamide (2.00 g, 5.91 mmol) in THF (50 mL), CH3MgBr (17.7 mL, 17.7 mmol, 1 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes, quenched with saturated aqueous NH4Cl solution (40 mL), and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 53% ACN (+0.05% TFA) in water to give (R)-N-[(1S)-1-[2,3-dichloro-6-(methoxymethoxy)phenyl]ethyl]-2-methylpropane-2-sulfinamide as a yellow oil (1.20 g, 57%): LCMS (ESI) C 14 H 21 Cl2NO3S [M + H] + Calculated for: 354, 356 (3 : 2) Found 354, 356 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 9.7 Hz, 2H), 7.03 (d, J = 9.0 Hz, 1H), 5.32 - 5.20 (m, 2H), 4.73 (d, J = 10.9 Hz, 1H), 3.53 (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 1.21 (s, 9H).

[0310] Step e: To a stirred solution of (R)-N-[(1S)-1-[2,3-dichloro-6-(methoxymethoxy)phenyl]ethyl]-2-methylpropane-2-sulfinamide (1.20 g, 3.39 mmol) in MeOH (9 mL) was added aqueous HCl solution (2 N, 3.00 mL) at room temperature. The reaction mixture was stirred for 3 h and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 17% ACN (+0.05% TFA) in water to give Intermediate 6 ((1S)-1-[2,3-dichloro-6-(methoxymethoxy)phenyl]ethanamine) as a pale yellow oil (0.600 g, 49%): LCMS (ESI) C 10 H 13 Cl2NO2[M + H] + Calculated for: 250, 252 (3:2) Found 250, 252 (3:2); 1 H NMR (300 MHz, CDCl3) δ 7.27 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 5.32 - 5.21 (m, 2H), 4.78 (q, J = 7.0 Hz, 1H), 3.52 (s, 3H), 1.51 (dd, J = 7.0, 0.6 Hz, 3H).

[0311] [Example 7] Intermediate 7 ((S)-N-[(1S)-2-amino-1-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]ethyl]-2-methylpropane-2-sulfinamide)

[0312] [Chemical Formula]

[0313] Step a: To a stirred solution of 1-chloro-4-(methoxymethoxy)-2-methylbenzene (25.0 g, 0.13 mol) in THF (300 mL) was added n-BuLi (53.6 mL, 0.13 mol, 2.5 M in hexane) dropwise over 30 min at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred for 1 h, then DMF (19.6 g, 0.27 mol) was added dropwise over 20 min at -78 °C. The resulting mixture was stirred for 1 h, quenched with saturated NH4Cl aqueous solution (300 mL) at 0 °C, and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (12 / 1) to give 5-chloro-2-(methoxymethoxy)-4-methylbenzaldehyde as a pale yellow solid (21.0 g, 73%): 1 H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.81 (s, 1H), 7.14 (s, 1H), 5.30 (s, 2H), 3.54 (s, 3H), 2.43 (s, 3H).

[0314] Step b: To a stirred solution of 5-chloro-2-(methoxymethoxy)-4-methylbenzaldehyde (3.00 g, 14.0 mmol) and (S)-2-methylpropan-2-sulfinamide (2.54 g, 21.0 mmol) in THF (30 mL) was added Ti(Oi-Pr)4 (11.9 g, 41.9 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 h, quenched with saturated aqueous NaHCO3 (50 mL), and filtered. The filtrate was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and mixed with CH3NO2 (30 mL) and K2CO3 (19.3 g, 140 mmol) at room temperature. The resulting reaction mixture was stirred for 16 h, diluted with water (50 mL), and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% ACN (+0.05% TFA) in water to give (S)-N-[(1S)-1-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]-2-nitroethyl]-2-methylpropan-2-sulfinamide as a yellow oil (5.00 g, 94%): LCMS (ESI) C 15 H 23 ClN2O5S [M + H] + Calcd for: 379, 381 (3:1) Found 379, 381 (3:1); 1 H NMR (300 MHz, CDCl3) δ 7.21 (s, 1H), 7.05 (s, 1H), 5.28 - 5.23 (m, 2H), 4.96 (dd, J = 12.8, 6.4 Hz, 1H), 4.90 - 4.77 (m, 2H), 3.52 (s, 3H), 2.35 (s, 3H), 1.25 (s, 9H).

[0315] Step c: To a stirred solution of (S)-N-[(1S)-1-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]-2-nitroethyl]-2-methylpropan-2-sulfinamide (5.00 g, 13.2 mmol) in AcOH (50 mL) was added Zn (13.0 g, 198 mmol) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h and filtered. The filter cake was washed with EA (3 × 30 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water (+10 mM NH4HCO3) to give Intermediate 7 ((S)-N-[(1S)-2-amino-1-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]ethyl]-2-methylpropan-2-sulfinamide) as a yellow oil (2.60 g, 56.47%): LCMS (ESI) C 15 H 25 ClN2O3S [M + H] + Calculated for: 349, 351 (3 : 1); Found 349, 351 (3 : 1); 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 7.28 (s, 1H), 7.04 (s, 1H), 6.17 (d, J = 8.4 Hz, 1H), 5.20 (s, 2H), 5.06 - 4.98 (m, 1H), 3.47 (s, 3H), 3.34 - 3.26 (m, 2H), 2.35 (s, 3H), 1.23 (s, 9H).

[0316] [Example 8] Intermediate 8 (3-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]propanoic acid)

[0317] [Chemical Structure]

[0318] Step a: To a solution of 5-chloro-2-(methoxymethoxy)-4-methylbenzaldehyde (0.300 g, 1.40 mmol) in EtOH (6 mL), malonic acid (0.160 g, 1.54 mmol) and AcONH4 (0.220 g, 2.79 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 8 h and basified to pH 8 with saturated aqueous NaHCO3. Boc2O (0.300 g, 1.38 mmol) was added to the mixture, stirred for 2 h, and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 30% ACN in water (+20 mM NH4HCO3) to give intermediate 8 (3-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethoxy)-4-methylphenyl]propanoic acid) as an off-white solid (0.130 g, 25%): LCMS (ESI) C 17 H 24 ClNO6[M + H] + Calculated for: 374, 376 (3 : 1); Found 374, 376 (3 : 1); 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.03 (s, 1H), 5.27 - 5.19 (m, 2H), 5.19 - 5.08 (m, 1H), 3.41 (s, 3H), 2.47 - 2.30 (m, 2H), 2.26 (s, 3H), 1.36 (s, 9H).

[0319] Examples 9 - 66 describe the synthesis of representative compounds of formula I disclosed herein.

[0320] [Example 9] Compound 3 (2-[amino(phenyl)methyl]-3,4-dichlorophenol) and Compound 5 (2-[amino(phenyl)methyl]-4,5-dichlorophenol)

[0321] [Chemical formula]

[0322] Step a: To a mixture of 3,4-dichlorophenol (1.00 g, 6.13 mmol), benzaldehyde (0.65 g, 6.13 mmol) and acetamide (0.44 g, 7.36 mmol), AlCl3 (0.13 g, 0.90 mmol) was added at room temperature. The reaction mixture was stirred at 110 °C for 1 h. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 2) to give N-[(4,5-dichloro-2-hydroxyphenyl)(phenyl)methyl]acetamide as an off-white solid (0.35 g, 18%): LCMS (ESI) C 15 H 13 Cl2NO2[M + H] + Calculated: 310, 312 (3 : 2), found 310, 312 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.35 - 7.27 (m, 2H), 7.26 - 7.16 (m, 3H), 6.99 (s, 1H), 6.33 (d, J = 8.8 Hz, 1H), 1.92 (s, 3H) and N-[(2,3-dichloro-6-hydroxyphenyl)(phenyl)methyl]acetamide was obtained as an off-white solid (0.25 g, 13%): LCMS (ESI) C 15 H 13 Cl2NO2[M + H] + Calculated: 310, 312 (3 : 2), found 310, 312 (3 : 2); 11H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.24 - 7.16 (m, 3H), 6.86 (t, J = 8.7 Hz, 2H), 1.98 (s, 3H).

[0323] Step b: A solution of N-[(4,5-dichloro-2-hydroxyphenyl)(phenyl)methyl]acetamide (42 mg, 0.14 mmol) in aqueous HCl (6N, 3 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column 19 mm × 250 mm, 10 μm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 55% B to 74% B in 6.5 min; detector: UV210 / 254 nm; retention time: 5.85 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 5 (2-[amino(phenyl)methyl]-4,5-dichlorophenol) as an off-white solid (7.9 mg, 21%): LCMS (ESI) C 13 H 11 Cl2NO [M + H - 17] + Calculated: 251, 253 (3 : 2), Found 251, 253 (3 : 2); 1 1H NMR (400 MHz, CD3OD) δ 7.45 - 7.34 (m, 4H), 7.33 - 7.26 (m, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 5.35 (s, 1H).

[0324] Step c: A solution of N-[(2,3-dichloro-6-hydroxyphenyl)(phenyl)methyl]acetamide (0.25 g, 0.81 mmol) in HCl aqueous solution (6N, 8 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column, 19 mm × 250 mm, 10 μm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 55%B to 74%B in 6.50 minutes; Detector: UV210 / 254 nm; Retention time: 5.85 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to obtain compound 3 (2-[amino(phenyl)methyl]-3,4-dichlorophenol) as an off-white solid (120 mg, 53%): LCMS (ESI) C 13 H 11 Cl2NO [M + H - 17] + Calculated value: 251, 253 (3:2), Found 251, 253 (3:2); 1 H NMR (300 MHz, CD3OD) δ 7.51-7.42 (m, 2H), 7.41-7.27 (m, 3H), 7.25 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 5.84 (s, 1H).

[0325] [Example 10] Compound 4 (4-[(4,5-dichloro-2-hydroxyphenyl)methyl]pyridine-3-carboxamide)

[0326] [Chemical formula]

[0327] Step a: A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (0.20 g, 0.89 mmol), Intermediate 1 (0.20 g, 0.74 mmol), Pd(PPh3)4 (86 mg, 0.07 mmol) and Na2CO3 (0.24 g, 2.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (2 / 1) to give 4-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridine-3-carbonitrile as an off-white solid (82 mg, 30%): LCMS (ESI) C 14 H 10 Cl2N2O [M + H] + Calculated for: 293, 295 (3 : 2), found 293, 295 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 8.83 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J = 5.3 Hz, 1H), 7.16 (s, 1H), 4.16 (s, 2H), 3.79 (s, 3H).

[0328] Step b: A mixture of 4-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridine-3-carbonitrile (82 mg, 0.28 mmol), H2O2 (95 mg, 2.80 mmol, 30% in water), and NaOH (11 mg, 0.28 mmol) in MeOH (5 mL) was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (12 / 1) to afford 4-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridine-3-carboxamide as an off-white solid (63 mg, 69%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated for: 311, 313 (3:2), found 311, 313 (3:2); 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 4.11 (s, 2H), 3.79 (s, 3H).

[0329] Step c: A solution of 4-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridine-3-carboxamide (30 mg, 0.10 mmol) in HI aqueous solution (57%, 1.5 mL) was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (5 mL) and neutralized to pH 7 with saturated aqueous NaHCO3 (20 mL). The mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-[(4,5-dichloro-2-hydroxyphenyl)methyl]pyridine-3-carboxylic acid as an off-white solid (20 mg, 70%): LCMS (ESI) C13 H9Cl2NO3[M + H] + Calculated values: 298, 300 (3:2), measured values: 298, 300 (3:2).

[0330] Step d: To a stirred solution of 4-[(4,5-dichloro-2-hydroxyphenyl)methyl]pyridine-3-carboxylic acid (20 mg, 0.07 mmol), HATU (51 mg, 0.13 mmol) and TEA (13 mg, 0.13 mmol) in DMF (2 mL), NH3 (0.34 mL, 0.14 mmol, 0.4 M in 1,4-dioxane) was added at room temperature. The reaction mixture was then stirred at room temperature for 1 h. The reaction was quenched with MeOH (0.5 mL). The resulting solution was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 27% B to 48% B in 9 min; detector: UV254 / 220 nm; retention time: 7.10 min. The combined fractions containing the product were concentrated under reduced pressure to give compound 4 (4-[(4,5-dichloro-2-hydroxyphenyl)methyl]pyridine-3-carboxamide) as an off-white solid (2 mg, 10%): LCMS (ESI) C 13 H 10 Cl2N2O2[M + H] + Calculated values: 297, 299 (3:2), measured values: 297, 299 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.60 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.92 (s, 1H), 4.17 (s, 2H).

[0331] [Example 11] Compound 6 (2-[amino(pyridin-4-yl)methyl]-4,5-dichlorophenol); and Compound 11 (2-[amino(pyridin-4-yl)methyl]-3,4-dichlorophenol)

[0332]

Chem.

[0333] Step a: To a mixture of 3,4-dichlorophenol (2.00 g, 12.27 mmol), pyridine-4-carbaldehyde (13.14 g, 12.27 mmol) and acetamide (0.87 g, 14.72 mmol) was added AlCl3 (0.25 g, 1.80 mmol) at room temperature. The mixture was then stirred at 110 °C for 1 h. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the crude product. The crude product was purified by preparative TLC eluting with DCM / MeOH (10 / 1) to give a mixture of N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide and N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide as a light brown solid (0.12 g, 3%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated: 311, 313 (3 : 2), Found 311, 313 (3 : 2).

[0334] Step b: A solution of N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide and N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide (0.12 g, 0.39 mmol) in aqueous HCl (6N, 3 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18OBD Prep column, 19 mm × 250 mm, 10 μm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: from 27% B to 67% B in 9 min; Detector: UV254 / 210 nm; Retention time: RT1: 7.67 min; RT2: 8.43 min. The fraction containing the desired product at 7.67 min was collected and concentrated under reduced pressure to obtain compound 6 (2-[amino(pyridin-4-yl)methyl]-4,5-dichlorophenol) as an off-white solid (8.5 mg, 6%): LCMS (ESI) C 12 H 10 Cl2N2O [M + H] + Calculated values: 269, 271 (3:2), Found 269, 271 (3:2); 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.1 Hz, 2H), 7.46 (s, 1H), 7.38 (d, J = 5.1 Hz, 2H), 6.92 (s, 1H), 5.24 (s, 1H). The fraction containing the desired product at 8.43 min was collected and concentrated under reduced pressure to obtain compound 11 (2-[amino(pyridin-4-yl)methyl]-3,4-dichlorophenol) as an off-white solid (28.5 mg, 20%): LCMS (ESI) C 12 H 10 Cl2N2O [M + H] + Calculated values: 269, 271 (3:2), Found 269, 271 (3:2); 1 H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.47 (m, 2H), 7.42 - 7.32 (m, 3H), 7.07 (br, 2H), 6.72 (d, J = 8.8 Hz, 1H), 5.66 (s, 1H).

[0335] [Example 12] Compound 7 (2-[amino(1H-pyrazol-4-yl)methyl]-3,4-dichlorophenol); and Compound 10 (2-[amino(1H-pyrazol-4-yl)methyl]-4,5-dichlorophenol)

[0336]

Chem.

[0337] Step a: To a mixture of 3,4-dichlorophenol (1.00 g, 6.13 mmol), 1H-pyrazole-4-carbaldehyde (0.59 g, 6.13 mmol) and acetamide (0.43 g, 7.36 mmol), AlCl3 (0.13 g, 0.90 mmol) was added at room temperature. The mixture was then stirred at 110 °C for 1 h. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 2) to give a mixture of N-[(4,5-dichloro-2-hydroxyphenyl)(1H-pyrazol-4-yl)methyl]acetamide and N-[(2,3-dichloro-6-hydroxyphenyl)(1H-pyrazol-4-yl)methyl]acetamide as a yellow solid (1.00 g, 54%): LCMS (ESI) C 12 H 11 Cl2N3O2 [M + H] + Calculated: 300, 302 (3 : 2), Found 300, 302 (3 : 2).

[0338] Step b: A solution of N-[(4,5-dichloro-2-hydroxyphenyl)(1H-pyrazol-4-yl)methyl]acetamide and N-[(2,3-dichloro-6-hydroxyphenyl)(1H-pyrazol-4-yl)methyl]acetamide (0.50 g, 1.67 mmol) in aqueous HCl solution (6N, 10 mL) was stirred at 100 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: Sunfire Prep C 18OBD column, 19 mm × 100 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: from 12% B to 28% B in 12 min; Detector: UV254 / 210 nm; Retention time: RT1: 8.05 min; RT2: 10.25 min. The fraction containing the desired product at 8.05 min was collected and concentrated under reduced pressure to obtain compound 10 (2-[amino(1H-pyrazol-4-yl)methyl]-4,5-dichlorophenol) as an off-white solid (56.4 mg, 9%): LCMS (ESI) C 10 H9Cl2N3O [M + H - 17] + Calculated values: 241, 243 (3:2), Found 241, 243 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.74 (s, 2H), 7.42 (s, 1H), 7.12 (s, 1H), 5.75 (s, 1H). The fraction containing the desired product at 10.25 min was collected and concentrated under reduced pressure to obtain compound 7 (2-[amino(1H-pyrazol-4-yl)methyl]-3,4-dichlorophenol) as an off-white solid (102.4 mg, 17%): LCMS (ESI) C 10 H9Cl2N3O [M + H - 17] + Calculated values 241, 243 (3:2), Found 241, 243 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.79 (s, 2H), 7.45 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.11 (s, 1H).

[0339] [Example 13] Compound 8 (2-[(6-aminopyridin-3-yl)methyl]-4,5-dichlorophenol)

[0340] [Chemical formula]

[0341] Step a: To a solution of Intermediate 1 (0.30 g, 1.11 mmol) and 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.29 g, 1.33 mmol) in 1,4-dioxane (6 mL) and water (1 mL), Na2CO3 (0.35 g, 3.33 mmol) and Pd(dppf)Cl2 (81 mg, 0.11 mmol) were added at room temperature. The reaction mixture was degassed three times with nitrogen. Under a nitrogen atmosphere, after stirring at 80 °C for 2 hours, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN (+0.05% TFA) in water to give 5-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridin-2-amine as a brown solid (0.24 g, 68%): LCMS (ESI) C 13 H 12 Cl2N2O [M + H] + Calculated: 283, 285 (3:2), Found 283, 285; 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 7.80 - 7.76 (m, 2H), 7.49 (s, 1H), 7.28 (s, 1H), 6.92 (d, J = 9.3 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 2H).

[0342] Step b: To a solution of 5-[(4,5-dichloro-2-methoxyphenyl)methyl]pyridin-2-amine (0.12 g, 0.42 mmol) in DCM (3 mL), BBr3 (0.42 g, 1.70 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice water (20 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 80% B in 9 minutes; detector: UV254 / 210 nm; retention time: 7.74 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 8 (2-[(6-aminopyridin-3-yl)methyl]-4,5-dichlorophenol) as a brown solid (26.2 mg, 22%): LCMS (ESI) C 12 H 10 Cl2N2O [M + H] + Calculated for 269, 271 (3:2), found 269, 271 (3:2); 1 H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.39 - 7.09 (m, 2H), 6.94 (s, 1H), 6.35 (d, J = 8.5 Hz, 1H), 5.77 (s, 2H), 3.59 (s, 2H).

[0343] The compounds described in Table 1 below were prepared starting from Intermediate 1 and the corresponding boronic acid available from commercial sources in a manner similar to that described for compound 8.

[0344] [Table 2]

[0345] [Example 14] Compound 9 (N-[(2,3-dichloro-6-hydroxyphenyl)(3-methylpyridin-4-yl)methyl]azetidine-3-carboxamide)

[0346]

Chemical Structure

[0347] Step a: To a stirred solution of intermediate 4 (0.81 g, 2.68 mmol) in THF (10 mL), n-BuLi (1.3 mL, 3.25 mmol, 2.5 M in hexane) was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. To the above mixture, 2-methyl-N-[(1Z)-(3-methylpyridin-4-yl)methylidene]propan-2-sulfinamide (0.40 g, 1.78 mmol) in THF (3 mL) was added dropwise at -78 °C over 5 min. The resulting mixture was stirred at -78 °C for an additional 2 h. The reaction was quenched at -78 °C with saturated aqueous NH4Cl solution (50 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN in water (+0.05% TFA) to give N-[(2,3-dichloro-6-methoxyphenyl)(3-methylpyridin-4-yl)methyl]-2-methylpropan-2-sulfinamide as a pale yellow oil (0.80 g, 90%): LCMS (ESI) C 18 H 22 Cl2N2O2S [M + H] + Calculated for: 401, 403 (3 : 2), found 401, 403 (3 : 2); 11H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 6.3 Hz, 1H), 8.60 (s, 1H), 8.50 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 9.0, 1.1 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 6.48 (s, 1H), 3.64 (s, 3H), 2.22 (s, 3H), 1.27 (d, J = 1.1 Hz, 9H).

[0348] Step b: To a stirred solution of N-[(2,3-dichloro-6-methoxyphenyl)(3-methylpyridin-4-yl)methyl]-2-methylpropane-2-sulfinamide (0.50 g, 1.25 mmol) in 1,4-dioxane (4 mL) was added dropwise aqueous HCl solution (4 N, 1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1-(2,3-dichloro-6-methoxyphenyl)-1-(3-methylpyridin-4-yl)methanamine as a pale yellow oil (0.50 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 14 H 14 Cl2N2O [M + H] + Calculated: 297, 299 (3 : 2), Found 297, 299 (3 : 2).

[0349] Step c: To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (0.51 g, 2.52 mmol) and HATU (1.28 g, 3.37 mmol) in DMF (10 mL) was added 1-(2,3-dichloro-6-methoxyphenyl)-1-(3-methylpyridin-4-yl)methanamine (0.37 g, 1.25 mmol) and TEA (0.51 g, 5.05 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 h. The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN (+0.05% TFA) in water to afford tert-butyl 3-[[(2,3-dichloro-6-methoxyphenyl)(3-methylpyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate as a pale yellow oil (0.46 g, 57% over 2 steps): LCMS (ESI) C 23 H 27 Cl2N3O4[M + H] + Calculated for: 480, 482 (3:2), found 480, 482 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.73 - 8.57 (m, 2H), 8.09 (d, J = 6.2 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 4.2 Hz, 1H), 4.20 - 4.09 (m, 3H), 4.04 (dd, J = 16.2, 9.7 Hz, 2H), 3.62 (s, 3H), 2.25 (s, 3H), 1.46 (s, 9H).

[0350] Step d: To a stirred mixture of tert-butyl 3-[[(2,3-dichloro-6-methoxyphenyl)(3-methylpyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate (0.20 g, 0.42 mmol) in DCM (3 mL), BBr3 (0.31 g, 1.25 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The reaction was quenched with MeOH (3 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XSelect CSH OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 33% B in 7 min; detector: UV220 / 254 nm; retention time: 6.63 min. The fractions containing the desired product were collected and concentrated under reduced pressure to afford compound 9 (N-[(2,3-dichloro-6-hydroxyphenyl)(3-methylpyridin-4-yl)methyl]azetidine-3-carboxamide) as a purple solid (4 mg, 2%): LCMS (ESI) C 17 H 17 Cl2N3O2[M + H] + Calculated for: 366, 368 (3:2), found 366, 368 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.57 (s, 2H), 7.97 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J = 8.9 Hz, 1H), 4.38 - 4.22 (m, 3H), 4.16 (dd, J = 10.9, 6.8 Hz, 1H), 3.95 - 3.83 (m, 1H), 2.28 (s, 3H).

[0351] [Example 15] Compound 12 (2-[amino(6-aminopyridin-3-yl)methyl]-4,5-dichlorophenol); and Compound 14 (2-[amino(6-aminopyridin-3-yl)methyl]-3,4-dichlorophenol)

[0352] [Chemistry]

[0353] Step a: A mixture of 3,4-dichlorophenol (0.50 g, 3.07 mmol), 6-bromopyridine-3-carbaldehyde (0.57 g, 3.07 mmol), acetamide (0.22 g, 3.68 mmol) and AlCl3 (61 mg, 0.46 mmol) was stirred at 110 °C for 1.5 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 2) to give N-[(6-bromopyridin-3-yl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide as a pale yellow solid (0.13 g, 9%): LCMS (ESI) C 14 H 11 BrCl2N2O2 [M + H] + Calculated: 389, 391, 393 (2 : 3 : 1), found 389, 391, 393 (2 : 3 : 1); 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.28 - 8.20 (m, 1H), 7.66 - 7.57 (m, 1H), 7.56 - 7.41 (m, 2H), 6.92 - 6.79 (m, 2H), 1.99 (s, 3H). Further, N-((6-bromopyridin-3-yl)(2,3-dichloro-6-hydroxyphenyl)methyl)acetamide was obtained as a pale yellow solid (0.17 g, 12%): LCMS (ESI) C 14 H 11 BrCl2N2O2 [M + H] + Calculated: 389, 391, 393 (2 : 3 : 1), found 389, 391, 393 (2 : 3 : 1); 11H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.32 - 8.24 (m, 1H), 7.67 - 7.46 (m, 3H), 7.01 (s, 1H), 6.30 (t, J = 9.0 Hz, 1H), 1.95 (s, 3H).

[0354] Step b: A degassed mixture of N-[(6-bromopyridin-3-yl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide (0.13 g, 0.33 mmol), trifluoroacetamide (75 mg, 0.67 mmol), methyl[2-(methylamino)ethyl]amine (88 mg, 1.00 mmol), CuI (6 mg, 0.03 mmol) and Cs2CO3 (0.33 mg, 1.00 mmol) in 1,4-dioxane (2 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL). The resulting mixture was extracted with DCM / MeOH (v / v = 10 / 1, 3 × 20 mL). The combined organic layers were then washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10 / 1) to give N-[(6-aminopyridin-3-yl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide as a pale yellow solid (32 mg, 24%): LCMS (ESI) C 14 H 13 Cl2N3O2 [M + H] + Calculated for: 326, 328 (3 : 2), found 326, 328 (3 : 2); 11H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.41 (s, 1H), 6.11 (d, J = 8.5 Hz, 1H), 5.90 (s, 2H), 1.90 (s, 3H).

[0355] Step c: A solution of N-[(6-aminopyridin-3-yl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide (31 mg, 0.10 mmol) in aqueous HCl (6N, 2 mL) was stirred at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: X Bridge C 18 OBD Prep column, 19 mm × 250 mm, 10 μm; mobile phase A: water containing 20 mmol / L of NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 27% B to 49% B in 6.5 min; detector: UV210 / 254 nm; retention time: 5.73 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 12 (2-[amino(6-aminopyridin-3-yl)methyl]-4,5-dichlorophenol) as a pale yellow solid (8.9 mg, 9%): LCMS (ESI) C 12 H 11 Cl2N3O [M + H] + Calculated for: 284, 286 (3 : 2), found 284, 286 (3 : 2); 1 1H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.7, 2.4 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.59 (d, J = 8.6 Hz, 1H), 5.21 (s, 1H).

[0356] Step d: A degassed mixture of N-[(6-bromopyridin-3-yl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide (0.17 g, 0.43 mmol), trifluoroacetamide (98 mg, 0.88 mmol), methyl[2-(methylamino)ethyl]amine (0.12 g, 1.31 mmol), CuI (8 mg, 0.04 mmol) and Cs2CO3 (0.43 g, 1.31 mmol) in 1,4-dioxane (3 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with DCM / MeOH (v / v = 10 / 1, 3 × 20 mL). The combined organic layers were then washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10 / 1) to give N-((6-aminopyridin-3-yl)(2,3-dichloro-6-hydroxyphenyl)methyl)acetamide as a pale yellow solid (38 mg, 23%): LCMS (ESI) C 14 H 13 Cl2N3O2[M + H] + Calculated for: 326, 328 (3 : 2), found 326, 328 (3 : 2).

[0357] Step e: A solution of N-[(6-aminopyridin-3-yl)(2,3-dichloro-6-hydroxyphenyl)methyl]acetamide (38 mg, 0.12 mmol) in aqueous HCl (6N, 2 mL) was stirred at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: X Bridge C 18OBD Prep column, 19 mm × 250 mm, 10 μm; Mobile phase A: water containing 20 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 6% B to 58% B in 9 min; Detector: UV210 / 254 nm; Retention time: 9.12 min. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 14 (2-[amino(6-aminopyridin-3-yl)methyl]-3,4-dichlorophenol) as an off-white solid (17 mg, 52%): LCMS (ESI) C 12 H 11 Cl2N3O [M + H] + Calculated: 284, 286 (3:2), Found 284, 286 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.7, 2.5 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 6.55 (dd, J = 8.7, 0.8 Hz, 1H), 5.70 (s, 1H).

[0358] [Example 16] Compound 13 (4-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]benzamide); and Compound 16 (4-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]benzonitrile)

[0359] [Chemical formula]

[0360] Step a: A mixture of 3,4-dichlorophenol (1.50 g, 9.20 mmol), 4-formylbenzonitrile (1.20 g, 9.20 mmol), acetamide (0.65 g, 11.04 mmol) and AlCl3 (0.18 g, 1.38 mmol) was stirred at 110 °C for 1.5 h. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 4) to give N-[(4-cyanophenyl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide as an off-white solid (0.36 g, 12%): LCMS (ESI) C 16 H 12 Cl2N2O2[M + H] + Calculated for: 335, 337 (3 : 2), Found 335, 337 (3 : 2); 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.75 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.46 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.01 (s, 1H), 6.38 (d, J = 8.7 Hz, 1H), 1.94 (s, 3H).

[0361] Step b: A solution of N-[(4-cyanophenyl)(4,5-dichloro-2-hydroxyphenyl)methyl]acetamide (0.36 g, 1.07 mol) in aqueous HCl (6N, 15 mL) was stirred at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% ACN in water containing 20 mmol / L NH4HCO3 to give compound 16 (4-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]benzonitrile) as an off-white solid (0.14 g, 45%): LCMS (ESI) C 14 H 10Cl2N2O [M + H - 17] + Calculated values: 276, 278 (3:2), measured values 276, 278 (3:2); 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.46 (s, 1H), 6.91 (s, 1H), 5.31 (s, 1H)

[0362] Step c: To a stirred mixture of 4-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]benzonitrile (50 mg, 0.17 mmol) and K2CO3 (47 mg, 0.34 mmol) in DMSO (3 mL) was added H2O2 (23 mg, 0.68 mmol, 30% in water) at 0 °C. The reaction mixture was then brought to room temperature and stirred for 10 minutes. The resulting mixture was quenched with saturated aqueous Na2SO3 (10 mL) and extracted with EA (2 × 10 mL). The combined organic phases were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 43% B in 6.5 minutes; detector: UV254 / 210 nm; retention time: 6.43 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 13 (4-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]benzamide) as an off-white solid (15.9 mg, 30%): LCMS (ESI) C 14 H 12 Cl2N2O2[M + H - 17] + Calculated values: 294, 296 (3:2), measured values 294, 296 (3:2); 11H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.18 (s, 1H), 6.90 (s, 1H), 5.40 (s, 1H).

[0363] [Example 17] Compound 15 (5 - [amino(4,5 - dichloro - 2 - hydroxyphenyl)methyl] - 1,2 - dihydropyridin - 2 - one)

[0364] [Chemical formula]

[0365] Step a: A degassed mixture of N - [(6 - bromopyridin - 3 - yl)(4,5 - dichloro - 2 - hydroxyphenyl)methyl]acetamide (0.51 g, 1.32 mmol), (E) - N - (phenylmethylene)hydroxylamine (0.21 g, 1.71 mmol), and Pd2(dba)3 (0.12 g, 0.13 mmol) in DMF (5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into water (30 mL). The mixture was extracted with a co - solvent of DCM / MeOH (v / v = 10 / 1, 3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give N - [(4,5 - dichloro - 2 - hydroxyphenyl)(6 - hydroxypyridin - 3 - yl)methyl]acetamide as a pale yellow oil (0.26 g, 59%): LCMS (ESI) C 14 H 12 Cl2N2O3[M + H] + Calculated value: 327, 329 (3 : 2), Found 327, 329 (3 : 2).

[0366] Step b: A solution of N-[(4,5-dichloro-2-hydroxyphenyl)(6-hydroxypyridin-3-yl)methyl]acetamide (65 mg, 0.20 mmol) in aqueous HCl solution (6 N, 2 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column, 19 mm × 250 mm, 10 μm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15% B to 68% B in 6.5 min; detector: UV210 / 254 nm; retention time: 5.07 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 15 (5-[amino(4,5-dichloro-2-hydroxyphenyl)methyl]-1,2-dihydropyridin-2-one) as an off-white solid (20 mg, 35%): LCMS (ESI) C 12 H 10 Cl2N2O2[M + H - 17] + Calculated for: 268, 270 (3 : 2), found 268, 270 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.64 (dd, J = 9.5, 2.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.33 (s, 1H), 6.92 (s, 1H), 6.54 (d, J = 9.6 Hz, 1H), 5.15 (s, 1H).

[0367] [Example 18] Compound 17 (1-[amino(pyridin-4-yl)methyl]naphthalen-2-ol)

[0368] [Chemical formula]

[0369] Step a: A solution of N-[(2-hydroxynaphthalen-1-yl)(pyridin-4-yl)methyl]acetamide (50 mg, 0.17 mmol) in concentrated HCl (0.6 mL) was stirred at 100 °C for 4 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was diluted with water (20 mL) at room temperature and the pH value was adjusted to 7 with saturated aqueous NaHCO3. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (8 / 1) to give compound 17 (1-[amino(pyridin-4-yl)methyl]naphthalen-2-ol) as a yellow solid (1.5 mg, 3%): LCMS (ESI) C 16 H 14 N2O [M + H] + Calculated: 251 Found 251; 1 H NMR (400 MHz, CD3OD) δ 8.46 - 8.40 (m, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.54 - 7.48 (m, 2H), 7.46 - 7.39 (m, 1H), 7.32 - 7.25 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.18 (s, 1H).

[0370] [Example 19] Compound 19 (N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide); and Compound 20 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide)

[0371] [Chemical formula]

[0372] Step a: A mixture of 3,4-dichlorophenol (2.00 g, 12.27 mmol), pyridine-4-carbaldehyde (13.14 g, 12.27 mmol) and acetamide (0.87 g, 14.72 mmol) was added with AlCl3 (0.25 g, 1.84 mmol) at room temperature. The mixture was then stirred at 110 °C for 1 h. After cooling to room temperature, the resulting mixture was quenched with water (50 mL) and extracted with EA (5 × 50 mL). The combined organic layers were dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to obtain the crude product. The crude product was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column, 19 mm × 250 mm, 10 μm; mobile phase A: water containing 20 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 28% B to 35% B in 7 min; detector: 210 / 254 nm; retention time: Rt1: 5.00 min, Rt2: 5.18 min.

[0373] Fractions containing the desired product eluting faster were collected and concentrated under reduced pressure to give compound 20 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide) as an off-white solid (50 mg, 1.31%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M+H] + Calculated for: 311, 313 (3:2), found 311, 313 (3:2); 1 H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.79 - 8.69 (m, 2H), 8.57 (d, J = 8.1 Hz, 1H), 7.95 - 7.83 (m, 3H), 6.93 - 6.88 (m, 2H), 2.04 (s, 3H).

[0374] Fractions containing the desired product that eluted later were collected and concentrated under reduced pressure to give compound 19 (N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide) as a light brown solid (22 mg, 0.6%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated for: 311, 313 (3:2), Found 311, 313 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.54 - 8.39 (m, 2H), 7.36 - 7.20 (m, 3H), 6.98 (s, 1H), 6.42 (s, 1H), 2.07 (s, 3H).

[0375] [Example 20] Compound 21 (2-[amino(2,3-dihydro-1H-isoindol-5-yl)methyl]-4,5-dichlorophenol)

[0376] [Chemical formula]

[0377] Step a: To a stirred solution of tert-butyl 5-bromo-2,3-dihydro-1H-isoindole-2-carboxylate (0.87 g, 2.93 mmol) in THF (8 mL), n-BuLi (1.2 mL, 2.93 mmol, 2.5 M in hexane) was added dropwise at -75 °C under an argon atmosphere. To the above solution, 4,5-dichloro-2-methoxybenzaldehyde (0.50 g, 2.44 mmol) was added dropwise at -75 °C over 30 minutes. The reaction mixture was stirred at -75 °C for 1 hour under an argon atmosphere. The resulting mixture was quenched at -75 °C with saturated aqueous NH4Cl solution (20 mL) and diluted with water (30 mL). The resulting mixture was extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 70% ACN (+0.05% TFA) in water to give tert-butyl 5-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]-2,3-dihydro-1H-isoindole-2-carboxylate as a yellow oil (0.64 g, 55%): LCMS (ESI) C 21 H 23 Cl2NO4[M + H - 56] + Calculated for: 368, 370 (3 : 2), Found 368, 370 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 7.43 (s, 1H), 7.30 - 7.16 (m, 3H), 6.94 (s, 1H), 6.01 (s, 1H), 4.67 - 4.56 (m, 4H), 3.79 (s, 3H), 1.51 (s, 9H).

[0378] Step b: To a stirred mixture of tert-butyl 5-[(4,5-dichloro-2-methoxyphenyl)(hydroxy)methyl]-2,3-dihydro-1H-isoindole-2-carboxylate (0.64 g, 1.51 mmol) in DCM (8 mL) was added Dess-Martin periodinane (0.96 g, 2.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with saturated aqueous Na2S2O3 solution (5 mL) at room temperature and diluted with water (30 mL). The resulting mixture was extracted with EA (2 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (2 × 30 mL) and brine (2 × 30 mL), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 80% ACN (+0.05% TFA) in water to afford tert-butyl 5-(4,5-dichloromethoxybenzoyl)-2,3-dihydro-1H-isoindole-2-carboxylate as a yellow solid (0.56 g, 79%): LCMS (ESI) C 21 H 21 Cl2NO4[M + H -15] + Calculated for: 407, 409 (3 : 2), found 407, 409 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 2H), 7.45 (s, 1H), 7.34 (dd, J = 17.0, 8.0 Hz, 1H), 7.11 (s, 1H), 4.79-4.66 (m, 4H), 3.77 (s, 3H), 1.55 (s, 9H).

[0379] Step c: To a stirred mixture of tert-butyl 5-(4,5-dichloro-2-methoxybenzoyl)-2,3-dihydro-1H-isoindole-2-carboxylate (0.56 g, 1.33 mmol) and Ti(OEt)4 (0.91 g, 3.98 mmol) in THF (10 mL), 2-methylpropan-2-sulfinamide (0.24 g, 1.99 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the resulting solution was quenched with water (30 mL) and filtered. The filtrate was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 5-[(1E)-(4,5-dichlor-2-methoxyphenyl)[(2-methylpropan-2-sulfinyl)imino]methyl]-2,3-dihydro-1H-isoindole-2-carboxylate as a yellow oil (0.69 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 25 H 30 Cl2N2O4S [M + H] + Calculated for: 525, 527 (3 : 2), found 525, 527 (3 : 2).

[0380] Step d: To a stirred solution of tert-butyl 5-[(1E)-(4,5-dichloro-2-methoxyphenyl)[(2-methylpropan-2-sulfinyl)imino]methyl]-2,3-dihydro-1H-isoindole-2-carboxylate (0.69 g, 1.31 mmol) in MeOH (5 mL) was added NaBH4 (0.20 g, 5.25 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 50% ACN (+0.05% TFA) in water to afford tert-butyl 5-[(4,5-dichloro-2-methoxyphenyl)[(2-methylpropan-2-sulfinyl)amino]methyl]-2,3-dihydro-1H-isoindole-2-carboxylate as a yellow solid (0.40 g, 51% over 2 steps): LCMS (ESI) C 25 H 32 Cl2N2O4S [M + H] + Calcd for: 527, 529 (3 : 2), found 527, 529 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.26 - 7.16 (m, 3H), 6.95 (s, 1H), 5.95 (s, 1H), 4.74 - 4.54 (m, 4H), 3.78 (s, 3H), 1.52 (s, 9H), 1.30 (s, 9H).

[0381] Step e: To a stirred mixture of tert-butyl 5-[(4,5-dichloro-2-methoxyphenyl)[(2-methylpropan-2-sulfinyl)amino]methyl]-2,3-dihydro-1H-isoindole-2-carboxylate (80 mg, 0.15 mmol) in DCM (2 mL), BBr3 (0.30 g, 1.21 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL) at room temperature. The mixture was neutralized to pH 9 with saturated aqueous NaHCO3 。 The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 50% B in 6.5 minutes; Detector: UV254 / 210 nm; Retention time: 5.83 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 21 (2-[amino(2,3-dihydro-1H-isoindol-5-yl)methyl]-4,5-dichlorophenol) as an off-white solid (33 mg, 49%): LCMS (ESI) C 15 H 14 Cl2N2O [M + H] + Calculated: 309, 311 (3:2), Found 309, 311 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 7.58 - 7.48 (m, 3H), 7.38 (s, 1H), 7.09 (s, 1H), 5.81 (s, 1H), 4.67 (s, 4H).

[0382] [Example 21] Compound 22 (3,4-dichloro-2-[(pyridin-4-yl)methyl]phenol)

[0383] [Chemical formula]

[0384] Step a: To a stirred solution of DIPA (1.16 g, 11.44 mmol) in THF (10 mL), n-BuLi (4.58 mL, 11.45 mmol, 2.5 M in hexane) was added at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 1 h. Then, a solution of Intermediate 2 (2.00 g, 7.63 mmol) in THF (15 mL) was added to the above solution, and the mixture was stirred at -65 °C for 1 h. Subsequently, a solution of pyridine-4-carbaldehyde (0.98 g, 9.16 mmol) in THF (5 mL) was added. The resulting solution was slowly warmed to room temperature over 1 h and stirred for 1 h. The reaction was quenched with water (5 mL) at room temperature and diluted with water (80 mL). The isolated aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15 / 1) to give the crude product. The crude product was then purified by reverse-phase chromatography eluting with 27% ACN (+0.05% TFA) in water to give 3,4-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenyl N,N-diethylcarbamate as a pale yellow solid (1.10 g, 39%): LCMS (ESI) C 17 H 18 Cl2N2O3 [M + H] + Calculated for: 369, 371 (3:2), found 369, 371 (3:2); 1 H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.72 - 8.37 (m, 2H), 7.60 - 7.28 (m, 2H), 7.20 (d, J = 5.1 Hz, 2H), 6.93 (d, J = 8.9 Hz, 1H), 3.54 - 3.05 (m, 4H), 1.44 - 0.92 (m, 6H).

[0385] Step b: To a stirred solution of 3,4-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenyl N,N-diethylcarbamate (0.20 g, 0.540 mmol) in DCM (1 mL) was added Et3SiH (0.63 g, 5.42 mol) and BF3·Et2O (0.77 g, 5.42 mmol) at room temperature. The reaction was stirred at 50 °C for 16 h. The reaction was quenched with MeOH (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 60% B in 6 min; detector: UV: 254 / 210 nm; retention time: 4.70 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 22 (3,4-dichloro-2-[(pyridin-4-yl)methyl]phenol) as an off-white solid (43.9 mg, 22%): LCMS (ESI) C 12 H9Cl2NO [M + H] + calculated: 254, 256 (3:2), found 254, 256 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.69 - 8.65 (m, 2H), 7.85 (d, J = 6.1 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.50 (s, 2H).

[0386] [Example 22] Compound 23 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridine-2-carboxamide)

[0387] [Chemical formula]

[0388] Step a: A solution of 4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridine-2-carbonitrile (0.20 g, 0.68 mmol) and NaOH (0.27 g, 6.78 mmol) in THF (3 mL) and H2O (2 mL) was stirred at 70 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25% B to 28% B in 10 min; detector: UV254 / 210 nm; retention time: 8.21 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 23 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridine-2-carboxamide) as an off-white solid (40.3 mg, 14%): LCMS (ESI) C 13 H 10 Cl2N2O3 [M + H] + Calculated for: 313, 315 (3:2), found 313, 315 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.64 (d, J = 5.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H).

[0389] [Example 23] Compound 24 (4-[(2,3-dichloro-6-hydroxyphenyl)methyl]pyridine-2-carboxamide)

[0390] [Chemical formula]

[0391] Step a: To a stirred solution of Intermediate 2 (1.00 g, 3.81 mmol) in THF (10 mL), LDA (2.3 mL, 4.58 mmol, 2 M in THF / hexane) was added at -78 °C under an argon atmosphere. The reaction was stirred at -78 °C for 1 hour. Then a solution of 4-formylpyridine-2-carbonitrile (0.60 g, 4.58 mmol) in THF (5 mL) was added to the solution. The reaction was stirred from -78 °C to -65 °C for 1 hour. The reaction was quenched with water (1 mL) and diluted with a co-solvent of EA (50 mL) and water (50 mL). The separated aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give (2-cyanopyridin-4-yl)(2,3-dichloro-6-hydroxyphenyl)methyl N,N-diethylcarbamate as a pale yellow solid (0.70 g, 46%): LCMS (ESI) C 18 H 17 Cl2N3O3 [M + H] + Calculated: 394, 396 (3 : 2), Found 394, 396 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 10.67 (s, 1H), 8.72 (d, J = 5.1, 1H), 7.78 (s, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.44 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 3.53 - 3.17 (m, 4H), 1.23 - 1.00 (m, 6H).

[0392] Step b: To a stirred solution of (2-cyanopyridin-4-yl)(2,3-dichloro-6-hydroxyphenyl)methyl N,N-diethylcarbamate (0.25 g, 0.63 mmol) in DCM (1 mL), Et3SiH (0.74 g, 6.34 mmol) and BF3·Et2O (1.35 g, 9.51 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 3 h under a nitrogen atmosphere. The reaction mixture was diluted with a co-solvent of EA (30 mL) and water (30 mL). The separated aqueous layer was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to afford 4-[(2,3-dichloro-6-hydroxyphenyl)methyl]pyridine-2-carbonitrile as an off-white solid (0.15 g, 59%): LCMS (ESI) C 13 H8Cl2N2O [M + H] + Calculated for: 279, 281 (3 : 2), found 279, 281 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 5.1 Hz, 1H), 7.61 (s, 1H), 7.48 - 7.43 (m, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 4.27 (s, 2H).

[0393] Step c: To a stirred solution of 4-[(2,3-dichloro-6-hydroxyphenyl)methyl]pyridine-2-carbonitrile (0.13 g, 0.47 mmol) and NaOH (37 mg, 0.93 mmol) in THF (2 mL), H2O2 (31.7 mg, 0.93 mmol, 30% in water) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with saturated aqueous Na2SO3 (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 70% B in 6 min; detector: 254 / 210 nm; retention time: 4.90 min. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 24 (4-[(2,3-dichloro-6-hydroxyphenyl)methyl]pyridine-2-carboxamide) as an off-white solid (72 mg, 52%): LCMS (ESI) C 13 H 10 Cl2N2O2 [M + H] + Calculated: 297, 299 (3:2), found 297, 299 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H), 7.41 (d, J = 5.0, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.30 (s, 2H).

[0394] [Example 24] Compound 25 (3,4-dichloro-2-[1-(pyridin-4-yl)ethyl]phenol)

[0395] [Chemical formula]

[0396] Step a: To a stirred solution of 3,4-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenyl N,N-diethylcarbamate (0.30 g, 0.81 mmol) in acetone (5 mL) was added CrO3 (0.24 g, 2.43 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was diluted with EA (30 mL) and water (30 mL). The separated aqueous layer was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to afford 3,4-dichloro-2-(pyridine-4-carbonyl)phenyl N,N-diethylcarbamate as a pale yellow oil (0.15 g, 50%): LCMS (ESI) C 17 H 16 Cl2N2O3 [M + H] + Calculated for: 367, 369 (3 : 2), found 367, 369; 1 H NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 7.69 (d, J = 4.9 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.8 Hz, 1H), 3.18 (q, J = 7.1 Hz, 2H), 3.08 (q, J = 7.2 Hz, 2H), 1.06 - 0.89 (m, 6H).

[0397] Step b: To a stirred mixture of methyltriphenylphosphonium bromide (0.52 g, 1.46 mmol) in THF (10 mL), t-BuOK (0.21 g, 1.87 mmol) was added at 0 °C under an argon atmosphere. The reaction was stirred at 0 °C for 15 minutes. Then to this solution was added 3,4-dichloro-2-(pyridine-4-carbonyl)phenyl N,N-diethylcarbamate (0.23 g, 0.63 mmol). The resulting mixture was stirred from 0 °C to room temperature for an additional 1 hour. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 21% ACN (+0.05% TFA) in water to give 3,4-dichloro-2-[1-(pyridin-4-yl)ethenyl]phenol as a pale yellow oil (70 mg, 42%): LCMS (ESI) C 13 H9Cl2NO [M + H] + Calculated for: 266, 268 (3 : 2), found 266, 268 (3 : 2); 1 H NMR (300 MHz, CD3OD) δ 8.71 (d, J = 7.1 Hz, 2H), 7.89 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 6.89 (dd, J = 8.9, 2.7 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 5.87 (d, J = 2.7 Hz, 1H).

[0398] Step c: To a stirred solution of 3,4-dichloro-2-[1-(pyridin-4-yl)ethenyl]phenol (70 mg, 0.26 mmol) in MeOH (2 mL), PtO2 (60 mg, 0.26 mmol) was added at room temperature. The reaction was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 1 hour. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 55% B to 70% B in 6 minutes; detector: UV: 254 / 210 nm; retention time: 5.57 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 25 (3,4-dichloro-2-[1-(pyridin-4-yl)ethyl]phenol) as an off-white solid (21.5 mg, 30%). LCMS (ESI) C 13 H 11 Cl2NO [M + H] + Calculated: 268, 270 (3:2), found 268, 270 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.44 - 8.33 (m, 2H), 7.32 - 7.29 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.99 (q, J = 7.2 Hz, 1H), 1.76 (d, J = 7.1 Hz, 3H).

[0399] [Example 25] Compound 26 (N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide)

[0400] [Chemical formula]

[0401] Step a: To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (81 mg, 0.40 mmol) and CDI (65 mg, 0.40 mmol) in DMF (1 mL) was added 2-[amino(pyridin-4-yl)methyl]-4,5-dichlorophenol (Compound 6) (90 mg, 0.33 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with water (20 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% ACN (+0.05% TFA) in water to afford tert-butyl 3-[[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate as a yellow oil (27 mg, 14%): LCMS (ESI) C 21 H 23 Cl2N3O4[M + H] + Calculated for: 452, 454 (3:2), found 452, 454 (3:2).

[0402] Step b: A mixture of tert-butyl 3-[[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate (26 mg, 0.06 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 40% B in 6 minutes; Detector: UV254 / 210 nm; Retention time: 5.11 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 26 (N-[(4,5-dichloro-2-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide) as an off-white solid (9.1 mg, 25%): LCMS (ESI) C 16 H 15 Cl2N3O2[M + H] + Calculated: 352, 354 (3:2), Found 352, 354 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.70 (d, J = 5.8 Hz, 2H), 7.79 (d, J = 5.8 Hz, 2H), 7.39 (s, 1H), 7.03 (s, 1H), 6.55 (s, 1H), 4.33 - 4.23 (m, 3H), 4.20 (dd, J = 10.8, 6.8 Hz, 1H), 3.92 - 3.80 (m, 1H).

[0403] [Example 26] Compound 27 (4,5-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenol)

[0404] [Chemical formula]

[0405] Step a: To a stirred solution of 1-bromo-4,5-dichloro-2-(prop-2-en-1-yloxy)benzene (0.20 g, 0.71 mmol) in THF (5 mL), i-PrMgCl (0.43 mL, 0.86 mmol, 2 M in THF) was added at -20 °C under a nitrogen atmosphere. The resulting mixture was stirred at -20 °C for 30 min under a nitrogen atmosphere. To the above mixture, a solution of pyridine-4-carbaldehyde (0.15 g, 1.42 mmol) in THF (2 mL) was added dropwise at -20 °C over 10 min. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% ACN (+0.05% TFA) in water to give [4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methanol as a pale yellow oil (0.15 g, 68%): LCMS (ESI) C 15 H 13 Cl2NO2[M + H] + Calculated for: 310, 312 (3 : 2), Found 310, 312 (3 : 2).

[0406] Step b: A stirred solution of Pd(PPh3)4 (12 mg, 0.01 mmol) and [4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methanol (0.33 g, 1.06 mmol) in THF (5 mL) was added NaBH4 (80 mg, 2.13 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The reaction was quenched with water (1 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 30% B in 6 min; detector: UV254 / 210 nm; retention time: 5.22 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 27 (4,5-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenol) as an off-white solid (100 mg, 35%): LCMS (ESI) C 12 H9Cl2NO2 [M + H] + Calculated: 270, 272 (3:2), found 270, 272 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.71 (d, J = 6.3 Hz, 2H), 8.07 (d, J = 6.1 Hz, 2H), 7.57 (s, 1H), 6.98 (s, 1H), 6.25 (s, 1H).

[0407] [Example 27] Compound 28 (2-[[2-(aminomethyl)pyridin-4-yl](hydroxy)methyl]-3,4-dichlorophenol)

[0408] [Chemical Structure]

[0409] Step a: To a stirred solution of (2-cyanopyridin-4-yl)(2,3-dichloro-6-hydroxyphenyl)methyl N,N-diethylcarbamate (0.1 g, 0.25 mmol) in THF (3 mL) was added DIBAl-H (2.5 mL, 2.53 mmol, 1 M in toluene) at room temperature. The reaction was stirred at 70 °C for 1 h. The reaction was quenched with aqueous HCl (2 N, 20 mL) and diluted with EA (3 × 20 mL). The organic solution was extracted with aqueous HCl (2 N, 2 × 20 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column, 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20% B to 35% B in 6 min; detector: UV: 210 nm; retention time: 4.77 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 28 (2-[[2-(aminomethyl)pyridin-4-yl](hydroxy)methyl]-3,4-dichlorophenol) as an off-white solid (27.5 mg, 26%): LCMS (ESI) C 13 H 12 Cl2N2O2[M + H] + Calculated for: 299, 301 (3:2), found 299, 301 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 5.2 Hz, 1H), 7.47 (s, 1H), 7.41 - 7.34 (m, 2H), 6.82 (d, J = 8.9 Hz, 1H), 6.51 (s, 1H), 4.26 (s, 2H).

[0410] [Example 28] Compound 29 (3,4-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenol); Compound 37 (3,4-dichloro-2-(hydroxy(pyridin-4-yl)methyl)phenol isomer 1); and Compound 34 (3,4-dichloro-2-(hydroxy(pyridin-4-yl)methyl)phenol isomer 2)

[0411]

Chem.

[0412] The absolute configurations of Compounds 34 and 37 were arbitrarily assigned.

[0413] Step a: To a stirred solution of Intermediate 3 (0.50 g, 1.77 mmol) in THF (6 mL), i-PrMgCl (1.3 mL, 2.66 mmol, 2 M in THF) was added dropwise at 0 °C under an argon atmosphere. After stirring at 0 °C for 0.5 h, pyridine-4-carbaldehyde (0.28 g, 2.66 mmol) was added at 0 °C. The reaction mixture was then stirred at 0 °C for an additional 1 h. The reaction mixture was quenched with water (30 mL). The resulting solution was extracted with EA (3 × 30 mL). The combined organic layers were then washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10 / 1) to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methanol as a pale yellow solid (0.26 g, 44%): LCMS (ESI) C 15 H 13 Cl2NO2[M + H] + Calculated: 310, 312 (3:2), Found 310, 312 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.47 - 8.39 (m, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.39 (dt, J = 4.8, 1.2 Hz, 2H), 7.00 (d, J = 9.0 Hz, 1H), 6.57 (s, 1H), 5.89 - 5.70 (m, 1H), 5.26 - 5.11 (m, 2H), 4.63 - 4.50 (m, 1H), 4.47 - 4.34 (m, 1H).

[0414] Step b: To a stirred solution of Pd(PPh3)4 (19 mg, 0.02 mmol) and [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methanol (0.26 g, 0.84 mmol) in THF (5 mL), NaBH4 (63 mg, 1.67 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (2 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep, 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 55% B in 5.5 min; detector: UV254 / 210 nm; retention time: 4.90 min. The combined fractions containing the product were concentrated under reduced pressure to afford compound 29 (3,4-dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenol) (0.15 g, 66%): LCMS (ESI) C 12 H9Cl2NO2 [M + H] + Calculated: 270, 272 (3:2), found 270, 272 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.74 - 8.68 (m, 2H), 7.98 (dt, J = 5.3, 1.1 Hz, 2H), 7.40 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 1.0 Hz, 1H).

[0415] Step c: 3,4-Dichloro-2-[hydroxy(pyridin-4-yl)methyl]phenol (0.15 g, 0.41 mmol) was separated by preparative chiral HPLC using the following conditions: column: Chiralpak IG, 20 × 250 mm, 5 μm; mobile phase A: Hex (+0.1% TFA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 10% B to 10% B in 22 min; detector: UV: 220 / 254 nm; retention times: RT1: 13.78 min; RT2: 17.75 min; temperature: 25 °C.

[0416] The enantiomer eluting faster at 13.78 minutes was obtained as a purple solid as Compound 37 (3,4-dichloro-2-(hydroxy(pyridin-4-yl)methyl)phenol isomer 1) (47 mg, 31%): LCMS (ESI) C 12 H9Cl2NO2 [M + H] + Calculated value: 270, 272 (3:2), found 270, 272 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.71 (d, J = 6.3 Hz, 2H), 7.98 (dd, J = 6.3, 1.4 Hz, 2H), 7.40 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 1.0 Hz, 1H).

[0417] The enantiomer eluting slower at 17.75 minutes was obtained as a purple solid as Compound 34 (3,4-dichloro-2-(hydroxy(pyridin-4-yl)methyl)phenol isomer 2) (55.7 mg, 37%): LCMS (ESI) C 12 H9Cl2NO2 [M + H] + Calculated value: 270, 272 (3:2), found 270, 272 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.74 - 8.68 (m, 2H), 7.98 (dt, J = 5.5, 1.1 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 1.0 Hz, 1H).

[0418] [Example 29] Compound 30 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridine-2-carbonitrile)

[0419] [Chemical Structure]

[0420] Step a: To a stirred solution of Intermediate 3 (0.80 g, 2.84 mmol) in THF (5 mL), i-PrMgBr (1.7 mL, 3.40 mmol, 2 M in THF) was added dropwise at -10 °C under a nitrogen atmosphere. After stirring for 1 hour, a solution of 4-formylpyridine-2-carbonitrile (0.45 g, 3.40 mmol) in THF (3 mL) was added dropwise to the reaction solution at -10 °C, and the mixture was stirred at -10 °C for 1 hour. The resulting solution was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give 4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridine-2-carbonitrile as a yellow oil (0.48 g, 50%): LCMS (ESI) C 16 H 12 Cl2N2O2 [M + H] + Calculated: 335, 337 (3 : 2), Found 335, 337 (3 : 2); 1 H NMR (300 MHz, CDCl3) δ 8.76 - 8.61 (m, 1H), 7.68 (dt, J = 1.8, 0.9 Hz, 1H), 7.53 - 7.43 (m, 2H), 6.84 (d, J = 9.0 Hz, 1H), 6.45 (s, 1H), 5.86 - 5.68 (m, 1H), 5.40 - 5.27 (m, 1H), 5.21 (dd, J = 17.3, 1.6 Hz, 1H), 4.62 - 4.47 (m, 1H), 4.38 (dd, J = 12.3, 5.6 Hz, 1H).

[0421] Step b: To a stirred mixture of 4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridine-2-carbonitrile (0.13 g, 0.39 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol) in THF (3 mL), NaBH4 (29 mg, 0.78 mmol) was added at room temperature. After stirring at room temperature for 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL). The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 52% B to 57% B in 6 min; detector: UV254 / 210 nm; retention time: 5.21 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 30 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridine-2-carbonitrile) as a pink solid (5.3 mg, 5%): LCMS (ESI) C 13 H8Cl2N2O2 [M + H] + Calculated for: 295, 297 (3:2), found 295, 297 (3:2). 1 H NMR (400 MHz, CD3OD) δ 8.67-8.56 (m, 1H), 7.92-7.83 (m, 1H), 7.61-7.54 (m, 1H), 7.38 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H).

[0422] [Example 30] Compound 31 (3,4-dichloro-2-[hydroxy(pyridin-3-yl)methyl]phenol)

[0423] [Chemical formula]

[0424] Step a: To a stirred solution of intermediate 3 (0.50 g, 1.77 mmol) in THF (5 mL), i-PrMgCl (1.07 mL, 2.13 mmol, 2 M in THF) was added dropwise at -30 °C under a nitrogen atmosphere and stirred for 30 minutes. To the above mixture, a solution of pyridine-3-carbaldehyde (0.38 g, 3.55 mmol) in THF (2 mL) was added dropwise at -30 °C under a nitrogen atmosphere. The resulting solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% ACN (+0.05% TFA) in water to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-3-yl)methanol as a yellow oil (0.50 g, 91%): LCMS (ESI) C 15 H 13 Cl2NO2[M + H] + Calculated: 310, 312 (3:2), found 310, 312 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.87 (s, 1H), 8.83 - 8.66 (m, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.95 (dd, J = 8.2, 5.7 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 5.94 - 5.75 (m, 1H), 5.27 - 5.14 (m, 2H), 4.56 (dd, J = 12.6, 5.3 Hz, 1H), 4.38 (dd, J = 12.7, 5.8 Hz, 1H).

[0425] Step b: A stirred solution of Pd(PPh3)4 (13 mg, 0.01 mmol) and [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-3-yl)methanol (0.35 g, 1.13 mmol) in THF (5 mL) was added NaBH4 (64 mg, 1.69 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 25% B in 6 minutes; detector: UV 210 nm; retention time: 5.25 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 31 (3,4-dichloro-2-[hydroxy(pyridin-3-yl)methyl]phenol) as an off-white solid (0.17 g, 39%): LCMS (ESI) C 12 H9Cl2NO2 [M + H] + calculated value: 270, 272 (3:2), found 270, 272 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.87 (dd, J = 2.1, 1.0 Hz, 1H), 8.75 - 8.68 (m, 1H), 8.43 - 8.38 (m, 1H), 7.98 - 7.90 (m, 1H), 7.40 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 1.0 Hz, 1H).

[0426] [Example 31] Compound 32 (1-[hydroxyl(pyridin-4-yl)methyl]naphthalen-2-ol)

[0427] [Chemical formula]

[0428] Step a: To a solution of 1-bromo-2-methoxynaphthalene (0.50 g, 2.11 mmol) in THF (8 mL), n-BuLi (0.9 mL, 2.25 mmol, 2.5 M in hexanes) was added dropwise at -65 °C under a nitrogen atmosphere. The reaction mixture was stirred at -65 °C for 0.5 h. Then pyridine-4-carbaldehyde (0.27 g, 2.53 mmol) was added at -65 °C. The reaction mixture was stirred at -65 °C for 0.5 h and then warmed to room temperature over 0.5 h. After stirring at room temperature for an additional 0.5 h, the reaction was quenched with saturated aqueous NH4Cl (10 mL). The mixture was extracted with EA (2 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN (+0.05% TFA) in water to afford (2-methoxynaphthalen-1-yl)(pyridin-4-yl)methanol as a light brown oil (0.32 g, 57%): LCMS (ESI) C 17 H 15 NO2 [M + H] + Calculated: 266, Found 266; 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 2H), 8.12 - 7.75 (m, 5H), 7.61 - 7.27 (m, 3H), 6.89 (s, 1H), 3.89 (s, 3H).

[0429] Step b: To a stirred solution of (2-methoxynaphthalen-1-yl)(pyridin-4-yl)methanol (0.10 g, 0.38 mmol) in DCM (5 mL), BBr3 (0.5 mL, 5.29 mmol) was added at room temperature. The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO3 (8 mL) and then the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column, 19 mm × 250 mm, 10 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 18% B to 20% B in 6 minutes; Detector: UV 210 nm; Retention time: 4.98 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain compound 32 (1-[hydroxyl(pyridin-4-yl)methyl]naphthalene-2-ol) as an off-white solid (44 mg, 47%): LCMS (ESI) C 16 H 13 NO2[M + H] + Calculated value: 252, Measured value 252; 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.73 - 8.52 (m, 2H), 7.95 (dd, J = 8.4, 1.4 Hz, 1H), 7.83 - 7.69 (m, 4H), 7.32 - 7.15 (m, 3H), 6.85 (s, 1H), 6.72 - 6.50 (br, 1H).

[0430] [Example 32] Compound 33 (N-([4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridin-2-yl]methyl)acetamide)

[0431] [Chemical formula]

[0432] Step a: A stirred solution of 2-[[2-(aminomethyl)pyridin-4-yl](hydroxy)methyl]-3,4-dichlorophenol (90 mg, 0.30 mmol) and Ac2O (61 mg, 0.60 mmol) in MeOH (1 mL) was added Et3N (61 mg, 0.60 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (1 mL), and then a solution of NaOH (84 mg, 2.11 mmol) in water (0.2 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18% B to 23% B in 6 min; detector: UV: 210 nm; retention time: 5.13 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 33 (N-([4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridin-2-yl]methyl)acetamide) as an off-white solid (47.3 mg, 31%): LCMS (ESI) C 15 H 14 Cl2N2O3 [M + H] + calculated: 341, 343 (3:2), found 341, 343 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.58 (d, J = 6.1 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 6.1 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 4.64 (s, 2H), 2.05 (s, 3H).

[0433] [Example 33] Compound 35 (3,4-dichloro-2-[hydroxy(2-methylpyridin-4-yl)methyl]phenol)

[0434] [Chemical]

[0435] Step a: To a stirred solution of intermediate 3 (0.50 g, 1.77 mmol) in THF (5 mL), i-PrMgCl (1.35 mL, 2.70 mmol) was added dropwise at -25 °C under a nitrogen atmosphere. The resulting mixture was stirred at -25 °C for 0.5 h under a nitrogen atmosphere. Then 2-methylpyridine-4-carbaldehyde (0.32 g, 2.66 mmol) in THF (5 mL) was added. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](2-methylpyridin-4-yl)methanol as a yellow solid (0.40 g, 70%): LCMS (ESI) C 16 H 15 Cl2NO2[M + H] + Calculated for: 324, 326 (3 : 2), found 324, 326 (3 : 2).

[0436] Step b: To a stirred solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](2-methylpyridin-4-yl)methanol (0.40 g, 1.23 mmol) and Pd(PPh3)4 (29 mg, 0.03 mmol) in THF (2 mL), NaBH4 (70 mg, 1.85 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column, 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 50% B in 5.5 min; detector: UV254 / 210 nm; retention time: 5.23 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 35 (3,4-dichloro-2-[hydroxy(2-methylpyridin-4-yl)methyl]phenol) as an off-white solid (0.20 g, 59%): LCMS (ESI) C 13 H 11 Cl2NO2[M + H] + Calculated for: 284, 286 (3:2), found 284, 286 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 6.3 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.84 (dd, J = 6.3, 1.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 1.0 Hz, 1H), 2.78 (s, 3H).

[0437] [Example 34] Compound 36 (2-[(2-aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol)

[0438] [Chemical Structure]

[0439] Step a: To a stirred solution of intermediate 3 (0.50 g, 1.77 mmol) in THF (8 mL), i-PrMgCl (1.1 mL, 2.12 mmol, 2 M in THF) was added dropwise at -20 °C under a nitrogen atmosphere. The resulting solution was stirred at -20 °C for 30 minutes under a nitrogen atmosphere. To the above solution, tert-butyl N-(4-formylpyridin-2-yl)carbamate (0.59 g, 2.66 mmol) was added at -20 °C. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give tert-butyl N-(4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridin-2-yl)carbamate as a pale yellow solid (0.30 g, 39%): LCMS (ESI) C 20 H 22 Cl2N2O4[M + H] + Calculated: 425, 427 (3 : 2), Found 425, 427 (3 : 2).

[0440] Step b: To a stirred solution of Pd(PPh3)4 (8 mg, 0.01 mmol) and tert-butyl N-(4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridin-2-yl)carbamate (0.30 g, 0.71 mmol) in THF (5 mL), NaBH4 (32 mg, 0.85 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was quenched with water (1 mL) and concentrated under reduced pressure to give tert-butyl N-[4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridin-2-yl]carbamate as a brown solid (0.20 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C17 H 18 Cl2N2O4[M + H + + Calculated values: 385, 387 (3:2), measured values 385, 387 (3:2).

[0441] Step c: To a stirred solution of tert-butyl N-[4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]pyridin-2-yl]carbamate (0.20 g, 0.52 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 22% B to 25% B in 6 minutes; detector: UV254 / 210 nm; retention time: 5.23 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 36 (2-[(2-aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol) as an off-white solid (99.4 mg, 32% over 2 steps): LCMS (ESI) C 12 H 10 Cl2N2O2[M + H] + Calculated values: 285, 287 (3:2), measured values 285, 287 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.73 (dd, J = 6.8, 0.7 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.45 (d, J = 1.5 Hz, 1H).

[0442] [Example 35] Compound 38 (N-((2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl)acetamide isomer 2); and ​Compound 41 (N-((2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl)acetamide isomer 1)

[0443]

Chem.

[0444] The absolute configurations of compounds 38 and 41 were arbitrarily assigned.

[0445] Step a: To a mixture of 3,4-dichlorophenol (12.00 g, 73.62 mmol), pyridine-4-carbaldehyde (7.89 g, 73.62 mol), and acetamide (5.22 g, 88.34 mmol) was added AlCl3 (1.79 g, 11.04 mmol) at room temperature. The mixture was then stirred at 110 °C for 1 h. After cooling to room temperature, the reaction was diluted with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the crude product. The crude product was purified by preparative HPLC: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 5% B to 40% B in 6.5 min; detector: UV210 / 254 nm; retention time: 5.00 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide as an off-white solid (0.30 g, 0.96%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated for: 311, 313 (3:2), found 311, 313 (3:2); 11H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.74 - 8.66 (m, 2H), 8.57 (d, J = 7.9 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.3, 3.5 Hz, 2H), 2.05 (s, 3H).

[0446] N-[(2,3-Dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]acetamide (40 mg, 0.09 mmol) was separated by chiral preparative HPLC using the following conditions: column: Chiralpak IG, 20 × 250 mm, 5 μm; mobile phase A: Hex (containing 8 mmol / L NH3·MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 7% B to 7% B in 33 min; detector: UV220 / 254 nm; retention time: RT1: 23.95 min; RT2: 27.02 min; temperature: 25 °C.

[0447] The enantiomer eluting faster at 23.95 min was obtained as an off-white solid as compound 41 (N-((2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl)acetamide isomer 1) (11.6 mg, 40%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated value: 311, 313 (3 : 2), found 311, 313 (3 : 2); 1 1H NMR (400 MHz, CD3OD) δ 8.48 - 8.42 (m, 2H), 7.39 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 5.2 Hz, 2H), 7.07 (s, 1H), 6.81 (d, J = 8.9 Hz, 1H), 2.13 (s, 3H).

[0448] The enantiomer that eluted later at 27.02 minutes was obtained as an off - white solid as compound 38 (N - ((2,3 - dichloro - 6 - hydroxyphenyl)(pyridin - 4 - yl)methyl)acetamide isomer 2) (9.6 mg, 33%): LCMS (ESI) C 14 H 12 Cl2N2O2[M + H] + Calculated value: 311, 313 (3:2), found 311, 313 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.53 - 8.47 (m, 2H), 7.43 - 7.37 (m, 3H), 7.08 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 2.14 (s, 3H).

[0449] [Example 36] Compound 39 (3,4 - dichloro - 2 - [hydroxy(3 - methylpyridin - 4 - yl)methyl]phenol)

[0450] [Chemical formula]

[0451] Step a: A solution of intermediate 3 (0.50 g, 2.07 mmol) in THF (5 mL) was added dropwise with i-PrMgCl (1.07 mL, 2.13 mmol, 2 M in THF) at 0 °C, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. Then, a solution of 3-methylpyridine-4-carbaldehyde (0.26 g, 2.13 mmol) in THF (2 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8 / 1) to obtain [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](3-methylpyridin-4-yl)methanol as a brown oil (0.48 g, 75%): LCMS (ESI) C 16 H 15 Cl2NO2[M + H] + Calculated: 324, 326 (3 : 2), Found 324, 326 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.41 - 8.37 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 5.0 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.43 (s, 1H), 5.86 - 5.72 (m, 1H), 5.25 (dd, J = 13.9, 9.1 Hz, 2H), 4.58 - 4.42 (m, 2H), 2.31 (s, 3H).

[0452] Step b: A stirred solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](3-methylpyridin-4-yl)methanol (0.48 g, 1.48 mmol) and Pd(PPh3)4 (0.17 g, 0.15 mmol) in THF (3 mL) was added NaBH4 (0.17 g, 4.44 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20% B to 60% B in 8 min; detector: UV254 / 210 nm; retention time: 6.25 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 39 (3,4-dichloro-2-[hydroxy(3-methylpyridin-4-yl)methyl]phenol) as an off-white solid (178.6 mg, 29%): LCMS (ESI) C 13 H 11 Cl2NO2[M + H] + Calculated for: 284, 286 (3:2), found 284, 286 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.67 (d, J = 6.1 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.60 (s, 1H), 2.21 (s, 3H).

[0453] [Example 37] Compound 40 (2-[(6-aminopyridin-3-yl)(hydroxy)methyl]-3,4-dichlorophenol)

[0454]

Chem.

[0455] Step a: To a stirred solution of 6-aminopyridine-3-carbaldehyde (0.40 g, 3.28 mmol) and DMAP (40 mg, 0.33 mmol) in DCM (5 mL), Boc2O (0.86 g, 3.93 mmol) and Et3N (0.40 g, 3.93 mmol) were added at room temperature. The resulting solution was stirred at room temperature for 2 h. The reaction was diluted with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (5 / 1) to afford tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-formylpyridin-2-yl)carbamate as an off-white solid (0.56 g, 47%): LCMS (ESI) C 16 H 22 N2O5[M + H] + Calculated: 323 Found 323.

[0456] Step b: To a stirred solution of Intermediate 3 (0.13 g, 0.46 mmol) in THF (5 mL), i-PrMgCl (0.28 mL, 0.56 mmol, 2 M in THF) was added dropwise at -20 °C under an argon atmosphere. The resulting mixture was stirred at -20 °C for 30 minutes under an argon atmosphere. To the above mixture, a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-formylpyridin-2-yl)carbamate (0.44 g, 1.38 mmol) in THF (2 mL) was added dropwise at -20 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 1) to give tert-butyl (5-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridin-2-yl)carbamate as a pale yellow oil (80 mg, 41%): LCMS (ESI) C 20 H 22 Cl2N2O4[M + H + + calculated: 425, 427 (3:2), found 425, 427 (3:2).

[0457] Step c: To a stirred mixture of tert-butyl (5-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]pyridin-2-yl)carbamate (80 mg, 0.19 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in THF (2 mL), NaBH4 (14 mg, 0.38 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (1 mL). The resulting mixture was concentrated under reduced pressure to give tert-butyl (5-(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl)pyridin-2-yl)carbamate as a brown oil (80 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C​17 H 18 Cl2N2O4[M + H] + Calculated values: 385, 387 (3:2), measured values 385, 387 (3:2).

[0458] Step d: To a stirred solution of tert-butyl (5-((2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.16 mmol) in DCM (2 mL) was added dropwise TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge C 18 OBD Prep column 100 Å, 10 μm, 19 mm×250 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 22% B to 27% B in 6 minutes; detector: UV254 / 210 nm; retention time: 5.13 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 40 (2-[(6-aminopyridin-3-yl)(hydroxy)methyl]-3,4-dichlorophenol) as an off-white solid (43 mg, 57% over 2 steps): LCMS (ESI) C 12 H 10 Cl2N2O2[M + H] + Calculated values: 285, 287 (3:2), measured values 285, 287 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 9.3 Hz, 1H), 7.79 (s, 1H), 7.38 (dd, J = 8.8, 1.8 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.84 (dd, J = 8.8, 1.8 Hz, 1H), 6.40 (s, 1H).

[0459] [Example 38] Compound 42 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide); Compound 50 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide isomer 1); and Compound 49 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide isomer 2)

[0460]

Chemical formula

[0461] The absolute configurations of Compounds 49 and 50 were arbitrarily assigned.

[0462] Step a: To a stirred solution of pyridine-4-carbaldehyde (5.00 g, 46.68 mmol) and Ti(OEt)4 (31.90 g, 140.04 mmol) in THF (50 mL), 2-methylpropan-2-sulfinamide (11.30 g, 93.36 mmol) was added dropwise at room temperature. The resulting solution was stirred at 70 °C for 12 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was filtered and the filtrate was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 2-methyl-N-[(1E)-(pyridin-4-yl)methylene]propan-2-sulfinamide as a pale yellow oil (7.00 g, 64%): LCMS (ESI) C 10 H 14 N2OS [M + H] + Calculated value: 211 Measured value 211; 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 4.8 Hz, 2H), 8.62 (d, J = 2.1 Hz, 1H), 7.75 - 7.69 (m, 2H), 1.31 (s, 9H).

[0463] Step b: To a stirred solution of intermediate 3 (2.10 g, 7.45 mmol) in THF (20 mL), i-PrMgCl (6.2 mL, 12.38 mmol, 2 M in THF) was added dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes under an argon atmosphere. To the above mixture, 2-methyl-N-[(1E)-(pyridin-4-yl)methylene]propan-2-sulfinamide (1.30 g, 6.19 mmol) in THF (5 mL) was added dropwise at 0 °C over 10 minutes. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give N-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]-2-methylpropan-2-sulfinamide as a pale yellow oil (1.00 g, 35%): LCMS (ESI) C 19 H 22 Cl2N2O2S [M + H] + Calculated: 413, 415 (3 : 2), Found 413, 415 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.58-8.52 (m, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.25-7.19 (m, 2H), 6.79 (d, J = 8.9 Hz, 1H), 6.31 (d, J = 10.9 Hz, 1H), 5.76 (s, 1H), 5.31-4.99 (m, 2H), 4.56-4.35 (m, 2H), 1.31 (s, 9H).

[0464] Step c: To a stirred solution of N-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]-2-methylpropane-2-sulfinamide (1.00 g, 2.42 mmol) in 1,4-dioxane (10 mL) was added dropwise aqueous HCl solution (6 N, 5 mL) at room temperature. The resulting solution was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give 1-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-1-(pyridin-4-yl)methanamine hydrochloride as a yellow solid (0.80 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 15 H 14 Cl2N2O [M + H] + Calculated for: 309, 311 (3 : 2), found 309, 311 (3 : 2).

[0465] Step d: To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (0.62 g, 3.10 mmol) and HATU (1.97 g, 5.17 mmol) in DMF (10 mL) were added 1-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-1-(pyridin-4-yl)methanamine hydrochloride (0.80 g, 2.33 mmol) and TEA (0.79 g, 7.76 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give tert-butyl 3-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)azetidine-1-carboxylate as a pale yellow oil (0.60 g, 50% over 2 steps): LCMS (ESI) C 24 H 27 Cl2N3O4[M + H] +Calculated values: 492, 494 (3:2), measured values 492, 494 (3:2); 1 1H NMR (400 MHz, CDCl3) δ 8.59 - 8.46 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.24 - 7.10 (m, 2H), 7.06 (dt, J = 4.7, 1.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 1H), 5.80 - 5.71 m, 1H), 5.30 - 5.22 (m, 1H), 5.20 (d, J = 17.3 Hz, 1H), 4.50 (dd, J = 12.5, 5.8 Hz, 1H), 4.38 (dd, J = 12.5, 5.2 Hz, 1H), 4.22 - 4.11 (m, 2H), 4.14 - 4.02 (m, 2H), 3.35 - 3.23 (m, 1H), 1.44 (s, 9H).

[0466] Step e: To a stirred solution of tert-butyl 3-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)azetidine-1-carboxylate (0.30 g, 0.61 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol) in THF (5 mL) was added NaBH4 (46 mg, 1.22 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to give tert-butyl 3-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate as a brown oil (0.30 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 21 H 23 Cl2N3O4 [M + H] + Calculated values: 452, 454 (3:2), measured values 452, 454 (3:2).

[0467] Step f: A solution of tert-butyl 3-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]azetidine-1-carboxylate (0.30 g, 0.66 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 8% B to 28% B in 12 minutes; detector: UV254 / 210 nm; retention time: 10.25 minutes. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 42 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide) as an off-white solid (83.5 mg, 38% over 2 steps): LCMS (ESI) C 16 H 15 Cl2N3O2[M + H] + Calculated for: 352, 354 (3 : 2), found 352, 354 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.44 (dd, J = 4.8, 2.0 Hz, 2H), 7.35 - 7.25 (m, 3H), 6.99 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.97 (d, J = 8.3 Hz, 2H), 3.95 - 3.84 (m, 1H), 3.84 - 3.71 (m, 1H).

[0468] Step g: N-[(2,3-Dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide (81 mg, 0.23 mmol) was separated by preparative chiral HPLC using the following conditions: column: Chiralpak IG UL001, 20×250 mm, 5 μm; mobile phase A: 3 / 1 HEX / DCM, mobile phase B: EtOH (+0.2% IPA); flow rate: 20 mL / min; gradient: 7% B to 7% B in 33 min; detector: UV: 220 / 254 nm; retention time: RT1: 10.90 min; RT2: 15.66 min; temperature: 25 °C.

[0469] The enantiomer eluting faster at 10.90 min was obtained as an off-white solid of compound 50 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide isomer 1) (19.3 mg, 24%): LCMS (ESI) C 16 H 15 Cl2N3O2[M + H] + Calculated for: 352, 354 (3:2), found 352, 354 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.47-8.41 (m, 2H), 7.30 (dd, J = 9.4, 7.2 Hz, 3H), 6.99 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.13-4.04 (m, 1H), 4.02-3.90 (m, 2H), 3.92-3.84 (m, 1H), 3.83-3.71 (m, 1H).

[0470] The enantiomer eluting slower at 15.66 min was obtained as an off-white solid of compound 49 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]azetidine-3-carboxamide isomer 2) (19.7 mg, 24%): LCMS (ESI) C 16 H 15 Cl2N3O2[M + H] + Calculated for: 352, 354 (3:2), found 352, 354 (3:2);1 1H NMR (400 MHz, CD3OD) δ 8.47 - 8.41 (m, 2H), 7.35 - 7.26 (m, 3H), 6.99 (s, 1H), 6.71 (d, J = 8.9 Hz, 1H), 4.13 - 4.04 (m, 1H), 4.02 - 3.84 (m, 3H), 3.84 - 3.71 (m, 1H).

[0471] [Example 39] Compound 43 (3,4 - dichloro - 2 - [hydroxy(3 - methylpyridin - 4 - yl)methyl]phenol isomer 2); and Compound 46 (3,4 - dichloro - 2 - [hydroxy(3 - methylpyridin - 4 - yl)methyl]phenol isomer 1)

[0472] [Chemical formula]

[0473] The absolute configurations of Compounds 43 and 46 were arbitrarily assigned.

[0474] Step a: 3,4 - dichloro - 2 - [hydroxy(3 - methylpyridin - 4 - yl)methyl]phenol (0.18 g, 0.45 mmol) was separated by preparative chiral HPLC using the following conditions: Column: Phenomenex Lux 5μ Cellulose - 3, 5×25 cm, 5μm; Mobile phase A: Hex(+0.1% TFA), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 21 minutes; Detector: UV: 220 / 254 nm; Retention time: RT1: 7.27 minutes; RT2: 12.71 minutes; Temperature: 25°C. The faster - eluting enantiomer at 7.27 minutes was obtained as an off - white solid as Compound 46 (3,4 - dichloro - 2 - [hydroxy(3 - methylpyridin - 4 - yl)methyl]phenol isomer 1) (69 mg, 38%): LCMS (ESI) C 13 H 11 Cl2NO2[M + H] +Calculated value: 284, 286 (3:2), measured value 284, 286 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 6.2 Hz, 1H), 8.53 (d, J = 14.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.61 (s, 1H), 2.21 (s, 3H).

[0475] The enantiomer eluting later at 12.71 minutes was obtained as an off-white solid (75.8 mg, 42%) as compound 43 (3,4-dichloro-2-[hydroxy(3-methylpyridin-4-yl)methyl]phenol isomer 2): LCMS (ESI) C 13 H 11 Cl2NO2[M + H] + Calculated value: 284, 286 (3:2), measured value 284, 286 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 6.1 Hz, 1H), 8.57 - 8.46 (m, 2H), 7.41 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.61 (s, 1H), 2.21 (s, 3H).

[0476] [Example 40] Compound 44 (2-[(2-aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol isomer 1); and Compound 45 (2-[(2-aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol isomer 2)

[0477] [Chemical formula]

[0478] The absolute configurations of compounds 44 and 45 were arbitrarily assigned.

[0479] Step a: 2-[(2-Aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol (96 mg, 0.24 mmol) was separated by preparative chiral HPLC using the following conditions: column: Chiralpak IF, 2 × 25 cm, 5 μm; mobile phase A: Hex(+0.1% TFA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 10% B to 10% B in 15 min; detector: UV: 220 / 254 nm; retention time: RT1: 8.29 min; RT2: 10.44 min; temperature: 25 °C.

[0480] The enantiomer eluting faster at 8.29 min was obtained as a purple solid as Compound 44 (2[((2-Aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol isomer 1) (31 mg, 32%): LCMS (ESI) C 12 H 10 Cl2N2O2[M + H] + Calculated: 285, 287 (3:2), found 285, 287 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 6.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.87 - 6.76 (m, 2H), 6.46 (d, J = 1.4 Hz, 1H).

[0481] The enantiomer eluting slower at 10.44 min was obtained as a purple solid as Compound 45 (2-[(2-Aminopyridin-4-yl)(hydroxy)methyl]-3,4-dichlorophenol isomer 2) (30 mg, 31%): LCMS (ESI) C 12 H 10 Cl2N2O2[M + H] + Calculated: 285, 287 (3:2), found 285, 287 (3:2); 11H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 6.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.87 - 6.76 (m, 2H), 6.46 (d, J = 1.3 Hz, 1H).

[0482] [Example 41] Compound 47 (2 - ((2 - (aminomethyl)pyridin - 4 - yl)(hydroxy)methyl)-3,4 - dichlorophenol isomer 1); and Compound 53 (2 - ((2 - (aminomethyl)pyridin - 4 - yl)(hydroxy)methyl)-3,4 - dichlorophenol isomer 2)

[0483] [Chemical formula]

[0484] The absolute configurations of Compounds 47 and 53 were arbitrarily assigned.

[0485] Step a: 2 - [[2 - (aminomethyl)pyridin - 4 - yl](hydroxy)methyl]-3,4 - dichlorophenol (25 mg, 0.06 mmol) was separated by chiral preparative HPLC using the following conditions: column: CHIRALPAK AD - H, inner diameter 2.0 cm × 25 cm; mobile phase A: Hex(+0.1% TFA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 10% B to 10% B in 18 minutes; detector: UV: 220 / 254 nm; retention time: RT1: 8.56 minutes; RT2: 14.42 minutes.

[0486] The enantiomer eluting faster at 8.56 minutes was obtained as Compound 47 (2 - ((2 - (aminomethyl)pyridin - 4 - yl)(hydroxy)methyl)-3,4 - dichlorophenol isomer 1) as a purple solid (8.2 mg, 32%): LCMS (ESI) C 13 H 12 Cl2N2O2[M + 1] +Calculated value: 299, 301 (3:2), measured value 299, 301 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 5.2 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 4.26 (s, 2H).

[0487] The enantiomer eluting later at 14.42 minutes was obtained as a purple solid as Compound 53 (2 - ((2 - (aminomethyl)pyridin - 4 - yl)(hydroxy)methyl)-3,4 - dichlorophenol isomer 2) (8 mg, 32%): LCMS (ESI) C 13 H 12 Cl2N2O2 [M + 1] + Calculated value: 299, 301 (3:2), measured value 299, 301 (3:2); 1 H NMR (300 MHz, CD3OD) δ 8.56 (d, J = 5.2 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 6.5 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 4.26 (s, 2H).

[0488] [Example 42] Compound 48 (4 - dichloro - 2 - [hydroxy(1H - indol - 6 - yl)methyl]phenol)

[0489]

Chemical Structure

[0490] Step a: To a stirred solution of Intermediate 5 (0.20 g, 0.61 mmol) in THF (5 mL), i-PrMgCl (0.34 mL, 0.67 mmol, 2 M in THF) was added at -15 °C under a nitrogen atmosphere. To the above mixture, a solution of tert-butyl 6-formyl-1H-indole-1-carboxylate (0.19 g, 0.79 mmol) in THF (2 mL) was added at -15 °C. The resulting mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL) at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to afford tert-butyl 6-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]-1H-indole-1-carboxylate as a yellow oil (0.24 g, 88%): LCMS (ESI) C 23 H 23 Cl2NO4[M + Na] + Calculated for: 470, 472 (3:2), found 470, 472 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.60 (d, J = 3.7 Hz, 1H), 7.49 (dd, J = 15.1, 8.6 Hz, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J = 3.8 Hz, 1H), 5.84 - 5.70 (m, 1H), 5.22 - 5.07 (m, 2H), 4.61 - 4.51 (m, 1H), 4.45 - 4.36 (m, 1H), 1.60 (s, 9H).

[0491] Step b: A solution of K2CO3 (0.59 g, 4.28 mmol) in H2O (1 mL) was added to a stirred solution of tert-butyl 6-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]-1H-indole-1-carboxylate (0.24 g, 0.54 mmol) in MeOH (3 mL, 0.01 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 3 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-6-yl)methanol as a yellow oil (0.16 g, 84%): LCMS (ESI) C 18 H 15 Cl2NO2[M + H - 18] + Calculated for: 330, 332 (3 : 2), Found 330, 332 (3 : 2).

[0492] Step c: NaBH4 (16 mg, 0.41 mmol) was added to a stirred solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-6-yl)methanol (0.12 g, 0.34 mmol) and Pd(PPh3)4 (4 mg, 0.004 mmol) in THF (3 mL) at room temperature under a nitrogen atmosphere. The reaction was quenched with water (3 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C 18Column 30×150 mm, 5 μm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 60% B in 7 minutes; detector: UV254 / 210 nm; retention time: 6.55 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 48 (3,4-dichloro-2-[hydroxy(1H-indol-6-yl)methyl]phenol) as an off-white solid (60 mg, 56%): LCMS (ESI) C 15 H 11 Cl2NO2[M + H - 18] + Calculated for: 290, 292 (3:2), found 290, 292 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.51 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 3.1 Hz, 1H), 7.10 (dd, J = 8.1, 1.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 3.1 Hz, 1H).

[0493] [Example 43] Compound 51 (3,4-dichloro-2-[hydroxy(1H-indol-4-yl)methyl]phenol)

[0494] [Chemical formula]

[0495] Step a: To a stirred solution of intermediate 5 (0.20 g, 0.61 mmol) in THF (3 mL), i-PrMgCl (0.36 mL, 0.73 mmol, 2 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. Then, 1H-indole-4-carbaldehyde (71 mg, 0.49 mmol) was added to the resulting mixture. The resulting solution was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 1) to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-4-yl)methanol as a pale yellow oil (60 mg, 22%): LCMS (ESI) C 18 H 15 Cl2NO2[M + Na] + Calculated for: 370, 372 (3 : 2), found 370, 372 (3 : 2).

[0496] Step b: To a stirred mixture of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-4-yl)methanol (60 mg, 0.17 mmol) and Pd(PPh3)4 (2 mg, 0.002 mmol) in THF (1 mL) was added NaBH4 (13 mg, 0.34 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (3 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column 19×250 mm, 10 μm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B to 60% B in 7 min; detector: UV254 / 210 nm; retention time: 5.98 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 51 (3,4-dichloro-2-[hydroxy(1H-indol-4-yl)methyl]phenol) as a purple solid (16.8 mg, 30%): LCMS (ESI) C 15 H 11 Cl2NO2[M - H] + Calculated for: 306, 308 (3:2), found 306, 308 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.35 (t, J = 8.5 Hz, 2H), 7.29 (d, J = 3.2 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.81 - 6.74 (m, 2H), 6.70 (d, J = 3.2 Hz, 1H).

[0497] [Example 44] Compound 52 (3,4-dichloro-2-[hydroxy(1H-indol-5-yl)methyl]phenol)

[0498] [Chemical Structure]

[0499] Step a: To a stirred solution of intermediate 5 (0.36 g, 1.10 mmol) in THF (3 mL), i-PrMgCl (0.83 mL, 1.65 mmol, 2 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. Then, 1H-indole-5-carbaldehyde (0.20 g, 1.38 mmol) was added to the resulting mixture. The resulting solution was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 1) to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-5-yl)methanol as a pale yellow oil (50 mg, 9%): LCMS (ESI) C 18 H 15 Cl2NO2[M + Na] + Calculated: 370, 372 (3 : 2), found 370, 372 (3 : 2).

[0500] Step b: To a stirred mixture of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-5-yl)methanol (50 mg, 0.14 mmol) and Pd(PPh3)4 (2 mg, 0.001 mmol) in THF (1 mL) was added NaBH4 (11 mg, 0.29 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (3 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column 30×150 mm, 5 μm; mobile phase A: water (+0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B to 60% B in 7 min; detector: UV254 / 210 nm; retention time: 5.88 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 52 (3,4-dichloro-2-[hydroxy(1H-indol-5-yl)methyl]phenol) as a purple solid (12 mg, 26%): LCMS (ESI) C 15 H 11 Cl2NO2[M + H -18] + Calculated for: 290, 292 (3:2), found 290, 292 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 12.3, 8.6 Hz, 2H), 7.26 - 7.16 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 6.47 - 6.39 (m, 2H).

[0501] [Example 45] Compound 54 (3,4-dichloro-2-[hydroxy(pyrazin-2-yl)methyl]phenol)

[0502] [Chemical formula]

[0503] Step a: To a solution of intermediate 5 (0.30 g, 0.91 mmol) in THF (3 mL), i-PrMgCl (0.5 mL, 1.00 mmol, 2 M in THF) was added dropwise at -10 to 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of pyrazine-2-carbaldehyde (0.15 g, 1.39 mmol) in THF (2 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h, then warmed to room temperature and stirred for an additional 0.5 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), and then the mixture was extracted with EA (2 × 20 mL). The organic phases were combined and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 2) to afford [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyrazin-2-yl)methanol as an off-white solid (0.12 g, 42%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated for: 311, 313 (3 : 2), Found 311, 313 (3 : 2).

[0504] Step b: To a solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyrazin-2-yl)methanol (0.10 g, 0.32 mmol) and Pd(PPh3)4 (19 mg, 0.02 mmol) in THF (3 mL), NaBH4 (24 mg, 0.64 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl (1 mL), and then the mixture was concentrated. The residue was purified by preparative HPLC using the following conditions: Column: XBridge C 18OBD Prep column, 30 mm × 150 mm, 5 μm; mobile phase A: water (+0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 39% B in 5 min; detector: UV220 / 254 nm; retention time: 4.10 min. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 54 (3,4-dichloro-2-[hydroxy(pyrazin-2-yl)methyl]phenol) as a pale pink solid (11 mg, 10%): LCMS (ESI) C 11 H8Cl2N2O2 [M + H] + Calculated: 271, 273 (3:2), found 271, 273 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.49 (s, 2H), 7.33 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H).

[0505] [Example 46] Compound 55 (3,4-dichloro-2-[hydroxy(pyrimidin-4-yl)methyl]phenol)

[0506] [Chemical formula]

[0507] Step a: To a solution of Intermediate 5 (0.30 g, 0.91 mmol) in THF (3 mL), i-PrMgCl (0.5 mL, 1.00 mmol, 2 M in THF) was added dropwise at -10 to 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h. Then a solution of pyrimidine-4-carbaldehyde (0.15 g, 1.39 mmol) in THF (2 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h and then warmed to room temperature over 0.5 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), and then the mixture was extracted with EA (2 × 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 2) to afford [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyrimidin-4-yl)methanol as an off-white solid (0.12 g, 42%): LCMS (ESI) C 14 H 12 Cl2N2O2 [M + H] + Calculated: 311, 313 (3:2), Found 311, 313 (3:2).

[0508] Step b: A solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyrimidin-4-yl)methanol (0.12 g, 0.39 mmol) and Pd(PPh3)4 (22 mg, 0.02 mmol) in THF (3 mL) was added with NaBH4 (29 mg, 0.77 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (1 mL), and then the mixture was concentrated. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD Prep column, 30 mm × 150 mm, 5 μm; mobile phase A: water (+0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 39% B in 5 min; detector: UV220 / 254 nm; retention time: 4.10 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 55 (3,4-dichloro-2-[hydroxy(pyrimidin-4-yl)methyl]phenol) as a pale pink solid (9 mg, 8%): LCMS (ESI) C 11 H8Cl2N2O2 [M + H] + Calculated: 271, 273 (3:2), found 271, 273 (3:2); 1 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.76 (d, J = 5.3 Hz, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H).

[0509] [Example 47] Compound 56 (3,4-dichloro-2-[hydroxy(1H-pyrazol-4-yl)methyl]phenol)

[0510] [Chemical formula]

[0511] Step a: To a solution of intermediate 5 (1.70 g, 5.17 mmol) in THF (7 mL), i-PrMgCl (3.1 mL, 6.20 mmol, 2 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. Then, tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (1.01 g, 5.17 mmol) in THF (2 mL) was added to the above solution at 0 °C over 5 min. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 35 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to afford [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-pyrazol-4-yl)methanol as an off-white solid (0.60 g, 39%): LCMS (ESI) C 13 H 12 Cl2N2O2 [M + H] + Calculated for: 299, 301 (3 : 2), found 299, 301 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 2H), 7.38 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.41 (s, 1H), 5.99 - 5.87 (m, 1H), 5.37 - 5.31 (m, 1H), 5.31 - 5.28 (m, 1H), 4.67 - 4.51 (m, 2H).

[0512] Step b: To a stirred solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-pyrazol-4-yl)methanol (0.26 g, 0.87 mmol) and Pd(PPh3)4 (10 mg, 0.01 mmol) in THF (3 mL) was added NaBH4 (66 mg, 1.74 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 67% B in 10 min; detector: UV254 / 210 nm; retention time: 9.65 min. The fractions containing the desired product were collected and concentrated under reduced pressure to afford compound 56 (3,4-dichloro-2-[hydroxy(1H-pyrazol-4-yl)methyl]phenol) as an off-white solid (95 mg, 42%): LCMS (ESI) C 10 H8Cl2N2O2 [M + H] + Calculated for: 259, 261 (3:2), found 259, 261 (3:2): 1 H NMR (400 MHz, CD3OD) δ 7.53 (s, 2H), 7.31 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H).

[0513] [Example 48] Compound 57 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-1H-pyrazole-4-carboxamide)

[0514] [Chemical Structure]

[0515] Step a: To a solution of 1H-pyrazole-4-carboxylic acid (0.25 g, 2.26 mmol) in DMF (2 mL) was added HATU (0.90 g, 2.426 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. Then a mixture of TEA (0.67 mL, 6.66 mmol) and 1-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-1-(pyridin-4-yl)methanamine (0.50 g, 1.62 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The reaction mixture was then extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (5 × 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography eluting with 50% ACN (+0.05% TFA) in water to give N-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]-1H-pyrazole-4-carboxamide as a pale yellow oil (0.20 g, 31%): LCMS (ESI) C 19 H 16 Cl2N4O2 [M + H] + Calculated for: 403, 405 (3:2), found 403, 405 (3:2).

[0516] Step b: To a solution of [N-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]-1H-pyrazole-4-carboxamide (0.20 g, 0.50 mmol) and Pd(PPh3)4 (19 mg, 0.02 mmol) in THF (3 mL) was added NaBH4 (38 mg, 0.99 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl solution (3 mL). The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Sunfire Prep C 18OBD column, 10 μm, 19 × 250 mm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 30% B in 10 minutes; Detector: UV220 / 254 nm; Retention time: 9.5 minutes. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 57 (9N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-1H-pyrazole-4-carboxamide) as an off-white solid (37.5 mg, 16%): LCMS (ESI) C 16 H 12 Cl2N4O2[M + H] + Calculated for: 363, 365 (3:2), Found 363, 365 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.72 - 8.65 (m, 2H), 8.19 (s, 2H), 7.85 - 7.79 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 6.87 (d, J = 8.9 Hz, 1H).

[0517] [Example 49] Compound 58 (3,4-dichloro-2-[hydroxy[2-(morpholin-4-yl)pyridin-4-yl]methyl]phenol)

[0518] [Chemical formula]

[0519] Step a: To a solution of intermediate 5 (0.30 g, 0.91 mmol) in THF (3 mL), i-PrMgCl (0.6 mL, 1.20 mmol, 2 M in THF) was added dropwise at -10 to 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of 2-chloropyridine-4-carbaldehyde (0.19 g, 1.37 mmol) in THF (2 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h and then warmed to room temperature over 0.5 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), and the mixture was then extracted with EA (2 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC eluting with PE / EA (1 / 2) to give (2-chloropyridin-4-yl)[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]methanol as an off-white solid (0.22 g, 70%): LCMS (ESI) C 15 H 12 Cl3NO2 [M + H] + Calcd for: 344, 346 (1:1), found 344, 346 (1:1).

[0520] Step b: (2-Chloropyridin-4-yl)[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]methanol (0.18 g, 0.52 mmol) and morpholine (5 mL, 5.22 mmol) were stirred at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was purified by reverse-phase chromatography eluting with 60% ACN in water (+0.05% TFA) to give [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl][2-(morpholin-4-yl)pyridin-4-yl]methanol as a light brown oil (0.15 g, 73%): LCMS (ESI) C 19 H 20 Cl2N2O3 [M + H] + Calcd for: 395, 397 (3:2), found 395, 397 (3:2).

[0521] Step c: A solution of [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl][2-(morpholin-4-yl)pyridin-4-yl]methanol (0.15 g, 0.38 mmol) and Pd(PPh3)4 (22 mg, 0.02 mmol) in THF (4 mL) was added with NaBH4 (29 mg, 0.76 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (1 mL), and then the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD Prep column, 30 mm × 150 mm, 5 μm; mobile phase A: water (+0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 25% B in 7 min; detector: UV220 / 254 nm; retention time: 6.12 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 58 (3,4-dichloro-2-[hydroxy[2-(morpholin-4-yl)pyridin-4-yl]methyl]phenol) as a pale pink solid (45 mg, 33%): LCMS (ESI) C 16 H 16 Cl2N2O3[M + H] + Calculated for: 355, 357 (3 : 2), found 355, 357 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.02 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 5.6 Hz, 1H), 6.38 (s, 1H), 3.80 (t, J = 4.9 Hz, 4H), 3.46 (t, J = 4.9 Hz, 4H).

[0522] [Example 50] Compound 59 (3,4-dichloro-2-[hydroxy(1H-indol-3-yl)methyl]phenol)

[0523] [Chemical formula]

[0524] Step a: To a stirred solution of intermediate 5 (0.70 g, 2.13 mmol) in THF (10 mL), i-PrMgCl (1.2 mL, 2.35 mmol, 2 M in THF) was added dropwise at -15 °C under a nitrogen atmosphere. The resulting solution was stirred at -15 °C for 30 minutes under a nitrogen atmosphere. To the above mixture, a solution of tert-butyl 3-formyl-1H-indole-1-carboxylate (0.68 g, 2.77 mmol) in THF (2 mL) was added dropwise at -15 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution (30 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give tert-butyl 3-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]-1H-indole-1-carboxylate as a pale yellow oil (0.80 g, 84%): LCMS (ESI) C 23 H 23 Cl2NO4[M - 18] + Calculated for: 430, 432 (3 : 2), found 430, 432 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.11 (d, J = 8.3 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.29 - 7.23 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 5.95 - 5.82 (m, 1H), 5.28 - 5.11 (m, 2H), 4.67 - 4.59 (m, 1H), 4.50 - 4.38 (m, 1H), 1.68 (s, 9H).

[0525] Step b: To a stirred solution of tert-butyl 3-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]indole-1-carboxylate (0.40 g, 0.892 mmol) in MeOH (3 mL) and water (1 mL) was added K2CO3 (0.62 g, 4.49 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to afford [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-3-yl)methanol as a pale yellow oil (0.20 g, 64%): LCMS (ESI) C 18 H 15 Cl2NO2[M + H - 18] + Calculated for: 330, 332 (3 : 2), found 330, 332 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.53 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.06 - 7.02 (m, 1H), 7.02 - 6.96 (m, 2H), 6.80 (s, 1H), 6.00 - 5.85 (m, 1H), 5.22 (dd, J = 34.5, 14.0 Hz, 2H), 4.67 - 4.51 (m, 2H).

[0526] Step c: To a stirred solution of Pd(PPh3)4 (3 mg, 0.002 mmol) and [2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](1H-indol-3-yl)methanol (80 mg, 0.23 mmol) in THF (2 mL) was added NaBH4 (10 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50% B to 65% B in 7 min; detector: UV254 / 220 nm; retention time: 6.03 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 59 (3,4-dichloro-2-[hydroxy(1H-indol-3-yl)methyl]phenol) as an off-white solid (6 mg, 7%): LCMS (ESI) C 15 H 11 Cl2NO2[M + H - 18] + Calculated for: 290, 292 (3:2), found 290, 292 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 12.8, 8.5 Hz, 2H), 7.16 - 7.10 (m, 1H), 7.10 - 7.02 (m, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.72 (s, 1H).

[0527] [Example 51] Compound 60 (5-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]-1-methyl-1,2-dihydropyridin-2-one)

[0528] [Chemical Structure]

[0529] Step a: To a solution of intermediate 5 (0.38 g, 1.16 mmol) in THF (3 mL), i-PrMgCl (0.7 mL, 1.40 mmol, 2 M in THF) was added at -65 °C under a nitrogen atmosphere. The resulting solution was stirred at -65 °C for 0.5 h under a nitrogen atmosphere. To the above solution, a solution of 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (0.19 g, 1.40 mmol) in THF (3 mL) was added at -65 °C. The reaction mixture was stirred at -65 °C to 0 °C for an additional 1 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 5-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]-1-methyl-1,2-dihydropyridin-2-one as a pale yellow solid (0.13 g, 33%): LCMS (ESI) C 16 H 15 Cl2NO3[M + H] + Calculated: 340, 342 (3 : 2), Found 340, 342 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.25 (s, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 9.3 Hz, 1H), 6.20 (d, J = 9.3 Hz, 1H), 5.98 - 5.84 (m, 1H), 5.36 - 5.27 (m, 2H), 4.65 - 4.48 (m, 2H), 3.53 (s, 3H).

[0530] Step b: A stirred solution of 2-(2,3-dichloro-6-methoxyphenyl)-2-(pyridin-4-yl)acetamide (0.13 g, 0.38 mmol) and Pd(PPh3)4 (4 mg, 0.004 mmol) in THF (3 mL) was added NaBH4 (29 mg, 0.76 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep C 18 OBD column 19×150 mm, 5 μm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 17% B to 48% B in 7 min; detector: UV254 / 220 nm; retention time: 5.97 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 60 (5-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]-1-methyl-1,2-dihydropyridin-2-one) as an off-white solid (20 mg, 17%): LCMS (ESI) C 13 H 11 Cl2NO3[M + H] + Calculated for: 300, 302 (3 : 2), found 300, 302 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 7.57 - 7.50 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 9.4 Hz, 1H), 6.23 (s, 1H), 3.57 (s, 3H).

[0531] [Example 52] Compound 61 (3,4-dichloro-2-(pyridine-4-carbonyl)phenol)

[0532] [Chemical formula]

[0533] Step a: To a stirred solution of Intermediate 4 (2.50 g, 8.25 mmol) in THF (15 mL), n-BuLi (4.29 mL, 10.73 mmol, 2.5 M in hexane) was added at -78 °C under a nitrogen atmosphere. The resulting solution was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. To the above mixture, a solution of N-methoxy-N-methylpyridine-4-carboxamide (2.06 g, 12.37 mmol) in THF (5 mL) was added dropwise at -78 °C over 10 minutes. The resulting mixture was stirred at -78 °C for an additional 1 hour. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to afford 4-(2,3-dichloro-6-methoxybenzoyl)pyridine as a yellow oil (1.00 g, 43%): LCMS (ESI) C 13 H9Cl2NO2 [M + H] + Calculated: 282, 284 (3 : 2), Found 282, 284 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.88 - 8.68 (m, 2H), 7.72 - 7.68 (m, 3H), 7.19 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H).

[0534] Step b: To a stirred solution of 4-(2,3-dichloro-6-methoxybenzoyl)pyridine (1.00 g, 3.55 mmol) in DCM (5 mL) was added BBr3 (4.44 g, 17.72 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (3 mL) at room temperature and neutralized to pH 7 with saturated aqueous NaHCO3 (30 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 5) to give compound 61 (3,4-dichloro-2-(pyridine-4-carbonyl)phenol) as a pale yellow oil (0.80 g, 84%): LCMS (ESI) C 12 H7Cl2NO2 [M + H] + Calculated for: 268, 270 (3 : 2), found 268, 270 (3 : 2); 1 1H NMR (400 MHz, CD3OD) δ 8.83 - 8.78 (m, 2H), 7.75 - 7.69 (m, 2H), 7.52 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H).

[0535] [Example 53] Compound 62 (3,4-dichloro-2-(pyridine-4-carbonyl)aniline)

[0536] [Chemical formula]

[0537] Step a: To a stirred solution of 3,4-dichloro-2-(pyridine-4-carbonyl)phenol (1.20 g, 4.48 mmol) and pyridine (1.06 g, 13.43 mmol) in DCM (10 mL) was added Tf2O (3.79 g, 13.43 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to afford 3,4-dichloro-2-(pyridine-4-carbonyl)phenyl trifluoromethanesulfonate as a brown solid (0.90 g, 50%): LCMS (ESI) C 13 H6Cl2F3NO4S [M + H] + Calculated for: 400, 402 (3 : 2), found 400, 402 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.89-8.84 (m, 2H), 7.98 (d, J = 9.1 Hz, 1H), 7.79-7.74 (m, 2H), 7.64 (d, J = 9.1 Hz, 1H).

[0538] Step b: To a stirred solution of 3,4-dichloro-2-(pyridine-4-carbonyl)phenyl trifluoromethanesulfonate (0.60 g, 1.50 mmol) in 1,4-dioxane (5 mL) was added 1-(4-methoxyphenyl)methanamine (0.62 g, 4.50 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was irradiated with microwave at 140 °C for 2 h. After cooling to room temperature, the resulting solution was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 3,4-dichloro-N-[(4-methoxyphenyl)methyl]-2-(pyridine-4-carbonyl)aniline as a yellow oil (0.12 g, 21%): LCMS (ESI) C 20 H 16 Cl2N2O2[M + H] + Calculated for: 387, 389 (3 : 2), found 387, 389 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.83 - 8.74 (m, 2H), 7.73 - 7.66 (m, 2H), 7.39 (d, J = 9.0 Hz, 1H), 7.19 - 7.10 (m, 2H), 6.88 - 6.82 (m, 2H), 6.72 (d, J = 9.0 Hz, 1H), 4.27 (s, 2H), 3.77 (s, 3H).

[0539] Step c: To a stirred solution of 3,4-dichloro-N-[(4-methoxyphenyl)methyl]-2-(pyridine-4-carbonyl)aniline (20 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C 18Column 30×150 mm, 5 μm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 44% B in 8 min; detector: UV: 220 nm; retention time: 6.88 min. The fraction containing the desired product was collected and concentrated under reduced pressure to give compound 62 (3,4-dichloro-2-(pyridine-4-carbonyl)aniline) as an off-white solid (10 mg, 39%): LCMS (ESI) C 12 H8Cl2N2O [M + H] + Calculated values: 267, 279 (3:2), found 267, 279 (3:2); 1 H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.77 (m, 2H), 7.64 (d, J = 5.1 Hz, 2H), 7.42 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H).

[0540] [Example 54] Compound 63 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-2-methoxyacetamide)

[0541] [Chemical formula]

[0542] Step a: To a solution of intermediate 4 (7.70 g, 36.61 mmol) in THF (50 mL), i-PrMgBr (20 mL, 39.94 mmol, 2 M in THF) was added at 0 °C under a nitrogen atmosphere. The solution was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. To the above solution, a solution of 2-methyl-N-[(pyridin-4-yl)methylidene]propan-2-sulfinamide (Example 35, step a) (7.00 g, 33.29 mmol) in THF (10 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 4 h under a nitrogen atmosphere. The reaction was quenched with water (80 mL). The resulting mixture was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropan-2-sulfinamide as a yellow oil (5.00 g, 39%): LCMS (ESI) C 17 H 20 Cl2N2O2S [M + H] + Calculated for: 387, 389 (3 : 2), found 387, 389 (3 : 2).

[0543] Step b: To a stirred mixture of N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropan-2-sulfinamide (1.00 g, 2.58 mmol) in DCM (20 mL), BBr3 (5.17 g, 20.66 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with water (5 mL) at 0 °C and neutralized to pH 8 with saturated aqueous NaHCO3. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 30% ACN in water containing 10 mmol / L NH4HCO3 to give 2-[amino(pyridin-4-yl)methyl]-3,4-dichlorophenol as a yellow solid (0.50 g, 65%): LCMS (ESI) C 12 H 10Cl2N2O [M + H] + Calculated values: 269, 271 (3:2), measured values 269, 271 (3:2).

[0544] Step c: To a mixture of 2-[amino(pyridin-4-yl)methyl]-3,4-dichlorophenol (0.37 g, 1.38 mmol) and Et3N (0.42 g, 4.12 mmol) in DMF (3 mL), HATU (0.78 g, 2.06 mmol) and 2-methoxyacetic acid (0.14 g, 1.51 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH (0.5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 2% B to 9% B in 2 min; detector: UV254 / 220 nm; retention time: 4.37 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 63 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-2-methoxyacetamide) as a yellow solid (82 mg, 17%): LCMS (ESI) C 15 H 14 Cl2N2O3[M + H] + Calculated values: 341, 343 (3:2), measured values 341, 343 (3:2); 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.68 (d, J = 5.6 Hz, 2H), 8.44 (d, J = 9.1 Hz, 1H), 7.57-7.40 (m, 3H), 6.93 (dd, J = 20.7, 9.0 Hz, 2H), 4.03 (q, J = 15.2 Hz, 2H), 3.37 (s, 3H).

[0545] [Example 55] Compound 64 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]benzamide)

[0546]

Chem.

[0547] Step a: To a stirred solution of intermediate 5 (0.30 g, 0.91 mmol) in THF (5 mL) was added i-PrMgCl (0.70 mL, 1.36 mmol, 2 M in THF) at 0 °C under a nitrogen atmosphere. After stirring for 0.5 h, 4-formylbenzonitrile (0.18 g, 1.37 mmol) was added to the reaction solution. The reaction was then stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (4 / 1) to give 4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]benzonitrile as a pale yellow solid (0.26 g, 73%): LCMS (ESI) C 17 H 13 Cl2NO2[M - H] + Calculated: 332, 334 (3 : 2), Found 332, 334 (3 : 2).

[0548] Step b: A solution of 4-[[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](hydroxy)methyl]benzonitrile (0.26 g, 0.78 mmol) and Pd(PPh3)4 (18 mg, 0.02 mmol) in THF (3 mL) was added with NaBH4 (59 mg, 1.56 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). Then the combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1 / 2) to give 4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]benzonitrile as a pale yellow solid (0.11 g, 43%): LCMS (ESI) C 14 H9Cl2NO2 [M - H] + Calculated for: 292, 294 (3 : 2), Found 292, 294 (3 : 2); 1 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.42 (s, 2H).

[0549] Step c: A mixture of 4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]benzonitrile (0.11 g, 0.37 mmol), NaOH (0.15 g, 3.74 mmol) and H2O2 (0.13 g, 3.74 mmol, 30%) in MeOH (2 mL) was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous Na2SO3 (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: X Bridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase A: water containing 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 34% B to 45% B in 7 min; detector: UV254 / 220 nm; retention time: 5.02 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 64 (4-[(2,3-dichloro-6-hydroxyphenyl)(hydroxy)methyl]benzamide) as an off-white solid (48 mg, 40%): LCMS (ESI) C 14 H 11 Cl2NO3[M + H] + Calculated for: 312, 314 (3:2), found 312, 314 (3:2); 1 H NMR (400 MHz, CD3OD) δ 7.84 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H).

[0550] [Example 56] Compound 65 ((2S)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 1); and Compound 68 ((2S)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 2)

[0551] [Chemical formula]

[0552] Step a: (2S)-1-[(tert-Butoxy)carbonyl]pyrrolidine-2-carboxylic acid (0.42 g, 1.94 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (5 mL) were stirred, and 1-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-1-(pyridin-4-yl)methanamine (0.40 g, 1.29 mmol) and Et3N (0.39 g, 3.88 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 35 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 40% ACN (+0.05% TFA) in water to give tert-butyl (2S)-2-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)pyrrolidine-1-carboxylate as a yellow solid (0.33 g, 45%): LCMS (ESI) C 25 H 29 Cl2N3O4[M + H] + Calculated: 506, 508 (3:2), Found 506, 508 (3:2); 1 H NMR (400 MHz, CDCl3) δ 8.56 - 8.44 (m, 2H), 7.47 - 7.37 (m, 1H), 7.24 - 7.12 (m, 3H), 6.79 (s, 1H), 5.96 - 5.69 (m, 1H), 5.31 - 5.05 (m, 2H), 4.67 - 4.21 (m, 3H), 3.59 - 3.34 (m, 2H), 2.54 - 2.26 (m, 1H), 2.06 - 1.81 (m, 3H), 1.48 (s, 9H).

[0553] Step b: A stirred solution of tert-butyl (2S)-2-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)pyrrolidine-1-carboxylate (0.30 g, 0.592 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol) in THF (2 mL) was added NaBH4 (45 mg, 1.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were then washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]pyrrolidine-1-carboxylate as a pale yellow solid (0.36 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 22 H 25 Cl2N3O4[M + H] + Calculated for: 466, 468 (3 : 2), Found 466, 468 (3 : 2).

[0554] Step c: To a stirred solution of tert-butyl (2S)-2-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]pyrrolidine-1-carboxylate (0.36 g, 0.77 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature. The reaction was stirred at room temperature for 40 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Xselect CSH OBD column 30×150 mm, 5 μm, n; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 20% B in 7 minutes; detector: UV254 / 220 nm; retention time: RT1: 5.02 minutes; RT2: 6.43 minutes. The fraction containing the desired product at 5.02 minutes was collected and concentrated under reduced pressure to give compound 65 ((2S)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 1) as a purple solid (37.3 mg, 10%): LCMS (ESI) C 17 H 17 Cl2N3O2[M + H] + Calculated for: 366, 368 (3:2), found 366, 368 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 6.2 Hz, 2H), 7.79 (s, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.20 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.48 (t, J = 7.8 Hz, 1H), 3.53 - 3.35 (m, 2H), 2.68 - 2.55 (m, 1H), 2.36 - 2.21 (m, 1H), 2.21 - 2.06 (m, 2H)) δ -77.18 (d, J = 12.3 Hz). The fraction containing the desired product at 6.43 minutes was collected and concentrated under reduced pressure to give compound 68 ((2S)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 2) as a purple solid (61.1 mg, 16%): LCMS (ESI) C 17 H 17Cl2N3O2[M + H] + Calculated values: 366, 368 (3:2), measured values 366, 368 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.77 - 8.68 (m, 2H), 7.90 - 7.76 (m, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.58 (d, J = 8.6 Hz, 1H), 3.47 - 3.35 (m, 2H), 2.50 - 2.40 (m, 1H), 2.13 - 1.99 (m, 2H), 1.99 - 1.88 (m, 1H).

[0555] [Example 57] Compound 66 ((2R)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 2) and Compound 67 ((2R)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 1)

[0556] [Chemical formula]

[0557] Step a: To a stirred mixture of (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (0.42 g, 1.94 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (5 mL), 1-[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl]-1-(pyridin-4-yl)methanamine (0.40 g, 1.29 mmol) and Et3N (0.39 g, 3.88 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 × 35 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 40% ACN (+0.05% TFA) in water to give tert-butyl (2R)-2-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)pyrrolidine-1-carboxylate as a yellow solid (0.33 g, 45%): LCMS (ESI) C 25 H 29 Cl2N3O4[M + H] + Calculated for: 506, 508 (3 : 2), found 506, 508 (3 : 2); 1 H NMR (400 MHz, CDCl3) δ 8.56-8.44 (m, 2H), 7.47-7.37 (m, 1H), 7.24-7.12 (m, 3H), 6.79 (s, 1H), 5.96-5.69 (m, 1H), 5.31-5.05 (m, 2H), 4.67-4.21 (m, 3H), 3.59-3.34 (m, 2H), 2.54-2.26 (m, 1H), 2.06-1.81 (m, 3H), 1.48 (s, 9H).

[0558] Step b: A stirred solution of tert-butyl (2R)-2-([[2,3-dichloro-6-(prop-2-en-1-yloxy)phenyl](pyridin-4-yl)methyl]carbamoyl)pyrrolidine-1-carboxylate (0.30 g, 0.592 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol) in THF (2 mL) was added NaBH4 (45 mg, 1.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were then washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2R)-2-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]pyrrolidine-1-carboxylate as a pale yellow solid (0.36 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 22 H 25 Cl2N3O4[M + H] + Calculated for: 466, 468 (3 : 2), found 466, 468 (3 : 2).

[0559] Step c: To a stirred solution of tert-butyl (2R)-2-[[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]carbamoyl]pyrrolidine-1-carboxylate (0.36 g, 0.77 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature. The reaction was stirred at room temperature for 40 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Xselect CSH OBD column 30×150 mm, 5 μm, n; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 20% B in 7 minutes; detector: UV254 / 220 nm; retention time: RT1: 5.02 minutes; RT2: 6.43 minutes. The fraction containing the desired product at 5.02 minutes was collected and concentrated under reduced pressure to give compound 67 ((2R)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 1) as a purple solid (32.3 mg, 9%): LCMS (ESI) C 17 H 17 Cl2N3O2[M + H] + Calculated for: 366, 368 (3:2), found 366, 368 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.76-8.66 (m, 2H), 7.75 (d, J = 5.8 Hz, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.19 (s, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.47 (dd, J = 8.5, 7.1 Hz, 1H), 3.52-3.36 (m, 2H), 2.70-2.57 (m, 1H), 2.36-2.23 (m, 1H), 2.23-2.10 (m, 2H). The fraction containing the desired product at 6.43 minutes was collected and concentrated under reduced pressure to give compound 66 ((2R)-N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide isomer 2) as a purple solid (27.3 mg, 7%): LCMS (ESI) C 17 H 17 Cl2N3O2[M + H]+ Calculated value: 366, 368 (3:2), measured value 366, 368 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.76 - 8.69 (m, 2H), 7.85 (d, J = 5.8 Hz, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.59 (dd, J = 8.6, 6.8 Hz, 1H), 3.50 - 3.35 (m, 2H), 2.55 - 2.38 (m, 1H), 2.11 - 1.99 (m, 2H), 1.99 - 1.85 (m, 1H);.

[0560] [Example 58] Compound 69 (N - [(2,3 - dichloro - 6 - hydroxyphenyl)(pyridin - 4 - yl)methyl] - 2 - methylpropanamide)

[0561] [Chemical Structure]

[0562] Step a: To a stirred mixture of 1 - (2,3 - dichloro - 6 - methoxyphenyl) - 1 - (pyridin - 4 - yl)methanamine (0.50 g, 1.77 mmol) and Et3N (0.36 g, 3.53 mmol) in DCM (6 mL), 2 - methylpropanoyl chloride (0.38 g, 3.53 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The organic phases were combined, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 10) to give N - [(2,3 - dichloro - 6 - methoxyphenyl)(pyridin - 4 - yl)methyl] - 2 - methylpropanamide as a yellow oil (0.24 g, 39%): LCMS (ESI) C 17 H 18 Cl2N2O2[M + H]+ Calculated value: 353, 355 (3:2), measured value 353, 355 (3:2).

[0563] Step b: To a solution of N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropanamide (0.35 g, 0.99 mmol) in DCM (5 mL) was added BBr3 (0.94 mL, 3.74 mmol) at 0 °C. The reaction was then stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (10 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Xselect CSH OBD Prep column 30 mm × 150 mm, 5 μm; mobile phase A: water (+0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 30% B in 10 min; detector: UV220 nm; retention time: 8.63 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 69 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-2-methylpropanamide) as an off-white solid (0.15 g, 45%): LCMS (ESI) C 16 H 16 Cl2N2O2 [M + H] + Calculated value: 339, 341 (3:2), measured value 339, 341 (3:2); 1 H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 5.9 Hz, 2H), 7.83 (d, J = 5.9 Hz, 2H), 7.45 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 2.81 - 2.70 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H).

[0564] [Example 59] Compound 70 (1-(2,3-dichloro-6-methoxyphenyl)-1-(pyridin-4-yl)methanamine)

[0565]

Chem.

[0566] Step a: To a stirred solution of intermediate 4 (11.00 g, 36.43 mmol) in THF (100 mL) was added i-PrMgBr (20 mL, 40.00 mmol, 2 M in THF), and the mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. Then 2-methyl-N-[(pyridin-4-yl)methylene]propan-2-sulfinamide (Example 35, Step a) (7.00 g, 33.20 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl solution (200 mL) at room temperature. The resulting mixture was extracted with EA (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropan-2-sulfinamide as a yellow oil (5.00 g, 35%): LCMS (ESI) C 17 H 20 Cl2N2O2S [M + H] + Calculated: 387, 389 (3 : 2), Found 387, 389 (3 : 2).

[0567] Step b: A stirred solution of N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropane-2-sulfinamide (0.50 g, 1.29 mmol) in 1,4-dioxane (2 mL) was added dropwise with aqueous HCl solution (2 mL, 12 N) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD Prep column, 19 mm × 150 mm, 5 μm; mobile phase A: water containing 10 mmol / L of NH4HCO3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 5% B to 18% B in 1 min; detector: UV220 / 254 nm; retention time: 7.28 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 70 (1-(2,3-dichloro-6-methoxyphenyl)-1-(pyridin-4-yl)methanamine) as an off-white solid (29 mg, 8%): LCMS (ESI) C 13 H 12 Cl2N2O [M + H] + Calculated for: 283, 285 (3 : 2), found 283, 285 (3 : 2); 1 H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.01 (d, J = 9.0 Hz, 1H), 5.85 (s, 1H), 3.71 (s, 3H).

[0568] [Example 60] Compound 71 (N-[(2,3-dichloro-6-hydroxyphenyl)(pyridin-4-yl)methyl]-N-methylazetidine-3-carboxamide)

[0569] [Chemical formula]

[0570] Step a: A solution of N-[(2,3-dichloro-6-methoxyphenyl)(pyridin-4-yl)methyl]-2-methylpropane-2-sulfinamide (1.00 g, 2.58 mmol) in THF (15 mL) was added with LiHMDS (2.58 mL, 5.16 mmol, 1 M in THF) at -65 °C over 5 minutes under a nitrogen atmosphere, and the mixture was stirred at -65 °C for 0.5 hour. Then a solution of CH3I (0.48 g, 3.36 mmol) was added dropwise at -65 °C. Then the reaction mixture was warmed to room temperature over 0.5 hour and stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution (30 mL) and then extracted with EA (2 × 20 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give N-[(2,3-dichloro-6-methoxyphenyl...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof 【Chemical 1】 wherein A is a heteroaryl containing N and optionally substituted by 1 to 5 R ５ ; and is optionally substituted by the structural moiety in formula I 【Chemical 2】 is [Chemical Formula 3] having the structure of; R １ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, (CR ６ R ７ ), ｎ３ OR ａ , (CR ６ R ７ ), ｎ３ NR ａ R ｂ , (CR ６ R ７ ), ｎ３ NR ａ (C=O)R ｂ , or (CR ６ R ７ ), ｎ３ CONR ａ R ｂ ; R ２ is H; R ５ Each occurrence of R is independently H, halogen, alkyl, cycloalkyl, optionally substituted saturated heterocyclic ring, optionally substituted aryl, optionally substituted heteroaryl, CN, CF ３ , OCF ３ , oxo, OR ａ , (CR ６ R ７ ), ｎ３ OR ａ , (C=O)R ｂ , (C=O)OR ｂ , SO ２ R ａ , (C=O)(CR ６ R ７ ), ｎ３ OR ｂ , (C=O)(CR ６ R ７ ), ｎ３ NR ａ R ｂ , (CR ６ R ７ ), ｎ３ NR ａ R ｂ , (CR ６ R ７ ), ｎ３ NR ａ SO ２ R ｂ , (CR ６ R ７ ), ｎ３ NR ａ , (C=O)R ｂ , (CR ６ R ７ ), ｎ３ NR ａ , (C=O)NR ａ R ｂ , or (CR ６ R ７ ), ｎ３ , (C=O)NR ａ R ｂ ; Alternatively, the two R ５ groups, together with the carbon or nitrogen atom to which they are attached, form a 3- to 7-membered optionally substituted saturated or aromatic carbocyclic or heterocyclic ring; R ６ and R ７ each occurrence of which is independently H, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ａ and R ｂ each occurrence of which is independently H, alkyl, alkenyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R ａ and R ｂ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; When applicable, R １ , R ５ , R ６ , R ７ , R ａ , and R ｂ 's alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl, and heteroaryl are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR ８ , -(CH ２ ) ０～２ OR ８ , N(R ８ ) ２ , (C=O)R ８ , (C=O)N(R ８ ) ２ , and oxo; and are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of; R ８ Each occurrence of R is, independently, H, alkyl, or an optionally substituted heterocycle; or two R ８ groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S; n ３ Each occurrence of which is independently an integer from 0 to 4).

2. A is (a): 【Chemical Formula 4】 (wherein, n ５ is an integer of 0 to 3 when the valence permits); or (b): 【Chemical Formula 5】 (wherein, n ５ is an integer of 0 to 3 when the valence permits); or (c): 【Chemical Formula 6】 (wherein, n ５ is an integer of 0 to 3 when the valence permits) The compound or a pharmaceutically acceptable salt thereof according to claim 1, having a structure selected from the group consisting of

3. (a) R １ is Me, OH, CH ２ OH, NH ２ CH ２ NH ２ CONH ２ CONHMe ２ CONMe ２ NH(CO)Me, or NMe(CO)Me; or (b) R １ is Me, OH, 【Chemical Formula 7】 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, selected from the group consisting of

4. (a) R ５ at least one occurrence of which is H, halogen, alkyl, cycloalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, CN, CF ３ , OCF ３ , OR ａ , (CR ６ R ７ ), ｎ３ OR ａ , (C=O)R ｂ , (C=O)OR ｂ , or SO ２ R ａ ; or (b) R ５ at least one occurrence of which is (C=O)(CR ６ R ７ ) ｎ３ OR ｂ , (C=O)(CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ SO ２ R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)R ｂ , (CR ６ R ７ ) ｎ３ NR ａ (C=O)NR ａ R ｂ , or (CR ６ R ７ ) ｎ３ (C=O)NR ａ R ｂ ; or (c) R ５ at least one occurrence of which is H, halogen, alkyl, OH, NH ２ , CN, CF ３ , OCF ３ , CONH ２ , CONHMe ２ , or CONMe ２ ; or (d) R ５ at least one occurrence of which is an optionally substituted heterocyclic ring containing 1 to 3 heteroatoms each selected from the group consisting of N, O, and S; or (e) R ５ at least one occurrence of 【Chemical 8】 (wherein the complex ring is optionally substituted by alkyl, OH, oxo, or (C=O)C when the valence permits) １～４ (optionally substituted by alkyl) a heterocyclic ring selected from the group consisting of; or (f) two Rs ５ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the groups together with the carbon atom to which they are attached form an optionally substituted 3- to 7-membered carbocyclic or heterocyclic ring.

5. R ６ and R ７ wherein each occurrence of R is independently H or alkyl, a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. (a) R ａ or R ｂ at least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or (b) R ａ or R ｂ at least one occurrence of which is independently H, Me, Et, Pr, or 【Chemical Formula 9】 (In the formula, when the valence permits, the complex ring is alkyl, OH, oxo, or (C=O)C １～４ optionally substituted by alkyl) a heterocyclic ring selected from the group consisting of; or (c) R ａ and R ｂ wherein R and R together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S, a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. The following: 【Chemical 10】 【Chem.】 【Chem.】 【Chem.】 the group consisting of A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of

8. (a) at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and (b) a pharmaceutically acceptable carrier or diluent, a pharmaceutical composition comprising

9. A medicament comprising at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7

10. A pharmaceutical composition for use in a method of treating a condition in a mammalian species in need thereof, comprising at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, said method comprising the step of administering to said mammalian species a therapeutically effective amount of said at least one compound or a pharmaceutically acceptable salt thereof, said condition being selected from the group consisting of cancer, immunological disorders, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and kidney diseases, optionally, said condition is (a) an immunological disorder which is graft rejection or an autoimmune disease, said autoimmune disease optionally being rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes; or (b) a central nervous system (CNS) disorder which is Alzheimer's disease; or (c) an inflammatory disorder which is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or inflammatory neuropathy; or (d) a gastrointestinal disorder which is inflammatory bowel disease; or (e) a metabolic disorder which is obesity or type II diabetes; or (f) a cardiovascular disorder which is ischemic stroke; or (g) a kidney disease which is chronic kidney disease, nephritis, or chronic renal insufficiency or selected from the group consisting of (h) cancer, graft rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathies, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof, optionally, a pharmaceutical composition, wherein the mammalian species is human.

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