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HK1076737B - Use of ep4 receptor ligands in the manufacture of a medicament for the treatment of il-6 involved diseases - Google Patents

Use of ep4 receptor ligands in the manufacture of a medicament for the treatment of il-6 involved diseases Download PDF

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HK1076737B
HK1076737B HK05108862.3A HK05108862A HK1076737B HK 1076737 B HK1076737 B HK 1076737B HK 05108862 A HK05108862 A HK 05108862A HK 1076737 B HK1076737 B HK 1076737B
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ethyl
phenyl
amino
imidazo
dimethyl
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HK05108862.3A
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HK1076737A1 (en
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下条正人
谷口加奈
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美国辉瑞有限公司
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Priority claimed from PCT/IB2003/001310 external-priority patent/WO2003086371A2/en
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Description

Use of EP4 receptor ligands for the manufacture of a medicament for the treatment of IL-6 related disorders
Technical Field
The present invention features novel uses of EP4 receptor ligands. The invention also includes methods of identifying agents that affect the activity of peripheral whole blood cells. Specifically, it includes the method for determining the regulation of PGE 2Assay of compounds whose mediated activity affects the secretion of IL-6 by peripheral whole blood cells.
The invention also features novel uses of EP4 receptor antagonists. The assay of the invention comprises contacting peripheral whole blood cells with a compound and PGE2 to test peripheral whole blood cell activity, and this can be determined from cellular activity by measuring IL-6 production.
Technical Field
Prostaglandin E2(Prostaglandin E2，PGE2) Are potential regulators associated with the pathogenesis of arthritis. PGE2Bind at least four subtypes of PGE receptors, designated EP1, EP2, EP3, and EP 4. Molecular studies have shown that all subtypes are 7-transmembrane receptors, whereas 7-transmembrane receptors belong to the superfamily of G protein-coupled receptors (Robert et al, am. Soc. Pharm. exp. Ther.46: 205-29, 1994). EP1 activation stimulates intracellular calcium release through a G protein-mediated mechanism; EP2 and EP4 activate adenylate cyclase (adenylate cyclase) via stimulatory G proteins, but respond differently to certain ligands; EP3 inhibits adenylyl cyclase via an inhibitory G-protein (Robert et al, supra, Negishi et al, Biochimica Biophys.acta 1259: 109-20, 1995).
It has been suggested that increased concentrations of interleukin (IL-6), a pleiotropic inflammatory cytokine, are contributing factors to a number of pathological disorders such as rheumatoid arthritis autoimmune diseases and atherosclerosis.
Interleukin-6 (IL-6) is a key cytokine required for protoplast induction, antibody secretion, B cell growth, activation of acute phase protein synthesis, T cell activation, hematopoietic stem cell growth, and maintenance of optical immune function. Its action ensures that the immune system is activated and nourished during infection and in response to other inflammatory stimuli. IL-6 has been described in detail as playing an important role in the generation and maintenance of chronic inflammatory diseases such as rheumatoid arthritis in mammals. In recent clinical studies, anti-IL-6 receptor antibodies improved limb rigidity, joint pain and swelling in patients with rheumatoid arthritis (Yoshizaki et al, Springer Semin Immunopathol. Vol.20, 247-. This evidence suggests that modulation of IL-6 production is a promising strategy for chronic inflammatory diseases
Atherosclerosis is a complex disease characterized by the deposition of cholesterol and the infiltration of monocytes into the subendothelial space, leading to foam cell generation (Ross R. (1993) Nature 362: 801-. The presence of macrophages and thymus-dependent lymphocytes in atherosclerotic lesions suggests that the immune system and inflammatory processes play an important role in the pathogenesis of atherosclerosis (Libby et al (1993) curr. Opui. Lipidol.4: 355-363).
In human atherosclerotic lesions, mRNA transcripts for IL-6 have been detected (Seine et al, cytokines 1994, 6, 87-91). This phenomenon was confirmed and developed by immunohistochemical studies. Immunohistochemical studies showed targeted expression of IL-6 protein by smooth muscle cells and macrophages in human (arterial) atherosclerotic plaques (Kishikawa H. et al, Virchows. Arch. A Pathol. Ant. Histopathol.1992, 423, 433-442). In addition, IL-6 has been shown to play an important role in the cell type in the atherosclerotic lesion component. IL-6 can produce increased amounts of tumor necrosis factor in THP-1 macrophages in response to Lipopolysaccharide (LPS) (Cochran FR et al, Immunopharmacology, 1992, 23, 97-103), suggesting that IL-6 plays an important role in stimulating macrophages to acquire their full inflammatory capacity. IL-6 has been shown to stimulate vascular smooth muscle cell growth in a platelet-derived growth factor-dependent manner (Ikeda U.S. et al, am.J.Physiol.1991, 260, H1713-H1717). Recent data show that apoproteineE-knockout mice develop atherosclerosis, which is associated with human pathology (Bourasa P-AK et al, Proc. Natl. Acad Sci USA 1996, 93, 10022 10027; Kauser K. et al, J. Vasc. Res.1996, 33(suppl 1)48, Abstract). Secretion of IL-6 from isolated aortas of apoE-KO mice indicates a positive correlation of the lesion regions of the same apoE-KO aortas. Immunohistochemical staining revealed that macrophages predominantly produced IL-6(Sukovich D.A. et al, ArteriosclerThromb Vase biol.1998, 18, 1498-. Therefore, IL-6 seems to play an important role in atherogenesis.
On the other hand, existing data support the following hypothesis: atherosclerosis is an inflammatory disease (Ross, r., et al, Nature, 1993, 362, 801-. Studies examining inflammatory markers have shown a relationship between increased inflammation and the risk of myocardial infarction (Rider, P.M. et al, N.Engl. J.Med., 1997, 336, 973-. Plate rupture (plaque rupture) leading to thrombosis is a major phenomenon in infarcts and has been shown to be associated with increased inflammation in the plate (van der Wal.A.C., et al, Circulation, 1994, 89, 36-44). Furthermore, a reduction in inflammatory response may be associated with a reduced risk of secondary ischemia (Rider, p.m., et al, n.engl.j.med, 1997, 336, 973-. It has been proposed that the beneficial effect of aspirin (a cyclooxygenase inhibitor) in reducing the risk of myocardial infarction is due in part to anti-inflammatory action. This evidence suggests that prostaglandins appear to play a pivotal role in atherosclerosis in addition to cytokines and growth factors.
Prostaglandins are usually produced by the enzyme cyclooxygenase-1 (COX-1), which is constitutively expressed by the endothelium (tissue), platelets, kidney and elsewhere in the blood vessel (Monkada, S. et al, Nature, 1976, 263, 663-. In addition, a cytokine-inducible cyclooxygenase enzyme, COX-2, has been detected in several different cell types. COX-2 expression is under basal conditions restricted and not regulated in inflammatory processes such as rheumatoid arthritis (needleleman, P. et al, J. Rheumatotol, 1997, 24(suppl 49), 6-8). COX2 was found in macrophages, in some smooth muscle cells and in epithelial cells in atherosclerotic lesions in humans (Christopher, S.R., et al, Arterioscler Thromb. Vasc. biol.1999, 19, 646-. E, a key and positive factor for inflammation, is recognized as a prostaglandin produced by the activation of COX22And I2Such as PGE2And/or PGI2Plays an important role in atherosclerotic lesions.
Evidence from several routes suggests that the production of prostaglandins and IL-6 by macrophages at the site of inflammation or atherosclerotic lesions is involved in the production and maintenance of the disease. In fact, it has been reported that PGE2 greatly enhances IL-6 production when human peripheral blood mononuclear cells are co-stimulated with PGE2 and titanium particles (Blaine, T.A. et al, J.bone Joint Surgery, 1997, 10, 1519-1528). In this study, we also showed that PGE2 enhanced IL-6 production in concanavalin a (cona) -treated human Peripheral Blood Mononuclear Cells (PBMCs). We have surprisingly found that an EP4 subtype selective antagonist inhibits IL-6 production in peripheral whole blood and PBMCs co-stimulated with PGE2 and ConA (see detailed description of the invention).
Disclosure of Invention
The invention is characterized in that the EP4 receptor ligand is applied to the preparation of the drugs for treating IL-6 related diseases. Preferably, the IL-6 related disease is selected from the group consisting of alcoholic cirrhosis (amylocirrhosis), amyloidosis (amyloidosis), atherosclerosis, heart diseases such as angina pectoris, myocardial infarction, (non-inflammatory) cardiomyopathy and myocarditis, sclerosis such as multiple sclerosis, and organ transplantation reactions.
A further aspect of the invention features a method of treating an IL-6 related disorder in a mammal, including a human, comprising administering an effective amount of an EP4 receptor ligand. Preferably, the IL-6 related disease is selected from the group consisting of alcoholic cirrhosis, amyloidosis, atherosclerosis, heart diseases such as angina pectoris, myocardial infarction, (non-inflammatory) cardiomyopathy and myocarditis, sclerosis such as multiple sclerosis, and organ transplant reactions.
The invention further relates to a pharmaceutical composition for the treatment of IL-6 related diseases comprising an EP4 receptor ligand. Preferably, the IL-6 related disease is selected from the group consisting of alcoholic cirrhosis, amyloidosis, atherosclerosis, heart diseases such as angina pectoris, myocardial infarction, (non-inflammatory) cardiomyopathy and myocarditis, sclerosis such as multiple sclerosis, and organ transplant reactions.
Preferably, the EP4 receptor ligand used in the present invention is a selective EP4 receptor antagonist.
In another preferred aspect, the EP4 receptor ligand (antagonist) is an aryl or heteroaryl fused imidazole compound of formula I
Or a pharmaceutically acceptable salt thereof, wherein
Y1，Y2，Y3And Y4Independently selected from N, CH or C (L);
R1is H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, C1-8Alkoxy, halogen substituted C1-8Alkoxy radical, C1-8alkyl-S (O) m-, Q1-, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or di- (C)1-8Alkyl) amino, C1-4alkyl-C (═ O) -N (R)3) -or C1-4alkyl-S (O) m-N (R)3) -, wherein saidC of (A)1-8Alkyl radical, C2-8Alkenyl and C2-8Alkynyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano, 2, 3-indanyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(＝O)-，Q1-O-，Q1-S(O)m-，Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S (O) m-, Q1-C1-4alkyl-C (O) -N (R)3)-，Q1-C1-4alkyl-N (R)3) -or C1-4alkyl-C (O) -N (R)3)-；
Q1Is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with: halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, R3N(R4)C(＝O)-，C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4) -or NH2(HN＝)C-；
A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical，C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(＝O)-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4) -and NH2(HN＝)C-；
B is halogen-substituted C1-6Alkylene radical, C3-7Cycloalkylene radical, C2-6Alkenylene radical, C2-6Alkynylene, -O-C1-5Alkylene radical, C1-2alkylene-O-C1-2Alkylene or C1-6Alkylene, optionally substituted with: oxo or C1-3An alkyl group;
W is NH, N-C1-4Alkyl, O, S, N-OR5Or a covalent bond;
R2is H, C1-4Alkyl, OH or C1-4An alkoxy group;
z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, R3C(＝O)N(R4)-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl, NH2(HN＝)C-，Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
L is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4)-，NH2(HN＝)C-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2-，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom;
m is 0, 1 or 2;
R3and R4Independently selected from H and C1-4An alkyl group;
R5is H, C1-4Alkyl radical, C1-4Alkyl- (O ═) C-or C1-4alkyl-O- (O ═) C —; and
Q2is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic ring; optionally containing up to three heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl- (O ═) C-, R3(R4)C(＝O)N-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkyl radicalSulfonylamino group, C3-7Cycloalkyl radical, C1-4alkyl-C (═ O) NH-or NH2(HN＝)C-。
In another preferred aspect, the EP4 receptor ligands (antagonists) disclosed in WO 00/16760 are aryl or heteroaryl fused imidazole compounds of formula II below or pharmaceutically acceptable salts thereof,
wherein R is1Is hydroxy, protected carboxy or carboxy-substituted lower alkyl; a carboxyl group; a protected carboxyl group; a carbamoyl group; a heterocyclic group; a cyano group; halogen (lower) alkylsulfonyloxy; lower alkoxy substituted with hydroxy or carbamoyl; carboxy, protected carboxy, carbamoyl or heterocyclyl substituted aryl; or amino optionally substituted with protected carboxy or lower alkylsulfonyl,
R2Is hydrogen or a lower alkyl group,
R3is aryl, optionally substituted with: the halogen(s) are selected from the group consisting of,
R4is aryl, optionally substituted with: the halogen(s) are selected from the group consisting of,
q is
[ wherein-A)1-is a single bond or a lower alkylene group,
is a ring (C)6-C9) Alk-ene, cyclo (C)3-C9) Alkane, bicyclo (C)6-C9) Alkalenes or bicyclic (C)6-C9) Alkane, -A3-Is a single bond orLower alkylene]And are and
x is O, NH or S.
In another aspect, the invention provides an assay method comprising culturing peripheral whole blood with a test compound and determining the effect of the compound on PGE 2-induced whole blood cell activity. Preferably, the measurable amount of cellular activity is an increase in cytokine release. Preferably, the effect of the compound is measured by comparing the effect to a control culture in the absence of the compound.
In another aspect, the invention provides an assay comprising activating peripheral whole blood cells with a combination of PGE2 and other stimulants such as concanavalin a, CD3 or titanium.
Those of ordinary skill in the art will have a complete understanding of the terminology used in the description and the appended claims. However, the following terms are described immediately below, unless otherwise specified.
"IL-6-associated disease" refers to a disease caused by IL-6, in which IL-6 activates the immune system and nourishes during infection.
Examples of IL-6 related diseases include those selected from the group consisting of alcoholic cirrhosis, amyloidosis, atherosclerosis, heart diseases such as angina pectoris, myocardial infarction, (non-inflammatory) cardiomyopathy and myocarditis, sclerosis such as multiple sclerosis, and organ transplant reactions.
"EP 4 receptor ligand" refers to compounds that bind to the EP4 receptor and includes stereoisomers of the compounds, pharmaceutically acceptable salts of the compounds or stereoisomers, prodrugs of the compounds or stereoisomers, or pharmaceutically acceptable salts of the prodrugs. Any additional pharmaceutically active compound that is also contemplated for use in combination with the EP4 receptor ligand may be a stereoisomer of the additional pharmaceutically active compound, a salt of the additional active compound or stereoisomer, a prodrug of the additional active compound or stereoisomer, or a salt of the prodrug.
"EP 4 receptor antagonist" refers to a chemical that reduces or alleviates the biological activity of the EP4 receptor. Such antagonists may include proteins such as anti-EP 4 antibodies, nucleotides, amino acids, peptide carbohydrates, small molecules (organic or inorganic), or any other compound or composition that reduces EP4 receptor activity by reducing the amount of EP4 receptor present in the cell, or reducing EP4 receptor binding or signaling activity (signalingity).
The term "alkyl", as used herein, refers to a straight or branched chain, saturated monovalent hydrocarbon radical including, but not limited to, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl and the like.
The term "alkenyl", as used herein, refers to a hydrocarbon group having at least one double bond, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, and the like.
The term "alkynyl", as used herein, refers to a hydrocarbon group having at least one trivalent bond, including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.
The term "halogen", as used herein, refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "cycloalkyl", as used herein, refers to a saturated carbocyclic group including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term "alkoxy", as used herein, refers to an O-alkyl group, wherein "alkyl" is as defined above.
The term "monocyclic aromatic ring", as used herein, refers to a monocyclic aromatic carbocyclic or heterocyclic ring (containing 0-4 heteroatoms selected from O, N and S), including, but not limited to, phenyl, pyrazolyl, furanyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thienyl (thiophenyl), pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, triazolyl, furazanyl (furazanyl), and the like.
The term "bicyclic aromatic ring", as used herein, refers to a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (containing 0-4 heteroatoms selected from O, N and S), including, but not limited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and the like.
The term "alkylene", as used herein, refers to a saturated hydrocarbon (straight or branched chain) in which one hydrogen atom is removed from each terminal carbon, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.
The term "cycloalkylene", as used herein, refers to divalent cycloalkyl radicals including, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.
The term "alkenylene", as used herein, refers to a straight or branched hydrocarbon chain spacer having at least one double bond, including, but not limited to, -CH ═ CH-, -CH ═ CHCH (CH) —3) -, etc.
The term "alkynylene", as used herein, refers to a straight or branched hydrocarbon chain spacer having at least one triple bond, including, but not limited to, -C.ident.C-, -C-C.ident.CCH 2-，-C≡CCH(CH3) -, etc.
The term "tricyclic group", as used herein, refers to a saturated carbocyclic group including, but not limited to, adamantyl, tricyclo [5.2.1.02，6]Decane, etc.
The term "two adjacent L groups are optionally linked together to form an alkylene chain having 3-4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom", as used herein, means, but is not limited to, -O-CH2-O-，-CH2-O-CH2-，-O-CH2CH2-，-CH2CH2-O-，-O-CH2CH2-O-，-CH2CH2CH2-O-，-O-CH2CH2CH2-，-CH2-O-CH2CH2-，-CH2CH2-O-CH2-, etc.
The term "aryl", as used herein, refers to an aromatic group including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, and the like.
The term "protecting group", as used herein, refers to a hydroxy or amino protecting group selected from typical hydroxy or amino protecting Groups described in Protective Groups in Organic Synthesis, T.W.Greene et al (John Wiley & Sons, 1991);
the term "treating," as used herein, refers to reversing, alleviating, inhibiting the development of, or preventing a disorder or condition to which the term applies, or one or more symptoms of the disorder or condition. The term "treatment", as used herein, refers to the act of treating, and "treating" is as defined immediately above.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Although the invention has been described in connection with specific embodiments thereof, it should be understood that other variations and modifications may be made which are also part of the invention, and which fall within the scope of the appended claims. This application is intended to cover any equivalents, variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. Additional guidance in the preparation and use of nucleotides and polypeptides can be found in textbooks that are standard in Molecular Biology, protein science, and Immunology (see, e.g., Davis et al, Basic Method in Molecular Biology, Elsever sciences publishing, Inc., New York, NY, 1986; Hames et al, Nucleic Acid Hybridization, IL Press, 1985; Molecular Cloning, Sambrook et al, Current Protocols in Molecular Biology, eds. Ausubel et al, John Wiley and Sons; Current Protocols Humanics, eds. Dratropho et al, John Wiley and Sons; Current Protocols in protein science, John E. Wiley and Colns; John et al, John Wiley and Colion, John et al, John society). All publications mentioned above are incorporated herein by reference in their entirety.
Description of the drawings
FIG. 1 shows bar graphs of stimulation of IL-6 secretion by PGE2 in ConA-treated human PBMC (shaded bars) and in ConA-untreated human PBMC (solid bars);
figure 2 is a graph showing that PGE2 stimulates IL-6 secretion in human PBMCs in the absence or presence of ConA-stimulation and that PGE2 concentration-dependent, and EP4 antagonist compound a: (N- [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide). Compound a significantly inhibited IL-6 secretion in ConA-treated PBMC;
figure 3 is a bar graph showing EP4 antagonist compound a and compound B: (3- { [1S) -2- (4, 5-diphenyl-1, 3-oxazol-2-yl) -2-cyclohexen-1-yl ] methyl } benzoic acid) effect of inhibiting IL-6 secretion in ConA-treated PBMC;
FIG. 4 is a graph showing the effect of PGE2 on IL-6 production when used in human whole blood;
FIG. 5 is a graph showing the effect of EP2 (butaprost), EP4 (11-deoxy-PGE 1) and EP1/EP3 (sulprostone) agonists on IL-6 production in HWBs;
FIG. 6 is a graph showing the effect of compound B (320-40,000nM) on IL-6 production in PGE 2-stimulated HWB;
FIG. 7 is a graph showing the effect of PGE2 on IL-6 production in ConA-stimulated Human Whole Blood (HWB);
Fig. 8 is a graph showing compound C: (N- [ ({2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide) (16-50,000nM) in HWB co-stimulated with ConA and PGE 2.
Detailed Description
The invention relates to application of an EP4 receptor ligand in preparing a medicament for treating IL-6 related diseases. The present invention is based on the following findings: after disease induction (experimental model of rheumatoid arthritis) by anti-type II collagen antibody, EP4 knockout mice have considerable resistance to the development of arthritic symptoms. The invention also relates to screening methods for identifying agents that inhibit EP4 activity in vivo for use in, for example, anti-rheumatoid arthritis therapy.
Method of treatment
Administering an agent assayed as an EP4 receptor ligand at a dose effective to treat an IL-6 associated disease selected from the group consisting of alcoholic cirrhosis, amyloidosis, atherosclerosis, heart disease, sclerosis, and organ transplant response. Such therapeutically effective amounts can be determined using routine optimization techniques, which in turn will depend on the particular condition being treated, the condition of the patient, the route of administration, the formulation, the judgment of the practitioner, and other factors which will be evident to those of ordinary skill in the art in light of this disclosure.
Agents that inhibit EP4 activity may be mixed into therapeutic compositions. EP4 receptor ligands include small molecules, nucleotides, e.g. nucleotides, amino acids, peptides, carbohydrates antisense to EP4 and anti-EP 4 antibodies. Preferably, these agents are combined with a pharmaceutically acceptable delivery vehicle or medium. Examples of EP4 antibodies include, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, Fab, F (ab') 2, and Fab expression library fragments, single chain antibody variable region gene fragment (scFV) molecules, and epitope-binding fragments thereof. Antisense Oligonucleotides which inhibit expression of the EP4 gene or mRNA are prepared according to standard techniques (see, e.g., Agrawal et al, Methods in Molecular Biology: Protocols for Oligonucleotides and Analogs, Vol.20 (1993)).
As used herein, pharmaceutically acceptable delivery vehicles include solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents that are compatible with drug administration.
The carrier may also include other active or inert ingredients, and/or the carrier may orient the joint tissue in accordance with the composition. The therapeutic composition is formulated to match the intended route of administration. Non-limiting examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., via absorption or inhalation), transdermal (topical), transmucosal (transmucosal), and rectal administration. Solutions or suspensions can be prepared as described in Remington's pharmaceutical Sciences (18th edition, Gennaro, eds., Mack Publishing Co, Easton, Pa. (1990)).
The therapeutic efficacy of EP4 inhibitors can be determined according to the present disclosure by standard therapeutic procedures in cell culture or experimental animals, e.g., determining ED50(effective therapeutic dose in 50% of the population).
The data obtained from cell culture assays and animal studies can be used to formulate a range of human doses. The dosage may vary depending on the formulation and route of administration. For the EP4 inhibitor in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range, including IC as measured in cell culture50. This information can be used to more precisely determine the dosage for human use. For example, high performance liquid chromatography can be used to determine the concentration in plasma.
One of ordinary skill in the art will appreciate that several factors can affect the dosage and the timing effective to treat a mammal, including, but not limited to, the severity of the disease or condition, previous treatments, the general health and/or age of the mammal, and other diseases suffered. Furthermore, treatment of a mammal with a therapeutically effective amount of an EP4 inhibitor includes simple treatment, or preferably, includes a series of treatments.
For anti-EP 4 antibodies, the preferred dose is typically 10mg/kg to 20mg/kg body weight. Typically, partially humanized antibodies and fully human antibodies have a longer half-life in humans than other antibodies. Thus, low doses can be obtained and the number of administrations is small. Modifications such as lipids can be used to stabilize the antibody, enhance absorption and tissue penetration. Methods for antibody lipocaling are described in Cruikshank et al (J.acquired Immune Deficiency Syndromes hum. Retrovirol.14: 193, 1997).
EP4 receptor ligands (e.g., antagonists) that can be administered include the following: ligands included in formula I (as further described below) and as described in u.s. provisional application 60/241,825 (filed 10/19/2000), and Akiyoshi et al, u.s. non-provisional application (filed 10/2001, entitled "aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic"). Said documents are incorporated herein by reference. Publication WO 02/32900. The entire teachings of WO 02/32900 are incorporated into this application by reference. Other EP4 inhibitors that can be administered include those disclosed in the following documents: EP 0985663, WO 00/15608, WO 00/03980, WO 98/55468, WO 01/62708, WO 01/42281, WO 01/02855, WO 01/10426, WO 99/47497, WO 00/16760, WO 00/18744, WO 00/16760, WO 00/21532, WO 00/18405, EP 0855389, GB 2330307, GB 2342799, and GB 2075503.
The present invention includes both the general and specific disclosures of the above-mentioned documents.
Example A
PGE2 stimulated IL-6 secretion in ConA-treated human PBMC.
PBMC were incubated with 5. mu.g per ml of ConA for 24 hours to enhance IL-6 secretion (FIG. 1). When PBMC cells were stimulated with ConA and various concentrations of PGE2 for 24 hours, 10, 100, and 1000M of PGE2 further enhanced IL-6 secretion by 3.5-, 5, 7-, and 10.1-fold compared to IL-6 secretion stimulated with ConA without PGE2 (fig. 1). In contrast, the use of 10-1000nM PGE2 did not affect IL-6 secretion in ConA unstimulated PBMCs.
PBMC were stimulated with 5. mu.g per ml of Con A alone or 10nM to 1000nM PGE2 for 24 hours at 37 ℃. Secreted IL-6 in the culture medium was measured by ELISA. Data are presented as mean ± standard deviation (fig. 1).
Effect of EP4 antagonists on IL-6 secretion in PBMCs.
Dependence of PGE2 concentration on IL-6 secretion by stimulated human PBMC in the absence and presence of ConA-stimulation, and compound a inhibitory effect.
At 37 ℃ in 5% CO2Next, PBMC were stimulated with 5. mu.g per ml of concanavalin A alone or 10nM to 1000nM PGE2 for 24 hours. To observe the effect of compound a, compound a was added at a 50 micromolar concentration (μ M) simultaneously with ConA and PGE2 and incubated for 24 hours. The data in parentheses are expressed as percent control of mitochondrial (mitocondorial) dehydrogenase activity (figure 2).
All concentrations of PGE2(10-1000nM) enhanced the production of IL-6 by Compound A (FIG. 2). Meanwhile, to ensure that compound a at a concentration of 50 micromolar was not toxic to PBMC, viable cells were examined using a cell counting kit using a colorimetric method after incubation for 24 hours. Cells treated with compound a showed similar activity as untreated cells. This suggests that the inhibitory effect of compound a on IL-6 secretion is not due to cytotoxicity. Figure 3 shows the dose response curves of compound a and compound B when PBMCs were stimulated with 5 μ g per ml ConA and 100nM PGE2 for 24 hours. Dose-dependent inhibition of IL-6 production, IC by Compound A and Compound B 50Values were 13 and 32nM, respectively.
Compound A and compound B inhibited IL-6 secretion in ConA-treated PBMC (FIG. 3). PBMCs were incubated with 5. mu.g per ml of Con A, 100nM PGE2 and various doses of EP4 antagonist for 24 hours at 37 ℃. Secreted IL-6 in the culture medium was measured by ELISA. Data are presented as mean ± standard deviation.
Example B: human Whole Blood (HWB) media was prepared and activated with PGE 2.
The method comprises the following steps:
peripheral Human Whole Blood (HWB) was collected from healthy volunteers into sample tubes (9 volumes to 1 volume of 3.8% trisodium citrate, Becton Dickinson) and refrigerated at 4 ℃ until the experiment. HWB (50. mu.l) was poured onto the assay plate and mixed with a plate blender for 10 seconds (intensity 4, TAITAC, Micromixer). The sample was placed at room temperature for 3 minutes, then 45 microliters of AIM medium was added and mixed with a plate mixer for 10 seconds (intensity 4). The samples were placed at room temperature for 3 minutes. A mixture of 10-10000nM PGE2 and 100 micromolar argatroban (100. mu.l) was added to the sample and mixed with a plate mixer for 10 seconds (intensity 4). Samples were run at 37 ℃ in 5% CO2Next, the cells were cultured for 24 hours. Then, the sample was stirred and centrifuged at 200g for 10 minutes. The supernatant was collected and the IL-6 concentration values were measured by ELISA-kit (cytoscreen).
As a result:
in this experiment, we have established an assay for PGE 2-induced IL-6 production using Human Whole Blood (HWB). To prevent fibrin synthesis, argatroban, a thrombin inhibitor, was added to the culture samples. The addition of 100 μ M argatroban inhibited fibrin production in blood samples during the 24 hour incubation period, but did not affect the amount of IL-6 production. Under these conditions, when blood samples were stimulated with PGE2 at 10, 100 and 1000nM, IL-6 concentrations in the assay mixtures were 1.5-10 ng/ml, 3-15 ng/ml and 4.5-20 ng/ml, respectively, (FIG. 4). Diluted human whole blood samples were stimulated with 10-10,000nM PGE2 and incubated at 37 ℃ for 24 hours. IL-6 concentration in the supernatant was determined by ELISA. Results are expressed as mean ± standard deviation of three representative experiments performed.
Example C: effect of EP agonists on IL-6 production in HWB.
The method comprises the following steps:
peripheral Human Whole Blood (HWB) was collected from healthy volunteers into sample tubes (9 volumes added to 1 volume of 38% trisodium citrate, Becton Dickinson) and refrigerated at 4 ℃ until the experiment. HWB (50. mu.l) was placed in an assay plate,mix with a plate mixer (intensity 4, TAITAC, Micromixer) for 10 seconds. The sample was placed at room temperature for 3 minutes, then 45 microliters of AIM medium was added and mixed for 10 seconds with a plate stirrer (intensity 4). The samples were placed at room temperature for 3 minutes. A mixture of 10-10000nM of each EP agonist and 100. mu.M of argatroban (100. mu.l) was added to the samples and mixed for 10 seconds with a plate stirrer (intensity 4). Samples were tested at 37 ℃ in 5% CO 2And culturing for 24 hours. Then, the sample was stirred and centrifuged at 200g for 10 minutes. The supernatant was collected and the IL-6 concentration was measured by ELISA-kit (cytoscreen).
As a result:
IL-6 production was enhanced with 1-10 micromolar concentration of butaprost (EP2 agonist) (FIG. 5). 11-deoxy-PGE 1(1-10 micromolar), an EP4 agonist, enhanced IL-6 production, while sulprostone (EP1/EP3 agonist) did not exceed the concentration of 10 micromolar (FIG. 5).
The effect of EP2 (butaprost), EP4 (11-deoxy-PGE 1) and EP1/EP3 (sulprostone) agonists on IL-6 production in HWB was measured separately. Each agonist was added to HWB at 37 deg.C in 5% CO2And (5) incubating for 24 hours. Results are expressed as mean ± standard deviation of three representative experiments performed. Experiments were performed on samples obtained from 3 individuals. Similar results were obtained from 3 persons.
Example D: effect of EP4 antagonists on IL-6 production in PGE 2-stimulated HWB.
Materials and methods:
peripheral Human Whole Blood (HWB) was collected from healthy volunteers into sample tubes (9 volumes added to 1 volume of 3.8% trisodium citrate, Becton Dickinson) and refrigerated at 4 ℃ until the experiment. Compound B (5. mu.l) or vehicle (AIM medium containing 0.2% DMSO) was added to 96-well plates. HWB (50. mu.l) was placed on an analysis plate and mixed with a plate mixer (intensity 4, TAITAC, Micromixer) for 10 seconds. The sample was placed at room temperature for 3 minutes, then 45 microliters of AIM medium was added and mixed for 10 seconds with a plate stirrer (intensity 4). The samples were placed at room temperature for 3 minutes. Adding into a sample A mixture of 100nM PGE2 and 100 micromolar argatroban (100. mu.l) was added and mixed for 10 seconds with a plate stirrer (intensity 4). Samples were tested at 37 ℃ in 5% CO2And culturing for 24 hours. Then, the sample was stirred and centrifuged at 200g for 10 minutes. The supernatant was collected and the IL-6 concentration was measured by ELISA-kit (cytoscreen).
As a result:
compound B inhibited PGE 2-stimulated IL-6 production in a dose-dependent manner (fig. 6). Effect of compound B (320-40,000nM) on the stimulation of IL-6 production in HWB by PGE 2-. Human whole blood samples containing compound B dilutions were stimulated with 10-10,000nM PGE2 and incubated at 37 ℃ for 24 hours. IL-6 concentration in the supernatant was determined by ELISA. Results are expressed as mean ± standard deviation of triplicate runs of a representative experiment.
Example E: IL-6 production in ConA and PGE2 Co-stimulated human Whole blood
The method comprises the following steps:
compound B (50. mu.l), ConA and PGE2 (50. mu.l, 1: 1) were diluted to the appropriate concentrations with AIM medium (Gibco) and placed in 96-well plates (assay plates). Peripheral blood was collected from healthy volunteers (9 volumes added to 1 volume of 3.8% trisodium citrate, Becton Dickinson). Human whole blood samples were diluted with the same volume of AIM medium and 100 microliters of the diluted blood samples were placed on the assay plates. The assay mixture final DMSO concentration was 0.25%. The mixture was analyzed at 37 ℃ in 5% CO 2And culturing for 24 hours. The assay mixture was then stirred and centrifuged at 200g for 10 minutes. The supernatant was collected and the IL-6 concentration was measured by ELISA-kit (cytoscreen).
As a result:
PGE2 dose-dependently enhanced IL-6 production from 10 to 1000nM (FIG. 7).
When blood samples were stimulated with 10, 100 and 1000nM PGE2, the IL-6 concentrations in the assay mixtures were 1.8-10.8 ng/ml, 4-20 ng/ml and 5.8-23 ng/ml, respectively. PGE2(10-1000nM) concentration gave sufficient IL-6 production to determine IC for EP4 antagonists50. In these mainIn an important finding, compound C showed a dose-dependent inhibition (fig. 8). Compound C competitively inhibited IL-6 production with PGE 2. Compound C has pA2 values of 6.3, 6.4, and 7.1 in three people. Diluted human whole blood samples were stimulated with 5. mu.g per ml of ConA and three different concentrations of PGE2(10-1000 nM). After incubation at 37 ℃ for 24 hours, the IL-6 concentration in the supernatant was determined. Diluted human whole blood was co-stimulated with 5. mu.g per ml of ConA and 100nM PGE2 and incubated at 37 ℃ for 24 hours. IL-6 concentration in the supernatant was determined by ELISA.
Pharmaceutically acceptable salts (e.g., antagonists) of the EP4 receptor ligands described herein include acid addition salts and base salts (including disalts) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate (besylate), bicarbonate/carbonate, bisulfate, camphorsulfonate, citrate, edisylate, ethanesulfonate, fumarate, glucoheptonate (gluceptate), gluconate, glucuronate (glucuronate), oxybenzoate, hydrochloride/chloride, bromide/bromide, hydrogen iodide/iodide, hydrogen phosphate, isethionate, D-and L-lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, 2-naphthalenesulfonate, nicotinate (hydroxypropyltheophylline), nitrate, or orotate, palmitate, phosphate, saccharate, stearate, succinate, sulfate, D-and L-tartrate, and tosylate.
Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine (benzathine), calcium, choline, diethylamine, dialkanolamine, glycine, lysine, magnesium, meglumine, alkylolamines, potassium, sodium, tromethamine (tromethamine) and zinc salts.
For reviews of suitable salts see Stah and Wermuth, Handbook of Pharmaceutical salts: properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).
Pharmaceutically acceptable salts (e.g., antagonists) of the EP4 receptor ligands mentioned herein can be conveniently prepared by mixing together the EP4 receptor ligand (e.g., antagonist) mentioned herein and, if desired, a suitable acid or base. The salt precipitates from the solution and is collected by filtration or recovered by evaporation of the solvent.
The pharmaceutically acceptable solvates according to the invention include hydrates and solvates in which the crystallization solvent may be isotopically substituted, such as D2O，d6-acetone, d6-DMSO。
Also within the scope of the invention are clathrates, drug-host inclusion complexes, wherein the drug and host are present in non-stoichiometric amounts as compared to the solvate described above. An overview of these complexes can be found in J PharmSci, 64(8), 1269-1288, Haleblian (1975, 8).
All references to EP4 receptor ligands (e.g., antagonists) set forth below include references to salts of the EP4 receptor ligands (e.g., antagonists), solvates and clathrates of the EP4 receptor ligands and salts thereof.
The present invention includes the EP4 receptor ligand (e.g., antagonist) polymorphs referred to herein as defined above.
Also within the scope of the present invention are "prodrugs" of the EP4 receptor ligands (e.g., antagonists) referred to herein. Thus, certain derivatives of the EP4 receptor ligands (e.g., antagonists) referred to herein have little or no pharmacological activity by themselves, but are metabolized to produce the EP4 receptor ligands (e.g., antagonists) referred to herein having the desired activity when administered into or into the human body. These derivatives are referred to as "prodrugs".
Prodrugs according to the invention may be obtained, for example, by replacing suitable functional groups in ligands of the EP4 receptors mentioned herein (e.g., antagonists) with certain moieties known to those of ordinary skill in the art as "pro-moieties", see, for example, "Design of Prodrugs", H Bundgaard (Elsevier, 1985).
Finally, certain EP4 receptor ligands (e.g., antagonists) mentioned herein may themselves be prodrugs of other EP4 receptor ligands (e.g., antagonists) mentioned herein.
The EP4 receptor ligands (e.g., antagonists) containing one or more asymmetric carbon atoms referred to herein may exist as two or more optical isomers. When the EP4 receptor ligands (e.g., antagonists) referred to herein contain an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers may be formed; tautomers may be formed when the EP4 receptor ligands (e.g., antagonists) referred to herein contain, for example, a ketone or oxime group. Thus a single compound may have more than one type of isomer. The present invention includes within its scope all optical isomers, geometric isomers and tautomeric forms of the EP4 receptor ligands (e.g., antagonists) referred to herein, including compounds having more than one type of isomer, and mixtures of one or more.
The cis/trans isomers are isolated according to conventional methods known to those of ordinary skill in the art, e.g., fractional crystallization and chromatography. Conventional methods for the preparation and isolation of the individual stereoisomers include conversion from a suitable optically pure precursor, for example by chiral HPLC, to give a racemic compound (or a racemic compound of a salt or derivative thereof), or fractional crystallisation of a diastereomeric salt formed by reaction of a racemic compound with a suitable optically active acid or base, for example tartaric acid.
The present invention also includes all pharmaceutically acceptable isotopic variations of the EP4 receptor ligands (e.g., antagonists) mentioned herein. Isotopic variations are defined as those in which at least one atom is replaced by an atom of the same atomic number but of a different atomic mass than the atoms usually found in nature.
Examples of suitable isotopes that may be included in the EP4 receptor ligands (e.g. antagonists) referred to herein include the following isotopes: hydrogen, e.g.2H and3h, carbon, e.g.13C and14c, nitrogen, e.g.15N, oxygen, e.g.17O and18o, phosphorus, e.g.32P, sulfur, e.g.35S, fluorine, e.g.18F, and chlorine, e.g.36Cl。
The EP4 receptor ligands (e.g., antagonists) referred to herein are substituted with isotopes such as deuterium, i.e.,2h, replacement, resulting in certain therapeutic benefits due to increased stability of metabolism, e.g., increased in vivo half-life or reduced required dose, is preferred in some circumstances.
Certain isotopic variations of the EP4 receptor ligands (e.g., antagonists) mentioned herein, for example, those containing a radioactive isotope, are useful in drug and/or basal tissue distribution studies. Radioisotope tritium, i.e.3H, and carbon-14, i.e.,14c is particularly useful for this purpose due to its ease of incorporation and ease of detection.
The isotopic variations of EP4 receptor ligands (e.g., antagonists) mentioned herein are generally prepared by conventional techniques known to those of ordinary skill in the art or by analogous procedures to those described in the accompanying examples or preparations using appropriate reagents.
The EP4 receptor ligands (e.g. antagonists) mentioned in the present invention may be lyophilized, spray dried, or evaporation dried to obtain a solid plug (solid plug), powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may also be used for this purpose.
The EP4 receptor ligands (e.g., antagonists) mentioned herein can be administered alone or in combination with other drugs, usually in a formulation with one or more pharmaceutical excipients. Examples of such drugs include COX-2 selective, COX-1 selective or non-selective NSAIDs (non-steroidal anti-inflammatory drugs), morphine-like substances, anticonvulsants, anti-sedatives, local anesthetics, disease-modifying anti-rheumatic drugs, or steroids. In combination with a COX-2 selective NSAID, are particularly advantageous for the prevention and treatment of pain, arthritis, alcoholic cirrhosis, amyloidosis, atherosclerosis, heart diseases such as angina pectoris, myocardial infarction, (non-inflammatory) cardiomyopathy and myocarditis, sclerosis such as multiple sclerosis, and organ transplant reactions. Examples of COX-2 selective NSAIDs are nimesulide, celecoxib, rofecoxib and valdecoxib. The term "adjuvant" as used herein refers to any other ingredient than the EP4 receptor ligand (e.g., antagonist) referred to herein. The choice of adjuvant will depend largely on the particular mode of administration.
Oral administration
The EP4 receptor ligands (e.g., antagonists) referred to herein may be administered orally. Oral administration involves glossopharyngeal, to allow the compound to enter the gastrointestinal tract, or buccal or sublingual administration to allow the compound to pass directly from the mouth into the bloodstream. Suitable formulations for oral administration include solid preparations such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid-filled), chewables, composite or nano-particles, gels, films (including muco-adhesive films), suppositories (ovules), sprays and liquid preparations.
Liquid preparations include suspensions, solutions, syrups and elixirs. The formulations may serve as fillers for soft or hard gelatin capsules and generally include a carrier, for example, water, ethanol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be reconstituted from solids, for example, from sachets.
The EP4 receptor ligands (e.g., antagonists) mentioned in the present invention may also be used in fast dissolving, rapidly-disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-.
A typical tablet therapeutic composition according to the invention comprises:
Composition (I) ％w/w
The EP4 receptor ligands (e.g., agonists) described herein 10.00
Microcrystalline cellulose 64.12
Lactose 21.38
Croscarmellose sodium 3.00
Magnesium stearate 1.50
*Regulating amount according to pharmaceutical activity
Typical tablets may be prepared using standard techniques known to formulators, for example, direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion. The tablets may comprise one or more layers and may be coated or uncoated.
Examples of suitable excipients for oral administration include carriers, for example, cellulose, calcium carbonate, calcium hydrogen phosphate, mannitol, and sodium citrate; granulation binders, for example, polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and gelatin; disintegrants, for example, sodium starch glycolate and silicates; lubricants, for example, magnesium stearate and stearic acid; wetting agents, for example, sodium lauryl sulfate; a preservative; an antioxidant; fragrances and colorants.
Solid formulations for oral administration may be formulated for immediate and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, directed and programmed-release. Details of suitable sustained release techniques, such as high energy dispersions, osmotic and coated granules can be found, for example, in Verma et al, pharmaceutical technology On-line, 25(2), 1-14 (2001). Other sustained release formulations are described in US patent No.6,106,864.
Parenteral administration
The EP4 receptor ligands (e.g., antagonists) mentioned herein may also be administered directly into the bloodstream, into muscles, or into internal organs. Suitable parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, ventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needles (including microscopic (operating) needles), syringes, needleless injection and infusion techniques.
Parenteral formulations are typically aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably having a pH of from 3 to 9), but, for some applications, may suitably be formulated as sterile non-aqueous solutions or as dry forms for use with a suitable carrier, such as sterile, pyrogen-free water.
Preparation of parenteral formulations under sterile conditions, e.g., by lyophilization, can be carried out by standard pharmaceutical techniques known to those of ordinary skill in the art.
The solubility of the EP4 receptor ligands (e.g. antagonists) mentioned herein for use in the preparation of parenteral solutions may be increased by suitable processing, for example, by the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of suitable formulation techniques such as the use of solubility enhancers.
The parenteral formulations may be formulated for immediate and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, targeted and programmed release.
Topical administration of drugs
The EP4 receptor ligands (e.g., antagonists) mentioned herein may also be administered topically to the skin or mucosa, either dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches (patches), wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be added, see, for example, J Pharm Sci, 88(10), 955-958, Finnin and Morgan (10 months 1999).
Other modes of topical administration include delivery via: iontophoresis, electroporation, sonophoresis and needle-or microneedle injection. The topical formulations may be formulated for immediate release and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, targeted and programmed release. Thus, the EP4 receptor ligands (e.g., antagonists) mentioned herein can be formulated in a multi-solid administration form, such as an implanted long-acting progesterone to provide long-term active compound release.
By inhalation or intranasal administration
The EP4 receptor ligands (e.g., antagonists) mentioned herein may also be administered intranasally or by inhalation, typically in the form of dry powders from dry powder inhalers (either alone; as a mixture, e.g., a dry mixture with lactose; or as mixed component particles, e.g., with phospholipid (s)). Or as an aerosol spray, from a pressurized container, pump, nebulizer, atomizer (preferably of fine particles produced by electrohydrodynamic methods, nebulizer), or nebulizer, with or without the use of a suitable propellant, such as dichlorofluoromethane.
The pressurized container, pump, spray, atomizer or sprinkler contains a solution or suspension of the active compound, which comprises, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative for dispersing, solubilizing, or prolonging the release of the active compound, a propellant as a solvent and optionally a surfactant, such as sorbitan trioleate or an oligolactic acid.
Prior to application to a dry powder or suspension formulation, the drug product may be micronized to a suitable size for delivery by inhalation (typically less than 5 microns). This can be accomplished by suitable comminuting methods, such as helical jet milling, fluidized bed jet mills, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Suitable solution formulations for nebulizers produce fine particles with electrohydrodynamics per actuation, containing from 1 microgram to 10mg of the EP4 receptor ligand (e.g., antagonist) mentioned herein, with actuation volumes that can vary from 1 microliter to 100 microliters. Typical formulations include EP4 receptor ligands (e.g., antagonists), propylene glycol, sterile water, ethanol and sodium chloride, as noted herein. Alternative antagonistic solvents that can be used in place of propylene glycol include glycerol and polypropylene glycol.
Capsules, blisters and cartridges (e.g., made from gelatin or HPMC) for use in an inhaler or insufflator may be formulated containing a powder mix of the EP4 receptor ligand (e.g., antagonist) mentioned herein, a suitable powder base such as lactose or starch and a performance modifier such as 1-leucine, mannitol, or magnesium stearate.
For dry powder inhalers and aerosols, the dosage unit is determined via a metering valve. Units according to the invention are typically arranged to be administered in metered doses or "puffs" (puffs).
Formulations for inhaled/intranasal administration may be formulated for immediate and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, targeted and programmed release.
Rectal/intravaginal administration
The EP4 receptor ligands (e.g. antagonists) mentioned herein may be administered rectally/intravaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a conventional suppository base, but various alternatives may be used, as appropriate.
Formulations for rectal/intravaginal administration may be formulated for immediate and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, targeted and programmed release.
Ocular/ANDIAL administration
The EP4 receptor ligands (e.g. antagonists) mentioned herein may also be administered directly to the eye or ear, typically in the form of isotonic, pH-adjusted drops of a sterile saline microsuspension or solution. Suitable other formulations for ocular and ANDIAL administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate or vesicular systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers, for example, agarose, can be added together with preservatives, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
The ophthalmic/ANDIAL formulations for administration may be formulated for immediate release and/or sustained release. Sustained release formulations include delayed-, sustained-, pulsed-, controlled-release binary-, targeted and programmed release.
Implementation techniques
The EP4 receptor ligands (e.g., antagonists) mentioned herein may also be used in combination with soluble macromolecular substances such as cyclodextrins or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability.
Drug-cyclodextrin complexes, for example, are found commonly in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. An alternative to direct complexation of the drug is that the cyclodextrin may act as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Most of these are used for these purposes as alpha-, beta-and gamma-cyclodextrins, examples of which can be found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.
Dosage form
The EP4 receptor ligands (e.g., antagonists) referred to herein may be administered to a mammal by oral, parenteral or topical routes. In general, most desirable dosages for administration of these compounds to humans range from 0.1mg to 3000mg, preferably from 1mg to 500mg, which may be single doses or divided doses throughout the day, but will vary depending upon the weight and condition of the patient being treated, the disease being treated and the particular route of administration chosen.
These doses are based on patients having an average body weight of about 65 to 70 kg. The physician will conveniently determine the dosage for patients outside this weight, such as infants and elderly. For example, dosages in the range of from 0.01mg to 10mg per kilogram of body weight per day for the treatment of pain associated with inflammation are well suited.
EP4 antagonists: aryl and heteroaryl fused imidazole compounds of formula I
Aryl and heteroaryl fused imidazole compounds of formula I below or pharmaceutically acceptable salts thereof.
In the compound of the formula I,
Y1，Y2，Y3and Y4Preferably independently selected from N, CH and c (l);
l is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, mono-or di- (C)1-4Alkyl) amino, halogen-substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4)-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom;
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5-12 membered monocyclic or bicyclic aromatic ring, or an 8-12 membered tricyclic group, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl- (O ═) C-, R3(R4)C(＝O)N-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl or C1-4alkyl-C (═ O) NH-.
More preferably Y1，Y2，Y3And Y4Independently selected from N, CH and c (l); l is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, mono-or di- (C)1-4Alkyl) amino, halogen-substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4)-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2-，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom;
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring, or an 8-12 membered tricyclic ring containing up to three heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted by: a halogen.
More preferably Y1，Y2，Y3And Y4Independently selected from N, CH and c (l);
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring or an 8-12 membered tricyclic ring, optionally containing 1 sulfur atom, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with: a halogen.
More preferably Y1，Y2，Y3And Y4Independently selected from N, CH and c (l);
l is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl, acetyl, R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are linked together to form methylenedioxy;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring system.
More preferably Y1，Y2，Y3And Y4Independently selected from N, CH and C-L;
l is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group,
more preferably Y1，Y2，Y3And Y4Selected from the group consisting of:
a)Y1and Y3Is C (L), Y2Is CH and Y4Is N;
b)Y1is CH, Y2And Y3Is C (L) and Y4Is N;
c)Y1，Y2and Y3Is C (L) and Y4Is N;
d)Y1and Y3Is C (L), Y2Is N and Y 4Is CH;
e)Y1is C (L), Y2，Y3And Y4Is CH;
f)Y1，Y3and Y4Is CH, Y2Is C (L);
g)Y1，Y2and Y3Is CH, Y4Is C (L);
h)Y1and Y2Is C (L), Y3And Y4Is CH;
i)Y1and Y3Is C (L), Y2And Y4Is CH;
i)Y1and Y4Is CH, Y2And Y3Is C (L);
k)Y1and Y2Is CH, Y3Is C (L) and Y4Is N;
l)Y1and Y3Is CH, Y2Is C (L) and Y4Is N;
m)Y1，Y2，Y3and Y4Is CH;
n)Y1and Y2Is C (L), Y3Is CH and Y4Is N;
o)Y1，Y2and Y4Is CH, and Y3Is C (L);
p)Y1and Y2Is C (L), Y3Is N and Y4Is CH;
q)Y1and Y3Is C (L), Y2And Y4Is N;
r)Y1is C (L), Y2And Y3Is CH, Y4Is N;
s)Y2is C (L), Y1And Y3Is CH, Y4Is N; and
t)Y1，Y2and Y3Is C (L), Y4Is CH.
L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Most preferably Y1，Y2，Y3And Y4Selected from the group consisting of:
a)Y1and Y3Is C (L), Y2Is CH and Y4Is N;
b)Y1is CH, Y2And Y3Is C (L) and Y4Is N;
c)Y1，Y2and Y3Is C (L) and Y4Is N;
d)Y1and Y3Is C (L), Y2Is N and Y4Is CH;
e)Y1is C (L) and Y2，Y3And Y4Is CH;
f)Y1，Y3and Y4Is CH, Y2Is C (L);
g)Y1，Y2and Y3Is CH, Y4Is C (L);
h)Y1and Y2Is C (L), Y3And Y4Is CH;
i)Y1and Y3Is C (L), Y2And Y4Is CH;
j)Y1and Y 4Is CH, Y2And Y3Is C (L); and
k)Y1，Y2and Y3Is C (L), Y4Is CH
L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
In the compound of the formula I,
R1preferably is H，C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, C1-8Alkoxy, halogen substituted C1-8Alkoxy radical, C1-8alkyl-S (O) m-, Q1-, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or di- (C)1-8Alkyl) amino, C1-4alkyl-C (═ O) -N (R)3) -or C1-4alkyl-S (O) m-N (R)3) -, wherein said C1-8Alkyl radical, C2-8Alkenyl and C2-8Alkynyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano, 2, 3-indanyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(＝O)-，Q1-O-，Q1-S(O)m-，Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S (O) m-, Q1-C1-4alkyl-C (O) -N (R)3)-，Q1-C1-4alkyl-N (R)3) -or C1-4alkyl-C (O) -N (R)3)-；
Q1Is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with: halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O) C-, R3N(R4)C(＝O)-，C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4) -or NH2(HN＝)C-；
m is 0 or 2; and
R3is H or C1-4An alkyl group, a carboxyl group,
more preferably R1Is H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, Q1-, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or di- (C)1-8Alkyl) amino, wherein said C1-8Alkyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano-, 2, 3-indanyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(O)-，Q1-O-，Q1-S-or Q1-C1-4alkyl-O-, or C1-4alkyl-C (O) -N (R)3)-；
Q1Is a 5-12 membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S, and optionally substituted with: halogen, C1-4Alkyl radical, C1-4Alkylsulfonyl and C1-4Alkyl C (═ O) -; and
m is a number of 0 or 2,
more preferably R 1Is H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, Q1-, or mono or di- (C)1-8Alkyl) amino, wherein said C1-8Alkyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano-, 2, 3-indanyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(＝O)-，Q1-O-，Q1-S-，Q1-C1-4alkyl-O-, or C1-4alkyl-C (O) -N (H) -;
Q1is a 5 or 6 membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S; and
m is a number of 0 or 2,
more preferably R1Is C1-5Alkyl radical, C3-7Cycloalkyl, or Q1-, mono or di- (C)1-8Alkyl) amino, wherein said C1-5Alkyl is optionally substituted with: c1-3Alkyl, hydroxy, oxo, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-, or C1-4alkyl-C (O) -N (H) -; and
Q1is a 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S. More preferably R1Is C1-5Alkyl, mono-or di- (C)1-8Alkyl) amino, pyrrolidinyl, or pyridinyl, optionally substituted with: c1-3Alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring contains 1 or 2 heteroatoms selected from N and S, or C 1-4alkyl-C (O) -N (H) -, most preferably R1Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl.
In the compound of the formula I,
R2preferably H or C1-4Alkyl, most preferably H.
In the compound of the formula I,
a is preferably a 5-6 membered monocyclic aromatic ring, optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to two groups selected from: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy and halogen substituted C1-4An alkoxy group; more preferably the 5-6 membered monocyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl or C1-4An alkoxy group; more preferably 5-6 membered monocyclic aromatic system optionally substituted by: halogen or C1-4An alkyl group; more preferably a 5-6 membered monocyclic aromatic ring system, most preferably phenyl or pyridyl.
In the compound of the formula I,
b is preferably C3-7Cycloalkylene or C1-6Alkylene, optionally substituted with: oxo or C1-3An alkyl group; more preferably B is optionally substituted by C1-3Substituted C of alkyl1-3An alkylene group; more preferably B is C 1-2Alkylene, optionally substituted with: a methyl group; most preferably B is ethylene or propylene.
In the compound of the formula I,
w is preferably NH, N-C1-4Alkyl, O or N-OH; more preferably NH, N-C1-2Alkyl or O, most preferably NH, N-CH3Or O.
In the compound of the formula I,
z is preferably a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to three heteroatoms selected from N, O and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl, hydroxy, C1-4Alkoxy, nitro, amino, cyano, HO-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, R3C(＝O)N(R4)-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C1-4alkyl-C (═ O) NH-, Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5-12 membered monocyclic or bicyclic aromatic ring, or an 8-12 membered tricyclic group, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, hydroxy, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-4Alkylthio, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl- (O ═) C-, R3(R4)C(＝O)N-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl or C1-4alkyl-C (═ O) NH-; more preferably Z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkoxy, nitro, amino, cyano, R3C(＝O)N(R4)-，C1-4alkyl-O (O ═) C-, Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring, or an 8-12 membered tricyclic ring containing up to three heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted by: halogen; more preferably Z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical，C1-4Alkoxy, nitro, amino, cyano, R 3C(＝O)N(R4)-，C1-4alkyl-O (O ═) C-, Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2；
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring or an 8-12 membered tricyclic ring, optionally containing 1 sulfur atom, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted by: halogen, more preferably Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted by: halogen; c1-4Alkyl, nitro, R3C(＝O)N(R4) -or Q2-；
R3And R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring system; more preferably Z is a 5-10 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted by: chlorine, bromine, methyl, nitro, CH3C (═ O) NH-, tert-butyl C (═ O) NH-, or phenyl, most preferably Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl, or benzothienyl; said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl are optionally substituted with one to three groups independently selected from the group consisting of: chlorine, bromine, methyl, acetylamino, 2, 2-dimethylpropionylamino, nitro and phenyl.
Preferred compounds of formula I include those wherein:
Y1，Y2，Y3and Y4Independently selected from N, CH and c (l);
R1is a compound of formula (I) wherein the compound is H,C1-8alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, C1-8Alkoxy, halogen substituted C1-8Alkoxy radical, C1-8alkyl-S (O) m-, Q1Pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or di- (C)1-8Alkyl) amino, C1-4alkyl-C (═ O) -N (R)3) -or C1-4alkyl-S (O) m-N (R)3) -, wherein said C1-8Alkyl radical, C2-8Alkenyl and C2-8Alkynyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano, 2, 3-indanyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(＝O)-，Q1-O-，Q1-S(O)m-，Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S (O) m-, Q1-C1-4alkyl-C (═ O) -N (R)3) -, or C1-4alkyl-C (═ O) -N (R)3)-；
Q1Is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, nitro, amino, mono-or di- (C) 1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O) C-, R3N(R4)C(＝O)-，C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4) -or NH2(HN＝)C-；
A is a 5-6 membered monocyclic aromatic ring, optionally containing up to 2 substituentsA heteroatom selected from O, N and S, wherein the 5-6 membered monocyclic aromatic ring is optionally substituted with up to 2 groups selected from: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy and halogen substituted C1-4An alkoxy group;
b is C3-7Cycloalkylene or C1-6Alkylene, optionally substituted with: oxo or C1-3An alkyl group;
w is NH, N-C1-4Alkyl, O or N-OH;
R2is H or C1-4An alkyl group;
z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl, hydroxy, C1-4Alkoxy, nitro, amino, cyano, HO-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, R3C(＝O)N(R4)-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C1-4alkyl-C (═ O) NH-, Q 2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
L is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, mono-or di- (C)1-4Alkyl) amino, halogen-substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4)-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2-，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom;
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5-12 membered monocyclic or bicyclic aromatic ring or an 8-12 membered tricyclic group, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl- (O ═) C-, R3(R4)C(＝O)N-，HO(O＝)C-，C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C 3-7Cycloalkyl or C1-4alkyl-C (═ O) NH-.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Independently selected from N, CH and c (l);
R1is H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-7Cycloalkyl radical, Q1-, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or di- (C)1-8Alkyl) amino, wherein said C1-8Alkyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano-, 2, 3-indanyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(O)-，Q1-O-，Q1-S-，Q1-C1-4alkyl-O-, or C1-4alkyl-C (O) -N (R)3)-；
Q1Is a 5-12 membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S, and optionally substituted with: halogen, C1-4Alkyl radical, C1-4Alkylsulfonyl and C1-4Alkyl C (═ O) -;
a is a 5-6 membered monocyclic aromatic ring, optionally substituted with: halogen, C1-4Alkyl or C1-4An alkoxy group;
b is C3-7Cycloalkylene or C1-6Alkylene, optionally substituted with: oxo or C1-3An alkyl group;
w is NH, N-C1-4Alkyl, O or N-OH;
R2is H or C1-4An alkyl group;
z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkoxy, nitro, amino, cyano, R3C(＝O)N(R4)-，C1-4alkyl-O (O ═) C-, Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
L is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy, mono-or di- (C)1-4Alkyl) amino, cyano, HO-C1-4Alkyl radical, C1-4Alkyl sulfonyl radicalAminosulfonyl radical, C1-4Alkyl C (═ O) -, HO (O ═ C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C3-7Cycloalkyl radical, R3C(＝O)N(R4)-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2-，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom;
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring, or an 8-12 membered tricyclic group containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted by: a halogen.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Independently selected from N, CH and c (l);
R1is H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl or C3-7Cycloalkyl, wherein said C1-8Alkyl is optionally substituted with: halogen, C1-3Alkyl, hydroxy, oxo, C 1-4alkoxy-C1-4alkyl-S (O) m-, C3-7Cycloalkyl-, cyano-, 2, 3-indanyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-，Q1-C(＝O)-，Q1-O-，Q1-S-，Q1-C1-4alkyl-O-, or C1-4alkyl-C (O) -N (R)3)-；
Q1Is a 5 or 6 membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S;
a is a 5-6 membered monocyclic aromatic ring system, optionally substituted with: halogen or C1-4An alkyl group;
b is or C3-7Cycloalkylene or C1-6Alkylene, optionally substituted with: oxo or C1-3An alkyl group;
w is NH, N-C1-4Alkyl, O or N-OH;
R2is H or C1-4An alkyl group;
z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted by: halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkoxy, nitro, amino, cyano, R3C(＝O)N(R4)-，C1-4alkyl-O (O ═) C-, Q2-S(O)m-，Q2-O-，Q2-N(R3) -or Q2-；
L is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, C1-4Alkyl C (═ O), HO (O ═) C-, C1-4alkyl-O (O ═) C-, C1-4Alkylsulfonylamino group, C 3-7Cycloalkyl radical, R3C(＝O)NR4-，R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2，Q2-C(＝O)-，Q2-O-，Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked together to form an alkylene chain having 3 to 4 members, wherein one or two (non-adjacent) carbon atoms are optionally replaced by an oxygen atom;
m is 0 or 2;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring or an 8-12 membered tricyclic ring, optionally containing 1 sulfur atom, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted by: a halogen.
Further preferred compounds of formula I include the following compounds, wherein
Y1，Y2，Y3And Y4Independently selected from N, CH and c (l);
R1is C1-5Alkyl or C3-7Cycloalkyl, wherein said C1-5Alkyl is optionally substituted with: c1-3Alkyl, hydroxy, oxo, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q1-, or C1-4alkyl-C (O) -N (H) -;
Q1is a 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S,
a is a 5-6 membered monocyclic aromatic ring system;
b is C1-3Alkylene, optionally substituted with: c1-3An alkyl group;
w is NH, N-C1-2Alkyl or O;
R2is H;
z is a 5-12 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted by: halogen, C 1-4Alkyl, nitro, R3C(＝O)N(R4) -or Q2-；
L is halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy, C1-4Alkoxy, halogen substituted C1-4Alkoxy, cyano, HO-C1-4Alkyl, acetyl, R3N(R4)C(＝O)-，R3N(R4)S(O)m-，Q2-，Q2-C (═ O) -, or two adjacent L groups are joined together to form a methylenedioxy group;
R3and R4Independently selected from H and C1-4An alkyl group; and
Q2is a 5 or 6 membered monocyclic aromatic ring system.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Independently selected from N, CH and C-L;
R1is C1-5Alkyl, optionally substituted with: c1-3Alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is a monocyclic aromatic ring containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C (O) -N (R)3)-；
A is phenyl;
b is C1-2Alkylene, optionally substituted with: a methyl group;
w is NH, N-CH3Or O;
R2is H;
z is a 5-10 membered monocyclic or bicyclic aromatic ring, optionally containing up to three heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted by: chlorine, bromine, methyl, nitro, CH3C (═ O) NH-, tert-butyl C (═ O) NH-, or phenyl; and
l is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH 2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Independently selected from N, CH and C-L;
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethylmethylamino, dimethylamino, pyrrolidinyl, pyridinyl, or 1-acetylamino-1-methylethyl;
a is phenyl;
b is ethylene or propylene;
w is NH, N-CH3Or O;
R2is H;
z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with 1-3 substituents independently selected from the group consisting of: chlorine, bromine, methyl, acetylamino, 2, 2-dimethylpropionylamino, nitro and phenyl; and
l is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Selected from the group consisting of:
a)Y1and Y3Is C (L), Y2Is CH and Y4Is N;
b)Y1is CH, Y2And Y3Is C (L) and Y4Is N;
c)Y1，Y2and Y3Is C (L), Y4Is N;
d)Y1and Y3Is C (L), Y2Is N and Y4Is CH;
e)Y1is C (L), Y2，Y3And Y4Is CH;
f)Y1，Y3and Y4Is CH, Y2Is C (L);
g)Y1，Y2and Y3Is CH, Y4Is C (L);
h)Y1and Y2Is C (L), Y3And Y4Is CH;
i)Y1and Y3Is C (L), Y2And Y4Is CH;
j)Y1and Y4Is CH, Y2And Y3Is C (L);
k)Y1and Y2Is CH, Y3Is C (L) and Y4Is N;
l)Y1and Y3Is CH, Y2Is C (L) and Y4Is N;
m)Y1，Y2，Y3and Y4Is CH;
n)Y1and Y2Is C (L), Y3Is CH and Y4Is N;
o)Y1，Y2and Y4Is CH, Y3Is C (L);
p)Y1and Y2Is C (L), Y3Is N and Y4Is CH;
q)Y1and Y3Is C (L), Y2And Y4Is N;
r)Y1is C (L), Y2And Y3Is CH, Y4Is N; and
s)Y2is C (L), Y1And Y3Is CH, Y4Is N;
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
a is phenyl;
b is ethylene or propylene;
w is NH, N-CH3Or O;
R2is H;
z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from the group consisting of: chlorine, bromine, methyl, acetylamino, 2, 2-dimethylpropionylamino, nitro and phenyl; and
L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Further preferred compounds of formula I include the following compounds, wherein:
Y1，Y2，Y3and Y4Selected from the group consisting of:
a)Y1and Y3Is C (L), Y2Is CH and Y4Is N;
b)Y1is CH, Y2And Y3Is C (L) and Y4Is N;
c)Y1，Y2and Y3Is C (L), Y4Is N；
d)Y1And Y3Is C (L), Y2Is N and Y4Is CH;
e)Y1is C (L), Y2，Y3And Y4Is CH;
f)Y1，Y3and Y4Is CH, Y2Is C (L);
g)Y1，Y2and Y3Is CH, Y4Is C (L);
h)Y1and Y2Is C (L), Y3And Y4Is CH;
i)Y1and Y3Is C (L), Y2And Y4Is CH; and
j)Y1and Y4Is CH, Y2And Y3Is C (L);
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
a is phenyl;
b is ethylene or propylene;
w is NH, N-CH3Or O;
R2is H;
z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from the group consisting of: chlorine, bromine, methyl, acetylamino, 2, 2-dimethylpropionylamino, nitro and phenyl; and
L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (═ O) NH2Trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are linked together to form methylenediamino.
Preferred individual compounds of formula I are the following:
3- (4- {2- [ ({ [ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (2, 4-dimethyl-1, 3-thiazol-5-yl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
n- [5- ({ [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] amino } sulfonyl) -1, 3, 4-thiadiazol-2-yl ] acetamide;
6-ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5H- [1, 3] dioxolo [4, 5-f ] benzimidazole;
6-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2-ethyl-5, 7-dimethyl-3- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] propyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate;
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-propyl-3H-imidazo [4, 5-b ] pyridine;
2-isopropyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2-butyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2-isobutyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-neopentyl-3H-imidazo [4, 5-b ] pyridine;
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridine;
3-4- [2- ({ [ (4-biphenylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 7-dimethyl-3- {4- [2- ({ [ (1-naphthylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 7-dimethyl-3- {4- [2- ({ [ (2-naphthylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (5-chloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (4, 5-dichloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- {4- [2- ({ [ (1-benzothien-2-ylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (2-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
5, 6-dichloro-2-ethyl-3- (4- {2- [ ([ (4-methylphenyl) sulfonyl) amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
5-chloro-2-ethyl-7-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
6-cyano-2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine;
4-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
7-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5-methoxy-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5-cyano-2-ethyl-1- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2-ethyl-5-hydroxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2-ethyl-4, 5-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } benzimidazole;
4, 6-dimethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
5, 6-dichloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl- (4-methylphenyl) sulfonylcarbamate;
6-chloro-5-trifluoromethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzoimidazol-1-yl) phenylethyl- (4-methylphenyl) sulfonylcarbamate;
5-chloro-6-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide (carboxamide);
2-ethyl-3- {4- [2- ({ [ ({3- [ hydroxy (oxo) amino ] phenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (4-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
n- [4- ({ [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] amino } sulfonyl) phenyl ] -2, 2-dimethylpropionamide;
3- (4- {2- [ ({ [ (2-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (3-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (5-chloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (5-bromo-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (2-bromophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
3- {4- [2- ({ [ ({ 4-chloro-3-nitrophenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- (4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
n { [ (2- {4- [ 2-ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide;
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (2-chlorophenyl) sulfonyl carbamate;
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] -2-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-methyl-2-pyridyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2- (4-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -2-thiophenesulfonamide;
2- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl carbamate;
2- {4- [4, 6-dimethyl-2- (3-phenylisopropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2-4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
(1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonyl carbamate;
2- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] -3-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
n- { [ (2- {4- [5, 7-dimethyl-2 (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2- {4- [2- (1, 1-dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide; and
a salt thereof.
Most preferably, the individual compounds of formula I are the following:
6-ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl) phenyl) -5H- [1, 3] dioxolo [4, 5-f ] benzimidazole;
6-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate;
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
3- (4- {2- [ ({ [ (2-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine;
2-ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
5, 6-dichloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine;
5-methoxy-2-ethyl-3- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole;
5-cyano-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2-ethyl-5-hydroxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
2-ethyl-4, 5-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzoimidazol-1-yl) phenylethyl- (4-methylphenyl) sulfonylcarbamate; and
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide;
2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- {4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
n- { [ (2- {4- [ 2-ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide;
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (2-chlorophenyl) sulfonyl carbamate;
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] -2-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-methyl-2-pyridyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2- (4-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -2-thiophenesulfonamide;
2- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate;
2-4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl carbamate;
2- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
(1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonyl carbamate;
2- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] -3-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate;
n- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide; and
n- { [ (2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide;
2- {4- [2- (1, 1-dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate;
2-4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate;
6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide; and
a salt thereof.
Synthesis of compounds of formula I.
Representative compounds of formula I and methods for their synthesis are described in the following examples 1-380. Additional general synthetic schemes are described in U.S. provisional 60/241,825 (filed 10/19/2000), and Akiyoshi et al, non-provisional application (filed 10/2001, entitled "aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents".
All operations in the following examples were carried out at room or ambient temperature, i.e. 18-25 ℃ unless otherwise stated; evaporation of the solvent is carried out under reduced pressure using a rotary evaporator, and the bath temperature is at most 60 ℃; the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction time was only illustrative; the resulting melting point (mp) is uncorrected (polymorphism can lead to different melting points); the structure and purification of all isolated compounds is ensured by at least one of the following techniques: TLC (Merck silica gel 60F 254 precoated TLC plates), mass spectrometry, Nuclear Magnetic Resonance (NMR), infrared absorption spectroscopy (IR) or microanalysis. The results are merely exemplary. Flash column chromatography was performed using Merck silica gel 60 (230-.
Low resolution mass spectral data (EI) were obtained on an automated 120(JEOL) mass spectrometer. Low resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) or ZMD (Micromass) mass spectrometer. Unless otherwise stated, NMR data were measured at 270MHz (JEOL JNM-LA 270 spectrometer) or 300MHz (JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent, in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard; the conventional abbreviations used are: s is singlet, d is doublet, t is triplet, q is quartet, quint is quintet, m is multiplet, br. is broad, etc. The IR chromatogram was measured with a Shimazu infrared spectrometer (IR-470). Chemical symbols have their usual meaning; bp (boiling point), mp (melting point), L (L), mL (mL), g (g), mg (mg), mol (mol), mmol (mmol molimels), eq. (eq.), quant. (quantitative yield).
Example 1
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ 4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 14, 6-dimethyl-3-nitro-2 (1H) -pyridone (pyridone)
Ethyl nitroacetate (80.0g, 601mmol) was mixed with aqueous ammonia (25% NH) at room temperature 3Dissolved in water, 400mL) was stirred for three days, and then the solution was concentrated by air drying. The residue was dissolved in water (450 mL). To the solution was added 2, 4-pentanedione (73.1g, 730mmol), pyridine (162mL, 200mmol) and acetic acid (11.4mL, 200mmol), and the mixture was stirred for another 7 days. The resulting precipitate was collected by filtration and dried under reduced pressure to give 35.0g (35%) of the title compound as a yellow solid:
1H-NMR(DMSO-d6)δ12.44(1H，br.s)，6.06(1H，s)，2.19(3H，s)，2.13(3H，s)。
step 22-chloro-4, 6-dimethyl-3-nitropyridine
A mixture of 4, 6-dimethyl-3-nitro-2 (1H) -pyridone (step 1, 10.0g, 29.7mmol) and phosphorus oxychloride (35mL, 187.3mmol) was stirred at 95 ℃ for 3 hours and then cooled to 45 ℃. Excess phosphorus oxychloride was distilled off at 45 ℃ under reduced pressure. The residue was cooled to room temperature and diluted with dichloromethane (75 mL). The resulting solution was cooled to 0 ℃ and 2N hydrochloric acid (50mL) was added dropwise to the solution. The organic layer was separated and washed with 2N hydrochloric acid (4X 25mL), 2N aqueous sodium hydroxide (2X 50mL) and brine (50 mL). The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure to give 10.0g (90%) of the title compound as a white solid:
1H-NMR(CDCl3)δ7.07(1H，s)，2.56(3H，s)，2.35(3H，s).
step 32- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
A mixture of 2-chloro-4, 6-dimethyl-3-nitropyridine (step 2, 1.3g, 7.0mmol) and 4-aminophenylethyl alcohol (1.4g, 10.2mmol) was heated in a sealed tube at 150 ℃ for 3 hours. The reaction mixture was cooled and purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) to give 1.6g (80%) of the title compound as an orange-yellow solid:
1H-NMR(CDCl3)δ：9.55(1H，br.s)，7.57(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.4Hz)，6.52(1H，s)，3.84(2H，t，J＝6.4Hz)，2.85(2H，t，J＝6.4Hz)，2.54(3H，s)，2.42(3H，s)。
Step 42- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol
To a stirred solution of 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 3, 1.6g, 5.6mmol) in ethyl acetate (15mL) was added 10% Pd-C (160 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to give 1.3g (92%) of the title compound as a pale yellow solid:
1H-NMR(CDCl3)δ：7.10(4H，s)，6.61(1H，s)，3.81(2H，t，J＝6.4Hz)，2.80(2H，t，J＝6.4Hz)，2.36(3H，s)，2.19(3H，s)。
step 52- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
To a stirred suspension of 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (step 4, 1.3g, 5.1mmol) in toluene (30mL) was added propionyl chloride (990mg, 10.7mmol) dropwise at 0 deg.C, and the reaction mixture was heated at reflux for 2 h. After cooling, the mixture was poured into water (50mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous sodium hydroxide (50mL) and brine (50mL), then dried (magnesium sulfate). Removal of the solvent gave 1.8g (quant.) of the title compound as a brown solid:
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，6.90(1H，s)，4.37(2H，t，J＝6.9Hz)，3.04(2H，t，J＝6.9Hz)，2.82(2H，q，J＝7.6Hz)，2.65(3H，s)，2.52(3H，s)，2.35(2H，q，J＝7.6Hz)，1.27(3H，t，J＝7.6Hz)，1.14(3H，t，J＝7.6Hz)。
step 62- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
To a solution of 2- {4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 5, 1.75g, 5.1mmol) in methanol/THF (v/v, 1: 1, 28mL) was added an aqueous 4NLiOH solution (4.6mL, 18.4mmol), and the resulting mixture was stirred at room temperature. After 3 hours, the mixture was concentrated. The residue was dissolved in water (30mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2: 1 to 0: 1) afforded 1.3g (86%) of the title compound as a pale brown solid:
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，6.91(1H，s)，3.81-3.75(2H，m)，3.47(1H.br.s)，2.92(2H，t，J＝6.9Hz)，2.81(2H，q，J＝7.6Hz)，2.66(3H，s)，2.51(3H，s)，1.27(3H，t，J＝7.6Hz)。
step 73- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
To a solution of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 6, 2.2g, 7.4mmol) in toluene (40mL) was added thionyl chloride (2.0mL, 23.6 mmol); the resulting mixture was stirred at 80 ℃ for 3 hours. Volatile components were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2: 1 to 1: 1) to give 2.1g (90%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，6.90(1H，s)，3.78(2H，t，J＝7.4Hz)，3.15(2H，t，J＝7.4Hz)，2.83(2H，q，J＝7.6Hz)，2.71(3H，s)，2.54(3H，s)，1.28(3H，t，J＝7.6Hz)。
Step 82- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
To a mixture of 3- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 7, 2.8g, 9.0mmol) and KI (1.5g, 9.0mmol) in DMF (50mL) was added sodium azide (1.2g, 18.0mmol) and the resulting mixture was stirred at 100 ℃ overnight. The reaction mixture was poured into water (100mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50mL) and brine (50mL), then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) to give 2.35g (85%) of the title compound as a white solid:
1H-NMR(CDCl3)δ7.41(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，6.90(1H，s)，3.59(2H，t，J＝7.1Hz)，2.99(2H，t，J＝7.1Hz)，2.83(2H，q，J＝7.6Hz)，2.65(3H，s)，2.52(3H，s)，1.27(3H，t，J＝7.6Hz)。
step 92- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
To a solution of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 8, 2.35g, 7.3mmol) in methanol (50mL) was added 10% Pd-C (200 mg). The resulting mixture was stirred for 4 hours under a hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with methylene chloride/methanol/triethylamine (100: 5: 1) to give 2.01g (94%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.39(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，6.90(1H，s)，3.05(2H，t，J＝7.3Hz)，2.88-2.78(4H，m)，2.65(3H，s)，2.51(3H，s)，1.28(3H，t，J＝7.6Hz)。
Step 102-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
To a solution of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 9, 1.2g, 4.0mmol) in dichloromethane (15mL) was added p-toluenesulfonyl isocyanate (805mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. After removal of the solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (20: 1) to give 110g (56%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.85(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，7.23(2H，d，J＝8.4Hz)，7.16(2H，d，J＝8.4Hz)，6.91(1H，s)，6.12(1H，br.s)，3.55-3.46(2H，m)，2.85(2H，t，J＝6.3Hz)，2.74-2.64(5H，m)，2.42(3H，s)，2.41(3H，s)，1.21(3H，t，J＝7.6Hz)。
example 2
2-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
To a solution of 2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 1, 5.0g, 10.2mmol) in methanol (20mL) was added a 2N aqueous solution of sodium hydroxide (5.1mL, 10.2 mmol). The resulting mixture was stirred at room temperature for 5 minutes and concentrated. The residual solid was collected by filtration and dried at 50 ℃ under reduced pressure to give the title compound as a white solid:
1H-NMR(DMSO-d6)δ7.60(2H，d，J＝8.2Hz)，7.31-7.39(4H，m)，7.14(2H，d，J＝8.2Hz)，6.96(1H，s)，3.15(2H，br.s)，2.66-2.75(4H，m)，2.53(3H，s)，2.40(3H，s)，2.28(3H，s)，1.20(3H，t，J＝7.6Hz)。
Example 3
2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
To a solution of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 6 example 1, 300mg, 1.0mmol) in dichloromethane (10mL) was added p-toluenesulfonyl isocyanate (237mg, 1.2 mmol). The resulting mixture was stirred at room temperature overnight. After removal of the solvent, the residual solid was recrystallized from ethyl acetate to yield 454mg (92%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.93(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，7.22(4H，s)，6.92(1H，s)，4.87(1H，br.s)，435(2H，t，J＝6.6Hz)，2.96(2H，t，J＝6.6Hz)，2.78(2H，q，J＝7.7Hz)，2.66(3H，s)，2.50(3H，s)，2.43(3H，s)，1.24(3H，t，J＝7.7Hz)。
example 4
2-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ methyl [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
To a mixture of 2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 1, 200mg, 0.41mmol) in THF (10mL) under ice-cooling was added dropwise Lithium Diisopropylamide (LDA) (2.0N in heptane/hexane/ethylbenzene, 0.8mL, 1.6mmol) over 10 minutes. After the addition was complete, the mixture was stirred at the same temperature for another 20 minutes. To the resulting mixture was added dropwise MeI (0.5mL) at 0 ℃ and stirred at room temperature for 15 hours. The mixture was poured into a phosphate buffer (100mL) solution and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50mL), dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10: 1) to give 10mg (5%) of the title compound as a colorless oil:
1H-NMR(CDCl3)δ：7.64(2H，d，J＝8.3Hz)，7.53-7.25(7H，m)，6.89(1H，s)，3.65-3.55(2H，m)，3.14(3H，s)，2.96(2H，t，J＝6.7Hz)，2.82(2H，q，J＝7.6Hz)，2.66(3H，s)，2.50(3H，s)，2.40(3H，s)，1.25(3H，t，J＝7.6Hz)。
Example 5
2-ethyl-5, 7-dimethyl-3- (4- {2- [ methyl ({ [ ((4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 1N- {2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } -N-methylamine
A mixture of 3- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 7 example 1, 627mg, 9.0mmol), methylamine solution (40% in methanol, 6mL) and water (6mL) was placed in a sealed tube and heated overnight at 130 ℃. The reaction mixture was partitioned between dichloromethane (50mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic extracts were washed with brine (50mL) and dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (5: 1) to give 523mg (85%) of the title compound as a white solid:
1H-NMR(CDCl3)δ7.41(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，6.90(1H，s)，4.73(1H，br.s)，2.93(4H，s)，2.82(2H，q，J＝7.5Hz)，2.65(3H，s)，2.51(3H，s)，2.49(3H，s)，1.28(3H，t，J＝7.5Hz)。
step 22-Ethyl-5, 7-dimethyl-3- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
To a solution of N- {2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } -N-methylamine (step 1, 523mg, 1.7mmol) in dichloromethane (10mL) and triethylamine (2mL) was added p-toluenesulfonyl isocyanate (400mg, 20 mmol). The resulting reaction mixture was stirred at room temperature for 6 hours. After removal of the solvent, the residue was purified by flash column chromatography on silica gel eluting with methylene chloride/methanol (10: 1) to give 358mg (42%) of the title compound as a white solid:
1H-NMR(CDCl3)δ7.93(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.3Hz)，7.14(2H，d，J＝8.4Hz)，6.92(1H，s)，3.66-3.49(2H，m)，3.51(3H，s)，2.93-2.70(4H，m)，2.65(3H，s)，2.50(3H，s)，2.38(3H，s)，1.24(3H，t，J＝7.2Hz)。
Example 6
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] propyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 11- (4-aminophenyl) -2-propanol
A mixture of 1- (4-nitrophenyl) -2-propanol (Schadt, F.L.; et al J.am.chem.Soc., 1978, 100, 228., 2.2g, 12.3mmol), iron powder (3.3g, 59.1mmol), ammonium chloride (370mg, 6.9mmol), ethanol (48mL) and water (24mL) was heated at reflux for 2 hours. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate (200mL) and washed with water (2X 100 mL). The organic layer was dried (magnesium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) gave 145g (78%) of the title compound as a yellow oil:
1H-NMR(CDCl3)δ：7.00(2H，d，J＝8.6Hz)，6.64(2H，d，J＝8.8Hz)，3.99-3.89(1H，m)，3.60(2H，br s)，2.72-2.52(2H，m)，1.22(3H，d，J＝6.2Hz)。
step 21- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-propanol
The title compound was prepared according to the procedure described for step 3 of example 1 from 1- (4-aminophenyl) -2-propanol (step 1) and 2-chloro-4, 6-dimethyl-3-nitropyridine (example 1, step 2).
1H-NMR(CDCl3)δ：9.59(1H，br.s)，7.58(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.4Hz)，6.53(1H，s)，4.13-4.01(1H，m)，2.82-2.64(2H，m)，2.55(3H，s)，2.44(3H，s)，1.25(3H，d，J＝6.2Hz)。
Step 31- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-propanol
A mixture of 1- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-propanol (step 2, 500mg, 1.66mmol), iron powder (440mg, 7.88mmol), ammonium chloride (80mg, 1.5mmol) in ethanol/water (v/v, 31: 8, 39mL) was heated at reflux for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with dichloromethane (200mL) and washed with water (2X 100 mL). The organic layer was dried (magnesium sulfate) and concentrated. Removal of the solvent gave 450mg (quant.) of the title compound as a brown solid: TLC Rf 0.10 (1: 1 with hexane/ethyl acetate).
Step 42- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared from 1- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-propanol (step 3) and propionyl chloride according to the procedure described in example 1, step 5.
TLC Rf 0.30 (1: 1 with hexane/ethyl acetate).
Step 51- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propanol
The title compound was prepared from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate (step 4) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.0Hz)，7.33(2H，d，J＝8.0Hz)，6.91(1H，s)，4.16-4.07(1H，m)，2.90-2.76(4H，m)，2.66(2H，s)，2.52(3H，s)，1.32-1.22(6H，m)。
Step 63- [4- (2-chloropropyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 1- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propanol (step 5).
TLC Rf was 0.50 (1: 1 with hexane/ethyl acetate).
Step 72- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroisopropyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 6).
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.4Hz)，6.91(1H，s)，3.81-3.74(1H，m)，2.95-2.79(4H，m)，2.66(3H，s)，2.52(3H，s)，1.35(3H，d，J＝6.6Hz)，1.27(3H，t，J＝7.5Hz)。
Step 81- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propylamine
The title compound was prepared from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl azide (step 7) according to the procedure described in example 1, step 9.
1H-NMR(CDCl3)δ：7.40-7.31(4H，m)，6.90(1H，s)，3.31-3.20(1H，m)，2.87-2.77(3H，m)，2.66-2.58(4H，m)，2.52(3H，s)，1.28(3H，t，J＝8.3Hz)，1.19(3H，d，J＝6.8Hz)。
Step 92-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] propyl } phenyl) 3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propylamine (step 8).
mp 128℃；MS(ESI)m/z 506.19(M+H)+；1H-NMR(CDCl3)δ：7.74(2H，d，J＝8.3Hz)，7.30-7.19(6H，m)，6.90(1H，s)，4.08-4.02(1H，m)，2.84-2.72(4H，m)，2.65(3H，s)，2.48(3H，s)，2.32(3H，s)，1.20-1.13(6H，m)。
Example 7
2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulphonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propanol (example 6, step 5).
mp 108℃；MS(ESI)m/z 507.18(M+H)+；1H-NMR(CDCl3)δ：7.91(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.3Hz)，7.23(4H，s)，6.91(1H，s)，5.10-5.04(1H，m)，2.95-2.76(4H，m)，2.65(3H，s)，2.50(3H，s)，2.41(3H，s)，1.28-1.21(6H，m)。
Example 8
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-propyl-3H-imidazo [4, 5-b ] pyridine
Step 12- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylbutyrate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (example 1, step 4) and butyryl chloride.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，6.92(1H，s)，4.39(2H，t，J＝6.4Hz)，3.09(2H，t，J＝6.4Hz)，2.77，(2H，t，J＝7.7Hz)，2.66(3H，s)，2.52(3H，s)，2.32(2H，t，J＝7.7Hz)，1.81-1.58(4H，m)，1.00-0.86(6H，m)。
Step 22- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylbutyrate (step 1).
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.0Hz)，7.32(2H，d，J＝8.0Hz)，6.90(1H，s)，4.00-3.89(2H，m)，2.97(2H，t，J＝6.4Hz)，2.78(2H，t，J＝7.8Hz)，2.65(3H，s)，2.51(3H，s)，1.80-1.64(2H，m)，0.92(3H，t，J＝7.4Hz)。
Step 33- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 2).
MS(EI)m/z 327(M+)。
Step 42- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridine (step 3).
MS(EI)m/z 334(M+)；1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.4Hz)，6.91(1H，s)，3.60(2H，t，J＝7.2Hz)，3.00(2H，t，J＝7.2Hz)，2.77(2H，t，J＝7.8Hz)，2.65(3H，s)，2.52(3H，s)，1.75-1.62(2H，m)，0.90(3H，t，J＝7.4Hz)。
Step 52- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，6.88(1H，s)，3.89(2H，br.s)，3.18(2H，t，J＝6.8Hz)，3.01(2H，t，J＝6.8Hz)，2.75(2H，t，J＝7.5Hz)，2.64(3H，s)，2.48(3H，s)，1.78-1.63(2H，m)，0.90(3H，t，J＝7.3Hz)。
Step 65, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-propyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5, 7-dimethyl-2-propyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 5).
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.23(2H，d，J＝8.3Hz)，7.16(2H，d，J＝8.3Hz)，6.90(1H，s)，6.10(1H，br.s)，3.58-3.46(2H，m)，2.87(2H，t，J＝6.4Hz)，2.71-2.59(5H，m)，2.42(3H，s)，2.40(3H，s)，1.74-1.61(2H，m)，0.89(3H，t，J＝7.0Hz)。
Example 9
2-isopropyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 15-bromo-4, 6-dimethyl-3-nitro-2-pyridinol
To a solution of 5-bromo-4, 6-dimethyl-3-nitro-2-pyridylamine (Heitsch, H.; et al, Bioorg. Med. chem.1997, 5, 673., 2.0g, 8.1mmol) in trifluoroacetic acid/water (v/v, 2: 1, 30mL) was added sodium nitrite (1.1g, 16mmol) in small portions at room temperature, and the reaction mixture was stirred overnight. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 2.2g (quant.) of the title compound:
1H-NMR(CDCl3)δ：2.53(3H，s)，2.38(3H，s)。
step 23-bromo-6-chloro-2, 4-dimethyl-5-nitropyridine
The title compound was prepared according to the procedure described in example 1, step 2, from 5-bromo-4, 6-dimethyl-3-nitro-2-pyridinol (step 1).
1H-NMR(CDCl3)δ：2.72(3H，s)，2.41(3H，s)。
Step 32- {4- [ (5-bromo-4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 3-bromo-6-chloro-2, 4-dimethyl-5-nitropyridine (step 2) and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：8.66(1H，br.s)，7.51(2H，d，J＝8.4Hz)，7.22(2H，d，J＝8.4Hz)，3.90-3.77(2H，m)，2.88(2H，t，J＝6.5Hz)，2.65(3H，s)，2.59(3H，s)。
Step 42- {4- [ (3-amino-5-bromo-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 4, from 2- {4- [ (5-bromo-4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } ethanol (step 3).
1H-NMR(CDCl3)δ：7.12(4H，s)，6.21(1H，s)，3.38(1H，br.s)，3.82(2H，t，J＝6.5Hz)，2.80(2H，t，J＝6.5Hz)，2.54(3H，s)，2.38(3H，s)。
Step 52- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 2-methylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5-bromo-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (step 4) and isobutyryl chloride.
MS(EI)m/z 457(M+)。
Step 62- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 2-methylpropionate (step 5) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，3.96(2H，t，J＝7.3Hz)，3.15-3.03(1H，m)，2.97(2H，t，J＝7.3Hz)，2.76(3H，s)，2.67(3H，s)，1.34(6H，d，J＝6.8Hz)。
Step 76-bromo-3- (4- (2-chloroethyl) phenyl ] -2-isopropyl-5, 7-dimethyl-3H imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 6).
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.3Hz)，7.32(2H，d，J＝8.3Hz)，3.81(2H，t，J＝7.3Hz)，3.19(2H，t，J＝7.3Hz)，3.15-3.02(1H，m)，2.76(3H，s)，2.66(3H，s)，1.33(6H，d，J＝6.9Hz)。
Step 82- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-bromo-3- [4- (2-chloroethyl) phenyl ] -2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 7).
MS(EI)m/z 412(M+)；
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，3.60(2H，t，J＝6.5Hz)，3.16-3.02(1H，m)，3.02(2H，t，J＝6.5Hz)，2.77(3H，s)，2.68(3H，s)，1.33(6H，d，J＝6.9Hz)。
Step 9[4- (2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 8).
H-NMR(CDCl3)δ：7.49(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.93(1H，s)，6.60(2H，br.s)，3.32-3.00(5H，m)，2.65(3H，s)，2.48(3H，s)，1.31(6H，d，J＝6.8Hz)。
Step 102-isopropyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from [4- (2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 9).
1H-NMR(CDCl3)δ：7.87(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，7.23(2H，d，J＝8.4Hz)，7.17(2H，d，J＝8.4Hz)，6.91(1H，s)，6.08(1H，br.s)，3.56-3.43(2H，m)，3.02-2.89(1H，m)，2.85(2H，t，J＝6.3Hz)，2.67(3H，s)，2.41(6H，s)，1.26(6H，d，J＝6.8Hz)。
Example 10
2-isopropyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-isopropyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 9).
MS(ESI)m/z 506(M+H)+。
Example 11
2-butyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylvalerate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5-bromo-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (example 9, step 4) and valeryl chloride.
MS(EI)m/z 485(M+)；
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，4.37(2H，t，J＝6.9Hz)，3.05(2H，t，J＝6.9Hz)，2.79(2H，t，J＝7.7Hz)，2.75(3H，s)，2.67(3H，s)，2.33(2H，t，J＝7.5Hz)，1.75-1.54(4H，m)，1.40-1.20(4H，m)，0.91(3H，t，J＝7.3Hz)，0.84(3H，t，J＝7.3Hz)。
Step 22- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl valerate (step 1).
MS(EI)m/z 401(M+)。
Step 36-bromo-2-butyl-3- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 2).
MS(EI)m/z 419(M+)。
Step 42- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-bromo-2-butyl-3- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 3).
MS(EI)m/z 426(M+)；
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，3.61(2H，t，J＝7.2Hz)，3.01(2H，t，J＝7.2Hz)，2.79(2H，t，J＝7.9Hz)，2.75(3H，s)，2.67(3H，s)，1.75-1.60(2H，m)，1.36-1.20(2H，m)，0.84(3H，t，J＝7.3Hz)。
Step 52- [4- (2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-bromo-2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 4).
1H-NMR(CDCl3)δ：7.59(2H，d，J＝8.3Hz)，7.35(2H，d，J＝8.3Hz)，6.90(1H，s)，3.52-3.22(4H，m)，3.01(2H，br.s)，2.90(2H，t，J＝7.7Hz)，2.74(3H，s)，2.56(3H，s)，1.79-1.62(2H，m)，1.41-1.23(2H，m)，0.84(3H，t，J＝7.5Hz)。
Step 62-butyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4- (methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-butyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 5).
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，7.22(2H，d，J＝8.3Hz)，7.14(2H，d，J＝8.3Hz)，6.91(1H，s)，6.09(1H，br.s)，3.56-3.44(2H，m)，2.84(2H，t，J＝6.4Hz)，2.70-2.59(5H，m)，2.42(3H，s)，2.41(3H，s)，1.69-1.43(2H，m)，1.30-1.18(2H，m)，0.80(3H，t，J＝7.3Hz)。
Example 12
2-butyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-butyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 11).
MS(ESI)m/z 520(M+H)+。
Example 13
2-isobutyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 3-methylbutyrate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (example 1, step 4) and isovaleryl chloride.
MS(EI)m/z 407(M+)。
Step 22- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 3-methylbutyrate (step 1).
MS(EI)m/z 323(M+)。
Step 33- [4- (2-chloroethyl) phenyl ] -2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 2).
MS(EI)m/z 341(M+)；
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.2Hz)，7.33(2H，d，J＝8.2Hz)，6.90(1H，s)，3.80(2H，t，J＝6.5Hz)，3.18(2H，t，J＝6.5Hz)，2.68(2H，d，J＝7.5Hz)，2.66(3H，s)，2.51(3H，s)，2.14-1.96(1H，m)，0.86(6H，d，J＝6.6Hz)。
Step 42- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 3).
MS(EI)m/z 348(M+)；
1H-NMR(CDCl3)7.42(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，6.91(1H，s)，3.60(2H，t，J＝6.5Hz)，3.00(2H，t，J＝6.5Hz)，2.69(2H，d，J＝7.5Hz)，2.65(3H，s)，2.52(3H，s)，2.08-1.98(1H，m)，0.87(6H，d，J＝6.7Hz)。
Step 52- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 4).
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.91(1H，s)，3.09(2H，t，J＝6.4Hz)，2.93(2H，t，J＝6.4Hz)，2.80(2H，br.s)，2.68(2H，d，J＝7.5Hz)，2.66(3H，s)，2.53(3H，s)，2.18-2.00(1H，m)，0.88(6H，d，J＝6.8Hz)。
Step 62-isobutyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-isobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 5).
1H-NMR(CDCl3)δ：7.85(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.21(2H，d，J＝8.3Hz)，7.12(2H，d，J＝8.3Hz)，6.91(1H，s)，6.14(1H，br.s)，3.55-3.42(2H，m)，2.82(2H，t，J＝6.3Hz)，2.65(3H，s)，2.53(2H，d，J＝7.3Hz)，2.41(3H，s)，2.39(3H，s)，2.10-1.92(1H，m)，0.81(6H，d，J＝6.6Hz)。
Example 14
2-isobutyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-isobutyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 13).
MS(ESI)m/z 520(M-)；
Example 15
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-neopentyl-3H-imidazo [4, 5-b ] pyridine
Step 12- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 3, 3-dimethylbutyrate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (example 1, step 4) and tert-butylacetyl chloride.
MS(EI)m/z 435(M+)。
Step 22- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 3, 3-dimethylbutyrate (step 1).
MS(EI)m/z 337(M+)。
Step 33- [4- (2-chloroethyl) phenyl ] -2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 2).
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.2Hz)，7.30(2H，d，J＝8.2Hz)，6.89(1H，s)，3.81(2H，t，J＝6.5Hz)，3.18(2H，t，J＝6.5Hz)，2.79(2H，s)，2.66(3H，s)，2.51(3H，s)，0.89(9H，s)。
Step 42- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 3).
MS(EI)m/z 362(M+)，1H-NMR(CDCl3)δ7.42(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，6.91(1H，s)，3.62(2H，t，J＝6.5Hz)，3.02(2H，t，J＝6.5Hz)，2.78(2H，s)，2.68(3H，s)，2.53(3H，s)，0.88(9H，s)。
Step 52- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 4).
MS(EI)m/z 336(M+)。
Step 62-neopentyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-neopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 5).
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，7.22(2H，d，J＝8.3Hz)，7.14(2H，d，J＝8.3Hz)，6.91(1H，s)，6.18(1H，br.s)，3.56-3.46(2H，m)，2.85(2H，t，J＝6.4Hz)，2.65(3H，s)，2.60(2H，s)，2.41(3H，s)，2.40(3H，s)，0.87(9H，s)。
Example 16
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-neopentyl-3H-imidazo [4, 5-b ] pyridine sodium salt
The title compound was prepared according to the procedure described for example 2 from 5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-neopentyl-3H-imidazo [4, 5-b ] pyridine (example 15).
MS(ESI)m/z 534(M+H)+。
Example 17
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridine
Step 1N- [4- (2-chloroethyl) phenyl ] -N- (4, 6-dimethyl-3-nitro-2-pyridyl) amine
The title compound was prepared from 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (example 1, step 3) according to the procedure described in example 1, step 7.
1H-NMR(CDCl3)δ：9.46(1H，br.s)，8.29(1H，d，J＝8.8Hz)，7.42(1H，d，J＝1.7Hz)，7.35(2H，d，J＝8.3Hz)，7.22(2H，d，J＝8.3Hz)，6.97(1H，dd，J＝8.8，1.7Hz)，3.77(2H，t，J＝7.2Hz)，3.13(2H，t，J＝7.2Hz)。
Step 2N2- [4- (2-chloroethyl) phenyl group]-4, 6-dimethyl-2, 3-pyridinediamine
The title compound was prepared according to the procedure described in example 6, step 3, from N- [4- (2-chloroethyl) phenyl ] -N- (4, 6-dimethyl-3-nitro-2-pyridinyl) amine (step 1).
MS(EI)m/z 383(M+)。
Step 33- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [ 45-b ] pyridine
To N2- [4- (2-chloroethyl) phenyl group]To a mixture of 4, 6-dimethyl-2, 3-pyridinediamine (step 2, 276mg, 1.0mmol) and 3- (1, 3-thiazol-2-yl) propionic acid (157mg, 1.0mmol) in dichloromethane (10mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (192mg, 1.0mmol) in one portion. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene (20mL) and heated at 150 ℃ for 5 hours. The reaction mixture was poured into water (50mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50mL) and dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) to give 210mg (53%) of the title compound:
MS(EI)m/z 396(M+)；1H-NMR(CDCl3)δ：7.63(1H，d，J＝3.4Hz)，7.39(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.15(1H，d，J＝3.4Hz)，6.93(1H，s)，3.78(2H，t，J＝7.4Hz)，3.69-3.50(2H，m)，3.39-3.20(2H，m)，3.15(2H，t，J＝7.4Hz)，2.66(3H，s)，2.53(3H，s)。
Step 42- (4- {5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridine (step 3).
MS(EI)m/z 403(M+)；1H-NMR(CDCl3)δ：7.63(1H，d，J＝3.5Hz)，7.38(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.15(1H，d，J＝3.5Hz)，6.93(1H，s)，3.63-3.54(4H，m)，3.34-3.26(2H，m)，2.98(2H，t，J＝7.4Hz)，2.68(3H，s)，2.53(3H，s)。
Step 52- (4- {5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethylamine
The title compound was prepared from 2- (4- {5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl azide (step 4) according to the procedure described in example 1, step 9.
MS(EI)m/z 377(M+)。
Step 65, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (1, 3-thiazol-2-yl) ethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- (4- {5, 7-dimethyl-2- [2- (1, 3-thiazol-2-yl) ethyl ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethylamine (step 5).
MS(ESI)m/z 575(M+H)+；1H-NMR(CDCl3)δ：7.83(2H，d，J＝8.3Hz)，7.61(1H，d，J＝3.5Hz)，7.32(2H，d，J＝8.3Hz)，7.19-7.15(3H，m)，7.07(2H，d，J＝8.2Hz)，6.91(1H，s)，6.21(1H，br.s)，3.52-3.40(4H，m)，3.20-3.13(2H，m)，2.81(2H，t，J＝6.1Hz)，2.65(3H，s)，2.44(3H，s)，2.41(3H，s)。
Example 18
3- {4- [2- ({ [ (4-biphenylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
Step 1 phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate
To a mixture of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 9, 1.55g, 5.3mmol in example 1) and triethylamine (0.80mL, 5.8mmol) in dichloromethane (26mL) was added dropwise phenylchloroformate (0.69mL, 5.5mmol) with ice-bath cooling. After the mixture was stirred at room temperature for 30 minutes, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic phases were dried (sodium sulfate) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90g (87%) of the title compound as light brown crystals:
1H-NMR(CDCl3)δ：7.43-7.11(9H，m)，6.91(1H，s)，5.50(1H，br.s)，3.57(2H，pseudo q，J＝6.9Hz)，2.98(2H，t，J＝6.9Hz)，2.83(2H，q，J＝7.6Hz)，2.66(3H，s)，2.52(3H，s)，1.28(3H，t，J＝7.6Hz)。
step 23- {4- [2- ({ [ (4-biphenylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
To a mixture of 4-biphenylsulfonamide (Greenlee, W.J.; Walsh, T.F.; et al Eur. Pat.appl., EP 617001(1994), 56mg, 0.24mmol) in DMF (3mL) was added NaH (60% oil dispersion, 20mg, 0.5mmol) at room temperature. After 5 min, phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (step 1, 100mg, 0.24mmol) was added. The mixture was stirred for an additional 1 hour. The mixture was poured into water (50mL) and extracted with (di) ether (2X 50 mL). The combined extracts were washed with water (50mL), brine (50mL), and then dried (magnesium sulfate). Removal of the solvent gave a white oily solid. Purification by preparative TLC (ethyl acetate) gave 66mg (50%) of the title compound as a colorless oil:
MS(ESI)m/z 554(M+H)+；1H-NMR(CDCl3)δ：8.06(2H，d，J＝8.6Hz)，7.13(2H，d，J＝8.6Hz)，7.60-7.53(2H，m)，7.48-7.36(3H，m)，7.21(2H，d，J＝8.4Hz)，7.12(2H，d，J＝8.3Hz)，6.92(1H，s)，6.11(1H，br.t，J＝5.5Hz)，3.54(2H，dt，J＝5.9，6.0Hz)，2.89(2H，d，J＝6.0Hz)，2.64(2H，q，J＝7.5Hz)，2.66(3H，s)，2.40(3H，s)，1.18(3H，t，J＝7.5Hz)。
Example 19
2-Ethyl-5, 7-dimethyl-3- {4- [2- ({ [ (1-naphthylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18, step 2, from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18, step 1) and 1-naphthylsulfonamide (Arnswald, M.; Neumann, W.P.Chem.Ber., 1991, 124, 1997; Khorgami, M.H.Synthesis, 1972, 574).
MS(ESI)m/z 528(M+H)+；1H-NMR(CDCl3)δ8.52-8.48(1H，m)，8.36(1H，dd，J＝1.1，7.3Hz)，8.11(1H，d，8.3Hz)，8.00-7.94(1H，m)，7.63-7.50(3H，m)，7.20(2H，d，J＝8.4Hz)，7.13(2H，d，J＝8.4Hz)，6.94(1H，s)，6.32(1H，br.t，J＝5.7Hz)，3.50(2H，dt，J＝5.9，6.0Hz)，2.82(2H，t，J＝6.2Hz)，2.68(2H，q，J＝7.5Hz)，2.65(3H，s)，2.41(3H，s)，1.21(3H，t，J＝7.5Hz)。
Example 20
2-Ethyl-5, 7-dimethyl-3- {4- [2- ({ [ (2-naphthylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18 step 2 from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18 step 1) and 2-naphthylsulfonamide.
MS(ESI)m/z 528(M+H)+；1H-NMR(CDCl3)δ：8.60(1H，s)，8.01-7.84(5H，m)，7.64-7.52(2H，m)，7.20-7.08(4H，m)，6.92(1H，s)，6.20(1H，t，J＝5.6Hz)，3.52-3.45(2H，q，J＝6.1Hz)，2.84-2.80(2H，t，J＝6.3Hz)，2.71-2.62(2H，q，J＝6.6Hz)，2.66(3H，s)，2.43(3H，s)，1.22-1.16(3H，t，J＝6.6Hz)。
Example 21
2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18, step 2, from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18, step 1) and 2-thiophenesulfonamide (Huang, h.c.; Reinhard, e.j.; Reitz, d.b. tetrahedron Lett, 1994, 35, 7201.; Graham, s.l.; Scholz, t.h. synthesis, 1986, 1031).
1H-NMR(CDCl3)δ：8.01(1H，s)，7.78(1H，dd，J＝1.3，4.9Hz)，7.63(1H，dd，J＝1.3，4.9Hz)，7.22(2H，d，J＝8.3Hz)，7.14(2H，d，J＝8.3Hz)，7.09(1H，dd，J＝3.8，5.0Hz)，6.92(1H，s)，6.05(1H，t，J＝5.3Hz)，3.53(2H，q，J＝6.2Hz)，2.96(3H，s)，2.88(3H，s)，2.87(2H，t，J＝6.2Hz)，2.67(2H，q，J＝7.5Hz)，2.65(3H，s)，2.43(3H，s)，1.20(3H，t，J＝7.5Hz)。
Example 22
3- (4- {2- [ ({ [ (5-chloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18 step 2 from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18 step 1) and 5-chloro-2-thiophenesulfonamide.
MS(ESI)m/z 518(M+H)+；1H-NMR(CDCl3)δ：7.99(1H，s)，7.58-7.56(1H，m)，7.23-7.15(4H，m)，6.94-6.92(1H，m)，6.04(1H，br)，3.53-3.51(2H，m)，2.87(2H，m)，2.73-2.65(2H，q，J＝7.6Hz)，2.65(3H，s)，2.44(3H，s)，1.21(3H，t，J＝7.6Hz)。
Example 23
3- (4- {2- [ ({ [ (4, 5-dichloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18 step 2 from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18 step 1) and 5, 6-dichloro-2-thiophenesulfonamide.
MS(ESI)m/z 552(M+H)+；1H-NMR(CDCl3)δ：7.49(1H，s)，7.27-7.14(4H，m)，6.84(1H，s)，3.47(2H，br)，2.75(2H，br)，2.69(2H，q，J＝7.6Hz)，2.64(3H，s)，2.38(3H，s)，1.22(3H，t，J＝7.6Hz)。
Example 24
3- {4- [2- ({ [ (1-benzothien-2-ylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18, step 1) and 1-benzothiophene-2-sulfonamide (Chern, j.; Leu, y.; et al j.med.chem., 1997, 40, 2276.; Graham, s.l.; Shepard, k.l.; et al j.med.chem., 1989, 32, 2548) according to the procedure described in example 1, step 2.
mp 128.0-130.0℃；MS(ESI)m/z 534(M+H)+；1H-NMR(DMSO-d6)δ8.05-8.00(3H，m)，7.50-7.42(2H，m)，7.36(2H，d，J＝7.4Hz)，7.32(2H，d，J＝7.4Hz)，6.96(1H，s)，6.61-6.56(1H，m)，3.34-3.28(2H，m)，2.80(2H，t，J＝6.6Hz)，2.68(2H，q，J＝7.5Hz)，2.54(3H，s)，2.40(3H，s)，1.19(3H，t，J＝7.5Hz)。
Example 25
3- (4- {2- [ ({ [ (2-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (example 1, step 9) and 2-chlorobenzenesulfonyl isocyanate.
MS(ESI)m/z 512(M+H)+；1H-NMR(CDCl3)δ：8.21-8.17(1H，d，7.7Hz)，7.57-7.43(3H，m)，7.32-7.22(4H，m)，6.93(s，1H)，6.34(1H，t，J＝5.6Hz)，3.56-3.49(2H，q，J＝6.3Hz)，2.89-2.85(2H，t，J＝6.4Hz)，2.80-2.71(q，2H，J＝7.6Hz)，2.67(3H，s)，2.49(3H，s)，1.28-1.22(3H，t，J＝7.6Hz)。
Example 26
2-ethyl-5-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (6-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared from 2-chloro-6-methyl-3-nitropyridine (Takayama, K.; Iwata, M.; Kono, N.; et al, Jpn. Kokai Tokkyo Koho, JP11292877(1999), Ding, C.Z.; Hunt, J.T., Kim, S.; et al, PCT Int.appl., WO 9730992(1997)) and 4-aminophenylethyl alcohol according to the procedure described in example 1, step 3.
1H-NMR(CDCl3)δ：8.24(1H，d，J＝9.1Hz)，7.28-7.33(4H，m)，6.65(1H，d，J＝9.2Hz)，3.89(2H，d，J＝6.4Hz)，2.89(2H，d，J＝6.4Hz)，2.81(3H，s)。
Step 22- {4- [ (3-amino-6-methyl-2-pyridyl) amino ] phenyl } ethanol
To a solution of 2- {4- [ (6-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1, 4.6g, 16.9mmol) in methanol (100mL) was added 10% Pd-C (300 mg). The resulting mixture was stirred under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1: 2 to 1: 5) to give 3.8g (92%) of the title compound as a yellow solid:
1H-NMR(CDCl3)δ：7.10-7.16(4H，m)，6.91(1H，d，J＝8.4Hz)，6.70(1H，d，J＝8.4Hz)，6.19(1H，s)，3.83(2H，t，J＝6.4Hz)，2.81(2H，t，J＝6.4Hz)，2.35(3H，s)。
Step 32- [4- (2-Ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-6-methyl-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
MS(EI)m/z 337(M+)。
Step 42- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.90(1H，d，J＝8.3Hz)，7.43(2H，d，J＝8.2Hz)，7.34(2H，d，J＝8.2Hz)，7.07(1H，d，J＝8.3Hz)，3.93(2H，t，J＝6.6Hz)，2.97(2H，t，J＝6.6Hz)，2.80(2H，q，J＝7.5Hz)，2.56(3H，s)，1.35(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
To a mixture of 2- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4, 217mg, 0.77mmol) in THF (20mL) was added diethyl azocarboxylate (DEAD) (0.3mL, 1.5mmol), triphenylphosphine (380mg, 1.5mmol) and diphenylphosphoryl azide (DPPA) (0.4mL, 1.5 mmol). The mixture was stirred at room temperature for 4.5 hours. After removal of the solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1: 1 to 1: 2) to give 70mg (30%) of the title compound as a brown oil:
1H-NMR(CDCl3)δ：7.90(1H，d，J＝8.1Hz)，7.34-7.44(4H，m)，7.08(1H，d，J＝8.1Hz)，3.60(2H，t，J＝7.1Hz)，3.00(2H，t，J＝7.1Hz)，2.80(2H，q，J＝7.5Hz)，2.57(3H，s)，1.35(3H，t，J＝7.5Hz)。
Step 62- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ7.91(1H，d，J＝8.1Hz)，7.42(2H，d，J＝8.3Hz)，7.32(2H，d，J＝8.3Hz)，7.06(1H，d，J＝8.1Hz)，3.13(2H，t，J＝6.8Hz)，2.95(2H，t，J＝6.8Hz)，2.81(2H，q，J＝7.6Hz)，2.55(3H，s)，1.34(3H，t，J＝7.6Hz)。
Step 72-Ethyl-5-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 6).
MS(ESI)m/z 476(M+H)+；1H-NMR(CDCl3)δ：7.95(1H，d，J＝8.0Hz)，7.84(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.2Hz)，7.17(2H，d，J＝8.2Hz)，7.10(1H，d，J＝8.0Hz)，6.17(1H，br.s)，3.52(2H，t，J＝6.6Hz)，2.86(2H，t，J＝6.6Hz)，2.69(2H，q，J＝7.5Hz)，2.49(3H，s)，2.41(3H，s)，1.27(3H，t，J＝7.5Hz)。
Example 27
2-Ethyl-5-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2, 2-ethyl-5-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 26).
1H-NMR(DMSO-d6)δ7.91(1H，d，J＝7.9Hz)，7.61(2H，d，J＝6.8Hz)，7.36(4H，s)，7.11-7.15(3H，m)，2.67-2.75(4H，m)，2.50(2H，br.s)，2.45(3H，s)，2.28(3H，s)，1.21-1.24(3H，m)。
Example 28
2-Ethyl-5-methoxy-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethylphenyl-3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (6-methoxy-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-6-methoxy-3-nitropyridine and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：10.59(1H，br.s)，8.38(1H，d，J＝9.2Hz)，7.59(2H，d，J＝8.3Hz)，7.23(2H，d，J＝8.3Hz)，6.20(1H，d，J＝9.2Hz)，3.94(3H，s)，3.87(2H，t，J＝6.6Hz)，2.87(2H，t，J＝6.6Hz)。
Step 22- {4- [ (3-amino-6-methoxy-2-pyridine) amino ] phenyl } ethanol
A mixture of 2- {4- [ (6-methoxy-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1, 3.52g, 12.17mmol), iron powder (3.4g, 60.84mmol) and ammonium chloride (325mg, 6.08mmol) in ethanol/water (v/v, 2: 1, 90mL) was heated at reflux for 1 hour. After cooling, the catalyst was removed and the filtrate was concentrated. The residue was extracted with ethyl acetate (100mL) and washed with water. The organic layer was dried (magnesium sulfate) and concentrated to give 3.41g (quant.) of the title compound as a black oil:
1H-NMR(CDCl3)δ7.48(2H，d，J＝8.4Hz)，7.14(2H，d，J＝8.4Hz)，7.04(1H，d，J＝8.2Hz)，6.75(1H，br.s)，6.13(1H，d，J＝8.2Hz)，3.87(3H，s)，3.83(2H，t，J＝6.6Hz)，2.81(2H，t，J＝6.6Hz)。
step 32- [4- (2-Ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-6-methoxy-2-pyridyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
TLC Rf 0.50 (hexane/ethyl acetate 2: 1).
Step 42- [4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.91(1H，d，J＝8.6Hz)，7.43(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，6.67(1H，d，J＝8.6Hz)，3.98-3.88(2H，m)，3.82(3H，s)，2.99(2H，t，J＝6.4Hz)，2.81(2H，q，J＝7.4Hz)，1.34(3H，t，J＝7.4Hz)。
Step 52- [4- (2-Ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26, step 5, from 2- ([4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ]) ethanol (step 4).
TLC Rf 0.78 (hexane/ethyl acetate 1/1).
Step 62- [4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.92(1H，d，J＝8.6Hz)，7.40-7.31(4H，m)，6.67(1H，d，J＝8.6Hz)，3.82(3H，s)，3.13-3.10(2H，m)，3.00-2.97(2H，m)，2.80(2H，q，J＝7.6Hz)，1.33(3H，t，J＝7.6Hz)。
Step 72-Ethyl-5-methoxy-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5-methoxy-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ7.95(1H，d，J＝8.7Hz)，7.74(2H，d，J＝8.4Hz)，7.34-7.27(6H，m)，6.69(1H，d，J＝8.7Hz)，6.55(1H，m)，3.79(3H，s)，3.60-3.53(2H，m)，2.90(2H，t，J＝6.8Hz)，2.77(2H，q，J＝7.4Hz)，1.30(3H，t，J＝7.4Hz)。
Example 29
2-Ethyl-5-methoxy-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5-methoxy-3- (4- [2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 28).
1H-NMR(DMSO-d6)δ7.94(1H，d，J＝8.4Hz)，7.59(2H，d，J＝8.1Hz)，7.41-7.34(4H，m)，7.12(2H，d，J＝8.1Hz)，6.68(1H，d，J＝8.4Hz)，3.71(3H，s)，3.14(2H，m)，2.75-2.68(4H，m)，2.27(3H，s)，1.20(3H，t，J＝7.5Hz)；IR(KBr)Vmax1597，1518，1489，1425，1389，1261，1130，1086cm-1。
Example 30
6-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (5-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-5-methyl-3-nitropyridine and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.96(1H，br.s)，8.32-8.31(2H，m)，7.55(2H，d，J＝8.3Hz)，7.24(2H，d，J＝8.3Hz)，3.85(2H，m)，2.86(2H，t，J＝6.6Hz)，2.32(3H，s)。
Step 22- {4- [ (3-amino-5-methyl-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (5-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.59(1H，m)，7.08-7.00(4H，m)，6.80(1H，m)，3.74(2H，t，J＝6.6Hz)，2.74(2H，t，J＝6.6Hz)，2.19(3H，s)。
Step 32- [4- (2-Ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5-methyl-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
TLC Rf 0.74 (dichloromethane/methanol 10: 1).
Step 42- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ8.12(1H，s)，7.84(1H，s)，7.44(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.1Hz)，3.91-3.85(2H，m)，2.96(2H，t，J＝6.7Hz)，2.82(2H，q，J＝7.5Hz)，2.46(3H，s)，1.36(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described for example 26 step 5 from 2- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：8.13(1H，s)，7.84(1H，s)，7.44(2H，d，J＝8.4Hz)，7.36(2H，d，J＝8.4Hz)，3.59(2H，t，J＝7.3Hz)，3.00(2H，t，J＝7.3Hz)，2.83(2H，q，J＝7.6Hz)，2.46(3H，s)，1.36(3H，t，J＝7.6Hz)。
Step 42- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.84(1H，s)，7.42(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，3.07(2H，t，J＝6.8Hz)，2.91-2.78(4H，m)，2.46(3H，s)，1.36(3H，t，J＝7.5Hz)。
Step 52-Ethyl-6-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The reaction was carried out according to the procedure described in step 10 of example 1 from 2- [4- (2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ8.04(1H，d，J＝1.8Hz)，7.86-7.82(3H，m)，7.33-7.21(6H，m)，6.27(1H，m)，3.52-3.49(2H，m)，2.87(2H，t，J＝6.8Hz)，2.76(2H，q，J＝7.6Hz)，2.45(3H，s)，2.41(3H，s)，1.30(3H，t，J＝7.6Hz)。
Example 31
6-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-6-methyl-3- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 30).
1H-NMR(DMSO-d6)δ8.04(1H，m)，7.84(1H，m)，7.60(2H，d，J＝8.1Hz)，7.36(4H，s)，7.12(2H，d，J＝8.1Hz)，3.13(2H，m)，2.78-2.71(4H，m)，2.39(3H，s)，2.27(3H，s)，1.22(3H，t，J＝7.5Hz)；IR(KBr)Vmax 1601，1518，1423，1375，1283，1250，1128，1084cm-1。
Example 32
6-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (5-chloro-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared from 2, 5-dichloro-3-nitropyridine (Marfat, A.; Robinson, R.P.US Pat. Appl., US 5811432 (1998); Haessig, R.; Siegrist, U.Eur.Pat.Appl., EP 483061(1992)) and 4-aminophenylethyl alcohol according to the procedure described in example 1, step 3.
1H-NMR(CDCl3)δ：10.00(1H，br.s)，8.51-8.50(1H，m)，8.41(1H，d，J＝2.4Hz)，7.53(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，3.88-3.87(2H，m)，2.88(2H，t，J＝6.6Hz)。
Step 22- {4- [ (3-amino-5-chloro-2-pyridinyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (5-chloro-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.73(1H，d，J＝2.2Hz)，7.19-7.01(4H，m)，6.97(1H，d，J＝2.2Hz)，6.12(1H，br.s)，3.81(2H，t，J＝6.4Hz)，2.80(2H，t，J＝6.4Hz)。
Step 32- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- {4- [ (3-amino-5-chloro-2-pyridinyl) amino ] phenyl } ethanol (step 2) according to the procedure described in example 1, step 5.
TLC Rf 0.43 (hexane/ethyl acetate 2: 1).
Step 42- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ8.23(1H，d，J＝2.1Hz)，8.01(1H，d，J＝2.1Hz)，7.45(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.09(1H，s)，3.92(2H，t，J＝6.4Hz)，2.95(2H，t，J＝6.4Hz)，2.83(2H，q，J＝7.4Hz)，1.36(3H，t，J＝7.4Hz)。
Step 52- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：8.25(1H，d，J＝2.2Hz)，8.02(1H，d，J＝2.2Hz)，7.46(2H，d，J＝8.3Hz)，7.35(2H，d，J＝8.3Hz)，3.60(2H，t，J＝7.2Hz)，3.00(2H，t，J＝7.2Hz)，2.84(2H，q，J＝7.5Hz)，1.37(3H，t，J＝7.5Hz)。
Step 62- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：8.22(1H，d，J＝2.1Hz)，8.01(1H，d，J＝2.1Hz)，7.45(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，3.13-3.08(2H，m)，2.95-2.78(4H，m)，1.36(3H，t，J＝7.6Hz)。
Step 76-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-chloro-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：8.20(1H，d，J＝2.2Hz)，8.03(1H，d，J＝2.2Hz)，7.77(2H，d，J＝8.1Hz)，7.38-7.27(6H，m)，6.51-6.48(1H，m)，3.57-3.50(2H，m)，2.90(2H，t，J＝6.8Hz)，2.81(2H，t，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Example 33
6-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 32).
1H-NMR(DMSO-d6)δ8.24-8.21(2H，m)，7.60(2H，d，J＝8.1Hz)，7.42-7.34(4H，m)，7.12(2H，d，J＝8.1Hz)，3.13(2H，m)，2.81-2.69(4H，m)，2.27(3H，s)，124(3H，t，J＝7.4Hz)；IR(KBr)Vmax，1597，1516，1421，1375，1246，1128，1084cm-1。
Example 34
2-Ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (5, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
A mixture of 2-chloro-5, 6-dimethyl-3-nitropyridine (Godard, A.; Rocca, P.; Pomel, V.; et al J., or gammet. chem., 1996, 517, 25.; Rocca, P.; Marsais, F.; Godard, A.; et al Tetrahedron Lett., 1993, 34, 2937., 3.3g, 17.5mmol), 4-aminophenylethyl alcohol (3.6g, 26.3mmol) and 2, 6-lutidine (3.7mL) in toluene (80mL) was stirred at reflux temperature for 19 hours. The mixture was diluted with ethyl acetate (100mL), washed with 1N aqueous sodium hydroxide (50mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) gave 1.8g (37%) of the title compound as an orange yellow solid:
1H-NMR(CDCl3)δ：8.24(1H，br.s)，7.68(2H，d，J＝8.6Hz)，7.24(2H，d，J＝8.6Hz)，3.88(2H，dt，J＝6.1，7.6Hz)，2.88(2H，t，J＝7.6Hz)，2.49(3H，s)，2.26(3H，s)，1.43(1H，t，J＝6.1Hz)。
step 22- {4- [ (3-amino-5, 6-dimethyl-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (5, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：6.97(2H，d，J＝8.4Hz)，6.92(2H，d，J＝8.4Hz)，6.71(1H，s)，6.22(1H，br s)，3.67(2H，t，J＝6.8Hz)，2.68(2H，t，J＝6.8Hz)，2.29(3H，s)，2.12(3H，s)。
Step 32- [4- (2-Ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ7.75(1H，br.s)，7.42(2H，d，J＝8.6Hz)，7.34(2H，d，J＝8.6Hz)，4.37(2H，t，J＝6.6Hz)，3.05(2H，t，J＝6.6Hz)，2.80(2H，q，J＝7.6Hz)，2.49(3H，s)，2.38(3H，s)，2.37-2.28(2H，m)，1.34(3H，t，J＝7.6Hz)，1.18(3H，t，J＝7.5Hz)。
Step 42- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
*MS(ESI)m/z 296(M+H)+；1H-NMR(CDCl3)δ：7.75(1H，br.s)，7.43(2H，d，J＝8.6Hz)，7.33(2H，d，J＝8.6Hz)，3.92(2H，br.t，J＝6.6Hz)，2.97(2H，t，J＝6.6Hz)，2.80(2H，q，J＝7.6Hz)，2.49(3H，s)，2.38(3H，s)，1.34(3H，t，J＝7.6Hz)。
Step 53- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.75(1H，br.s)，7.43(2H，d，J＝8.6Hz)，7.36(2H，d，J＝8.6Hz)，3.80(2H，t，J＝7.3Hz)，3.18(2H，t，J＝7.3Hz)，2.81(2H，q，J＝7.6Hz)，2.50(3H，s)，2.38(3H，s)，1.34(3H，t，J＝7.6Hz)。
Step 62- [4- (2-Ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 5).
1H-NMR(CDCl3)δ：7.75(1H，br.s)，7.42(2H，d，J＝8.4Hz)，7.36(2H，d，J＝8.4Hz)，3.60(2H，t，J＝7.3Hz)，3.00(2H，t，J＝7.3Hz)，2.80(2H，q，J＝7.6Hz)，2.49(3H，s)，2.38(3H，s)，1.34(3H，t，J＝7.6Hz)。
Step 72- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.76(1H，br.s)，7.41(2H，d，J＝7.9Hz)，7.33(2H，d，J＝7.9Hz)，3.12(2H，t，J＝6.9Hz)，2.95(2H，t，J＝6.9Hz)，2.79(2H，q，J＝6.9Hz)，2.47(3H，s)，2.37(3H，s)，1.33(3H，t，J＝6.9Hz)。
Step 82-Ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 492(M+H)+；1H-NMR(CDCl3)δ：7.87(2H，d，J＝8.2Hz)，7.79(1H，s)，7.31(2H，d，J＝8.2Hz)，7.23(2H，d，J＝8.1Hz)，7.15(2H，d，J＝8.1Hz)，6.24(1H，m)，3.51(2H，m)，285(2H，t，J＝6.1Hz)，2.66(2H，q，J＝7.4Hz)，2.39(3H，s)，2.38(3H，s)，2.36(3H，s)，1.25(3H，t，J＝7.4Hz)。
Example 35
2-ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] aminocarbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5, 6-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (example 34).
mp 156.0-158.5℃；
1H-NMR(DMSO-d6)δ7.58(1H，s)，7.48(2H，d，J＝8.1Hz)，7.19-7.13(4H，m)，6.98(2H，d，J＝8.1Hz)，6.01(1H，br.s)，3.15-2.98(2H，m)，2.59-2.55(2H，m)，2.50(2H，q，J＝7.6Hz)，2.19(3H，s)，2.13(3H，s)，2.09(3H，s)，1.01(3H，t，J＝7.6Hz)。
Example 36
2- [4- (2-Ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-5, 6-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (example 34, step 4).
MS(ESI)m/z 493(M+H)+，1H-NMR(DMSO-d6)δ7.94(2H，d，J＝8.4Hz)，7.78(1H，s)，7.33(2H，d，J＝8.1Hz)，7.25-7.16(4H，m)，4.35(2H，t，J＝6.6Hz)，2.93(2H，t，J＝6.6Hz)，2.73(2H，q，J＝7.4Hz)，2.46(3H，s)，2.43(3H，s)，2.39(3H，s)，1.28(3H，t，J＝7.4Hz)。
Example 37
5, 6-dichloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (5, 6-dichloro-3-nitro-2-pyridinyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 34, step 1, from 3-nitro-2, 5, 6-trichloropyridine (Horn, u.; Mutterer, f.; Weis, c.d. helv.chim.acta., 1976, 59, 190.) and 4-aminophenylethyl alcohol.
MS(EI)m/z 327(M+)；1H-NMR(CDCl3)δ：10.11(1H，br.s)，8.58(1H，s)，7.57(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，3.93-3.86(2H，m)，2.89(2H，t，J＝6.6Hz)。
Step 22- [4- [ (3-amino-5, 6-dichloro-2-pyridinyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (5, 6-dichloro-3-nitro-2-pyridinyl) amino ] phenyl } ethanol (step 1).
MS(EI)m/z 297(M+)。
Step 32- [4- (2-Ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5, 6-dichloro-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
TLC Rf 0.63 (ethyl acetate/hexane 1: 1).
Step 42- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate (step 3).
MS(EI)m/z 335(M+)；1H-NMR(CDCl3)δ：8.11(1H，s)，7.46(2H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，3.97(2H，t，J＝6.2Hz)，2.99(2H，t，J＝6.2Hz)，2.82(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 53- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：8.13(1H，s)，7.45(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.1Hz)，3.80(2H，t，J＝7.2Hz)，3.19(2H，t，J＝7.2Hz)，2.82(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 62- [4- (2-Ethyl-5.6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridine (step 5).
MS(EI)m/z 360(M+)；1H-NMR(CDCl3)δ：8.11(1H，s)，7.44(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，3.61(2H，t，J＝7.2Hz)，3.00(2H，t，J＝7.2Hz)，2.81(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
Step 72- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
To a solution of 2- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 6, 69mg, 0.2mmol) in methanol (10mL) was added Lindlar catalyst (5 mg). The resulting mixture was stirred under hydrogen atmosphere for 6 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated. Purification by preparative TLC (dichloromethane/methanol 10: 1) gave 60mg (94%) of the title compound as a colourless solid:
MS(EI)m/z 334(M+)；1H-NMR(CDCl3)δ：8.11(1H，s)，7.43(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，3.11(2H，t，J＝6.6Hz)，2.92(2H，t，J＝6.6Hz)，2.81(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
step 85, 6-dichloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5, 6-dichloro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 7).
mp 188.0-189.0℃；
MS(ESI)m/z 532(M+H)+；
1H-NMR(CDCl3)δ：8.12(1H，s)，7.77(2H，d，J＝8.4Hz)，7.36-7.25(6H，m)，6.49(1H，br.t，J＝5.9Hz)，3.54(2H，dt，J＝5.9，7.0Hz)，2.90(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.5Hz)，2.41(3H，s)，1.33(3H，t，J＝7.5Hz)。
Example 38
5-chloro-2-ethyl-6-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (6-chloro-5-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 34, step 1, from 2, 6-dichloro-5-methyl-3-nitropyridine (Horn, u.; Mutterer, f.; Weis, c.d. helv. chim. acta., 1976, 59, 190) and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：10.05(1H，br.s)，8.34(1H，s)，7.57(2H，d，J＝7.7Hz)，7.24(2H，d，J＝7.7Hz)，3.86(2H，t，J＝5.9Hz)，2.87(2H，t，J＝5.9Hz)，2.33(3H，s)。
Step 22- {4- [ (3-amino-6-chloro-5-methyl-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (6-chloro-5-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.14-7.08(4H，m)，6.86(1H，s)，6.21(1H，br.s)，3.79(2H，t，J＝6.4Hz)，2.78(2H，t，J＝6.4Hz)，2.33(3H，s)。
Step 32- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-6-chloro-5-methyl-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
MS(EI)m/z 371(M+)。
Step 42- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3).
MS(EI)m/z 315(M+)；1H-NMR(CDCl3)δ7.87(1H，s)，7.42(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，3.92(2H，t，J＝6.6Hz)，2.96(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.7Hz)，2.47(3H，s)，1.34(3H，t，J＝7.7Hz)。
Step 53- [4- (2-chloroethyl) phenyl ] -5-chloro-2-ethyl-5-methyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 333(M+)；1H-NMR(CDCl3)δ：7.88(1H，s)，7.42(2H，d，J＝8.3Hz)，7.33(2H，d，J＝8.3Hz)，3.79(2H，t，J＝7.3Hz)，3.17(2H，t，J＝7.3Hz)，2.80(2H，q，J＝7.0Hz)，2.48(3H，s)，1.35(3H，t，J＝7.0Hz)。
Step 62- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -5-chloro-2-ethyl-5-methyl-3H-imidazo [4, 5-b-pyridine (step 5).
1H NMR(CDCl3)δ：7.87(1H，s)，7.42(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.4Hz)，3.59(2H，t，J＝7.1Hz)，2.98(2H，t，J＝7.1Hz)，2.81(2H，q，J＝7.6Hz)，2.48(3H，s)，1.35(3H，t，J＝7.6Hz)。
Step 72- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.88(1H，s)，7.40(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，3.07(2H，t，J＝6.8Hz)，2.87(2H，t，J＝6.8Hz)，2.80(2H，q，J＝7.3Hz)，2.48(3H，s)，1.34(3H，t，J＝7.3Hz)。
Step 85-chloro-2-ethyl-6-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 7).
mp 205-206℃；
MS(ESI)m/z 512(M+H)+；
1H-NMR(CDCl3)δ：7.90(1H，s)，7.79(2H，d，J＝8.3Hz)，733-7.23(6H，m)，6.46(1H，br.s)，3.55-3.49(2H，m)，2.88(2H，t，J＝6.8Hz)，2.76(2H，q，J＝7.6Hz)，2.48(3H，s)，2.41(3H，s)，1.31(3H，t，J＝7.6Hz)。
Example 39
5-chloro-2-ethyl-7-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (6-chloro-4-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared from 2, 6-dichloro-4-methyl-3-nitropyridine (Inubushi, A.; Kawano, E.; Shimada, Ke.; et al PCTInt. Appl., WO 9802442(1998)) and 4-aminophenylethyl alcohol according to the procedure described in example 34, step 1.
1H-NMR(CDCl3)δ：9.56(1H，s)，7.49(2H，d，J＝8.4Hz)，7.22(2H，d，J＝8.4Hz)，6.64(1H，s)，3.84(2H，t，J＝6.4Hz)，2.84(2H，t，J＝6.4Hz)，2.55(3H，s)。
Step 22- {4- [ (3-amino-6-chloro-4-methyl-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (6-chloro-4-methyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
MS(EI)m/z 277(M+)。
Step 32- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-6-chloro-4-methyl-2-pyridinyl) amino ] phenyl } ethanol (step 2).
TLC Rf 0.46 (ethyl acetate/hexane 1: 1).
Step 42- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3).
MS(EI)m/z 315(M+)；1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.07(1H，s)，4.00-3.85(2H，m)，2.97(2H，t，J＝6.6Hz)，2.83(2H，q，J＝7.5Hz)，2.68(3H，s)，1.30(3H，t，J＝7.5Hz)。
Step 53- [4- (2-chloroethyl) phenyl ] -5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.1Hz)，7.07(1H，s)，3.79(2H，t，J＝7.3Hz)，3.17(2H，t，J＝7.3Hz)，2.83(2H，q，J＝7.5Hz)，2.68(3H，s)，1.30(3H，t，J＝7.5Hz)。
Step 62- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridine (step 5).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.6Hz)，7.33(2H，d，J＝8.6Hz)，7.07(1H，s)，3.56(2H，t，J＝7.2Hz)，2.99(2H，t，J＝7.2Hz)，2.83(2H，q，J＝7.5Hz)，2.68(3H，s)，1.29(3H，t，J＝7.5Hz)。
Step 72- [ (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine.
To a mixture of 2- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 6, 57mg, 0.2mmol) and THF (5mL) at room temperature was added triphenylphosphine (47mg, 0.2 mmol). After the addition was complete, stirring was continued at the same temperature for another 3 hours. To the resulting mixture was added water (0.1mL) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated to give a colorless solid. Purification by preparative TLC (dichloromethane/methanol/triethylamine ═ 10: 1) gave 13mg (25%) of the title compound as a colourless solid:
MS(EI)m/z 313(M+)。
Step 85-chloro-2-ethyl-7-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 512(M+H)+；1H-NMR(CDCl3)δ：7.80(2H，d，J＝8.4Hz)，7.34-7.23(6H，m)，7.09(1H，s)，6.37(1H，br s)，3.56-3.52(2H，m)，2.88(2H，t，J＝6.8Hz)，2.77(2H，q，J＝7.5Hz)，2.69(3H，s)，2.42(3H，s)，1.26(3H，t，J＝7.5Hz)。
Example 40
2-ethyl-7-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6- [ (methylsulfonyl) amino ] -3H-imidazo [4, 5-b ] pyridine
Step 12- {4- [ (4-methyl-3.5-dinitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-4-methyl-3, 5-dinitropyridine (Czuba, rocz. chem., 1967, 41, 479) and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：8.90(1H，s)，8.50(1H，br.s)，7.40(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，3.82(2H，t，J＝6.6Hz)，2.84(2H，t，J＝6.6Hz)，2.62(3H，s)。
Step 22- {4- [ (3-amino-4-methyl-5-nitro-2-pyridyl) amino ] phenyl } ethanol
To a mixture of 2- {4- [ (4-methyl-3, 5-dinitro-2-pyridyl) amino ] phenyl } ethanol (step 1, 4.2g, 13.1mmol), triethylamine (9.6mL, 68.9mmol), 10% Pd-C (624mg, 0.59mmol) in acetonitrile (14mL) at 0 deg.C, a solution of formic acid (2.3mL, 61.0mmol) in acetonitrile (6.2mL) was added dropwise over 30 minutes. After stirring at room temperature for 5 hours, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL). The solution was washed with 1N aqueous sodium hydroxide (50mL), brine (50mL), dried (magnesium sulfate), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1: 1 to 1: 2) gave 2.2g (60%) of the title compound as red crystals:
1H-NMR(CDCl3)δ：8.42(1H，s)，7.42(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，6.7(1H，br s)，3.85(2H，t，J＝6.4Hz)，2.86(2H，t，J＝6.6Hz)，2.47(3H，s)。
Step 32- [4- (2-Ethyl-7-methyl-6-nitro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-4-methyl-5-nitro-2-pyridinyl) amino ] phenyl } ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：9.03(1H，s)，7.48(2H，d，J＝8.6Hz)，7.33(2H，d，J＝8.4Hz)，4.38(2H，t，J＝6.9Hz)，3.07(2H，t，J＝6.9Hz)，3.03(3H，s)，2.87(2H，q，J＝7.6Hz)，2.35(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.4Hz)，1.13(3H，t，J＝7.4Hz)。
Step 42- [4- (6-amino-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
A suspension of 2- [4- (2-ethyl-7-methyl-6-nitro-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 3, 2.5g, 6.6mmol), 10% Pd-C (250mg, 0.23mmol) in methanol (100mL) was stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and the filtrate was concentrated to give 2.4g (99%) of the title compound as a brown oil:
1H-NMR(CDCl3)δ：7.82(1H，s)，7.41(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.4Hz)，4.35(2H，t，J＝7.0Hz)，3.51(2H，br.s)，3.03(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.5Hz)，2.53(3H，s)，2.35(2H，q，J＝7.5Hz)，1.29(3H，t，J＝7.5Hz)，1.44(3H，t，J＝7.5Hz)。
step 52- (4- { 2-Ethyl-7-methyl-6- [ (methylsulfonyl) amino ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethylpropionate
To a mixture of 2- [4- (6-amino-2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 4, 1.0g, 3.0mmol) and pyridine (280mg, 3.5mmol) in dichloromethane (18mL) at 0 deg.C was added methanesulfonyl chloride (372mg, 3.3 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (10mL) and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with ethyl acetate (gradient elution from 1: 1 to 1: 2) afforded 890mg (70%) of the title compound as an amber oil:
1H-NMR(CDCl3)δ：8.26(1H，s)，7.43(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.2Hz)，7.00(1H，br.s)，4.35(2H，t，J＝7.0Hz)，3.03-3.01(5H，m)，2.85(2H，q，J＝7.5Hz)，2.75(3H，s)，2.35(2H，q，J＝7.5Hz)，1.30(3H，t，J＝7.5Hz)，1.14(3H，t，J＝7.5Hz)。
Step 6N- { 2-Ethyl-3- [4- (2-hydroxyethyl) phenyl ] -7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide
The title compound was prepared from 2- (4- { 2-ethyl-7-methyl-6- [ (methylsulfonyl) amino ] -3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl propionate (step 5) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ8.22(1H，s)，7.46(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.4Hz)，6.52(1H，br.s)，3.93(2H，t，J＝6.6Hz)，3.03(3H，s)，2.97(2H，t，J＝6.6Hz)，2.85(2H，q，J＝7.6Hz)，2.76(3H，s)，1.32(3H，t，J＝7.4Hz)。
Step 7N- {3- [4- (2-chloroethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 7, from N- { 2-ethyl-3- [4- (2-hydroxyethyl) phenyl ] -7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide (step 6).
TLC Rf was 0.40 (ethyl acetate).
Step 8N- {3- [4- (2-azidoethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- {3- [4- (2-chloroethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide (step 7).
1H-NMR(CDCl3)δ：8.26(1H，s)，7.44(2H，d，J＝8.1Hz)，7.34(2H，d，J＝8.1Hz)，6.65(1H，br.s)，3.59(2H，t，J＝7.0Hz)，3.03(3H，s)，2.99(2H，t，J＝7.1Hz)，2.86(2H，q，J＝7.4Hz)，2.75(3H，s)，1.31(3H，t，J＝7.5Hz)。
Step 9N- {3- [4- (2-aminoethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 9, from N- {3- [4- (2-azidoethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide (step 8).
TLC Rf was 0.05 (ethyl acetate).
Step 102-Ethyl-7-methyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6- [ (methylsulfonyl) amino ] -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from N- {3- [4- (2-aminoethyl) phenyl ] -2-ethyl-7-methyl-3H-imidazo [4, 5-b ] pyridin-6-yl } methanesulfonamide (step 9).
mp 166℃；MS(ESI)m/z 571.25(M+H)+；1H-NMR(CDCl3)δ：8.16(1H，s)，7.81(2H，d，J＝8.1Hz)，7.31-7.18(6H，m)，6.39(1H，br.s)，3.48-3.46(2H，m)，3.00(3H，s)，2.82-2.71(7H，m)，2.39(3H，s)，1.26(3H，t，J＝7.2Hz)。
EXAMPLE 41
6-cyano-2-ethyl-5, 7-dimethyl-3- (4- {2[ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
Step 16-hydroxy-2, 4-dimethylnicotinoyl nitrile (nicotinonitril)
To a mixture of 6-amino-2, 4-dimethylnicotinonitrile (Sato, K.; Bull. chem. Soc. Jpn., 1969, 42, 2319., 22.4g, 152mmol) in 5% aqueous sulfuric acid (600mL) was added dropwise a solution of sodium nitrite (25.2g, 365mmol) in water (100mL) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The resulting precipitate was collected by filtration to yield 10.2g (45%) of the title compound:
1H-NMR(DMSO-d6)δ12.27(1H，br.s)，6.17(1H，s)，2.38(3H，s)，2.20(3H，s)。
step 26-hydroxy-2, 4-dimethyl-5-nitronicotinoyl nitrile
To a stirred mixture of nitric acid (fuming, 36mL) and sulfuric acid (18mI) was added 6-hydroxy-2, 4-dimethylnicotinonitrile (step 1, 9.0g, 60.8mmol) in one portion. After the mixture was stirred at room temperature for 1 hour, the mixture was poured into water (100mL) and neutralized with a 2N aqueous solution of sodium hydroxide. The resulting precipitate was collected by filtration to yield 3.2g (27%) of the title compound:
1H-NMR(DMSO-d6)δ2.28(3H，s)，2.11(3H，s)。
Step 36-chloro-2, 4-dimethyl-5-nitronicotinoylnitrile
A mixture of 6-hydroxy-2, 4-dimethyl-5-nitronicotinonitrile (step 2, 3.2g, 16.6mmol) and phosphorus oxychloride (20mL) was stirred at 100 ℃ for 16 h. After cooling, the mixture was poured into water (100 mL). The resulting mixture was extracted with dichloromethane (3X 100 mL). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated to give 2.3g (66%) of the title compound as a brown solid:
1H-NMR(DMSO-d6)δ2.82(3H，s)，2.52(3H，s)。
step 46- [4- (2-hydroxyethyl) anilino ] -2, 4-dimethyl-5-nitronicotinonitrile
The title compound was prepared according to the procedure described in example 1, step 3, from 6-chloro-2, 4-dimethyl-5-nitronicotinonitrile (step 3) and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.37(1H，br.s)，7.51(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，3.89-3.87(2H，m)，2.89(2H，t，J＝6.4Hz)，2.72(3H，s)，2.65(3H，s)，1.46(1H，t，J＝5.8Hz)。
Step 55-amino-6- [4- (2-hydroxyethyl) anilino ] -2, 4-dimethylnicotinoyl nitrile
The title compound was prepared according to the procedure described in example 1, step 4, from 6- [4- (2-hydroxyethyl) anilino ] -2, 4-dimethyl-5-nitronicotinoyl nitrile (step 4).
1H-NMR(CDCl3)δ：7.49(2H，d，J＝8.6Hz)，7.19(2H，d，J＝8.4Hz)，6.98(1H，br.s)，3.89-3.82(2H，m)，3.11(2H，br.s)，2.85(2H，t，J＝6.6Hz)，2.58(3H，s)，2.38(3H，s)，1.44(1H，t，J＝5.6Hz)。
Step 62- [4- (6-cyano-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 5-amino-6- [4- (2-hydroxyethyl) anilino ] -2, 4-dimethylnicotinoyl nitrile (step 5) and propionyl chloride.
TLC Rf 0.4 (hexane/ethyl acetate 1: 1).
Step 72-Ethyl-3- [4- (2-hydroxyethyl) phenyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-cyano-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl propionate (step 6).
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，4.01-3.94(2H，m)，3.49-3.47(1H，m)，3.00(2H，t，J＝6.3Hz)，2.86(3H，s)，2.83(2H，q，J＝7.4Hz)，2.74(3H，s)，1.32(3H，t，J＝7.6Hz)。
Step 83- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 7, from 2-ethyl-3- [4- (2-hydroxyethyl) phenyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile (step 7).
TLC Rf 0.8 (hexane/ethyl acetate 1: 1).
Step 93- [4- (2-azidoethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile (step 8).
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.2Hz)，3.62(2H，t，J＝7.1Hz)，3.02(2H，t，J＝7.1Hz)，2.86(3H，s)，2.82(2H，q，J＝7.6Hz)，2.73(3H，s)，1.31(3H，t，J＝7.6Hz)。
Step 103- [4- (2-aminoethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 9, from 3- [4- (2-azidoethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile (step 9).
TLC Rf 0.05 (hexane/ethyl acetate 1: 1).
Step 116-cyano-2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 3- [4- (2-aminoethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-6-carbonitrile (step 10).
mp 133℃；MS(ESI)m/z 517.12(M+H)+；1H-NMR(CDCl3)δ：7.78(2H，d，J＝8.1Hz)，7.37-7.25(6H，m)，6.46(1H，br.s)，3.56-3.54(2H，m)，2.92(2H，t，J＝7.0Hz)，2.85(3H，s)，2.76(2H，q，J＝6.0Hz)，2.68(3H，s)，2.41(3H，s)，1.29(3H，t，J＝6.2Hz)。
Example 42
2-Ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine
Step 12- {4- [ (2, 6-dimethyl-3-nitro-4-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 4-chloro-2, 6-dimethyl-3-nitropyridine (Tanaka, a.; et al, j.med.chem., 1999, 41, 4408) and 4-aminophenylethyl alcohol.
1H NMR(CDCl3)δ：8.74(1H，br.s)，7.31(2H，d，J＝8.2Hz)，7.18(2H，d，J＝8.2Hz)，6.68(1H，s)，3.95-3.89(2H，m)，2.91(2H，t，J＝6.6Hz)，2.72(3H，s)，2.36(3H，s)。
Step 22- {4- [ (3-amino-2, 6-dimethyl-4-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 4, from 2- {4- [ (2, 6-dimethyl-3-nitro-4-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.19(2H，d，J＝8.4Hz)，7.01(2H，d，J＝8.6Hz)，6.76(1H，s)，5.82(1H，br.s)，3.87(2H，t，J＝6.4Hz)，3.18(2H，br.s)，2.85(2H，t，J＝6.4Hz)，2.44(3H，s)，2.35(3H，s)。
Step 32- [4- (2-Ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylpropionate
A mixture of 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridyl) amino ] phenyl } ethanol (step 2, 24g, 9.3mmol), propionic anhydride (13mL, 101mmol) and propionic acid (13mL, 174mmol) was stirred at 120 ℃ for 16 h. After cooling, the mixture was diluted with 2N aqueous sodium hydroxide (150mL) and extracted with dichloromethane (3X 150 mL). The combined organic extracts were washed with brine (50mL), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with methylene chloride/methanol (gradient from 20: 1 to 10: 1) gave 2.3g (69%) of the title compound as a brown oil:
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.2Hz)，6.72(1H，s)，4.38(2H，t，J＝6.9Hz)，3.07(2H，t，J＝7.1Hz)，2.88(3H，s)，2.82(2H，q，J＝7.6Hz)，2.56(3H，s)，2.36(2H，q，J＝7.6Hz)，1.29(3H，t，J＝7.6Hz)，1.15(3H，t，J＝7.7Hz)。
step 42- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.1Hz)，6.73(1H，s)，4.00(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.4Hz)，2.88(3H，s)，2.81(2H，q，J＝7.5Hz)，2.54(3H，s)，1.29(3H，t，J＝7.5Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (step 4).
TLC Rf ═ 0.1 (ethyl acetate).
Step 61- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine (step 5).
1H-NMR(CDCl3)δ7.46(2H，d，J＝8.0Hz)，7.29(2H，d，J＝7.7Hz)，6.72(1H，s)，3.62(2H，t，J＝6.9Hz)，3.02(2H，t，J＝6.9Hz)，2.88(3H，s)，2.81(2H，q，J＝7.4Hz)，2.56(3H，s)，1.29(3H，t，J＝7.6Hz)。
Step 72- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine (step 6).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.2Hz)，7.26(2H，d，J＝8.4Hz)，6.73(1H，s)，3.08(2H，t，J＝6.9Hz)，2.90-2.78(4H，m)，2.88(3H，s)，2.56(3H，s)，1.30(3H，t，J＝7.3Hz)。
Step 82-Ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] aminocarbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine (step 7).
mp 143℃；
MS(ESI)m/z 492.12(M+H)+；
1H-NMR(CDCl3)δ7.77(2H，d，J＝8.3Hz)，7.38(2H，d，J＝8.4Hz)，7.25(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.4Hz)，6.77(1H，s)，3.58-3.51(2H，m)，2.92(2H，t，J＝7.0Hz)，2.89(3H，s)，2.79(2H，q，J＝7.5Hz)，2.53(3H，s)，2.38(3H，s)，1.28(3H，t，J＝7.5Hz)。
Example 43
2-ethyl-1- (4- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.47(1H，s)，8.21(1H，dd，J＝1.5，8.8Hz)，7.40-7.16(6H，m)，681-6.70(1H，m)，3.91(2H，t，J＝6.5Hz)，2.90(2H，t，J＝6.5Hz)。
Step 22- [4- (2-Aminoanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 4, from 2- [4- (2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.15-6.96(4H，m)，6.82-6.66(4H，m)，5.14(1H，s)，3.80(2H，t，J＝6.6Hz)，3.75(2H，br.s)，2.79(2H，t，J＝6.6Hz)。
Step 32- [4- (2-Ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-aminoanilino) phenyl ] ethanol (step 2) and propionyl chloride.
MS(EI)m/z 322(M+)；1H-NMR(CDCl3)δ：7.79(1H，d，J＝7.7Hz)，7.43(2H，d，J＝8.6Hz)，7.34-7.06(5H，m)，4.38(2H，t，J＝7.0Hz)，3.07(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.5Hz)，1.15(3H，t，J＝7.6Hz)。
Step 42- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.81-7.75(1H，m)，7.45(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，7.25-7.08(3H，m)，3.98(2H，t，J＝6.5Hz)，3.00(2H，t，J＝6.5Hz)，2.80(2H，q，J＝7.5Hz)，1.26(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 26 step 5 from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 291(M+)；1H-NMR(CDCl3)δ：7.81-7.76(1H，m)，7.43(2H，d，J＝8.3Hz)，7.40-7.06(5H，m)，3.62(2H，t，J＝6.5Hz)，3.04(2H，t，J＝6.5Hz)，2.80(2H，q，J＝7.5Hz)，1.27(3H，t，J＝7.5Hz)。
Step 62- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.80-7.74(1H，m)，7.45-7.06(7H，m)，3.06(2H，t，J＝6.5Hz)，2.89(2H，t，J＝6.5Hz)，2.76(2H，q，J＝7.5Hz)，1.26(3H，t，J＝7.5Hz)。
Step 72-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.75(1H，d，J＝8.8Hz)，7.71(2H，d，J＝8.3Hz)，7.39-7.14(8H，m)，7.07(1H，d，J＝8.8Hz)，6.68(1H，br.s)，3.62-3.54(2H，m)，2.94(2H，t，J＝6.3Hz)，2.79(2H，q，J＝7.0Hz)，2.41(3H，s)，1.33(3H，t，J＝7.0Hz)。
Example 44
2- [4- { 2-Ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 43, step 4).
1H-NMR(CDCl3)δ7.93(2H，d，J＝8.3Hz)，7.85-7.75(2H，m)，7.40-7.15(7H，m)，7.08(1H，d，J＝8.8Hz)，4.77(1H，br.s)4.36(2H，t，J＝6.4Hz)，3.00(2H，t，J＝6.4Hz)，2.78(2H，q，J＝7.0Hz)，2.44(3H，s)，1.32(3H，t，J＝7.0Hz)。
Example 45
4-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino) carbonyl) amino) ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (3-methyl-2-nitroanilino) phenyl ] ethanol
A mixture of 2-nitro-3-methylaniline (Newman, M.S.; Kannan R.J. or g.chem., 1976, 41, 3356., 1.9g, 12.4mmol), 4-bromophenylethyl alcohol (2.5g, 12.4mmol), potassium carbonate (1.7g, 12.4mmol) and CuI (230mg, 1.24mmol) was placed in a sealed tube and heated at 200 ℃ for 2 hours. After cooling, the mixture was poured into water (100mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous sodium hydroxide (100mL) and brine (100mL), then dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) gave 700mg (21%) of the title compound as an orange oil:
1H-NMR(CDCl3)δ：7.77(1H，br.s)，7.09-7.45(6H，m)，6.69(1H，d，J＝6.3Hz)，3.83(2H，t，J＝6.6Hz)，2.82(2H，t，J＝6.6Hz)，2.59(3H，s)。
Step 22- [4- (2-amino-3-methylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [4- (3-methyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.02(2H，d，J＝8.2Hz)，6.95(1H，d，J＝7.7Hz)，6.91(1H，d，J＝7.0Hz)，6.65(1H，dd，J＝7.0Hz，7.7Hz)，6.62(2H，d，J＝8.2Hz)，5.15(1H，br.s)，3.75(2H，t，J＝6.6Hz)，2.73(2H，t，J＝6.6Hz)，2.19(3H，s)。
Step 32- [4- (2-Ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-3-methylanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.6 (hexane: ethyl acetate 1: 1).
Step 42- [ 2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.41-7.43(2H，m)，7.29(2H，d，J＝6.4Hz)，7.07(2H，d，J＝6.4Hz)，6.91-6.94(1H，m)，3.97(2H，t，J＝6.6Hz)，2.99(2H，t，J＝6.6Hz)，2.84(2H，q，J＝7.5Hz)，2.71(3H，s)，1.27(3H，t，J＝7.5Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-4-methyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ7.43(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.07-7.09(2H，m)，6.90-6.95(1H，m)，3.81(2H，t，J＝7.2Hz)，3.19(2H，t，J＝7.2Hz)，2.84(2H，q，J＝7.5Hz)，2.72(3H，s)，1.27(3H，t，J＝7.5Hz)。
Step 62- [4- (2-Ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] 2-ethyl-4-methyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.0Hz)，7.31(2H，d，J＝8.0Hz)，7.05-7.09(2H，m)，6.90-6.94(1H，m)，3.61(2H，t，J＝7.0Hz)，3.01(2H，t，J＝7.0Hz)，2.84(2H，q，J＝7.5Hz)，2.72(3H，s)，1.27(3H，t，J＝7.5Hz)。
Step 72- [4- (2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared from 2- [4- (2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6) according to the procedure described in example 1, step 9.
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.3Hz)，7.28(2H，d，8.3Hz)，7.04-7.11(2H，m)，6.86-6.95(1H，m)，3.07(2H，t，J＝6.6Hz)，2.87(2H，t，J＝6.6Hz)，2.84(2H，q，J＝7.5Hz)，2.71(3H，s)，1.27(3H，t，J＝7.5Hz)。
Step 82-Ethyl-4-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-4-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 477(M+H)+，1H-NMR(DMSO-d6)δ7.65(2H，d，J＝7.7Hz)，7.33-7.41(4H，m)，7.15(2H，d，J＝7.7Hz)，7.01-7.07(2H，m)，6.86(1H，d，J＝6.8Hz)，3.19(2H，br.s)，2.68-2.74(4H，m)，2.56(3H，s)，2.28(3H，s)，1.21(3H，t，J＝7.1Hz)；IR(KBr)vmax 3390，1602，1519，1429，1230，1130，1085cm-1。
Example 46
4-methyl-2-ethyl-3- (4- {2- [ { [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-4-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 45).
1H-NMR(DMSO-d6)δ7.65(2H，d，J＝7.7Hz)，7.33-7.41(4H，m)，7.15(2H，d，J＝7.7Hz)，7.01-7.07(2H，m)，6.86(1H，d，J＝6.8Hz)，3.19(2H，br.s)，2.68-2.74(4H，m)，2.56(3H，s)，2.28(3H，s)，1.21(3H，t，J＝7.1Hz)；IR(KBr)Vmax3390，1602，1519，1429，1230，1130，1085cm-1。
Example 47
2-ethyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (4-methyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for step 1, example 45 from 4-methyl-2-nitroaniline and 4-iodophenylethylalcohol.
1H-NMR(CDCl3)δ9.35(1H，br.s)，8.00(1H，s)，7.33-7.09(6H，m)，3.91-3.89(2H，m)，2.89(2H，t，J＝6.4Hz)，2.30(3H，s)。
Step 22- [ (2-amino-4-methylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for example 28 step 2, from 2- [ (4-methyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.05(2H，d，J＝8.3Hz)，6.98(1H，d，J＝7.7Hz)，6.67-6.64(3H，m)，6.58-6.55(1H，m)，5.06(1H，br.s)，3.80-3.78(4H，m)，2.77(2H，t，J＝6.4Hz)，2.28(3H，s)。
Step 32- [4- (2-Ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-4-methylanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
TLC Rf 0.33 (hexane/ethyl acetate 2: 1).
Step 42- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ7.55(1H，s)，7.43(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.99-6.95(2H，m)，3.99(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.7Hz)，2.47(3H，s)，1.32(3H，t，J＝7.7Hz)
Step 52- [4- (2-Ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
TLC Rf 0.74 (hexane/ethyl acetate 1: 1).
Step 62- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.55(1H，s)，7.43(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.01-6.95(2H，m)，4.85(2H，br.s)，3.30-3.25(2H，m)，3.16-3.11(2H，m)，2.76(2H，q，J＝7.6Hz)，2.45(3H，s)，1.31(3H，t，J＝7.6Hz)。
Step 72-Ethyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(DMSO-d6)δ7.76(2H，d，J＝8.4Hz)，7.42-7.36(6H，m)，7.00-6.91(2H，m)，6.53-6.49(1H，m)，3.29-3.24(2H，m)，2.79-2.65(4H，m)，2.40(3H，s)，2.33(3H，s)，1.20(3H，t，J＝7.4Hz)。
Example 48
2-Ethyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 47).
1H-NMR(DMSO-d6)δ7.60(2H，d，J＝7.7Hz)，7.42-7.33(5H，m)，7.13(2H，d，J＝7.7Hz)，6.96(2H，m)，3.16(2H，m)，2.71-2.66(4H，m)，2.39(3H，s)，2.27(3H，s)，1.20(3H，t，J＝7.5Hz)；IR(KBr)vmax 1599，1514，1285，1232，1130，1086cm-1。
Example 49
2-butyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] butyl } phenyl) -1H-benzimidazole
Step 12- [4- (2-butyl-5-methyl-1H-benzimidazol-1-yl) phenyl ] ethylvalerate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [ (2-amino-4-methylanilino) phenyl ] ethanol (example 47, step 2) and valeryl chloride.
1H-NMR(CDCl3)δ：7.56-7.55(1H，m)，7.43-7.40(2H，m)，7.29-7.26(2H，m)，7.02-6.94(2H，m)，4.38(2H，t，J＝6.9Hz)，3.06(2H，t，J＝6.9Hz)，2.75(2H，t，J＝7.4Hz)，2.47(3H，s)，2.33(2H，t，J＝7.4Hz)，1.80-1.55(4H，m)，1.41-1.23(4H，m)，0.94-0.83(6H，m)。
Step 22- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl valerate (step 1).
1H-NMR(CDCl3)δ7.55(1H，s)，7.44(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，7.02-6.95(2H，m)，3.99(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.75(2H，t，J＝7.3Hz)，2.47(3H，s)，1.79-1.68(2H，m)，1.36-1.23(2H，m)，0.85(3H，t，J＝7.3Hz)。
Step 32- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (2-butyl-6-methyl-1H-benzoimidazol-1-yl) phenyl ] ethanol (step 2).
1H-NMR(CDCl3)δ：7.56(1H，s)，7.42(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.03-6.95(2H，m)，3.61(2H，t，J＝6.9Hz)，3.01(2H，t，J＝6.9Hz)，2.75(2H，t，J＝7.3Hz)，2.47(3H，s)，1.80-1.68(2H，m)，1.37-1.26(2H，m)，0.85(3H，t，J＝7.3Hz)。
Step 32- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 2).
1H-NMR(CDCl3)δ7.55(1H，s)，7.40(2H，d，J＝8.3Hz)，7.26(2H，d，J＝8.3Hz)，7.01-6.94(2H，m)，3.15(2H，t，J＝7.3Hz)，2.98(2H，t，J＝7.3Hz)，2.74(2H，t，J＝7.7Hz)，2.46(3H，s)，1.77-1.67(2H，m)，1.35-1.28(2H，m)，0.84(3H，t，J＝7.7Hz)。
Step 42-butyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 3).
1H-NMR(CDCl3)δ：7.76(2H，d，J＝8.2Hz)，7.54(1H，m)，7.31-7.21(6H，m)，7.03-6.95(2H，m)，6.67-6.63(1H，m)，3.61-3.54(2H，m)，2.91(2H，t，J＝7.1Hz)，2.73(2H，t，J＝7.3Hz)，2.47(3H，s)，2.40(3H，s)，1.76-1.65(2H，m)，1.36-1.28(2H，m)，0.83(3H，t，J＝7.3Hz)。
Example 50
2-butyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] butyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-butyl-5-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -1H-benzimidazole (example 49).
mp 130-140℃；
1H-NMR(DMSO-d6)δ7.59(2H，d，J＝7.8Hz)，7.40-7.31(5H，m)，7.11(2H，d，J＝7.8Hz)，6.98-6.92(2H，m)，3.15(2H，m)，2.71-2.66(4H，m)，2.39(3H，s)，2.26(3H，s)，1.67-1.57(2H，m)，1.31-1.21(2H，m)，0.79(3H，t，J＝7.5Hz)；IR(KBr)Vmax1599，1514，1400，1130，1086cm-1。
Example 51
6-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (5-methyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-fluoro-4-methylnitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ9.51(1H，br.s)，8.10(1H，d，J＝8.8Hz)，7.20-7.31(4H，m)，6.98(1H，s)，6.58(1H，d，J＝8.4Hz)，3.91(2H，t，J＝6.4Hz)，2.89(t，J＝6.4Hz)，2.27(3H，s)。
Step 22- [4- (2-amino-5-methylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [4- (5-methyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.07(2H，d，J＝8.3Hz)，6.93(1H，s)，6.81(1H，d，J＝8.1Hz)，6.70-6.72(3H，m)，3.81(2H，t，J＝6.4Hz)，3.61(2H，br.s)，2.78(2H，t，J＝6.4Hz)，2.22(3H，s)。
Step 32- [4- (2-Ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-5-methylanilino) phenyl ] ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：7.64(1H，d，J＝8.3Hz)，7.42(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.0Hz)，7.08(1H，d，J＝8.3Hz)，6.87(1H，s)，4.38(2H，t，J＝6.9Hz)，3.06(2H，t，J＝6.9Hz)，2.76(2H，q，J＝7.5Hz)，2.41(3H，s)，2.36(2H，q，J＝7.7Hz)，1.35(3H，t，J＝7.5Hz)，1.15(3H，t，J＝7.7Hz)。
Step 42- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.64(1H，d，J＝8.1Hz)，7.45(2H，d，J＝8.1Hz)，7.19-7.30(2H，m)，7.08(1H，d，J＝8.1Hz)，6.88(1H，s)，3.99(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.6Hz)，2.40(3H，s)，1.33(3H，t，J＝7.6Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-6-methyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.65(1H，d，J＝8.2Hz)，7.43(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，7.07(1H，d，J＝8.2Hz)，6.88(1u，s)，3.82(2H，t，J＝7.0Hz)，3.19(2H，t，7.0Hz)，2.77(2H，q，J＝7.6Hz)，2.41(3H，s)，1.33(3H，t，J＝7.6Hz)。
Step 62- [4- (2-Ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-6-methyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.64(1H，d，J＝8.2Hz)，7.43(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，7.08(1H，d，J＝8.2Hz)，6.87(1H，s)，3.62(2H，t，J＝7.0Hz)，3.01(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.6Hz)，2.37(3H，s)，1.33(3H，t，J＝7.6Hz)。
Step 72- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.64(1H，d，J＝8.3Hz)，7.40(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，7.07(1H，d，J＝8.3Hz)，6.88(1H，s)，3.07(2H，br.s)，2.87(2H，t，J＝6.8Hz)，2.76(2H，q，J＝7.6Hz)，2.40(3H，s)，1.33(3H，t，J＝7.6Hz)。
Step 86-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.3Hz)，7.66(1H，d，J＝8.0Hz)，7.27-7.38(6H，m)，7.09(1H，d，J＝8.0Hz)，6.88(1H，s)，3.59-3.63(2H，m)，2.95(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.5Hz)，2.41(3H，s)，2.39(3H，s)，1.33(3H，t，J＝7.5Hz)。
Example 52
6-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 51).
mp 151-165℃；
1H-NMR(DMSO-d6)δ7.64(2H，d，J＝8.0Hz)，7.51(1H，d，J＝8.2Hz)，7.33-7.42(4H，m)，7.15(2H，d，J＝8.0Hz)，7.02(1H，dd，J＝1.4Hz，8.2Hz)，6.87(1H，s)，3.18(2H，br.s)，2.65-2.78(4H，m)，2.34(3H，s)，2.78(3H，s)，1.21(3H，t，J＝7.6Hz)。
Example 53
7-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (2-methyl-6-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for step 1, example 45 from 6-methyl-2-nitroaniline and 4-bromophenylethyl alcohol.
1H-NMR(CDCl3)δ：8.28(1H，br.s)，7.96(1H，d，J＝8.4Hz)，7.39-7.44(1H，m)，7.02-7.12(3H，m)，6.72(2H，d，J＝8.4Hz)，3.82(2H，t，J＝6.5Hz)，2.81(2H，t，J＝6.5Hz)，2.08(3H，s)。
Step 22- [4- (2-amino-6-methylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [4- (2-methyl-6-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：6.97-7.03(3H，m)，6.66(2H，d，J＝7.6Hz)，6.52(2H，d，J＝7.6Hz)，4.97(1H，br.s)，3.86(2H，br.s)，3.79(2H，t，J＝6.4Hz)，2.76(2H，t，J＝6.4Hz)，2.16(3H，s)。
Step 32- [4- (2-Ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-6-methylanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.6 (hexane: ethyl acetate 1: 1).
Step 42- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ7.63(1H，d，J＝8.0Hz)，7.38-7.41(2H，m)，7.26-7.31(2H，m)，7.14(1H，dd，J＝7.4Hz，8.0Hz)，6.91(1H，d，J＝7.4Hz)，3.98(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.63(2H，q，J＝7.5Hz)，1.89(3H，s)，1.31(3H，t，J＝7.5Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-7-methyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.64(1H，d，J＝8.1Hz)，7.26-7.39(4H，m)，7.14(1H，dd，J＝7.4Hz，8.1Hz)，6.91(1H，d，J＝7.4Hz)，3.81(2H，t，J＝7.2Hz)，3.19(2H，d，J＝7.2Hz)，2.63(2H，q，J＝7.6Hz)，1.88(3H，s)，1.32(3H，t，J＝7.6Hz)。
Step 62- [4- (2-Ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-7-methyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ7.64(1H，d，J＝7.4Hz)，7.39(2H，d，J＝8.0Hz)，7.31(2H，d，J＝8.0Hz)，7.14(1H，dd，J＝7.4Hz，8.1Hz)，6.91(1H，d，J＝8.1Hz)，3.61(2H，t，J＝6.8Hz)，3.02(2H，t，J＝6.8Hz)，2.63(2H，q，J＝7.6Hz)，1.89(3H，s)，1.31(3H，t，J＝7.5Hz)。
Step 72- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ7.64(1H，d，J＝7.9Hz)，7.36(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，7.14(1H，dd，J＝7.5Hz，7.9Hz)，6.91(1H，d，J＝7.5Hz)，3.06(2H，t，J＝6.8Hz)，2.87(2H，t，J＝6.8Hz)，2.63(2H，q，J＝7.5Hz)，1.89(3H，s)，1.32(3H，t，J＝7.5Hz)。
Step 82-Ethyl-7-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-7-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 477(M+H)+，1H-NMR(CDCl3)δ：7.75(2H，d，J＝8.3Hz)，7.62(1H，d，J＝7.9Hz)，7.28-7.33(5H，m)，7.14(2H，d，J＝7.6Hz)，6.91(1H，d，J＝7.9Hz)，6.72(1H，br.s)，3.58(2H，d，J＝6.8Hz)，2.93(2H，t，J＝6.8Hz)，2.62(2H，q，J＝7.6Hz)，2.41(3H，s)，1.86(3H，s)，1.29(3H，t，J＝7.6Hz)。
Example 54
7-methyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-7-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -1H benzimidazole (example 53).
1H-NMR(DMSO-d6)δ7.63(2H，d，J＝7.4Hz)，7.47(1H，d，J＝8.1Hz)，7.36(4H，s)，7.15(2H，d，J＝7.7Hz)，7.06(1H，dd，J＝7.2Hz，8.1Hz)，6.87(1H，d，J＝7.2Hz)，5.99(1H，br.s)，3.16(2H，br.s)，2.76(2H，br.s)，2.52(2H，q，J＝7.6Hz)，2.28(3H，s)，1.82(3H，s)，1.19(3H，t，J＝7.6Hz)；IR(KBr)Vmax，3400，1610，1525，1290，1132，1095，820，751cm-1。
Example 55
4-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (3-chloro-2-nitroanilino) phenyl ] ethanol
A mixture of 2, 6-dichloronitrobenzene (Norman, M.H; Chen, N.; et al, PCTInt.Appl., WO9940091(1999), Spada, A.P.; Fink, C.A.; Myers, M.R. PCTInt.Appl., WO9205177(1992), 6.3g, 32.8mmol), 4-aminophenylethyl alcohol (4.9g, 36mmol) and sodium acetate (3.2g, 39.3mmol) was heated in a sealed tube at 160 ℃ for 3 hours. After cooling, the mixture was poured into water (100mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous sodium hydroxide (100mL) and brine (100mL), then dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) gave 4.57g (72%) of the title compound as a red oil:
1H-NMR(CDCl3)δ：7.09-7.28(6H，m)，6.91(1H，dd，J＝2.0，7.1Hz)，3.87(2H，t，J＝6.6Hz)，2.86(2H，t，J＝6.6Hz)。
step 22- [4- (2-amino-3-chloroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- (3-chloro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ7.06-7.10(3H，m)，7.00(1H，dd，J＝1.0Hz，7.9Hz)，6.62-6.73(3H，m)，5.16(1H，br.s)，4.14(2H，br.s)，3.81(2H，t，J＝6.1Hz)，2.77(2H，t，J＝6.1Hz)。
Step 32- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-3-chloroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.5 (hexane: ethyl acetate 1: 1).
Step 42- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.6Hz)，7.26-7.31(3H，m)，7.09(1H，d，J＝7.9Hz)，6.96(1H，dd，J＝0.9Hz，7.9Hz)，3.99(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.6Hz)，2.84(2H，q，J＝7.5Hz)，1.30(3H，t，J＝7.5Hz)。
Step 54-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.6Hz)，7.30(2H，d，J＝8.6Hz)，7.27(1H，s)，7.10(1H，d，J＝8.1Hz)，6.98(1H，d，J＝8.1Hz)，3.81(2H，t，J＝7.1Hz)，3.19(2H，t，J＝7.1Hz)，2.84(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 62- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 4-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.2Hz)，7.29-7.33(3H，m)，7.10(1H，dd，J＝8.1Hz，7.7Hz)，6.96(1H，d，J＝7.7Hz)，3.62(2H，t，J＝7.1Hz)，3.02(2H，t，J＝7.1Hz)，2.84(2H，q，J＝7.6Hz)，1.30(3H，t，J＝7.6Hz)。
Step 72- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.29-7.33(3H，m)，7.09(1H，dd，J＝7.7Hz，7.9Hz)，7.99(1H，d，J＝7.9Hz)，3.07(2H，t，J＝6.8Hz)，2.87(2H，t，J＝6.8Hz)，2.85(2H，q，J＝7.6Hz)，1.30(3H，t，J＝7.6Hz)。
Step 84-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (4-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 498(M+H)+；1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.5Hz)，7.28-7.38(7H，m)，7.09(1H，d，J＝7.9Hz)，6.97(1H，d，J＝7.9Hz)，6.69(1H，br.s)，3.58(2H，t，J＝6.9Hz)，2.94(2H，t，J＝6.9Hz)，2.83(2H，q，J＝7.5Hz)，2.40(3H，s)，1.31(3H，t，J＝7.5Hz)。
Example 56
4-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 4-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 54).
1H-NMR(DMSO-d6)δ7.62(2H，d，J＝8.0Hz)，7.41(4H，s)，7.29(1H，d，J＝6.6Hz)，7.12-7.18(3H，m)，7.02-7.04(1H，m)，3.18(2H，br.s)，2.70-2.79(4H，m)，2.27(3H，s)，1.23(3H，t，J＝7.4Hz)；IR(KBr)Vmax，3385，1602，1519，1433，1174，1130，1085，813cm-1。
Example 57
5-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (4-chloro-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 5-dichloronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.42(1H，s)，8.20(1H，d，J＝2.0Hz)，7.35-7.10(6H，m)，3.96-3.85(2H，m)，2.91(2H，t，J＝7.0Hz)。
Step 22- [4- (2-amino-4-chloroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 6, step 3, from 2- [4- (4-chloro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.30-7.05(4H，m)，6.83-6.62(3H，m)，5.15(1H，br.s)，3.86-3.75(2H，m)，3.75(2H，br.s)，2.77(2H，t，J＝7.0Hz)。
Step 32- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4-chloroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：7.75(1H，d，J＝2.0Hz)，7.43(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.0Hz)，7.15(1H，dd，J＝2.0，8.6Hz)，6.99(1H，d，J＝8.6Hz)，4.38(2H，t，J＝7.0Hz)，3.07(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.5Hz)，1.24(3H，t，J＝7.5Hz)，1.15(3H，t，J＝7.5Hz)。
Step 42- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.75(1H，d，J＝2.0Hz)，7.46(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.15(1H，dd，J＝2.0，8.6Hz)，7.00(1H，d，J＝8.6Hz)，3.99(2H，t，J＝6.5Hz)，3.00(2H，t，J＝6.5Hz)，2.78(2H，q，J＝7.5Hz)，1.26(3H，t，J＝7.5Hz)。
Step 52- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 26 step 5 from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 325(M+)；1H-NMR(CDCl3)δ：7.75(1H，d，J＝2.0Hz)，7.45(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.15(1H，dd，J＝2.0，8.6Hz)，6.99(1H，d，J＝8.6Hz)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.5Hz)，1.26(3H，t，J＝7.5Hz)。
Step 62- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.75(1H，d，J＝2.0Hz)，7.41(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.3Hz)，7.14(1H，dd，J＝2.0，8.6Hz)，6.99(1H，d，J＝8.6Hz)，3.08(2H，t，J＝7.0Hz)，2.86(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 75-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.76(1H，d，J＝1.8Hz)，7.72(2H，d，J＝8.4Hz)，7.39(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.3Hz)，7.17(1H，dd，J＝8.6，1.8Hz)，7.00(1H，d，J＝8.6Hz)，6.73(1H，br.s)，3.59-3.53(2H，m)，2.94(2H，t，J＝7.0Hz)，2.81(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Example 58
2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 57 step 4).
1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.4Hz)，7.74(1H，d，J＝2.0Hz)，7.34(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，7.16(1H，dd，J＝8.5，2.0Hz)，6.99(1H，d，J＝8.5Hz)，4.74(1H，br.s)，4.37(2H，t，J＝6.8Hz)，3.01(2H，t，J＝6.8Hz)，2.75(2H，q，J＝7.6Hz)，1.33(3H，t，J＝7.6Hz)。
Example 59
6-chloro-2-ethyl-1- (4- {2- [ ({ [ 4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (5-chloro-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-dichloronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.52(1H，br.s)，8.16(1H，d，J＝9.2H)，7.33(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.2Hz)，7.13(1H，d，J＝2.2Hz)，6.71(1H，dd，J＝9.2，2.2Hz)，3.92(q，2H，J＝6.4Hz)，2.92(t，2H，J＝6.4Hz)。
Step 22- [ (2-amino-5-chloroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (5-chloro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ7.12-7.09(3H，m)，6.92(1H，dd，J＝8.4，2.4Hz)，6.78-6.70(3H，m)，5.16(1H，br.s)，3.83(2H，t，J＝6，6Hz)，2.81(2H，t，J＝6.6Hz)。
Step 32- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-5-chloroanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：7.67(1H，d，J＝8.6Hz)，7.44(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.22(1H，dd，J＝8.4，2.0Hz)，7.07(1H，d，J＝2.0Hz)，4.38(2H，t，J＝7.0Hz)，3.07(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)，1.15(3H，t，J＝7.5Hz)。
Step 42- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.67(1H，d，J＝8.6Hz)，7.46(2H，d，J＝8.6Hz)，7.30-7.26(3H，m)，7.22(1H，dd，J＝8.6，2.2Hz)，7.08(1H，d，J＝2.0Hz)，3.99(2H，q，J＝6.4Hz)，3.01(2H，t，J＝6.4Hz)，2.78(2H，q，J＝7.6Hz)，1.72(1H，t，J＝5.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 52- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 325(M+)。
Step 62 [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.67(1H，d，J＝8.6Hz)，7.41(2H，d，J＝8.4Hz)，7.31-7.19(3H，m)，7.12(1H，d，J＝2.0Hz)，4.66(2H，br.s)，3.23-3.17(2H，m)，3.08-3.04(2H，m)，2.75(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)。
Step 76-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.74(2H，d，J＝8.4Hz)，7.67(1H，d，J＝8.4Hz)，7.37(2H，d，J＝8.4Hz)，7.30-7.20(6H，m)，7.05(1H，d，J＝2.0Hz)，6.73(1H，m)，3.62-3.55(2H，m)，2.93(2H，t，J＝7.2Hz)，2.77(2H，t，J＝7.5Hz)，1.32(3H，t，J＝7.5Hz)。
Example 60
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 59).
1H-NMR(DMSO-d6)δ7.64(1H，d，J＝8.6Hz)，7.59(2H，d，J＝8.1Hz)，7.38(4H，m)，7.22(1H，dd，J＝8.6，2.0Hz)，7.11(2H，d，J＝8.1Hz)，7.05(1H，d，J＝2.0Hz)，3.15(2H，m)，2.74-2.66(4H，m)，2.25(3H，s)，1.21(3H，t，J＝7.4Hz)；IR(KBr)Vmax，1601，1516，1398，1178，1130，1084cm-1。
Example 61
4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenethyl- (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 1 from 2- [4- (6-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 59 step 4).
mp 183-187℃；
1H-NMR(DMSO-d6)δ7.75(2H，d，J＝8.1Hz)，7.66(1H，d，J＝8.6Hz)，7.43(4H，s)，7.40(2H，d，J＝8.1Hz)，7.24(1H，dd，J＝8.6，2.0Hz)，7.03(1H，d，J＝2.0Hz)，4.27(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.6Hz)，2.70(2H，q，J＝7.5Hz)，2.34(3H，s)，1.22(3H，t，J＝7.5Hz)；IR(KBr)Vmax1744，1516，1352，1225，1165cm-1。
Example 62
2-butyl-6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] butyl } phenyl) -1H-benzimidazole
Step 12- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethylvalerate
The title compound was prepared according to the procedure described for step 5 of example 1 from 2- [ (2-amino-5-chloroanilino) phenyl ] ethanol (example 59 step 2) and valeryl chloride.
1H-NMR(CDCl3)δ：7.66(1H，d，J＝8.4Hz)，7.44(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，7.22(1H，dd，J＝8.4，2.0Hz)，7.06(1H，d，J＝2.0Hz)，4.38(2H，t，J＝6.8Hz)，3.07(2H，t，J＝6.8Hz)，2.74(2H，t，J＝7.7Hz)，2.33(2H，t，J＝7.5Hz)，1.81-1.70(2H，m)，1.66-1.56(2H，m)，1.40-1.28(4H，m)，0.94-0.84(6H，m)。
Step 22- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethyl valerate (step 1).
1H-NMR(CDCl3)δ：7.66(1H，d，J＝8.6Hz)，7.46(2H，d，J＝8.1Hz)，7.29-7.26(2H，m)，7.22(1H，dd，J＝8.6，2.0Hz)，7.07(1H，d，J＝2.0Hz)，4.00(2H，q，J＝6.4Hz)，3.01(2H，t，J＝6.4Hz)，2.75(2H，t，J＝7.5Hz)，2.24-2.19(1H，m)，1.81-1.71(2H，m)，1.37-1.26(2H，m)，0.87(3H，t，J＝7.3Hz)
Step 32- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described for example step 4 from 2- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 2).
1H-NMR(CDCl3)δ：7.66(1H，d，J＝8.6Hz)，7.45(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.22(1H，dd，J＝8.6，2.0Hz)，7.07(1H，d，J＝2.0Hz)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.74(2H，t，J＝7.5Hz)，1.80-1.70(2H，m)，1.40-1.26(2H，m)，0.86(2H，t，J＝7.3Hz)
Step 32- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 2).
1H-NMR(CDCl3)δ：7.66(1H，d，J＝8.6Hz)，7.43(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，7.21(1H，dd，J＝8.6，2.0Hz)，7.08(1H，d，J＝2.0Hz)，3.11(2H，t，J＝7.1Hz)，2.91(2H，t，J＝7.1Hz)，2.74(2H，t，J＝7.4Hz)，1.81-1.70(2H，m)，1.41-1.27(2H，m)，0.86(3H，t，J＝7.4Hz)。
Step 42-butyl-6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-butyl-6-chloro-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 3).
1H-NMR(CDCl3)δ：7.75(2H，d，J＝8.4Hz)，7.66(1H，d，J＝8.2Hz)，7.38(2H，d，J＝8.4Hz)，7.30-7.20(6H，m)，7.05(1H，d，J＝2.0Hz)，6.77-6.72(1H，m)，3.61-3.55(2H，m)，2.96-2.92(2H，m)，2.74(2H，t，J＝7.5Hz)，2.39(3H，s)，1.78-1.67(2H，m)，1.35-1.26(2H，m)，0.84(3H，t，J＝7.3Hz)。
Example 63
2-butyl-6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] butyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-butyl-6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 62).
mp 137-145℃；
1H-NMR(DMSO-d6)δ7.65-7.63(1H，m)，7.59(2H，d，J＝7.8Hz)，7.38(4H，s)，7.23-7.20(1H，m)，7.12(2H，d，J＝7.8Hz)，7.04(1H，s)，3.15(2H，m)，2.72-2.67(4H，m)，2.26(3H，s)，1.66-1.61(2H，m)，1.29-1.22(2H，m)，0.79(3H，t，J＝7.5Hz)；IR(KBr)Vmax，1603，1520，1458，1396，1130，1086cm-1。
Example 64
7-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (2-chloro-6-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 3-dichloronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：8.11(1H，br.s)，8.00(1H，dd，J＝1.5Hz，8.5Hz)，7.61(1H，dd，J＝1.5Hz，7.9Hz)，7.12(2H，d，J＝8.4Hz)，7.03(1H，dd，J＝7.9Hz，8.5Hz)，6.80(2H，d，J＝8.4Hz)，3.82(2H，t，J＝6.6Hz)，2.81(2H，d，J＝6.6Hz)。
Step 22- [4- (2-amino-6-chloroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- (2-chloro-6-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.04(2H，d，J＝7.8Hz)，6.97(1H，dd，J＝7.9Hz，8.0Hz)，6.82(1H，dd，J＝1.5Hz，7.9Hz)，6.66(1H，dd，J＝1.5Hz，8.0Hz)，6.59(2H，d，J＝7.8Hz)，5.36(1H，br.s)，3.94(2H，br.s)，3.78(2H，t，J＝6.6Hz)，2.75(2H，d，J＝6.6Hz)。
Step 32- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-6-chloroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.6 (hexane: ethyl acetate 1: 1).
Step 42- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-amino-6-chloroanilino) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ7.68(1H，dd，J＝1.9Hz，7.0Hz)，7.39(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，7.11-7.20(2H，m)，3.97(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.65(2H，q，J＝7.6Hz)，1.32(3H，t，J＝7.6Hz)。
Step 57-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.69(1H，dd，J＝2.2Hz，7.1Hz)，7.37(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，7.11-7.17(2H，m)，3.81(2H，t，J＝7.3Hz)，3.19(2H，t，J＝7.3Hz)，2.65(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)。
Step 62- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 7-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.69(1H，dd，J＝1.8Hz，7.4Hz)，7.38(2H，d，J＝8.2Hz)，7.34(2H，d，J＝8.2Hz)，7.11-7.28(2H，m)，3.60(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.64(2H，q，J＝76Hz)，1.32(3H，t，J＝7.6Hz)。
Step 72- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described for example 37 step 7 from 2- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.69(1H，d，J＝7.9Hz)，7.35(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.11-7.19(2H，m)，3.06(2H，t，J＝6.8Hz)，2.88(2H，t，J＝6.8Hz)，2.65(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)。
Step 87-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (7-chloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 498(M+H)+；1H-NMR(CDCl3)δ：7.74(2H，d，J＝8.4Hz)，7.69(1H，dd，J＝1.9Hz，7.4Hz)，7.29-7.32(6H，m)，7.11-7.20(2H，m)，6.72(1H，br.s)，3.59(2H，t，J＝6.9Hz)，2.93(2H，t，J＝6.9Hz)，2.64(2H，q，J＝7.6Hz)，2.42(3H，s)，1.31(3H，t，J＝7.6Hz)。
Example 65
7-chloro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 7-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 64).
1H-NMR(DMSO-d6)δ7.62-7.64(3H，m)，7.31-7.39(4H，m)，7.14-7.20(4H，m)，6.00(1H，br.s)，3.17(2H，br.s)，2.75(2H，br.s)，2.55(2H，q，J＝7.8Hz)，2.29(3H，s)，1.21(3H，t，J＝7.8Hz)；IR(KBr)Vmax 3380，2891，1605，1520，1425，1285，1126，1075，798cm-1。
Example 66
5-fluoro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (4-fluoro-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 5-difluoronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ9.32(1H，s)，7.88-7.93(1H，m)，7.11-7.30(5H，m)，3.90(2H，t，J＝6.2Hz)，2.90(2H，t，J＝6.2Hz)。
Step 22- [4- (2-amino-4-fluoroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [4- (4-fluoro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：6.98-7.06(3H，m)，6.60(2H，d，J＝8.2Hz)，6.49(1H，dd，J＝2.8Hz，12.8Hz)，6.41(1H，dd，J＝2.8Hz，8.4Hz)，4.99(1H，br.s)，3.94(2H，br.s)，3.79(2H，br.s)，2.76(2H，t，J＝6.4Hz)。
Step 32- [4- (2-Ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4-fluoroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
MS(EI)m/z 340(M+)。
Step 42- [4- (2-ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-amino-4-fluoroanilino) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ7.40-7.47(3H，m)，7.28(2H，d，J＝8.0Hz)，6.88-7.02(2H，m)，3.98(2H，t，J＝6.3Hz)，3.01(2H，t，J＝6.3Hz)，2.78(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-fluoro-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42-7.46(3H，m)，7.31(2H，d，J＝8.1Hz)，6.89-7.02(2H，m)，3.81(2H，t，J＝7.1Hz)，3.19(2H，t，J＝7.1Hz)，2.78(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 62- [4- (2-Ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-fluoro-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ7.43-7.45(3H，m)，7.31(2H，d，J＝8.2Hz)，6.89-7.02(2H，m)，3.62(2H，t，J＝7.0Hz)，3.01(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 72- [4- (2-ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：7.40-7.46(3H，m)，7.27-7.29(2H，m)，6.87-6.99(2H，m)，3.06(2H，t，J＝7.1Hz)，2.87(2H，t，J＝7.1Hz)，2.78(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
Step 85-fluoro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethylphenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 481(M+H)+；1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.2Hz)，7.35-7.45(3H，m)，7.24-7.29(4H，m)，6.87-7.00(2H，m)，6.73(1H，br.s)，3.57(2H，t，J＝7.0Hz)，2.93(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.6Hz)，2.39(3H，s)，1.31(3H，t，J＝7.6Hz)。
Example 67
5-fluoro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 5-fluoro-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 66).
mp 135-146℃；
MS(ESI)m/z 481(M+H)+；1H-NMR(DMSO-d6)δ7.62(2H，d，J＝8.1Hz)，7.39-7.48(5H，m)，6.97-7.15(4H，m)，5.92(1H，br.s)，2.67-2.76(4H，m)，2.51(2H，br.s)，2.27(3H，s)，1.23(3H，t，J＝7.6Hz)。
Example 68
2-butyl-6-fluoro-1- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -1H-benzimidazole
Step 12- [4- (5-fluoro-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-difluoronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.61(1H，br.s)，8.26(1H，dd，J＝6.1，9.5Hz)，7.32(2H，d，J＝8.2Hz)，7.22(2H，d，J＝8.3Hz)，6.78(1H，dd，J＝2.6，11.3Hz)，6.47(1H，ddd，J＝2.2，7.2，9.7Hz)，3.91(2H，dt，J＝6.2，6.2Hz)，2.91(2H，t，J＝6.4Hz)，1.52(1H，t，J＝5.7Hz)。
Step 22- [4- (2-amino-5-fluoroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- (5-fluoro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.12(2H，d，J＝8.4Hz)，6.87(1H，dd，J＝2.7，10.1Hz)，6.83(2H，d，J＝8.4Hz)，6.72(1H，dd，J＝5.7，8.6Hz)，6.63(1H，ddd，J＝2.7，8.4，8.4Hz)，5.30(1H，s)，3.83(2H，t，J＝6.4Hz)，2.80(2H，t，J＝6.4Hz)。
Step 32- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylvalerate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-5-fluoroanilino) phenyl ] ethanol (step 2) and valeryl chloride.
1H-NMR(CDCl3)57.67(1H，dd，J＝4.8，8.8Hz)，7.44(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.1Hz)，7.04-6.95(1H，m)，6.76(1H，dd，J＝2.6，8.8Hz)，4.38(2H，t，J＝6.8Hz)，3.07(2H，t，J＝6.8Hz)，2.74(2H，t，J＝7.5Hz)，2.33(2H，t，J＝7.7Hz)，1.81-1.55(4H，m)，1.42-1.25(4H，m)，6.91(3H，t，J＝7.3Hz)，0.87(3H，t，J＝7.3Hz)。
Step 42- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethyl valerate (step 3).
1H-NMR(CDCl3)δ7.67(1H，dd，J＝4.8，88Hz)，7.46(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.3Hz)，6.99(1H，ddd，J＝2.4，9.0，9.5Hz)，4.10-3.85(2H，m)，3.01(2H，t，J＝6.4Hz)，2.74(2H，t，J＝7.7Hz)，1.84-1.69(2H，m)，1.41-1.27(2H，m)，0.87(3H，t，J＝7.3Hz)。
Step 52- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 26 step 5 from 2- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 337(M+)；1H-NMR(CDCl3)δ：7.68(1H，dd，J＝4.8，8.8Hz)，7.45(2H，d，J＝8.1Hz)，7.30(2H，d，J＝8.1Hz)，7.04-6.94(1H，m)，6.77(1H，dd，J＝2.4，8.6Hz)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝6.8Hz)，2.74(2H，t，J＝7.7Hz)，1.86-1.69(2H，m)，1.41-1.2(2H，m)，0.86(3H，t，J＝7.3Hz)。
Step 62- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ7.67(1H，dd，J＝4.8，8.8Hz)，7.42(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.2Hz)，7.05-6.95(1H，m)，6.78(1H，dd，J＝2.6，8.6Hz)，3.08(2H，t，J＝7.1Hz)，2.88(2H，t，J＝6.8Hz)，2.75(2H，t，J＝7.5Hz)，1.82-1.69(2H，m)，1.41-1.24(2H，m)，0.87(3H，t，J＝7.3Hz)。
Step 72-butyl-6-fluoro-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonylamino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-butyl-6-fluoro-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.4Hz)，7.68(1H，dd，J＝4.6，8.8Hz)，7.38(2H，d，J＝8.4Hz)，7.32-7.24(4H，m)，7.00(1H，ddd，J＝2.4，8.8，11.2Hz)，6.75(1H，dd，J＝2.4，8.6Hz)，3.64-3.54(2H，m)，2.94(2H，t，J＝7.0Hz)，2.74(2H，d，J＝7.5Hz)，1.80-1.65(2H，m)，1.40-1.20(2H，m)，0.84(3H，t，J＝7.3Hz)。
Example 69
2-butyl-6-fluoro-1- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-butyl-6-fluoro-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole (example 69).
1H-NMR(DMSO-d6)δ7.70-7.57(3H，m)，7.39(4H，br)，7.14(2H，d，J＝8.0Hz)，7.11-7.02(1H，m)，8.85(1H，dd，j＝2.4，9.2Hz)，3.48-3.34(2H，m)，3.17(2H，br)，2.80-2.65(4H，m)，2.28(3H，s)，1.72-1.55(2H，m)，1.35-1.20(2H，m)，0.80(3H，t，J＝7.1Hz)；IR(KBr)Vmax3387，2872，1601，1516，1479，1400，1130，1086cm-1.
Example 70
2-ethyl-6-fluoro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-5-fluoroanilino) phenyl ] ethanol (example 68, step 2) and propionyl chloride.
MS(EI)m/z 340(M+)；1H-NMR(CDCl3)δ7.67(1H，dd，J＝4.8，8.8Hz)，7.43(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，6.99(1H，ddd，J＝2.5，8.8，9.5Hz)，6.77(1H，dd，J＝2.5，8.8Hz)，4.38(2H，t，J＝6.6Hz)，3.07(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.4Hz)，2.35(2H，q，J＝7.4Hz)，1.35(3H，t，J＝7.4Hz)，1.14(3H，t，J＝7.4Hz)。
Step 22- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 1).
1H-NMR(CDCl3) δ: 7.67(1H, dd, J ═ 4.8, 8.8Hz), 7.45(2H, d, J ═ 8.4Hz), 7.29(2H, d, J ═ 8.4Hz), 6.99(1H, ddd, J ═ 2.5, 8.8, 9.5 hr z), 6.78(1H, dd, J ═ 2.5, 8.8Hz), 3.99(2H, t, J ═ 6.6Hz), 3.00(2H, t, J ═ 6.6Hz), 2.77(2H, q, J ═ 7.5Hz), 1.35(3H, t, J ═ 7.5 Hz).
Step 36-fluoro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 2).
MS(EI)m/z 302(M+)。
Step 42- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-fluoro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole (step 3).
MS(EI)m/z 309(M+)；1H-NMR(CDCl3)δ：7.68(1H，dd，J＝4.8，8.8Hz)，7.44(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，6.99(1H，ddd，J＝2.5，8.8，9.6Hz)，6.77(1H，dd，J＝2.5，8.8Hz)，3.62(2H，t，J＝6.9Hz)，3.02(2H，t，J＝6.9Hz)，2.77(2H，q，J＝7.4Hz)，1.34(3H，t，J＝7.4Hz)
Step 52- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 4).
1H-NMR(CDCl3)δ：7.68(1H，dd，J＝4.8，8.8Hz)，7.43(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，6.98(1H，ddd，J＝2.4，8.8，8.8Hz)，6.82(1H，dd，J＝2.4，8，8Hz)，3.37(2H，br.s)，3.18(2H，t，J＝7.1Hz)，3.01(2H，t，J＝7.1Hz)，2.76(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)。
Step 62-Ethyl-6-fluoro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-fluoro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 5).
1H-NMR(CDCl3)δ7.73(2H，d，J＝8.4Hz)，7.68(1H，dd，J＝8.7，4.9Hz)，7.37(2H，d，J＝8.4Hz)，7.32-7.23(4H，m)，7.00(1H，ddd，J＝9.5，8.7，2.5Hz)，6.79-6.69(2H，m)，3.63-3.53(2H，m)，2.94(2H，t，J＝7.5Hz)，2.76(2H，q，J＝7.5Hz)，2.40(3H，s)，1.32(3H，t，J＝7.5Hz)。
Example 71
5-methoxy-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (4-methoxy-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-5-methoxynitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.33(1H，br.s)，7.63(1H，d，J＝3.0Hz)，7.17-7.27(5H，m)，7.04-7.08(1H，m)，3.88(2H，br.s)，3.82(3H，s)，2.88(2H，t，J＝6.6Hz)。
Step 22- [4- { 2-amino-4-methoxyanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [4- (4-methoxy-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.03(2H，d，J＝8.6Hz)，6.98(1H，d，J＝8.4Hz)，6.59(2H，d，J＝8.6Hz)，6.28-6.36(2H，m)，3.77-3.85(5H，m)，2.76(2H，t，J＝6.6Hz)。
Step 32- [4- (2-Ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4-methoxyanilino) phenyl ] ethanol (step 2).
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.0Hz)，7.12-7.29(3H，m)，6.97(1H，d，J＝8.8Hz)，6.82(1H，dd，J＝2.4Hz，8.8Hz)，4.37(2H，t，J＝6.7Hz)，3.86(3H，s)，3.05(2H，t，J＝6.7Hz)，2.77(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)，1.14(3H，t，J＝7.5Hz)。
Step 42- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.2Hz)，7.27-7.30(3H，m)，6.98(1H，d，J＝8.8Hz)，6.82(1H，dd，J＝2.3Hz，8.8Hz)，3.98(2H，t，J＝6.5Hz)，3.86(3H，s)，2.99(2H，t，J＝6.5Hz)，2.77(2H，q，J＝7.6Hz)，1.33(3H，t，J＝7.6Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-methoxy-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.2Hz)，7.26-7.33(3H，m)，6.99(1H，d，J＝8.8Hz)，6.82(1H，dd，J＝2.5Hz，8.8Hz)，3.86(3H，s)，3.81(2H，t，J＝7.2Hz)，3.18(2H，t，J＝7.2Hz)，2.78(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 61- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl ether
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-methoxy-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.4Hz)，7.27-7.32(3H，m)，6.98(1H，d，J＝8.8Hz)，6.82(1H，dd，J＝2.3Hz，8.8Hz)，3.87(3H，s)，3.61(2H，t，J＝6.9Hz)，3.01(2H，t，J＝6.9Hz)，2.76(2H，q，J＝7.7Hz)，1.34(3H，t，J＝7.7Hz)。
Step 72- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl ether (step 6).
1H-NMR(CDCl3)δ：7.39(2H，d，J＝8.2Hz)，7.26-7.30(3H，m)，6.99(1H，d，J＝8.7Hz)，6.82(1H，dd，J＝2.3Hz，8.7Hz)，3.86(3H，s)，3.07(2H，t，J＝6.9Hz)，2.84(2H，t，J＝6.9Hz)，2.77(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 85-methoxy-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
1H-NMR(CDCl3)δ：7.74(2H，d，J＝8.2Hz)，7.23-7.34(7H，m)，6.97(1H，d，J＝8.7Hz)，6.82(1H，dd，J＝1.8Hz，8.7Hz)，6.67(1H，br.s)，3.86(3H，s)，3.57(2H，t，J＝6.4Hz)，2.92(2H，t，6.4Hz)，2.75(2H，q，J＝7.6Hz)，2.40(3H，s)，1.31(3H，t，J＝7.6Hz)。
Example 72
5-methoxy-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 5-methoxy-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 72).
mp 163-175℃；
1H-NMR(DMSO-d6)δ7.60(2H，d，J＝7.5Hz)，7.34-7.41(4H，m)，7.12-7.18(3H，m)，6.97(1H，d，J＝8.7Hz)，6.78(1H，d，J＝8.7Hz)，3.78(3H，s)，2.66-2.76(4H，m)，2.50(2H，br.s)，2.78(3H，s)，1.22(3H，t，J＝7.6Hz)；IR(KBr)Vmax，3363，2833，1596，1404，1128，1085，1026，950cm-1。
Example 73
2- [4- (2-Ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 1 from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl ] ethanol (example 71, step 4).
mp 95-98℃；
MS(ESI)m/z 494(M+H)+；
1H-NMR(CDCl3)δ：7.93(2H，d，J＝8.2Hz)，7.23-7.30(3H，m)，7.16(2H，d，J＝8.2Hz)，7.06(2H，d，J＝8.3Hz)，6.92(1H，d，J＝8.8Hz)，6.81(1H，dd，J＝2.2Hz，8.6Hz)，4.33(2H，t，J＝6.3Hz)，3.84(3H，s)，2.93(2H，t，J＝6.3Hz)，2.68(2H，q，J＝7.5Hz)，2.37(3H，s)，1.22(3H，t，J＝7.5Hz)；IR(KBr)Vmax1743，1596，1517，1487，1444，1278，1159，1074，813cm-1。
Example 74
2-Ethyl-6-methoxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (5-methoxy-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-4-methoxynitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ9.74(1H，br.s)，8.18(1H，d，J＝9.5Hz)，7.30(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，6.55(1H，d，J＝2.8Hz)，6.34(1H，dd，J＝9.5，2.8Hz)，3.90(2H，m)，3.74(3H，s)，2.90(3H，t，J＝6.6Hz)。
Step 22- [ (2-amino-5-methoxyanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (5-methoxy-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.09(2H，d，J＝8.4Hz)，6.80(2H，d，J＝8.4Hz)，6.76-6.73(2H，m)，6.54(1H，dd，J＝8.6，2.8Hz)，3.81(2H，t，J＝6.6Hz)，3.71(3H，s)，2.79(2H，t，J＝6.6Hz)。
Step 32- [4- (2-Ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-5-methoxyanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
MS(EI)m/z 352(M+)。
Step 42- [4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.63(1H，d，J＝8.8Hz)，7.45(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，6.89(1H，dd，J＝8.8，2.6Hz)，6.56(1H，d，J＝2.6Hz)，4.00(2H，t，J＝6.6Hz)，3.75(3H，s)，3.01(2H，t，J＝6.6Hz)，2.74(2H，q，J＝7.5Hz)，1.32(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described for example 26 step 4 from 2- (4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl) ethanol (step 4).
TLC Rf was 0.50 (1: 1 with hexane/ethyl acetate).
Step 62- [4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl) ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ7.65(1H，d，J＝8.8Hz)，7.41(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，6.89(1H，dd，J＝8.8，2.4Hz)，6.56(1H，d，J＝2.4Hz)，3.76(3H，s)，3.09(2H，t，J＝7.0Hz)，2.89(2H，t，J＝7.0Hz)，2.75(2H，q，J＝7.5Hz)，1.32(3H，t，J＝7.5Hz)。
Step 72-Ethyl-6-methoxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-6-methoxy-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3) δ: 7.75(2H, d, J ═ 8.2Hz), 7.62(1H, d, J ═ 8.7Hz), 7.35-7.23(6H, m), 6.89(1H, dd, J ═ 8.7, 2.5Hz), 6.66(1H, m), 6.55(1H, d, J ═ 2.5 hr z), 3.72(3H, s), 3.59-3.57(2H, m), 2.93(2H, t, J ═ 7.0Hz), 2.73(2H, q, J ═ 7.6Hz), 1.29(3H, t, J ═ 7.6 Hz).
Example 75
2-Ethyl-6-methoxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-6-methoxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 74).
1H-NMR(DMSO-d6)δ7.59(2H，d，J＝8.3Hz)，7.50(1H，d，J＝8.8Hz)，7.41-7.35(4H，m)，7.12(2H，d，J＝8.3Hz)，6.80(1H，dd，J＝8.8，2.4Hz)，6.53(1H，d，J＝2.4Hz)，3.67(3H，s)，3.15(2H，m)，2.73-2.62(4H，m)，1.19(3H，t，J＝7.7Hz)；IR(KBr)Vmax，1595，1516，1485，1454，1400，1157，1128，1086cm-1
Example 76
5-trifluoromethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-1H-benzimidazole
Step 12- [ 2-nitro-4- (trifluoromethyl) anilino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2-chloro-5-trifluoromethylnitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.68(1H，br.s)，8.50(1H，s)，7.51(1H，dd，J＝2.2Hz，9.2Hz)，7.33(2H，d，J＝8.2Hz)，7.19-7.26(3H，m)，3.92(2H，t，J＝6.3Hz)，2.92(2H，t，J＝6.3Hz)。
Step 22- [ 2-amino-4- (trifluoromethyl) anilino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 26, step 2, from 2- [ 2-nitro-4- (trifluoromethyl) anilino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.10-7.16(3H，m)，6.97(2H，d，J＝8.2Hz)，6.82(2H，d，J＝8.2Hz)，3.82(2H，t，J＝6.6Hz)，2.79(2H，t，J＝6.6Hz)。
Step 32- {4- [ 2-Ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [ 2-amino-4- (trifluoromethyl) anilino ] phenyl } ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：8.05(1H，s)，7.42-7.47(2H，m)，7.27-7.31(2H，m)，7.13(2H，d，＝8.4Hz)，4.39(2H，t，J＝7.0Hz)，3.08(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.6Hz)，2.36(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)，1.14(3H，t，J＝7.6Hz)。
Step 42- {4- [ 2-Ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- {4- [ 2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.05(1H，s)，7.49(1H，d，J＝8.4Hz)，7.44(2H，d，J＝8.6Hz)，7.30(2H，d，J＝8.6Hz)，7.16(1H，d，J＝8.4Hz)，4.01(2H，t，J＝6.4Hz)，3.03(2H，t，J＝6.4Hz)，2.80(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 52- {4- [ 2-Ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- {4- [ 2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 4).
1H-NMR(CDCl3)δ：8.05(1H，s)，7.22-7.48(5H，m)，7.15(1H，d，J＝8.4Hz)，3.62(2H，t，J＝6.8Hz)，3.02(2H，t，J＝6.8Hz)，2.80(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 62- {4- [ 2-Ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine
The title compound was prepared from 2- {4- [ 2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl azide (step 5) according to the procedure described in example 1, step 9.
1H-NMR(CDCl3)δ：8.05(1H，s)，7.44(3H，d，J＝8.8Hz)，7.29(2H，d，J＝8.8Hz)，7.16(1H，d，J＝8.6Hz)，3.09(2H，t，J＝6.8Hz)，2.89(2H，t，J＝6.8Hz)，2.81(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 75-trifluoromethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [ 2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine (step 6).
MS(ESI)m/z 533(M+H)+；1H-NMR(CDCl3)δ：8.03(1H，s)，7.80(2H，d，J＝8.2Hz)，7.73(2H，d，J＝8.2Hz)，7.38-7.43(3H，m)，7.26-7.29(2H，m)，7.13(1H，d，J＝8.4Hz)，6.70(1H，br.s)，3.57(2H，t，6.7Hz)，2.94(2H，t，J＝6.7Hz)，2.80(2H，q，J＝7.6Hz)，2.43(3H，s)，1.34(3H，t，J＝7.6Hz)。
Example 77
5-trifluoromethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 5-trifluoromethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 76).
1H-NMR(DMSO-d6)δ8.02(1H，s)，7.61-7.66(4H，m)，7.48-7.51(1H，m)，7.24-7.28(3H，m)，7.14(2H，d，7.9Hz)，3.09(2H，br.s)，2.60-2.83(4H，m)，2.22(3H，s)，1.13(3H，t，J＝7.5Hz)。
Example 78
5-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 11- {4- [4- (2-hydroxyethyl) anilino ] -3-nitrophenyl } ethanone (ethanone)
A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger, H.; Schreiber, O.LiebigsAnn. chem., 1961, 641, 81., 2g, 10mmol), 4-aminophenylethyl alcohol (1.64g, 12mmol) and sodium bicarbonate (1g, 12mmol) in DMF (60mL) was heated at 150 ℃ for 3 hours. After cooling, the mixture was poured into water (100mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous sodium hydroxide (100mL) and brine (100mL), then dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) gave 1.36g (45%) of the title compound as an orange oil:
1H-NMR(CDCl3)δ：9.83(1H，br.s)，8.20(1H，d，J＝2.1Hz)，7.94(1H，dd，J＝2.1Hz，9.3Hz)，7.34(2H，d，J＝8.2Hz)，7.24(2H，d，J＝8.2Hz)，7.16(1H，d，J＝9.3Hz)，3.91(2H，t，J＝6.6Hz)，2.92(2H，t，J＝6.6Hz)，2.57(3H，s)。
step 21- { 3-amino-4- [4- (2-hydroxyethyl) anilino ] phenyl } ethanone
The title compound was prepared from 1- {4- [4- (2-hydroxyethyl) anilino ] -3-nitrophenyl } ethanone (step 1) according to the procedure described in example 1, step 4.
1H-NMR(CDCl3)δ：7.41(1H，d，J＝2.0Hz)，7.37(1H，dd，J＝2.0Hz，8.2Hz)，7.11-7.17(3H，m)，6.94(2H，d，J＝8.2Hz)，5.72(1H，br.s)，3.85(2H，t，J＝6.6Hz)，3.65(2H，br.s)，2.83(2H，t，J＝6.6Hz)，2.52(3H，s)。
Step 32-4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl) ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 1- { 3-amino-4- [4- (2-hydroxyethyl) anilino ] phenyl } ethanone (step 2) and propionyl chloride.
TLC Rf 0.4 (hexane/ethyl acetate 1: 1).
Step 41- { 2-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } ethyl propionate
The title compound was prepared according to the procedure described in example 1, step 6, from 2-4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl) ethylpropionate (step 3).
1H-NMR(CDCl3)δ8.39(1H，d，J＝1.2Hz)，7.89(1H，dd，J＝1.2Hz，8.6Hz)，7.48(2H，d，J＝7.4Hz)，7.30(2H，d，J＝7.4Hz)，7.13(1H，d，J＝8.6Hz)，4.00(2H，t，J＝6.4Hz)，3.02(2H，t，J＝6.4Hz)，2.80(2H，q，J＝7.6Hz)，2.68(3H，s)，1.38(2H，t，J＝7.6Hz)。
Step 51- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone
The title compound was prepared according to the procedure described in example 1, step 7, from 1- { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } ethanone (step 4).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.2Hz)，7.90(1H，dd，J＝1.2Hz，8.4Hz)，7.47(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.13(1H，d，J＝8.4Hz)，3.83(2H，t，J＝7.3Hz)，3.21(2H，t，J＝7.3Hz)，2.82(2H，q，J＝7.6Hz)，2.68(3H，s)，1.38(3H，t，J＝7.6Hz)。
Step 61- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone
The title compound was prepared according to the procedure described in example 1, step 8, from 1- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone (step 5).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.5Hz)，7.90(1H，dd，J＝1.5Hz，8.6Hz)，7.46(2H，d，J＝8.3Hz)，7.12(2H，d，J＝8.3Hz)，7.02(1H，d，J＝8.6Hz)，3.63(2H，t，J＝6.9Hz)，3.03(2H，t，J＝6.9Hz)，2.80(2H，q，J＝7.4Hz)，2.67(3H，s)，1.37(3H，t，J＝7.4Hz)。
Step 71- {1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone
The title compound was prepared according to the procedure described in example 37, step 7, from 1- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone (step 6).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.7Hz)，7.90(1H，dd，J＝1.7Hz，8.6Hz)，7.43(2H，d，J＝8.2Hz)，7.30(2H，d，J＝8.2Hz)，7.13(1H，d，J＝8.6Hz)，3.08(2H，t，J＝6.7Hz)，2.88(2H，t，J＝6.7Hz)，2.80(2H，q，J＝7.6Hz)，2.68(3H，s)，1.38(3H，t，J＝7.6Hz)。
Step 85-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 1- {1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } ethanone (step 7).
MS(ESI)m/z 505(M+H)+，1H-NMR(CDCl3)δ8.40(1H，d，J＝1.1Hz)，7.88(1H，dd，J＝1.1Hz，8.6Hz)，7.73(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.27-7.31(4H，m)，7.10(1H，d，J＝8.6Hz)，6.74(1H，br.s)，3.59(2H，t，J＝6.9Hz)，2.95(2H，t，J＝6.9Hz)，2.80(2H，q，J＝7.6Hz)，2.67(3H，s)，2.40(3H，s)，1.36(3H，t，J＝7.6Hz)。
Example 79
5-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 5-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 78).
mp 155-160℃；
1H-NMR(DMSO-d6)δ8.32(1H，d，J＝1.6Hz)，7.81(1H，dd，J＝1.6Hz，8.6Hz)，7.62(2H，d，J＝8.1Hz)，7.42(4H，s)，7.12-7.17(3H，m)，3.18(2H，br.s)，2.71-2.79(4H，m)，2.63(3H，s)，2.27(3H，s)，1.25(3H，t，J＝7.4Hz)；IR(KBr)Vmax，3373，1676，1604，1519，1294，1130，1085，885，813cm-1
Example 80
2-Ethyl-5-methylsulfonyl-1- (4- {2- [ ({ [ (4-
Tosyl ] amino) carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- {4- [4- (methylsulfonyl) -2-nitroanilino ] phenyl } ethanol
2-chloro-5-methylsulfonylnitrobenzene (Kavalek, J.; et al, Collection, Czech, chem. Commun, 1971, 36, 209., 2g, 8.5mmol), 4-aminophenylethyl alcohol (1.4g, 10.2mmol) and Na were reacted at 100 deg.C2CO3A mixture of (1.4g, 12.7mmol) in ethanol was stirred for 16 h. Insoluble matter was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 4) to give 960mg (34%) of the title compound as a yellow solid:
1H-NMR(CDCl3)δ：9.84(1H，br.s)，8.82(1H，d，J＝2.1Hz)，7.79(1H，dd，J＝2.1Hz，9.1Hz)，7.36(2H，d，J＝8.4Hz)，7.22-7.38(3H，m)，3.94(2H，br.s)，3.07(3H，s)，2.93(2H，t，J＝6.6Hz)。
Step 22- {4- [ 2-amino-4- (methylsulfonyl) anilino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [4- (methylsulfonyl) -2-nitroanilino ] phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.31(1H，s)，7.28(1H，s)，7.16-7.21(3H，m)，6.96(2H，d，J＝8.5Hz)，5.56(1H，br.s)，3.86(2H，t，J＝6.4Hz)，3.76(2H，br.s)，3.03(3H，s)，2.84(2H，t，J＝6.4Hz)。
Step 32- {4- [ 2-Ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethylpropionate
The title compound was prepared from 2- {4- [ 2-amino-4- (methylsulfonyl) anilino ] phenyl } ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
TLC Rf 0.8 (dichloromethane/methanol 10: 1).
Step 42- {4- [ 2-Ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- {4- [ 2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.38(1H，d，J＝1.4Hz)，7.77(1H，dd，J＝1.4Hz，8.6Hz)，7.50(2H，d，J＝8.4Hz)，7.24-7.32(2H，m)，7.22(1H，d，J＝8.6Hz)，4.01(t，J＝6.6Hz)，3.08(3H，s)，3.02(2H，t，J＝6.6Hz)，2.82(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl (methylsulfonyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [ 2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 4).
1H-NMR(CDCl3)δ：8.38(1H，d，J＝1.6Hz)，7.78(1H，d，J＝1.6Hz，8.6Hz)，7.49(2H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.23(1H，d，J＝8.6Hz)，3.84(2H，t，J＝6.9Hz)，3.22(2H，t，J＝6.9Hz)，3.08(3H，s)，2.82(2H，q，J＝7.5Hz)，1.38(3H，t，J＝7.5Hz)。
Step 61- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl sulfone
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-5- (methylsulfonyl) -1H-benzimidazole (step 5).
1H-NMR(CDCl3) δ: 8.38(1H, d, J ═ 1.5Hz), 7.78(1H, dd, J ═ 1.5 hr z, 8.6Hz), 7.49(2H, d, J ═ 8.6Hz), and8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.21(1H，d，J＝8.6Hz)，3.64(2H，t，J＝6.9Hz)，3.08(3H，s)，3.03(2H，t，J＝6.9Hz)，2.83(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
step 72- {4- [ 2-Ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl sulfone (step 6).
1H-NMR(CDCl3)δ：8.38(1H，d，J＝1.7Hz)，7.77(1H，dd，J＝1.7Hz，8.6Hz)，7.46(2H，d，J＝8.4Hz)，7.21-7.30(3H，m)，3.03-3.08(5H，m)，2.89(2H，t，J＝6.7Hz)，2.82(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 82-Ethyl-5- (methylsulfonyl) -1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [ 2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine (step 7).
1H-NMR(CDCl3)δ8.37(1H，d，J＝1.6Hz)，7.75(1H，dd，J＝1.6Hz，8.6Hz)，7.74(2H，d，J＝8.4Hz)，7.43(2H，d，J＝8.2Hz)，7.27-7.32(4H，m)，7.18(1H，d，J＝8.6Hz)，6.70(1H，br.s)，3.59(2H，t，J＝6.8Hz)，3.08(3H，s)，2.96(2H，t.J＝6.8Hz)，2.82(2H，q，J＝7.6Hz)，2.41(3H，s)，1.35(4H，t，J＝7.6Hz)。
Example 81
2-Ethyl-5-methylsulfonyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5- (methylsulfonyl) -1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 80).
mp 171-178℃；
1H-NMR(DMSO-d6)δ8.08(1H，br.s)，7.51-7.62(3H，m)，7.32(4H，s)，7.16(1H，d，J＝8.6Hz)，7.03(2H，d，J＝7.3Hz)，3.09-3.25(7H，m)，2.63-2.66(2H，m)，2.16(3H，s)，1.13(3H，t，J＝7.3Hz)；IR(KBr)Vmax，3386，1604，1519，1396，1299，1128，1085，962，887cm-1。
Example 82
5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (4-cyano-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 4-chloro-3-nitrobenzonitrile and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.80(1H，br.s)，8.54(1H，d，J＝2.0Hz)，7.50(1H，dd，J＝9.1，2.0Hz)，7.36(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，7.16(1H，d，J＝9.1Hz)，3.94-3.91(2H，m)，2.93(2H，t，J＝6.6Hz)，1.81(1H，m)。
Step 22- [ (2-amino-4-cyanoanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (4-cyano-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.18-7.10(3H，m)，7.01-6.95(4H，m)，6.09(1H，m)，3.97(2H，br.s)，3.83-3.82(2H，m)，2.83(2H，t，J＝6.8Hz)，2.31(1H，m)
Step 32- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [ (2-amino-4-cyanoanilino) phenyl ] ethanol (step 2).
MS(EI)m/z 347(M+)。
Step 42- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：8.09(1H，s)，7.50-7.43(3H，m)，7.32-7.28(2H，m)，7.15(1H，d，J＝8.2Hz)，4.00(2H，q，H＝6.4Hz)，3.01(2H，t，J＝6.4Hz)，2.81(2H，t，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 52- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
TLC Rf 0.83 (dichloromethane/methanol 10: 1).
Step 62- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：8.09(1H，s)，7.47-7.42(3H，m)，7.29-7.26(2H，m)，7.15(1H，d，J＝8.4Hz)，3.09(2H，t，J＝6.8Hz)，2.91(2H，t，J＝6.8Hz)，2.81(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 75-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) ethylamine (step 6).
1H-NMR(CDCl3)δ：8.05(1H，d，J＝0.9Hz)，7.75(2H，d，J＝8.4Hz)，7.43-7.40(3H，m)，7.30-7.26(4H，m)，7.12(1H，d，J＝8.4Hz)，6.74(1H，m)，3.60-3.58(2H，m)，2.96(2H，t，J＝7.0Hz)，2.81(2H，q，J＝7.5Hz)，2.41(3H，s)，1.34(3H，t，J＝7.5Hz)。
Example 83
5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 82).
1H-NMR(DMSO-d6)δ8.19(1H，d，J＝1.5Hz)，7.59(2H，d，J＝7.9Hz)，7.54(1H，dd，J＝8.4，1.5Hz)，7.41(4H，s)，7.23(1H，d，J＝8.4Hz)，7.11(2H，d，J＝7.9Hz)，3.14(2H，m)，2.78-2.70(4H，m)，2.26(3H，s)，1.24(3H，t，J＝7.4Hz)。
Example 84
2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
Step 12-Ethyl-1- (4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide
To a mixture of 2- [4- (5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 82 step 4, 200mg, 0.68mmol), DMSO (0.06mL, 0.82mmol) and methanol (10mL) was added 30% aqueous hydroperoxide (0.12mL, 1.0mmol) and 0.2M aqueous sodium hydroxide (0.06 mL). The mixture was stirred at 50 ℃ for 4 hours. Then, it was cooled, and the mixture was poured into water (50mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous sodium hydroxide (50mL) and brine (50mL), then dried (sodium sulfate) and concentrated to give the title compound as a light yellow solid:
1H-NMR(CDCl3)δ：8.23(1H，d，J＝1.1Hz)，7.96(1H，br.s)，7.76(1H，dd，J＝1.1Hz，8.4Hz)，7.42-7.51(4H，m)，7.25(1H，br.s)，7.09(1H，d，J＝8.4Hz)，3.70(2H，t，J＝6.6Hz)，2.85(2H，t，J＝6.9Hz)，2.76(2H，q，J＝7.4Hz)，1.24(3H，t，J＝7.4Hz)。
step 21- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 7, from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide (step 1).
1H-NMR(CDCl3) δ: 8.17(1H, d, J ═ 1.7Hz), 7.79(1H, dd, J ═ 1.7Hz, 8.5Hz), 7.46(2H, d, J ═ 8.3Hz), 7.33(2H, d, J ═ 8.3Hz), 7.15(1H, d, J ═ 8.5 hr z), 3.83(2H, t, J ═ 7.0Hz), 3.21(2H, t, J ═ 7.0Hz), 2.82(2H, q, J ═ 7.6Hz), 1.37(3H, t, J ═ 7.6 Hz).
Step 31- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide (step 2).
1H-NMR(CDCl3)δ：8.17(1H，d，J＝1.5Hz)，7.78(1H，dd，J＝1.5Hz，8.4Hz)，7.46(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，7.13(1H，d，J＝8.4Hz)，3.62(2H，t，J＝6.8Hz)，3.03(2H，t，J＝6.8Hz)，2.81(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 41- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide (step 3).
1H-NMR(CDCl3)δ8.21(1H，d，J＝1.5Hz)，7.79(1H，dd，J＝1.5Hz，8.4Hz)，7.43(2H，d，J＝8.2Hz)，7.28-7.31(2H，m)，7.13(1H，d，J＝8.4Hz)，3.05(2H，t，J＝6.7Hz)，2.88(2H，t，J＝6.7Hz)，2.81(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 52-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide (step 4).
MS(ESI)m/z 506(M+H)+，1H-NMR(CD3OD)δ8.13(1H，s)，7.65-7.73(3H，m)，7.32(2H，d，J＝8.2Hz)，7.16-7.21(4H，m)，7.00(1H，d，J＝8.6Hz)，3.31(2H，t，J＝6.9Hz)，2.75(2H，t，J＝6.9Hz)，2.69(2H，q，J＝7.6Hz)，2.21(3H，s)，C1-48(3H，t，J＝7.6Hz)。
Example 85
6-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 13- [4- (2-hydroxyethyl) anilino ] -4-nitrobenzonitrile
The title compound was prepared according to the procedure described in example 1, step 3, from 3-chloro-4-nitrobenzonitrile (Tsuji, K chem. pharm. Bull.1992, 40, 2399) and 4-aminophenylethyl alcohol.
MS(EI)m/z 383(M+)。
Step 23- [4- (2-chloroethyl) anilino ] -4-nitrobenzonitrile
The title compound was prepared from 3- [4- (2-hydroxyethyl) anilino ] -4-nitrobenzonitrile (step 1) according to the procedure described in example 1, step 7.
1H-NMR(CDCl3)δ：9.46(1H，br.s)，8.29(1H，d，J＝8.8Hz)，7.42(1H，d，J＝1.7Hz)，7.35(2H，d，J＝8.3Hz)，7.22(2H，d，J＝8.3Hz)，6.97(1H，dd，J＝8.8，1.7Hz)，3.77(2H，t，J＝7.2Hz)，3.13(2H，t，J＝7.
Step 34-amino-3- [4- (2-chloroethyl) anilino ] benzonitrile
The title compound was prepared from 3- [4- (2-chloroethyl) anilino ] -4-nitrobenzonitrile (step 2) according to the procedure described in example 1, step 4.
MS(EI)m/z 383(M+)。
Step 41- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-6-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 5, from 4-amino-3- [4- (2-chloroethyl) anilino ] benzonitrile (step 3) and propionyl chloride.
MS(EI)m/z 309(M+)；1H-NMR(CDCl3)δ：7.82(1H，d，J＝8.6Hz)，7.53(1H，dd，J＝8.6，2.0Hz)，7.48(2H，d，J＝8.3Hz)，7.42(1H，d，J＝2.0Hz)，7.31(2H，d，J＝8.3Hz)，3.84(2H，t，J＝7.0Hz)，3.21(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.4Hz)，1.39(3H，t，J＝7.4Hz)。
Step 52- [4- (6-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-6-carbonitrile (step 4).
MS(EI)m/z 316(M+)；1H-NMR(CDCl3)δ：7.83(1H，d，J＝8.4Hz)，7.54(1H，dd，J＝8.4，2.0Hz)，7.50(2H，d，J＝8.3Hz)，7.40(1H，d，J＝2.0Hz)，7.30(2H，d，J＝8.3Hz)，3.64(2H，t，J＝6.5Hz)，3.04(2H，t，J＝6.5Hz)，2.83(2H，q，J＝7.3Hz)，1.37(3H，t，J＝7.3Hz)。
Step 62- [4- (6-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(DMSO-d6)δ8.11(2H，br.s)，7.87(1H，d，J＝8.4Hz)，7.64(1H，dd，J＝8.4，2.0Hz)，7.60-7.53(5H，m)，3.20-3.02(4H，m)，2.79(2H，q，J＝7.4Hz)，1.28(3H，t，J＝7.4Hz)。
Step 76-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.83(1H，d，J＝8.4Hz)，7.74(2H，d，J＝8.4Hz)，7.53(1H，dd，J＝8.4，1.5Hz)，7.43(2H，d，J＝8.4Hz)，7.39(1H，d，J＝1.5Hz)，7.33(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，6.75(1H，br.s)，365-3.54(2H，m)，2.97(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.5Hz)，2.42(3H，s)，1.37(3H，t，J＝7.5Hz)。
Example 86
2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-6-carboxamide
To a solution of 6-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 85, 162mg, 0.33mmol) in 2-methyl-2-propanol (10mL) was added powdered KOH (66mg, 10 mmol). The resulting mixture was heated at reflux for 3 hours. After removal of the solvent, the reaction mixture was partitioned between dichloromethane (50mL) and phosphate buffer (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50mL), dried (sodium sulfate) and concentrated. The residual solid was recrystallized from ethyl acetate to yield 105mg (63%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.79(2H，d，J＝8.4Hz)，7.75(1H，d，J＝8.8Hz)，7.71-7.63(2H，m)，7.35-7.25(4H，m)，7.16(2H，d，J＝8.4Hz)，6.75(2H，br.s)，6.55(1H，br.s)，3.54(2H，t，J＝6.4Hz)，2.88(2H，t，J＝6.4Hz)，2.79(2H，q，J＝7.5Hz)，2.40(3H，s)，1.34(3H，t，J＝7.5Hz)。
example 87
5- [ (tert-butylamino) sulfonyl ] -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 1N- (tert-butyl) -4-chloro-3-nitrobenzenesulfonamide
To a mixture of tert-butylamine (5.1g, 70mmol) in dichloromethane (200mL) was added dropwise a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (179g, 70mmol) in dichloromethane (100mL) at room temperature over 30 minutes, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (100mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (50mL) and brine (20mL), dried (sodium sulfate), and concentrated to give 21.3g (quant.) of the title compound as a yellow solid:
1H-NMR(CDCl3)δ：8.38(1H，d，J＝2.0Hz)，8.02(1H，dd，J＝2.0，8.6Hz)，7.70(1H，d，J＝8.6Hz)，4.95(1H，br.s)，1.28(9H，s)。
Step 2N- (tert-butyl) -4- [4- (2-hydroxyethyl) anilino ] -3-nitrobenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 3, from N- (tert-butyl) -4-chloro-3-nitrobenzenesulfonamide (step 1) and 4-aminophenylethyl alcohol.
MS(EI)m/z 393(M+)；1H-NMR(CDCl3) δ: 9.76(1H, br.s), 8.75(1H, d, J ═ 2.0Hz), 7.74(1H, dd, J ═ 2.0, 8.5 hr z), 7.35(2H, d, J ═ 8.3Hz), 7.24(2H, d, J ═ 8.3Hz), 7.17(1H, d, J ═ 8.5Hz), 4.42(1H, br.s), 3.97-3.88(2H, m), 2.94(2H, t, J ═ 7.0Hz), 1.27(9H, s).
Step 3N- (tert-butyl) -4- [4- (2-chloroethyl) anilino ] -3-nitrobenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 7, from N- (tert-butyl) -4- [4- (2-hydroxyethyl) anilino ] -3-nitrobenzenesulfonamide (step 2).
MS(EI)m/z 411(M+)；1H-NMR(CDCl3)δ：9.77(1H，br.s)，8.77(1H，d，J＝2.0Hz)，7.77(1H，dd，J＝2.0，8.4Hz)，7.34(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.18(1H，d，J＝8.4Hz)，4.46(1H，br.s)，3.76(2H，t，J＝6.8Hz)，3.13(2H，t，J＝6.8Hz)，1.28(9H，s)。
Step 43-amino-N- (tert-butyl) -4- [4- (2-chloroethyl) anilino ] benzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 4, from N- (tert-butyl) -4- [4- (2-chloroethyl) anilino ] -3-nitrobenzenesulfonamide (step 3).
1H-NMR(CDCl3)δ：7.31(1H，d，J＝2.0Hz)，7.26(1H，dd，J＝2.0，8.3Hz)，7.15(1H，d，J＝8.3Hz)，7.14(2H，d，J＝8.4Hz)，6.89(2H，d，J＝8.4Hz)，5.49(1H，br.s)，4.64(1H，br.s)，3.77(2H，br.s)，3.69(2H，t，J＝7.4Hz)，3.02(2H，t，J＝7.4Hz)，1.24(9H，s)。
Step 5N- (tert-butyl) -1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 5, from 3-amino-N- (tert-butyl) -4- [4- (2-chloroethyl) anilino ] benzenesulfonamide (step 4) and propionyl chloride.
MS(EI)m/z 419(M+)；1H-NMR(CDCl3)δ8.34(1H，d，J＝2.0Hz)，7.74(1H，dd，J＝2.0，8.3Hz)，7.47(2H，d，J＝8.6Hz)，7.33(2H，d，J＝8.6Hz)，7.16(1H，d，J＝8.3Hz)，4.62(1H，br.s)，3.83(2H，t，J＝7.0Hz)，3.21(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.4Hz)，1.39(3H，t，J＝7.4Hz)，1.24(9H，s)。
Step 61- [4- (2-azidoethyl) phenyl ] -N (tert-butyl) -2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- (tert-butyl) -1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-sulfonamide (step 5).
MS(EI)m/z 426(M+)，1H-NMR(CDCl3)δ：8.33(1H，d，J＝2.0Hz)，7.73(1H，dd，J＝2.0，8.4Hz)，7.48(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，7.14(1H，d，J＝8.4Hz)，4.47(1H，br.s)，3.62(2H，t，J＝7.0Hz)，3.03(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.2Hz)，1.38(3H，t，J＝7.2Hz)1.24(9H，s)。
Step 71- [4- (2-aminoethyl) phenyl ] -N- (tert-butyl) -2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -N- (tert-butyl) -2-ethyl-1H-benzimidazole-5-sulfonamide (step 6).
1H-NMR(CDCl3)δ：8.34(1H，d，J＝1.9Hz)，7.74(1H，dd，J＝1.9，8.3Hz)，7.44(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.15(1H，d，J＝8.3Hz)，4.88(1H，br.s)，3.09(2H，t，J＝7.0Hz)，2.95(2H，t，J＝7.0Hz)，2.83(2H，q，J＝7.4Hz)，1.37(3H，t，J＝7.4Hz)，1.23(9H，s)。
Step 85- [ (tert-butylamino) sulfonyl ] -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -N- (tert-butyl) -2-ethyl-1H-benzimidazole-5-sulfonamide (step 7).
MS(ESI)m/z 598(M+H)+，1H-NMR(CDCl3)δ：8.32(1H，d，J＝1.3Hz)，7.77-7.69(3H，m)，7.41(2H，d，J＝8.3Hz)，7.33-7.25(4H，m)，7.11(1H，d，J＝8.6Hz)，6.65(1H，br.s)，4.59(1H，s)，3.63-3.53(2H，m)，2.95(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.6Hz)，2.41(3H，s)，1.36(3H，t，J＝7.6Hz)1.23(9H，s)。
Example 88
5- (aminosulfonyl) -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
A solution of 5- [ (tert-butylamino) sulfonyl ] -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 87, 330mg, 0.55mmol) in trifluoroacetic acid (10mL) was heated at 80 ℃ for 2H. The mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10: 1) to give 215mg (73%) of the title compound:
MS(ESI)m/z 542(M+H)+ 1H-NMR(CDCl3)δ：8.32(1H，d，J＝1.3Hz)，7.77-7.69(3H，m)，7.41(2H，d，J＝8.3Hz)，7.33-7.25(4H，m)，7.11(1H，d，J＝8.6Hz)，6.65(1H，br.s)，4.59(1H，s)，3.63-3.53(2H，m)，2.95(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.6Hz)，2.41(3H，s)，1.36(3H，t，J＝7.6Hz)1.23(9H，s)。
Example 89
2-Ethyl-1- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -5- [ (methylsulfonyl) amino ] -1H-benzimidazole
Step 12- [4- (2, 4-dinitroanilino) phenyl ] ethanol
The title compound was prepared from 2-chloro-1, 5-dinitrobenzene and 4-aminophenylethyl alcohol following the procedure described in step 3, example 1.
1H-NMR(CDCl3)δ：9.95(1H，s)，9.18(1H，d，J＝2.4Hz)，8.16(1H，dd，J＝2.7，9.7Hz)，7.39(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.1Hz)，7.16(1H，d，J＝9.5Hz)，3.93(2H，dt，J＝5.7，6.2Hz)，2.94(2H，t，J＝6.8Hz)，1.50(1H，t，J＝5.7Hz)。
Step 22- [4- (2-amino-4-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 40, step 2, from 2- [4- (2, 4-dinitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.73-7.67(2H，m)，7.22(2H，d，J＝8.3Hz)，7.11(1H，d，J＝9.3Hz)，7.04(2H，d，J＝8.3Hz)，5.80(1H，s)，3.88(2H，dt，J＝5.7，6.0Hz)，3.69(2H，br.s)，2.87(2H，t，J＝6.4Hz)，C1-48(1H，br)。
Step 32- [4- (2-Ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4-nitroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：8.68(1H，d，J＝2.2Hz)，8.13(1H，dd，J＝2.2，9.0Hz)，7.48(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，7.13(1H，d，J＝8.97Hz)，4.39(2H，t，J＝6.8Hz)，3.09(2H，t，J＝7.0Hz)，2.81(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.5Hz)，1.38(3H，t，J＝7.5Hz)，1.15(3H，q，J＝7.5Hz)。
Step 42- [4- (5-amino-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
To a mixture of 2- [4- (2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethylpropionate (step 3, 1.12g, 3.0mmol) in ethanol/water (v/v, 2: 1, 15mL) at room temperature was added ammonium chloride (80mg, 1.5mmol) and iron powder (840mg, 15 mmol). The mixture was heated at reflux for 4 hours. Filter through a pad of Celite. The filtrate was concentrated and the residue was dissolved in dichloromethane (200mL) and then dried (magnesium sulfate). Removal of the solvent gave 0.84g (83%) of the title compound as a yellow oil:
1H-NMR(CDCl3)δ7.41(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.6Hz)，7.10(1H，d，J＝1.8Hz)，6.89(1H，d，J＝8.4Hz)，6.63(1H，dd，J＝2.2，8.4Hz)，4.37(2H，t，J＝7.0Hz)，3.05 82H，t，J＝7.1Hz)，2.79(2H，q，J＝7.5Hz)，2.35(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.50Hz)，1.14(3H，t，J＝7.7Hz)。
Step 52- (4- { 2-Ethyl-5- [ (methylsulfonyl) amino ] -1-benzimidazol-1-yl } phenyl) ethylpropionate
To a stirred mixture of 2- [4- (5-amino-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate (step 4, 1.18g, 3.50mmol) in dichloromethane (20mL) was added methanesulfonyl chloride (0.40mL, 5.25mmol) and pyridine (0.42mL, 5.25mmol) at room temperature. After stirring for 6 hours, the mixture was poured into 10% aqueous citric acid (100mL) and extracted with ethyl acetate (100 mL). The aqueous layer was made basic with saturated aqueous sodium bicarbonate (100mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100mL) and dried (magnesium sulfate) and concentrated to give 1.28g (88%) of the title compound as a brown amorphous:
1H-NMR(CDCl3)δ：8.47(1H，s)，7.66(1H，d，J＝1.7Hz)，7.50(2H，d，J＝8.4Hz)，7.42(1H，dd，J＝2.0，8.8Hz)，7.41(2H，d，J＝8.4Hz)，7.09(1H，d，J＝8.8Hz)，4.39(2H，t，J＝7.0Hz)，3.09(2H，t，J＝6.8Hz)，3.00(2H，q，J＝7.7Hz)，2.36(2H，q，J＝7.7Hz)，1.42(3H，t，J＝7.7Hz)，1.15(3H，t，J＝7.5Hz)。
step 62-Ethyl (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 6, from 2- (4- { 2-ethyl-5- [ (methylsulfonyl) amino ] -1H-benzimidazol-1-yl } phenyl) ethyl propionate (step 5).
1H-NMR(CDCl3)δ：7.63(1H，d，J＝1.8Hz)，7.46(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.4Hz)，7.18(1H，dd，J＝2.1，8.6Hz)，7.07(1H，d，J＝8.6Hz)，6.68(1H，br)，3.99(2H，t，J＝6.4Hz)，3.01(2H，t，J＝6.8Hz)，2.98(3H，s)，2.79(2H，q，J＝7.4Hz)，1.35(3H，t，J＝7.6Hz)。
Step 7N- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 7, from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } methanesulfonamide (step 6).
1H-NMR(CDCl3)δ：7.74-6.85(7H，m)，3.83(2H，t，J＝7.1Hz)，3.21(2H，t，J＝7.1Hz)，2.98(3H，s)，2.85(2H，q，J＝7.5Hz)，1.38(3H，t，J＝7.5Hz)。
Step 8N- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 7).
1H-NMR(CDCl3)δ：7.64(1H，br)，7.45(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.1Hz)，7.19(1H，dd，J＝1.8，8.8Hz)，7.07(1H，d，J＝8.4Hz)，6.81(1H，s)，3.62(2H，t，J＝6.8Hz)，3.02(2H，t，J＝7.0Hz)，2.98(3H，s)，2.79(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
Step 9N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 9, from N- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 8).
MS(EI)m/z 358(M+)。
Step 10N- {1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 9).
MS(ESI)m/z 556(M+H)；1H-NMR(CDCl3)δ：9.49(1H，s)，7.76(2H，d，J＝7.1Hz)，7.51(1H，br)，7.42-7.34(6H，m)，7.07(1H，d，J＝8.6Hz)，7.01(1H，d，J＝8.6Hz)，6.53(1H，br)，3.40-3.33(2H，m)，2.89(3H，s)，2.81-2.66(4H，m)，2.33(3H，s)，1.21(3H，t，J＝7.5Hz)；IR(KBr)Vmax，1697，1684，1508，1458，1148cm-1。
Example 90
2-Ethyl-5-hydroxy-1- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 11- [4- (2-bromoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ol
A mixture of 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-methoxy-1H-benzimidazole (example 71, step 5, 600mg, 1.9mmol) in 48% hydrobromic acid (60mL) was stirred at 100 ℃ for 6H. After cooling, the mixture was neutralized with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50mL), dried (sodium sulfate), and concentrated to give 890mg (quant.) of the title compound as a pale yellow solid:
1H-NMR(CDCl3)δ：7.64(4H，s)，7.16(2H，m)，6.97-7.01(1H，m)，3.86(2H，t，J＝7.1Hz)，3.30(2H，t，J＝7.1Hz)，2.92(2H，q，J＝7.8Hz)，1.29(3H，t，J＝7.8Hz)。
Step 21- [4- (2-bromoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl-tert-butyl (dimethyl) silyl ether
A mixture of 1- [4- (2-bromoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ol (step 1, 200mg, 0.58mmol), tert-butyldimethylsilyl chloride (100mg, 0.7mmol) and imidazole (47mg, 1.45mmol) in DMF (5mL) was stirred at room temperature for 3H. The reaction mixture was poured into water (50mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) to give 119mg (45%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.20(2H，d，J＝8.4Hz)，7.10(2H，d，J＝8.4Hz)，7.01(1H，d，J＝2.3Hz)，6.72(1H，d，J＝8.6Hz)，6.52(1H，dd，J＝2.3Hz，8.6Hz)，3.45(2H，t，J＝7.4Hz)，3.07(2H，t，J＝7.4Hz)，2.56(2H，q，J＝7.5Hz)，1.14(3H，t，J＝7.5Hz)，0.79(9H，s)，0.05(6H，s)。
step 31- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl tert-butyl (dimethyl) silyl ether
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-bromoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl-tert-butyl (dimethyl) silyl ether (step 2).
1H-NMR(CDCl3)δ：7.20(2H，d，J＝8.3Hz)，7.02-7.12(3H，m)，6.70(1H，d，J＝8.6Hz)，6.50-6.54(1H，m)，3.39(2H，t，J＝6.9Hz)，2.79(2H，t，J＝6.9Hz)，2.55(2H，q，J＝7.6Hz)，1.13(3H，t，J＝7.6Hz)，0.79(9H，s)，0.00(6H，s)。
Step 42- [4- (5- { [ tert-butyl (dimethyl) silyl ] oxy } -2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described for example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl tert-butyl (dimethyl) silyl ether (step 3).
1H-NMR(CDCl3)δ：7.18(2H，d，J＝8.2Hz)，7.02-7.08(3H，m)，6.72(1H，d，J＝8.6Hz)，6.52(1H，dd，J＝2.2Hz，8.6Hz)，2.86(2H，t，J＝6.6Hz)，2.66(2H，t，J＝6.6Hz)，2.55(2H，q，J＝7.5Hz)，1.13(3H，t，J＝7.5Hz)，0.79(9H，s)，0.00(6H，s)。
Step 55- { [ tert-butyl (dimethyl) silyl ] oxy } -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5- { [ tert-butyl (dimethyl) silyl ] oxy } -2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 4).
1H-NMR(CDCl3)δ7.53(2H，d，J＝8.3Hz)，7.02-7.13(7H，m)，6.70(1H，d，J＝8.6Hz)，6.52(1H，dd，J＝2.2Hz，8.6Hz)，6.46(1H，br.s)，3.37(2H，t，J＝6.4Hz)，2.71(2H，t，J＝6.4Hz)，2.53(2H，q，J＝7.6Hz)，2.18(3H，s)，1.11(3H，t，J＝7.6Hz)，0.79(9H，s)，0.00(6H，s)。
Step 62-Ethyl-5-hydroxy-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
To a solution of 5- { [ tert-butyl (dimethyl) silyl ] oxy } -2-ethyl-1- (4- {2- [ ([ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (step 5, 78mg, 0.13mmol) in THF (5mL) was added tetrabutylammonium fluoride (1.0M in THF, 0.16mL, 0.16mmol) at 0 deg.C. The mixture was stirred at 0 ℃ for 2.5 hours and then concentrated. The residue was dissolved in water (30mL) and extracted with dichloromethane (50 mL). The organic layer was dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with methylene chloride/methanol (gradient from 20: 1 to 10: 1) to give 57mg (92%) of the title compound as a white amorphous form:
MS(ESI)m/z 479(M+H)+；1H-NMR(DMSO-d6)δ7.76(2H，d，J＝7.6Hz)，7.35-7.39(6H，m)，6.96(1H，s)，6.85(1H，d，J＝8.6Hz)，6.65(1H，d，J＝8.6Hz)，6.51(1H，br.s)，3.17(2H，br.s)，2.76(2H，t，6.6Hz)，2.67(2H，q，J＝7.6Hz)，2.34(3H，s)，1.20(3H，t，J＝7.6Hz)。
example 91
2-Ethyl-4, 5-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (3, 4-dimethyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for example 45 step 1 from 3, 4-dimethyl-2-nitroaniline and 4-bromophenylethylethylethanol.
1H-NMR(CDCl3)δ：7.16(2H，d，J＝8.4Hz)，7.09(1H，s)，7.03(2H，d，J＝8.4Hz)，6.91(1H，s)，3.89-3.81(2H，m)，2.83(2H，t，J＝6.4Hz)，2.27(3H，s)，2.25(3H，s)
Step 22- [ (2-amino-3, 4-dimethylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (3, 4-dimethyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.02(2H，d，J＝8.6Hz)，6.86(1H，d，J＝7.9Hz)，6.62-6.58(3H，m)，5.09(1H，br.s)，3.77(2H，t，J＝6.6Hz)，2.74(2H，t，J＝6.6Hz)，2.27(3H，s)，2.11(3H，s)
Step 32- [4- (2-Ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-3, 4-dimethylanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
MS(EI)m/z 350(M+)。
Step 42- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)57.42(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，6.99(1H，d，J＝8.3Hz)，6.82(1H，d，J＝8.3Hz)，3.98(2H，t，J＝6.6Hz)，2.99(2H，t，J＝6.6Hz)，2.82(2H，q，J＝7.5Hz)，2.63(3H，s)，2.39(3H，s)，1.26(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.6Hz)，7.30(2H，d，J＝8.6Hz)，7.00(1H，d，J＝8.2Hz)，6.82(1H，d，J＝8.2Hz)，3.61(2H，t，J＝7.1Hz)，3.01(2H，t，J＝7.1Hz)，2.83(2H，q，J＝7.6Hz)，2.63(3H，s)，2.39(3H，s)，1.26(3H，t，J＝7.6Hz)。
Step 62- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-I-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.39(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，6.99(1H，d，J＝8.2Hz)，6.83(1H，d，J＝8.2Hz)，3.09(2H，t，J＝6.6Hz)，2.92-2.79(4H，m)，2.63(3H，s)，2.39(3H，s)，1.27(3H，t，J＝7.6Hz)
Step 72-Ethyl-4.5-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-4, 5-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ7.76(2H，d，J＝8.2Hz)，7.30-7.19(6H，m)，7.00(1H，d，J＝8.2Hz)，6.81(1H，d，J＝8.2Hz)，6.65(1H，m)，3.56-3.54(2H，m)，2.89(2H，t，J＝6.9Hz)，2.80(2H，q，J＝7.6Hz)，2.59(3H，s)，2.38(6H，s)，1.22(3H，t，J＝7.6Hz)。
Example 92
2-Ethyl-4, 5-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-45-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 91).
1H-NMR(DMSO-d6)δ7.59(2H，d，J＝8.4Hz)，7.39-7.30(4H，m)，7.12(2H，d，J＝8.4Hz)，6.94(1H，d，J＝8.3Hz)，6.77(1H，d，J＝8.3Hz)，3.13(2H，m)，2.74-2.67(4H，m)，2.48(3H，s)，2.30(3H，s)，2.27(3H，s)，1.19(3H，t，J＝7.5Hz)；IR(KBr)v max 1599，1516，1425，1227，1128，1086cm-1。
Example 93
4, 6-dimethyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (3, 5-dimethyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 4, 6-dimethyl-2-fluoronitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：8.08(1H，br.s)，7.22(2H，d，J＝8.4Hz)，7.13(2H，d，J＝8.4Hz)，6.91(1H，s)，6.51(1H，s)，3.89(2H，t，J＝6.4Hz)，2.87(2H，t，J＝6.4Hz)，2.47(3H，s)，2.22(3H，s)。
Step 22- [4- (2-amino-3, 5-dimethylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 4, from 2- [4- (3, 5-dimethyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：6.97-7.04(2H，m)，6.78(1H，s)，6.74(1H，s)，6.59-6.67(1H，s)，5.15(1H，br.s)，3.76(2H，t，J＝6.6Hz)，2.74(2H，t，J＝6.6Hz)，2.18(3H，s)，2.17(3H，s)。
Step 32- [4- (2-Ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl ] phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-3, 5-dimethylanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.7 (hexane/ethyl acetate 1: 1).
Step 42- [4- (2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-amino-3, 5-dimethylanilino) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，6.90(1H，s)，6.71(1H，s)，3.98(2H，t，J＝6.4Hz)，2.99(2H，t，J＝6.4Hz)，2.81(2H，q，J＝7.3Hz)，2.65(3H，s)，2.36(3H，s)，1.24(3H，t，J＝7.3Hz)。
Step 51- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.0Hz)，7.30(2H，d，J＝8.0Hz)，6.90(1H，s)，6.71(1H，s)，3.81(2H，t，J＝7.2Hz)，3.19(2H，t，J＝7.2Hz)，2.81(2H，q，J＝7.7Hz)，2.67(3H，s)，2.37(3H，s)，1.25(3H，t，J＝7.7Hz)。
Step 62- [4- (2-Ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ7.42(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，6.90(1H，s)，6.69(1H，s)，3.62(2H，t，J＝7.0Hz)，3.01(2H，d，J＝7.0Hz)，2.81(2H，q，J＝7.5Hz)，2.66(3H，s)，2.36(3H，s)，1.25(3H，t，J＝7.5Hz)。
Step 72- [4- (2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)67.40(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，6.89(1H，s)，6.71(1H，s)，3.07(2H，t，J＝6.9Hz)，2.77-2.89(4H，m)，2.67(3H，s)，2.36(3H，s)，1.25(3H，t，J＝7.6Hz)。
Step 82-Ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 7).
mp 108-112℃；
MS(ESI)m/z 491(M+H)+；
1H-NMR(CDCl3)δ：7.75(2H，d，J＝8.2Hz)，7.18-7.29(6H，m)，6.89(1H，s)，6.67(1H，s)，6.62(1H，br.s)，3.51(2H，br.s)，2.86(2H，br.s)，2.76(2H，q，J＝7.4Hz)，2.63(3H，s)，2.37(3H，s)，2.33(3H，s)，1.20(3H，t，J＝7.4Hz)。
Example 94
5, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (4, 5-dimethyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for step 1, example 45 from 4, 5-dimethyl-2-nitroaniline and 4-bromophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.39(1H，br.s)，7.96(1H，s)，7.27(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，7.01(1H，s)，3.91(2H，q，H＝6.4Hz)，2.90(2H，t，J＝6.4Hz)，2.20(3H，s)，2.19(3H，s)。
Step 22- [ (2-amino-4, 5-dimethylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (4, 5-dimethyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ7.04(2H，d，J＝8.4Hz)，6.86(1H，s)，6.64(2H，d，J＝8.4Hz)，6.61(1H，s)，3.79(2H，t，J＝6.6Hz)，2.76(2H，t，J＝6.6Hz)，2.19(3H，s)，2.12(3H，s)
Step 32- [4- (2-Ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-4, 5-dimethylanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
MS(EI)m/z 350(M+)。
Step 42- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.52(1H，s)，7.44(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.87(1H，s)，4.00(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.76(2H，q，J＝7.5Hz)，2.36(3H，s)，2.29(3H，s)，1.31(3H，t，J＝7.5Hz)。
Step 52- [4- (2-Ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
TLC Rf 0.70 (hexane/ethyl acetate 1: 1).
Step 62- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ：7.53(1H，s)，7.40(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，6.87(1H，s)，3.17(2H，t，J＝7.3Hz)，3.00(2H，t，J＝7.3Hz)，2.76(2H，q，J＝7.5Hz)，2.36(3H，s)，2.29(3H，s)，1.31(3H，t，J＝7.5Hz)。
Step 72-Ethyl-5.6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.79(2H，d，J＝8.1Hz)，7.48(1H，s)，7.29-7.15(6H，m)，6.86(1H，s)，6.60(1H，br.s)，3.57-3.55(2H，m)，2.91-2.89(2H，m)，2.70(2H，q，J＝7.5Hz)，2.39(3H，s)，2.35(3H，s)，2.27(3H，s)，1.25(3H，t，J＝7.5Hz)。
Example 95
5, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 94).
1H-NMR(DMSO-d6)δ7.60(2H，d，J＝8.1Hz)，7.39-7.32(5H，m)，7.13(2H，d，J＝8.1Hz)，6.86(1H，s)，3.16(2H，m)，2.73-2.64(4H，m)，2.29(3H，s)，2.27(3H，s)，2.23(3H，s)，1.20(3H，t，J＝7.4Hz)；
IR(KBr)Vmax 1599，1516，1468，1404，1283，1236，1130，1086cm-1。
Example 96
5, 6-dichloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl } -1H-benzimidazole
Step 12- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4, 5-trichloronitrobenzene and 4-aminophenylethyl alcohol.
MS(EI)m/z 327(M+)。
Step 22- [4- (2-amino-4, 5-dichloroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)57.16(1H，s)，7.11(2H，d，J＝8.0Hz)，6.87(1H，s)，6.74(2H，d，J＝8.0Hz)，5.10(1H，br.s)，3.90-3.60(2H，m)，2.79(2H，t，J＝7.0Hz)。
Step 32- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4, 5-dichloroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
MS(EI)m/z 390(M+)；1H-NMR(CDCl3)δ：7.84(1H，s)，7.45(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，7.16(1H，s)，4.37(2H，t，J＝6.8Hz)，3.09(2H，t，J＝6.8Hz)，2.77(2H，q，J＝7.5Hz)，2.36(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)，1.16(3H，t，J＝7.5Hz)。
Step 42- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.84(1H，s)，7.47(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.0Hz)，7.18(1H，s)，4.10-3.94(2H，m)，3.01(2H，t，J＝6.4Hz)，2.77(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 52- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 26 step 5 from 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
MS(EI)m/z 359(M+)；1H-NMR(CDCl3)δ：7.85(1H，s)，7.46(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，7.17(1H，s)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.76(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 62- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)57.84(1H，s)，7.43(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，7.22(1H，s)，3.14(2H，t，J＝7.2Hz)，2.97(2H，t，J＝7.2Hz)，2.76(2H，q，J＝7.6Hz)，2.10(2H，br.s)，1.34(3H，t，J＝7.6Hz)。
Step 75, 6-dichloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：8.01(1H，s)，7.70(2H，d，J＝8.3Hz)，7.46(2H，d，J＝8.3Hz)，7.36-7.29，(3H，m)7.24(2H，d，J＝8.3Hz)，6.81(1H，br.s)，3.57-3.46(2H，m)，3.06-2.88(4H，m)，2.38(3H，s)，1.43(3H，t，J＝6.9Hz)。
Example 97
2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 96, step 4).
1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.4Hz)，7.85(1H，s)，7.37(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.16(1H，s)，4.72(1H，br.s)，4.38(2H，t，J＝6.8Hz)，3.03(2H，t，J＝6.8Hz)，2.75(2H，q，J＝7.5Hz)，2.44(3H，s)，1.34(3H，t，J＝7.5Hz)。
Example 98
5, 6-dichloro-2-ethyl-1- (4- {2- [ hydroxy ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 11- [4- (2- { (tert-Butoxycarbonyl) [ (tert-butoxycarbonyl) oxy ] amino } ethyl) phenyl ] -5, 6-dichloro-2-ethyl-1H-benzimidazole
To a stirred mixture of 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 96, 100mg, 0.3mmol), N, O-bis-tert-butoxycarbonylhydroxylamine (Bailie, L.C.; Batsanov, A.; Bearder, J.R.; whitening, D.A.J.Chem.Soc.Perkin Trans.1, 1998, 20, 3471, 140mg, 0.6mmol) and triphenylphosphine (158mg, 0.6mmol) in THF (10mL) was added diethyl azocarboxylate (DEAD) (0.1mL, 0.6 mmol). The mixture was stirred at room temperature for 2.5 hours under nitrogen atmosphere. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) to give 174mg (quant.) of the title compound as a yellow amorphous:
1H-NMR(CDCl3)δ：7.84(1H，s)，7.46(2H，d，J＝8.4Hz)，7.25(2H，d，J＝8.4Hz)，7.16(1H，s)，3.92(2H，t，J＝6.7Hz)，3.05(2H，t，J＝6.7Hz)，2.76(2H，q，J＝7.6Hz)，1.56(9H，s)，1.46(9H，s)，1.33(3H，t，J＝7.6Hz)。
Step 2N- {2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } hydroxylamine
A mixture of 1- [4- (2- { (tert-butoxycarbonyl) [ (tert-butoxycarbonyl) oxy ] amino } ethyl) phenyl ] -5, 6-dichloro-2-ethyl-1H-benzimidazole (step 1, 174mg, 0.3mmol) and 2N hydrochloric acid (3mL) in ethyl acetate (20mL) was stirred at room temperature for one day. The reaction mixture was poured into water (100mL), neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50mL), dried (sodium sulfate), and concentrated to give 162mg (quant.) of the title compound as a yellow oil:
1H-NMR(CDCl3)δ：10.35(2H，br.s)，7.89(1H，s)，7.46-7.50(2H，m)，7.29(2H，d，J＝6.8Hz)，7.17(1H，s)，3.37(2H，t，J＝6.9Hz)，3.12(2H，t，J＝6.9Hz)，2.80(2H，q，J＝6.9Hz)，1.34(3H，m)。
step 35, 6-dichloro-2-ethyl-1- (4- {2- [ hydroxy ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The reaction was carried out according to the procedure described in step 10 of example 1 from N- {2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } hydroxylamine (step 2).
MS(ESI)m/z 547(M+H)+；1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.4Hz)，7.79(2H，d，J＝7.2Hz)，7.34-745(2H，m)，7.13-7.18(4H，m)，3.85(1H，br.s)，3.05(2H，br.s)，2.66-2.80(4H，m)，2.38(3H，s)，1.32(3H，t，J＝7.4Hz)；IR(KBr)vmax 1654，1517，1452，1164，1095，869cm-1。
Example 99
5, 6-dichloro-2-ethyl-1- (4- { cis-3- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] cyclobutyl } phenyl) -1H-benzimidazole
Step 1 trans-3-Phenylcyclobutylbenzoate
To a mixture of cis-3-phenylcyclobutanol (Eckehard, V.D., et al, Chezn. Ber., 1993, 126, 2759, 4.6g, 30.2mmol), triphenylphosphine (3.3g, 59.1mmol) and benzoic acid (7.6mg, 62.3mmol) was added diethyl azocarboxylate (DEAD) (10.9g, 62.3mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 minutes, and then the mixture was concentrated. The residue was dissolved in ether (100mL), washed with saturated aqueous sodium bicarbonate (50mL), water (50mL), and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10: 1) gave 6.52g (86%) of the title compound as a pale yellow oil:
1H-NMR(CDCl3)δ：7.71-7.20(10H，m)，5.49-5.41(1H，m)，3.82-3.72(1H，m)，2.78-2.64(4H，m)。
Step 2 trans-3-phenylcyclobutanol
To a solution of trans-3-phenylcyclobutylbenzoate (step 1, 6.5g, 26.0mmol) in methanol (100mL) was added an aqueous 4N LiOH solution (20mL, 80mmol) and the resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated. The residue was dissolved in water (100mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (5: 1) gave 3.65g (93%) of the title compound as a colorless oil:
1H-NMR(CDCl3)δ：7.34-7.16(5H，m)，4.60-4.51(1H，m)，3.69-3.59(1H，m)，2.55-2.37(4H，m)。
step 3 trans-3- (4-nitrophenyl) cyclobutanol
To a mixture of nitric acid (fuming, 2.3mL) and acetic anhydride (25mL) was added dropwise a mixture of trans-3-phenylcyclobutylbenzoate (step 2, 3.7g, 24.6mmol) and sulfuric acid in acetic anhydride (25mL) at-23 ℃. The resulting mixture was stirred in the cold bath for 1.5 hours. The mixture was poured into ice water (200mL) and extracted with dichloromethane (2X 100 mL). The organic layer was washed with water and brine (100mL), then dried (sodium sulfate) and concentrated. The oily residue was dissolved in methanol (100mL) and 4N aqueous LiOH (50mL) was added. The resulting mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in water (100mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) gave 2.7g (56%) of the title compound as a pale yellow oil:
MS(EI)m/z 193(M+)；1H-NMR(CDCl3)δ：8.18(2H，d，J＝8.6Hz)，7.38(2H，d，J＝8.6Hz)，4.62-4.52(1H，m)，3.81-3.71(1H，m)，2.54-2.45(4H，m)。
Step 4 trans-3- (4-aminophenyl) cyclobutanol
To a mixture of trans-3- (4-nitrophenyl) cyclobutanol (step 3, 1.0g, 4.9mmol) in methanol (20mL) was added 10% Pd-C (50 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The palladium catalyst was removed by filtration and washed with methanol (100mL) and ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give 0.9g (quant.) of the title compound as a pale yellow solid:
MS(EI)m/z 163(M+)，1H-NMR(CDCl3)δ：7.03(2H，d，J＝8.3Hz)，6.66(2H，d，J＝8.3Hz)，4.56-4.47(1H，m)，3.58-3.48(3H，m)，2.48-2.31(2H，m)，1.73(1H，d，J＝5.1Hz)。
step 5 trans-3- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] cyclobutanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4, 5-trichloronitrobenzene and trans-3- (4-aminophenyl) cyclobutanol (step 4).
1H-NRM(CDCl3)δ：9.40(1H，br.s)，8.27(1H，s)，7.33(2H，d，J＝8.1Hz)，7.22(2h，D，J＝8.1Hz)，7.19(1H，s)，4.63-455(1H，m)，3.73-3.63(1H，m)，2.57-2.43(4H，m)。
MS(EI)m/z：352(M+)。
Step 6 trans-3- [4- (2-amino-4, 5-dichloroanilino) phenyl ] cyclobutanol
The title compound was prepared according to the procedure described in example 6, step 3, from trans-3- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] cyclobutanol (step 5).
1H-NMR(CDCl3)δ：7.16(1H，s)，7.12(2H，d，J＝8.6Hz)，6.86(1H，s)，6.75(2H，d，J＝8.6Hz)，5.08(1H，br.s)，4.58-4.49(1H，m)，3.77(2H，br.s)，3.62-3.52(1H，m)，2.50-2.34(4H，m)。
Step 7 trans-3- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] cyclobutylpropionate
The title compound was prepared from trans-3- [4- (2-amino-4, 5-dichloroanilino) phenyl ] cyclobutanol (step 6) and propionyl chloride according to the procedure described in example 1, step 5.
TLC Rf 0.56 (ethyl acetate/hexane 1: 1).
Step 8 Trans-3- [4- (5, 6-dichloro-2-Ethyl-1H-Benzimidazol-1-yl) phenyl ] Cyclobutanol
The title compound was prepared from trans-3- [4- (2-amino-4, 5-dichloroanilino) phenyl ] cyclobutylpropionate (step 7) according to the procedure described in example 1, step 6.
MS(EI)m/z：360(M+)；1H-NMR(CDCl3)δ：7.85(1H，br.s)，7.45(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，7.18(1H，br.s)，4.65-4.55(1H，m)，3.83-3.73(1H，m)，2.77(2H，q，J＝7.5Hz)，2.63-2.48(4H，m)，1.34(3H，t，J＝7.5Hz)。
Step 9 cis-3- (4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl) cyclobutyl azide
To a mixture of trans-3- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] cyclobutanol (step 8, 572mg, 1.6mmol), triphenylphosphine (623mg, 2.4mmol) and diphenylphosphoryl azide (DPPA) (655mg, 2.4mmol) in THF (8mL) at room temperature was added diethyl azocarboxylate (415mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 3 hours, then the mixture was diluted with ethyl acetate (100mL), washed with water (100mL) and brine (100 mL). The organic layer was dried (sodium sulfate) and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) gave 506mg (83%) of the title compound as a colorless solid:
MS(EI)m/z：385(M+)；1H-NMR(CDCl3)δ：7.84(1H，br.s)，7.42(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.17(1H，br.s)，3.98-3.88(1H，m)，3.37-3.25(1H，m)，2.89-2.75(2H，m)，2.77(2H，q，J＝7.6Hz)，2.34-2.23(2H，m)，1.34(3H，t，J＝7.6Hz)。
step 10 cis-3- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] cyclobutylamine
The title compound was prepared according to the procedure described in example 37, step 7, from cis-3- [4- (5, 6-dichloro-2-ethyl-1-benzimidazol-1-yl) phenyl ] cyclobutyl azide (step 9).
MS(EI)m/z 359(M+)；1H-NMR(CDCl3)δ：7.84(1H，br.s)，7.41(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.17(1H，br.s)，3.55-3.43(1H，m)，3.24-3.12(1H，m)，2.87-2.73(4H，m)，1.91-1.80(2H，m)，1.34(3H，t，J＝7.5Hz)。
Step 115, 6-dichloro-2-ethyl-1- (4- { cis-3- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] cyclobutyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from cis-3- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] cyclobutylamine (step 10).
MS(ESI)m/z 557(M+H)+；1H-NMR(CDCl3)δ：7.85(1H，br.s)，7.79(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.1Hz)，7.36(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.4Hz)，7.17(1H，br.s)，4.35-4.26(1H，m)，3.35-3.25(1H，m)，2.93-2.83(2H，m)，2.78(2H，q，J＝7.6Hz)，2.46(3H，s)，2.19-2.07(2H，m)，1.34(3H，t，J＝7.6Hz)。
Example 100
5, 6-dichloro-1- (4- {1, 1-dimethyl-2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-2-ethyl-1H-benzimidazole
Step 12- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] -2-methylpropanenitrile
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4, 5-trichloronitroaniline and 2- (4-aminophenyl) -2-methylpropanenitrile (Axton, C.A.; et al J.Chern.Soc.Perkin Trans.1, 1992, 17, 2203).
1H-NMR(CDCl3)δ：9.38(1H，br)，8.31(1H，s)，7.54(2H，d，J＝8.58Hz)，7.30-7.22(3H，m)，1.75(6H，s)。
Step 22- [4- (2-amino-4, 5-dichloroanilino) phenyl ] -2-methylpropanenitrile
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- (4, 5-dichloro-2-nitroanilino) phenyl ] -2-methylpropanenitrile (step 1).
1H-NMR(CDCl3)δ：7.41(1H，s)，7.30(2H，d，J＝8.4Hz)，7.09(1H，s)，6.90(1H，s)，6.80(2H，d，J＝8.4Hz)，5.22(2H，s)，1.62(6H，s)。
Step 32- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -2-methylpropanenitrile
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-4, 5-dichloroanilino) phenyl ] -2-methylpropanenitrile (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：7.91(1H，s)，7.78(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，7.24(1H，s)，283(2H，q，J＝7.5Hz)，1.89(6H，s)，1.42(3H，t，J＝7.3Hz)。
Step 45, 6-dichloro-1- (4- {1, 1-dimethyl-2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-1H-benzimidazole
Under hydrogen atmosphere (4.5 Kg/cm)2) Reacting 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl at room temperature]A mixture of-2-methylpropanenitrile (step 3, 102mg, 0.28mmol), PtO2 (one part), chloroform (0.5mL) in ethanol (15mL) was stirred. After 8 hours, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was suspended in dichloromethane (10 mL). To the suspension at room temperature was added p-toluenesulfonyl isocyanate (0.3mL, 1.96mmol) and triethylamine (0.3mL, 2.1 mmol). After 0.5 hour, the mixture was concentrated. The residue was dissolved in dichloromethane (100mL), washed with 10% aqueous citric acid (50mL), water (50mL), and brine (50 mL). The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by preparative TLC (ethyl acetate/hexane ═ 2: 1) to give 62mg (37%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：7.83(1H，s)，7.67(2H，d，J＝9.3Hz)，7.55(2H，d，J＝9.3Hz)，7.38-7.22(4H，m)，7.18(1H，s)，3.45(1H，br)，2.76(2H，q，J＝8.4Hz)，2.34(3H，s)，1.37(6H，s)，1.31(3H，t，J＝8.2Hz)。
example 101
Step 1 Ethyl [4- (4, 5-dichloro-2-nitroanilino) phenyl ] acetate
The title compound was prepared according to the procedure described in example 1, step 3, from ethyl 2, 4, 5-trichloronitrobenzene and 4-aminophenyl acetate.
1H-NMR(CDCl3)δ：9.41(1H，s)，8.32(1H，s)，7.37(2H，d，J＝8.4Hz)，7.28(1H，s)，7.22(2H，d，J＝8.3Hz)，4.19(2H，q，J＝7.1Hz)，3.66(2H，s)，1.29(3H，t，J＝7.1Hz)。
Step 2 Ethyl [4- (2-amino-4, 5-dichloroanilino) phenyl ] acetate
The title compound was prepared according to the procedure described in example 28, step 2, from ethyl [4- (4, 5-dichloro-2-nitroanilino) phenyl ] acetate (step 1).
1H-NMR(CDCl3)δ：7.16(1H，s)，7.15(2H，d，J＝7.5Hz)，6.86(1H，s)，6.72(2H，d，J＝7.1Hz)，5.12(1H，br.s)，4.15(2H，q，J＝7.0Hz)，3.79(2H，br)，3.54(2H，s)，1.26(3H，t，J＝7.1Hz)。
Step 3 Ethyl [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] acetate
The title compound was prepared according to the procedure described in example 1, step 5, from ethyl [4- (2-amino-4, 5-dichloroanilino) phenyl ] acetate (step 2) and propionyl chloride.
1H-NMR(CDCl3)δ：7.84(1H，s)，7.52(2H，d，J＝8.2Hz)，7.30(2H，d，J＝8.4Hz)，7.19(1H，s)，4.22(2H，q，J＝7.1Hz)，3.75(2H，s)，2.77(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)，1.32(3H，t，J＝7.1Hz)。
Step 4 [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] acetic acid
To a mixture of ethyl [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] acetate (step 3, 1.30g, 3.4mmol) in methanol at room temperature was added 2N aqueous sodium hydroxide (3.4 mL). After 1h, the mixture was concentrated and the residue was diluted with water (200mL) and the mixture was washed with diethyl ether (100 mL). The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate/THF (v/v, 1: 1, 300 mL). The organic extracts were washed with water (200mL), brine (200mL), and dried (magnesium sulfate). Removal of the solvent gave 1.02g (86%) of the title compound as a white powder:
1H-NMR(CDCl3)δ：7.94(1H，s)，7.56-7.45(4H，m)，7.26(1H，s)，3.72(2H，s)，2.72(2H，q，J＝7.3Hz)，1.22(3H，t，J＝7.5Hz)。
step 52- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] acetamide
Reacting [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl]A mixture of acetic acid (step 4, 0.81g, 2.3mmol) and thionyl chloride (di) chloride (10mL) was stirred for 0.5 h and concentrated. To the residue was added aqueous ammonia (28% NH in water)350 mL). The mixture was extracted with ethyl acetate/THF (v/v, 1: 1, 200 mL). The extract was washed with brine (2X 100mL), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (20: 1) to give 349mg (44%) of the title compound as a yellow solid:
1H-NMR(CDCl3)δ：7.93(1H，s)，7.58(1H，br)，7.51(2H，d，J＝8.4Hz)，7.47(2H，d，J＝8.4Hz)，7.27(1H，s)，7.00(1H，br)，3.51(2H，s)，2.71(2H，q，J＝7.5Hz)，1.21(3H，t，J＝7.5Hz)。
step 62- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -N- ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) acetamide
A mixture of 2- [4- (5, 6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl ] acetamide (step 5, 105mg, 030mmol), p-toluenesulfonylcyanato (0.07mL, 0.45mmol), toluene (10mL) and THF (5mL) was heated at reflux temperature. After 6 hours, a further 0.1mL of p-toluenesulfonyl isocyanate was added and the mixture was heated for 3 hours. The mixture was cooled and left at room temperature for two days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to yield 150mg (92%) of the title compound as a colorless amorphous solid:
1H-NMR(CDCl3)δ：9.78(1H，s)，7.95(2H，d，J＝8.3Hz)，7.84(1H，s)，7.54(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.0Hz)，7.32(2H，d，J＝8.4Hz)，7.18(1H，s)，3.78(2H，s)，2.77(2H，q，J＝7.5Hz)，2.4(3H，s)，1.35(3H，t，J＝7.5Hz)。
Example 102
5, 6-dichloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethylformate
A stirred mixture of 2- [ (4, 5-dichloro-2-anilino) phenyl ] ethanol (450mg, 1.42mmol) and formic acid (7mL) was refluxed for 4 hours. After cooling, the mixture was made basic with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (50 mL). The extract was dried (magnesium sulfate) to give 480mg (quant.) of the title compound as a brown oil:
1H-NMR(CDCl3)δ8.10(1H，s)，8.08(1H，s)，7.95(1H，s)，7.61(1H，s)，7.49-7.41(4H，m)，4.47(2H，t，J＝6.8Hz)，3.10(2H，t，J＝6.8Hz)。
step 22- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethyl formate (step 1).
1H-NMR(CDCl3)δ：8.08(1H，s)，7.96(1，s)，7.61(1H，s)，7.49-7.40(4H，m)，3.97(2H，q，J＝6.4Hz)，2.99(2H，t，J＝6.4Hz)。
Step 32- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 2).
MS(EI)m/z 332(M+)。
Step 42- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 3).
1H-NMR(CDCl3)δ：8.09(1H，s)，7.96(1H，s)，7.62(1H，s)，7.45-7.38(4H，m)，3.06(2H，m)，2.87(2H，t，J＝6.6Hz)。
Step 55, 6-dichloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5, 6-dichloro-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 3).
1H-NMR(CDCl3)δ8.11(1H，s)，7.96(1H，s)，7.72(2H，d，J＝8.4Hz)，7.58(1H，s)，7.38(4H，s)，7.28(2H，d，J＝8.4Hz)，6.72(1H，m)，3.56(2H，q，J＝6.9Hz)，2.92(2H，t，J＝6.9Hz)，2.38(3H，s)。
Example 103
5, 6-dichloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 5, 6-dichloro-1- (4-2- [ ([ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 102).
1H-NR(DMSO-d6)δ8.55(1H，s)，7.97(1H，s)，7.71(1H，s)，7.50-7.44(4H，m)，7.29(2H，d，J＝8.4Hz)，7.01(2H，d，J＝8.4Hz)，3.02(2H，m)，2.61(2H，m)，2.16(3H，s)；IR(KBr)v max 1601，1516，1487，1450，1128，1084cm-1.
Example 104
6-chloro-5-trifluoromethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12- [ (5-chloro-4-trifluoromethyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-dichloro-5-trifluoromethylnitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ9.69(1H，br.s)，8.58(1H，s)，7.37(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，7.19(1H，s)，3.93(2H，t，J＝6.4Hz)，2.94(2H，t，J＝6.4Hz)。
Step 22- [ (2-amino-5-chloro-4-trifluoromethylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for example 28 step 2 from 2- [ (5-chloro-4-trifluoromethyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.17-7.15(3H，m)，7.05(1H，s)，6.92-6.88(2H，m)，5.48(1H，br.s)，3.85(2H，t，J＝6.6Hz)，2.83(2H，t，J＝6.6Hz)。
Step 32- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-5-chloro-4-trifluoromethylanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
MS(EI)424(M+)。
Step 42- (4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ8.11(1H，s)，7.50(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.21(1H，s)，4.03-3.98(2H，m)，3.02(2H，t，J＝6.4Hz)，2.79(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 52- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：8.11(1H，s)，7.49(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.20(1H，s)，3.63(2H，t，J＝6.9Hz)，3.03(2H，t，J＝6.9Hz)，2.79(2H，q，J＝7.4Hz)，1.36(3H，t，J＝7.4Hz)。
Step 62- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ8.11(1H，s)，7.45(2H，d，J＝8.3Hz)，7.29-7.26(2H，m)，7.23(1H，s)，3.11(2H，t，J＝7.0Hz)，2.92(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)。
Step 72-Ethyl-6-chloro-5-trifluoromethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：8.09(1H，s)，7.74(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.2Hz)，7.30-7.26(4H，m)，7.18(1H，s)，6.76(1H，m)，3.59(2H，q，J＝7.0Hz)，2.96(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Example 105
6-chloro-5-trifluoromethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl } -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-6-chloro-5-trifluoromethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 104).
1H-NMR(DMSO-d6)δ8.15(1H，s)，7.59(2H，d，J＝8.4Hz)，7.46-7.39(4H，m)，7.33(1H，s)，7.12(2H，d，J＝8.4Hz)，3.15(2H，m)，2.78-2.71(4H，m)，1.24(3H，t，J＝7.5Hz)；IR(KBr)vm，1601，1518，1431，1398，1348，1306，1128，1084cm-1。
Example 106
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl- (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 1 from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 1 step 404).
mp 170-173℃；
1H-NMR(CDCl3)δ：8.12(1H，s)，7.94-7.91(2H，m)，7.41-7.24(6H，m)，7.19(1H，s)，4.39(2H，t，J＝6.8Hz)，3.04(2H，t，J＝6.8Hz)，2.78(2H，q，J＝7.6Hz)，2.44(3H，s)，1.35(3H，t，J＝7.6Hz)；IR(KBr)max 1746，1518，1342，1232，1159，1132，1086cm-1。
Example 107
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl- (4-methylphenyl) sulfonylcarbamate sodium salt.
The title compound was prepared according to the procedure described for example 2 from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl- (4-methylphenyl) sulfonyl carbamate (example 106).
1H-NMR(DMSO-d6)δ8.15(1H，s)，7.59(2H，d，J＝8.1Hz)，7.47(4H，s)，7.34(1H，s)，7.15(2H，d，J＝8.1Hz)，3.96(2H，t，J＝6.6Hz)，2.86(2H，t，J＝6.6Hz)，2.75(2H，q，J＝7.4Hz)，2.28(3H，s)，1.24(3H，t，J＝7.4Hz)。
Example 108
5-chloro-6-methyl-1- (4- {2- [ ({ [ (4-tolyl) sulfonyl) amino ] carbonyl) amino } ethyl } phenyl) -1H-benzimidazole
Step 12- [ (4-chloro-5-methyl-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 5-dichloro-4-methylnitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ：9.40(1H，s)，8.20(1H，s)，7.31(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，7.05(1H，s)，3.93-3.91(2H，m)，2.91(2H，t，J＝6.4Hz)，2.29(3H，s)
Step 22- [ (2-amino-4-chloro-5-methylanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [ (4-chloro-5-methyl-2-nitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.06(2H，d，J＝8.6Hz)，6.93(1H，s)，6.79(1H，s)，6.67(2H，d，J＝8.6Hz)，3.80(2H，d，J＝6.4Hz)，2.77(2H，t，J＝6.4Hz)，2.21(3H，s)。
Step 32- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- [ (2-amino-4-chloro-5-methylanilino) phenyl ] ethanol (step 2) and propionyl chloride according to the procedure described in example 1, step 5.
MS(EI)m/z 370(M+)。
Step 42- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.74(1H，s)，7.47(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.3Hz)，6.93(1H，s)，4.00(2H，t，J＝6.6Hz)，3.02(2H，t，J＝6.6Hz)，2.76(2H，q，J＝7.5Hz)，2.39(3H，s)，1.32(3H，t，J＝7.5Hz)。
Step 52- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure for example 26 step 5 from 2- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.75(1H，s)，7.45(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.27(1H，s)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.76(2H，q，J＝7.5Hz)，2.40(3H，s)，1.33(3H，t，J＝7.5Hz)。
Step 62- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (5-chloro-2-ethyl-6-methyl-1H-benzoimidazol 1-yl) phenyl ] ethyl azide (step 5).
1H-NMR(CDCl3)δ7.75(1H，s)，7.42(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.3Hz)，6.93(1H，s)，3.10(2H，t，J＝7.0Hz)，2.90(2H，t，J＝7.0Hz)，2.76(2H，q，J＝7.5Hz)，2.40(3H，s)，1.33(3H，t，J＝7.5Hz)。
Step 72-Ethyl-5-chloro-6-methyl-1- (4- {2- [ ([ [ (4-methylphenyl) sulfonyl ] amino ] carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylamine (step 6).
1H-NMR(CDCl3)δ：7.75-7.72(3H，m)，7.38-7.23(6H，m)，6.91(1H，s)，6.73-6.69(1H，m)，3.62-3.55(2H，m)，2.94(2H，t，J＝6.8Hz)，2.75(2H，q，J＝7.6Hz)，2.40(3H，s)，2.37(3H，s)，1.30(3H，t，J＝7.6Hz)。
Example 109
5-chloro-6-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 2-ethyl-5-chloro-6-methyl-1- (4- {2- [ ([ [ (4-methylphenyl) sulfonyl ] amino ] carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (example 108).
1H-NMR(DMSO-d6)δ7.68(1H，s)，7.60(2H，d，J＝8.1Hz)，7.41-7.35(4H，m)，7.13(2H，d，J＝8.1Hz)，7.05(1H，s)，3.17-3.15(2H，m)，2.75-2.65(4H，m)，2.34(3H，s)，2.27(3H，s)，1.20(3H，t，J＝7.5Hz)；IR(KBr)Vmax 1599，1516，1456，1402，1128，1084，1001cm-1.
Example 110
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- [ (methylsulfonyl) amino ] -1H-benzimidazole
Step 12- [4- (5-chloro-2, 4-dinitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-dichloro-1, 5-dinitrobenzene and 4-aminophenylethyl alcohol.
1H-NMR(CDCl3)δ9.81(1H，br.s)，9.07(1H，s)，7.40(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.17(1H，s)，3.95(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.6Hz)。
Step 22- [4- (2-amino-5-chloro-4-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 40, step 2, from 2- [4- (5-chloro-2, 4-dinitroanilino) phenyl ] ethanol (step 1).
1H-NMR(CDCl3)δ：7.54(1H，s)，7.24(2H，d，J＝8.6Hz)，7.11(1H，s)，7.03(2H，d，J＝8.6Hz)，5.76(1H，br.s)，3.89(2H，t，J＝6.4Hz)，3.65(2H，br.s)，2.87(2H，t，J＝6.4Hz)，1.28(1H，s)。
Step 32- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- (2-amino-5-chloro-4-nitroanilino) phenyl ] ethanol (step 2) and propionyl chloride.
TLC Rf 0.8 (hexane/ethyl acetate 1: 2).
Step 42- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared from 2- [4- (2-amino-5-chloro-4-nitroanilino) phenyl ] ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.34(1H，s)，7.50(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.0Hz)，7.19(1H，s)，4.00(2H，t，J＝6.3Hz)，3.02(2H，t，J＝6.3Hz)，2.79(2H，q，J＝7.6Hz)，1.62(1H，s)，1.36(3H，t，J＝7.6Hz)。
Step 56-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-5-nitro-1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：8.34(1H，s)，7.50(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.19(1H，s)，3.84(2H，t，J＝7.0Hz)，3.22(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 66-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylamine
The title compound was prepared according to the procedure described in example 89, step 4, from 6-chloro-1- [4- (2 chloroethyl) phenyl-2-ethyl-5-nitro-1H-benzimidazole (step 5).
1H-NMR(CDCl3)δ7.43(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.6Hz)，7.16(1H，s)，7.02(1H，s)，3.96(2H，br.s)，3.81(2H，t，J＝7.1Hz)，3.19(2H，t，J＝7.1Hz)，2.74(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)。
Step 7N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 40, step 5, from N-6-chloro-1- [4- (2-chloroethyl) phenyl-2-ethyl-1H-benzimidazol-5-yl } amine (step 6).
1H-NMR(CDCl3)δ：7.70(1H，s)，7.55(2H，d，J＝7.9Hz)，7.50(2H，d，J＝7.9Hz)，7.13(1H，s)，3.95(2H，t，J＝7.0Hz)，3.16(2H，t，J＝7.0Hz)，2.97(3H，s)，2.71(2H，q，J＝7.6Hz)，1.21(3H，t，J＝7.6Hz)。
Step 8N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 7).
1H-NMR(CDCl3)δ：7.47(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.16(1H，s)，6.78(1H，s)，3.63(2H，t，J＝6.9Hz)，2.98-3.05(5H，m)，2.77(2H，q，J＝7.4Hz)，1.35(3H，t，J＝7.4Hz)。
Step 9N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide
The title compound was prepared according to the procedure described in example 37, step 7, from N-1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 8).
1H-NMR(CDCl3)δ8.03(1H，s)，7.43(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，7.17(1H，s)，3.33(2H，br.s)，3.08(2H，t，J＝7.0Hz)，2.96(3H，s)，2.88(2H，t，J＝7.0Hz)，2.77(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 106-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethylphenyl) -5- [ (methylsulfonyl) amino ] -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } methanesulfonamide (step 9).
mp 101-123℃；MS(ESI)m/z 590(M+H)+，1H-NMR(CDCl3)δ8.04(1H，s)，7.73(2H，d，J＝8.2Hz)，7.42(2H，d，J＝8.2Hz)，7.25-7.33(4H，m)，7.16(1H，s)，6.68(1H，br.s)，3.58(2H，t，J＝7.2Hz)，2.93-2.98(5H，m)，2.77(2H，q，J＝7.5Hz)，2.45(3H，s)，1.35(3H，t，J＝7.5Hz)；IR(KBr)Vmax 1654，1517，1467，1336，1151，1089，972cm-1。
Example 111
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
Step 12-chloro-4- [4- (2-hydroxyethyl) anilino ] -5-nitrobenzonitrile
The title compound was prepared from 2, 4-dichloro-5-nitrobenzonitrile (Grivsky, E.M.; Hitching, G.H.Ind.Chim.Belge., 1974, 39.490) and 4-aminophenylethyl alcohol following the procedure described in example 1, step 3.
1H-NMR(CDCl3)δ：9.81(1H，br.s)，8.56(1H，s)，7.39(2H，d，J＝8.3Hz)，7.23(2H，d，J＝8.3Hz)，7.15 5(1H，s)，3.93(2H，t，J＝6.2Hz)，2.94(2H，t，J＝6.2Hz)，1.62(1H，br.s)。
Step 25-amino-2-chloro-4- [4- (2-hydroxyethyl) anilino ] benzonitrile
The title compound was prepared according to the procedure described in example 28, step 2, from 2-chloro-4- [4- (2-hydroxyethyl) anilino ] -5-nitrobenzonitrile (step 1).
1H-NMR(CDCl3)δ：7.23(4H，d，J＝8.3Hz)，6.99-7.33(2H，m)，3.88(2H，t，J＝6.1Hz)，3.56(1H，br.s)，2.87(2H，t，J＝6.1Hz)。
Step 32- [4- (6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 5-amino-2-chloro-4- [4- (2-hydroxyethyl) anilino ] benzonitrile (step 2) and propionyl chloride.
TLC Rf 0.5 (hexane/ethyl acetate 1: 2).
Step 46-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：8.04(1H，s)，7.52(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.19(1H，s)，4.02(2H，t，J＝6.5Hz)，3.03(2H，t，J＝6.5Hz)，2.80(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 56-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide
To a mixture of 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carbonitrile (step 4, 2.4g, 7.4mmol), DMSO (0.7mL, 8.8mmol) and methanol (100mL) was added 30% aqueous hydrogen peroxide (1.3mL, 11mmol) and 0.2M aqueous sodium hydroxide (0.7mL, 0.14 mmol). The mixture was stirred at 50 ℃ for 2 hours. The solvent was removed and the resulting precipitate was collected by filtration. The precipitate was washed with water and dried under reduced pressure to give 1.9g (76%) of the title compound as a pale purple solid:
1H-NMR(DMSO-d6)δ7.69(1H，br.s)，7.61(1H，s)，7.33-7.40(4H，m)，6.95(1H，s)，4.64(1H，br.s)，3.59(2H，t，J＝6.4Hz)，2.74(2H，t，J＝6.4Hz)，2.62(2H，q，J＝7.4Hz)，1.11(3H，t，J＝7.4Hz)。
step 66-chloro-1- [ (4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 7, from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide (step 5).
1H-NMR(DMSO-d6)δ7.71(1H，br.s)，7.62(1H，s)，7.36-7.47(5H，m)，6.95(1H，s)，3.85(2H，t，J＝7.1Hz)，3.06(2H，t，J＝7.1Hz)，2.63(2H，q，J＝7.6Hz)，1.11(3H，t，J＝7.6Hz)。
Step 71- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide (step 6).
1H-NMR(DMSO-d6)δ7.80(1H，br.s)，7.71(1H，s)，7.46-7.57(5H，m)，7.04(1H，s)，3.65(2H，t，J＝6.9Hz)，2.98(2H，t，J＝6.9Hz)，2.72(2H，q，J＝7.5Hz)，1.21(3H，t，J＝7.5Hz)。
Step 81- [4- (2-aminoethyl } phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described for example 37 step 7 from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (step 7).
1NMR(CDCl3)δ：7.80(1H，s)，7.71(1H，s)，7.39-7.50(5H，m)，7.08(1H，s)，2.49-2.89(6H，m)，1.21(3H，t，J＝7.4Hz)。
Step 96-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (step 8).
mp 152-163℃；
MS(ESI)m/z 540(M+H)+；
1H-NMR(DMSO-d6)δ7.81(1H，br.s)，7.72-7.75(3H，m)，7.51(1H，br.s)，7.33-7.44(6H，m)，7.06(1H，s)，3.26(2H，br.s)，2.68-2.80(4H，m)，2.34(3H，s)，1.23(3H，t，J＝7.5Hz)；IR(KBr)Vmax，3395，1664，1519，1396，1161，1089，991cm-1。
Example 112
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxylic acid
A mixture of 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide (example 111, 140mg, 0.26mmol) and KOH (63mg, 0.8mmol) in methanol (10mL) was stirred at 100 ℃ for one day. The mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30mL), dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with methylene chloride/methanol (10: 1) to give 36mg (25%) of the title compound as a white solid:
mp 145-150℃；
MS(ESI)m/z 541(M+H)+，
1H-NMR(DMSO-d)δ8.10(1H，s)，7.76(2H，d，J＝7.9Hz)，7.36-7.47(6H，m)，7.10(1H，s)，3.28(2H，m)，2.69-2.81(4H，m)，2.34(3H，s)，1.24(3H，t，J＝7.5Hz)；IR(KBr)Vmax，3450，1701，1517，1340，1163，1091，900cm-1。
Example 113
N- [ 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazol-5-yl ] acetamide
Step 1N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } acetamide
To a solution of 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylamine (example 110, step 6, 100mg, 0.3mmol) in pyridine (7mL) was added acetyl chloride (0.03mL, 0.33mmol) dropwise under nitrogen at 0 ℃. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured into water (20mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous sodium hydroxide (30mL), brine (30mL), and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 3) to give 110mg (98%) of the title compound as a white solid:
1H-NMR(CDCl3)δ：8.66(1H，s)，7.56(1H，br.s)，7.45(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.12(1H，s)，3.82(2H，t，J＝7.1Hz)，3.19(2H，t，J＝7.1Hz)，2.77(2H，q，J＝7.6Hz)，2.26(3H，s)，1.34(3H，t，J＝7.6Hz)。
step 2N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } acetamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } acetamide (step 1).
1H-NMR(DMSO-d6)δ8.66(1H，s)，7.55(1H，br.s)，7.45(2H，d，J＝8.1Hz)，7.30(2H，d，J＝8.1Hz)，7.11(1H，s)，3.62(2H，t，J＝7.1Hz)，3.02(2H，t，J＝7.1Hz)，2.76(2H，q，J＝7.6Hz)，2.26(3H，s)，1.34(3H，t，J＝7.6Hz)。
Step 3N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } acetamide
The title compound was prepared according to the procedure described in example 37, step 7, from N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } acetamide (step 2).
1H-NMR(CDCl3)δ：8.66(1H，s)，7.55(1H，br.s)，7.42(2H，d，J＝6.6Hz)，7.27-7.29(2H，m)，7.12(1H，s)，3.08(2H，t，J＝6.9Hz)，2.88(2H，t，J＝6.9Hz)，2.75(2H，q，J＝7.4Hz)，2.26(3H，s)，1.34(3H，t，J＝7.4Hz)。
Step 4N- [ 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazol-5-yl ] acetamide
The title compound was prepared according to the procedure described in example 1, step 10, from N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } acetamide (step 3).
mp 125-133℃；
MS(ESI)m/z 554(M+H)+；
1H-NMR(CDCl3)δ：8.64(1H，s)，7.74(2H，d，J＝8.4Hz)，7.55(1H，br.s)，7.25-7.39(1H，s)，7.08(1H，s)，3.53-3.61(2H，m)，2.94(2H，t，J＝7.1Hz)，2.75(2H，q，J＝7.4Hz)，2.41(3H，s)，2.27(3H，s)，1.32(3H，t，J＝7.4Hz)；IR(KBr)Vmax 3390，1676，1517，1240，1161，1089，1018，972cm-1.
Example 114
6-Ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazole
Step 12- [ (6-Nitro-1, 3-benzodioxol-5-yl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described for step 1, example 45 from 5-amino-6-nitro-1, 3-benzodioxole and 4-bromophenylethyl alcohol.
1H-NMR(CDCl3)δ：10.07(1H，br.s)，7.62(1H，s)，7.29(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)，6.58(1H，s)，5.98(2H，s)，3.90(2H，t，J＝6.6Hz)，2.90(2H，t，J＝6.6Hz)。
Step 22- (4- [ (6-amino-1, 3-benzodioxol-5-yl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (6-nitro-1, 3-benzodioxol-5-yl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.26(1H，s)，7.04(2H，d，J＝8.2Hz)，6.60(2H，d，J＝8.2Hz)，6.39(1H，s)，5.87(2H，s)，4.96(1H，br.s)，3.80(2H，t，J＝6.4Hz)，3.64(2H，br.s)，2.76(2H，t，J＝6.4Hz)。
Step 32- [4- (6-Ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) -phenyl ] ethylpropionate
The title compound was prepared from 2- {4- [ (6-amino-1, 3-benzodioxol-5-yl) amino ] phenyl } ethanol (step 2) and propionol according to the procedure described in example 1, step 5.
TLC Rf 0.5 (hexane/ethyl acetate 1: 2).
Step 42- [4- (6-ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethanol;
the title compound was prepared from 2- {4- [ (6-amino-1, 3-benzodioxol-5-yl) amino ] phenyl } ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.19(1H，s)，6.53(1H，s)，5.94(2H，s)，3.98(2H，t，J＝6.4Hz)，2.99(2H，t，J＝6.4Hz)，2.73(2H，q，J＝7.4Hz)，1.31(3H，t，J＝7.4Hz)。
Step 55- [4- (2-chloroethyl) phenyl ] -6-ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-ethyl-5H [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethanol (step 4).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，7.19(1H，s)，6.54(1H，s)，5.94(2H，s)，3.81(2H，t，J＝7.1Hz)，3,19(2H，t，J＝7.1Hz)，2.72(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 62- [4- (6-Ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 5- [4- (2-chloroethyl) phenyl ] -6-ethyl-5H [1, 3] dioxolo [4, 5-f ] benzimidazole (step 5).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.19(1H，s)，6.53(1H，s)，5.93(2H，s)，3.60(2H，t，J＝7.1Hz)，3.00(2H，t，J＝7.1Hz)，2.73(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 72- [4- (6-Ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethylamine
The title compound was prepared from 2- [4- (6-ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethyl azide (step 6) according to the procedure described in step 9 of example 1.
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.2Hz)，7.22-7.28(2H，m)，7.19(1H，s)，6.54(1H，s)，5.93(2H，s)，3.05(2H，t，J＝6.8Hz)，2.86(2H，t，J＝6.8Hz)，2.73(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 86-Ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5H- [1, 3] dioxolo [4, 5-f ] benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (6-ethyl-5H- [1, 3] dioxolo [4, 5-f ] benzimidazol-5-yl) phenyl ] ethylamine (step 7).
MS(ESI)m/z 507(M+H)+；1H-NMR(DMSO-d6)δ7.75(2H，d，J＝8.1Hz)，7.35-7.37(6H，m)，7.16(1H，s)，6.55(1H，s)，5.97(2H，s)，2.76(2H，t，J＝6.9Hz)，2.65(2H，q，J＝7.6Hz)，2.50(2H，br.s)，2.34(3H，s)，1.18(3H，t，J＝7.6Hz)。
Example 115
6-Ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5H- [1, 3] dioxolo [4, 5-f ] benzimidazole, sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-ethyl-5- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5H- [1, 3] dioxolo [4, 5-f) benzimidazole (example 114).
mp 140-155℃.；IR(KBr)Vmax，3384，2873，1600，1519，1460，1155，1128，1085，1037，945，813cm-1。
Example 116
2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazole
Step 17-Nitro-2, 3-dihydro-1, 4-benzodioxin-6-amine
Iron powder (9.6g, 172.5mmol) was added to a mixture of 6, 7-dinitro-2, 3-dihydrobenzo [1, 4] dioxin (Takakis, I.M.; Hadjimihalakis, P.M.J.Heterocyclic.Chem., 1991, 28, 625, 13g, 57.8mmol) and acetic acid (150mL) at room temperature, and the mixture was refluxed for 30 minutes. After cooling, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1: 1 to 1: 2) to give 3.22g (28%) of the title compound as an orange-yellow solid:
1H-NMR(CDCl3)δ：7.67(1H，s)，6.23(1H，s)，5,85(2H，br.s)，4.19-4.33(4H，m)。
step 22- {4- [ (7-Nitro-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 45, step 1, from 7-nitro-2, 3-dihydro-1, 4-benzodioxin-6-amine (step 1) and 4-bromophenylethyl alcohol.
1H-NMR(CDCl3)δ7.77(1H，s)，7.26(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.4Hz)，6.64(1H，s)，4.20-4.31(4H，m)，3.89(2H，t，J＝6.4Hz)，2.88(2H，t，J＝6.4Hz)。
Step 32- {4- [ (7-amino-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (7-nitro-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] phenyl } ethanol.
1H-NMR(CDCl3)δ：7.02-7.05(2H，m)，6.62-6.65(3H，m)，6.33(1H，s)，5.00(1H，br.s)，4.15-4.24(4H，m)，3.79(2H，t，J＝6.6Hz)，3.53(2H，br.s)，2.76(2H，t，J＝6.6Hz)。
Step 42- [4- (2-Ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- {4- [ (7-amino-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] phenyl } ethanol (step 3) and propionyl chloride according to the procedure described in example 1, step 5.
TLC Rf 0.5 (hexane: ethyl acetate 1: 2).
Step 52- [4- (2-Ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared from 2- {4- [ (7-amino-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] phenyl } ethyl propionate (step 4) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.25-7.28(3H，m)，6.58(1H，s)，4.21-4.27(4H，m)，3.97(2H，t，J＝6.6Hz)，2.98(2H，t，J＝6.6Hz)，2.74(2H，q，J-7.3Hz)，1.31(3H，t，J＝7.3Hz)。
Step 61- [4- (2-chloroethyl) phenyl ] -2-ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-6, 7-dihydro-1H [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethanol (step 5).
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.1Hz)，7.26-7.39(3H，m)，6.58(1H，s)，4.25(4H，s)，3.80(2H，t，J＝7.3Hz)，3.20(2H，t，J＝7.3Hz)，2.74(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 72- [4- (2-Ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethyl azide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f) benzimidazole (step 6).
1H-NMR(CDCl3)δ：7.40(2H，d，J＝8.3Hz)，7.24-7.29(3H，m)，6.57(1H，s)，4.21-4.26(4H，m)，3.59(2H，t，J＝7.0Hz)，2.99(2H，t，J＝7.0Hz)，2.73(2H，q，J＝7.5Hz)，1.30(3H，t，J＝7.5Hz)。
Step 82- [4- (2-Ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (2-ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethyl azide (step 6).
1H-NMR(CDCl3)δ：77.40(2H，d，J＝8.3Hz)，7.24-7.27(3H，m)，6.62(1H，s)，4.21(4H，s)，3.24-3.26(2H，m)，3.11(2H，t，J＝6.9Hz)，2.72(2H，q，J＝7.4Hz)，1.30(3H，t，J＝7.4Hz)。
Step 92-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl)) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazol-1-yl) phenyl ] ethylamine (step 8).
MS(ESI)m/z 521(M+H)+；1H-NMR(CDCl3)δ：7.76(2H，d，J＝8.4Hz)，7.18-7.31(7H，m)，6.64(1H，br.s)，6.56(1H，br.s)，4.24(4H，s)，3.56(2H，t，J＝6.9Hz)，2.90(2H，t，J＝6.9Hz)，2.70(2H，q，J＝7.6Hz)，2.41(3H，s)，1.27(3H，t，J＝7.6Hz)。
Example 117
2-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazole, sodium salt
The title compound was prepared from 2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -6, 7-dihydro-1H- [1, 4] dioxino [2, 3-f ] benzimidazole (example 116) according to the procedure described in example 2.
mp 162-173℃；
1H-NMR(DMSO-d6)δ7.83(2H，d，J＝8.0Hz)，7.58(2H，d，J＝8.6Hz)，7.54(2H，d，J＝8.0Hz)，7.35(2H，d，J＝8.6Hz)，7.29(1H，s)，6.68(1H，s)，4.42(4H，s)，3.38(2H，br.s)，2.94(2H，t，J＝6.9Hz)，2.86(2H，q，J＝7.6Hz)，2.49(3H，s)，1.39(3H，t，J＝7.6Hz)；IR(KBr)Vmax，3360，2875 1596，1516，1468，1335，1167，1130，1064，920cm-1。
Example 118 example 161
The following compounds were prepared according to the following method:
to a solution of the desired commercial sulfonamide (0.05mmol) in DMF (1mL) was added a suspension of NaH (0.1mmol) in DMF (0.5 mL). The mixture was shaken for 5 minutes. To the mixture was added a solution of phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18 step 1, 7mg, 0.05mmol) in DMF (0.5mL) and the mixture was shaken for 30 min at rt. DMF was removed by nitrogen sparging and the residue was dissolved in water (3mL) and loaded onto 0.5g/3mLBondElute SCX. The solid phase was washed with MeOH (5mL) and then eluted with 10% HCl/MeOH (3 mL). The eluate was concentrated under reduced pressure to give the title compound.
Example 118
3- (4- {2- [ [ ({ [ (3, 4-dichlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) 2-ethyl-5, 7-dimethyl 3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 546.6(M+H)+。
Example 119
2-Ethyl-3- {4- [2- ({ [ ({ 3-nitrophenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 523.3(M+H)+。
Example 120
3- (4- {2- [ ({ [ (4-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 512.5(M+H)+。
Example 121
2-Ethyl-3- {4- [2- ({ [ ({ 4-nitrophenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 523.3(M+H)+。
Example 122
N- [4- ({ [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] amino } sulfonyl) phenyl ] -2, 2-dimethylpropanamide, hydrochloride
MS(ESI)m/z 577.5(M+H)+。
Example 123
3- (4- {2- [ ({ [ (2-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 512.4(M+H)+。
Example 124
3- (4- {2- [ ({ [ (3-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 512.5(M+H)+。
Example 125
3-4- {2- [ ({ [ (5-chloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 518.6(M+H)+。
Example 126
3- (4- {2- [ ({ [ (5-bromo-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ES1)m/z 564.2(M+H)+。
Example 127
2-Ethyl-3- {4- [2- ({ [ ({ 2-methyl-5-nitro-phenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 537.3(M+H)+。
Example 128
3- (4- {2- [ ({ [ (3, 4-dimethoxyphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 538.4(M+H)+。
Example 129
3- (4- {2- [ ({ [ (4-butylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 534.5(M+H)+。
Example 130
2-ethyl-3- (4- {2- [ ({ [ (4-methoxyphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 508.4(M+H)+。
Example 131
2-Ethyl-5, 7-dimethyl-3- [4- (2- { [ ({ [5- (phenylthio) -2-thienyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 592.4(M+H)+。
Example 132
3- (4- {2- [ ({ [ (3, 5-dichlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 546.6(M+H)+。
Example 133
3- (4- {2- [ ({ [ (2-bromophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 558.0(M+H)+。
Example 134
3- (4- {2- [ ({ [ (4, 5-dichloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 552.6(M+H)+。
Example 135
3- [4- (2- { [ ({ [2- (2, 4-dichlorophenoxy) phenyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 638.8(M+H)+。
Example 136
3- (4- {2- [ ({ [ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride salt
MS(ESI)m/z 530.3(M+H)+。
Example 137
3- (4- {2- [ ({ [ (2, 4-dimethyl-1, 3-thiazol-5-yl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 523.2(M+H)+。
Example 138
3- (4- {2- [ ({ [ (4-cyanophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 503.2(M+H)+。
Example 139
3- (4- {2- [ ({ [ (3, 4-difluorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 514.3(M+H)+。
Example 140
3- (4- {2- [ ({ [ (2, 5-dichloro-3-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 5523(M+H)+。
Example 141
N- [5- ({ [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] amino } sulfonyl) -1, 3, 4-thiadiazol-2-yl ] acetamide, hydrochloride salt
MS(ESI)m/z 543.0(M+H)+。
Example 142
3- {4- [2- ({ [ ({ 4-chloro-3-nitrophenyl } sulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 557.2(M+H)+。
Example 143
3- (4- {2- [ ({ [ (4-butoxyphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 550.4(M+H)+。
Example 144
3- [4- (2- { [ ({ [2, 6-dichloro-4- (trifluoromethyl) phenyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 614.4(M+H)+。
Example 145
3- [4- (2- { [ ({ [4- (1-adamantyl) phenyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 612.4(M+H)+。
Example 146
3- (4- {2- [ ({ [ (4, 5-dibromo-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 642.0(M+H)+。
Example 147
2-Ethyl-5, 7-dimethyl-3- [4- (2- [ ({ [5- (2-thienylthio) -2-thienyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 598.2(M+H)+。
Example 148
3- (4- {2- [ ({ [ (4-tert-butylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 534.4(M+H)+。
Example 149
3- (4- {2- [ ({ [ (4-amino-3-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 527.3(M+H)+。
Example 150
2-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (2, 4, 5-trichlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 580.4(M+H)+。
Example 151
3- (4- {2- [ ({ [ (2, 5-dimethoxyphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 538.3(M+H)+。
Example 152
3- (4- {2- [ ({ [ (6-ethoxy-1, 3-benzothiazol-2-yl) sulfonyl ] azepinyl } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 579.1(M+H)+。
Example 153
3- (4- {2- [ ({ [ (2-amino-4-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 527.2(M+H)+。
Example 154
2-Ethyl-5, 7-dimethyl-3- [4- (2- { [ ({ [5- (2-thienylsulfonyl) -2-thienylsulfonyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 630.2(M+H)+。
Example 155
3- [4- (2- { [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 580.2(M+H)+。
Example 156
3- {4- [2- ({ [ (2, 3-dihydro-1, 4-benzodioxin-6-ylsulfonyl) amino ] carbonyl } amino) ethyl ] phenyl } -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 536.2(M+H)+。
Example 157
2-Ethyl-5, 7-dimethyl-3- [4- (2- { [ ({ [2- (phenylthio) phenyl ] sulfonyl } amino) carbonyl ] amino } ethyl) phenyl ] -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 586.3(M+H)+。
Example 158
3- (4- {2- [ ({ [ (4-chloro-2, 5-dimethylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 540.3(M+H)+。
Example 159
3- (4- {2- [ ({ [ (3-bromo-5-chloro-2-thienyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 598.1(M+H)+。
Example 160
2-Ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-vinylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, hydrochloride
MS(ESI)m/z 504.4(M+H)+。
Example 161
Methyl 2, 4-dichloro-5- ({ [ ({2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] amino } sulfonyl) benzoate, hydrochloride
MS(ESI)m/z 604.5(M+H)+。
Example 162 example 194
The following compounds were prepared according to the following method:
to the desired commercial mixture of carbonic acid and dichloromethane was added 1-ethyl-3- (3-dimethylaminoisopropyl) carbodiimide hydrochloride (WSC) (0.05mmol, 0.5mL) and then to the reaction mixture was added a solution of 3-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) pyridine (0.03mmol) in dichloromethane (0.5mL) at room temperature. The reaction mixture was stirred at room temperature for three days, and then at 40 ℃ for one day. The solvent was removed, the residue dissolved in MeOH (1mL), and the solution filtered through a membrane filter. The filtrate was purified by preparative LC/MS (Shiseido cap cell pack UG80C18 (4.6X 50mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10)) to give the title compound.
3-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) pyridine was prepared as follows:
step 1, 3- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } propanoic acid
To a solution of 2-chloro-4, 6-dimethyl-3-nitropyridine (17.9g, 96mmol) and methyl 3- (4-aminophenyl) propionate (19g, 96nmol) in DMSO (100mL) was added N, N-diisopropylethylamine (26g, 200mmol), and the reaction mixture was heated at 140 ℃ overnight. The reaction mixture was partitioned between water (400mL) and ethyl acetate/toluene (v/v, 2: 1, 300 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate/toluene (v/v, 2: 1, 200 mL). The combined organic extracts were washed with brine (200mL), dried (sodium sulfate) and concentrated. To a solution of the residual oil in methanol (100mL) was added 2N aqueous sodium hydroxide (150mL, 300mmol) and the resulting mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was washed with ethyl acetate (200 mL). The aqueous phase was acidified with 2N hydrochloric acid (200mL, 400mmol) and extracted with ethyl acetate (3X 200 mL). The extract was washed with brine (200mL), dried (sodium sulfate) and concentrated to give 23.2g (77%) of the title compound as a pale brown solid.
1H-NMR(CDCl3)δ：9.57(1H，s)，7.56(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.4Hz)，6.52(1H，s)，2.95(2H，t，J＝7.5Hz)，2.66(2H，t，J＝7.5Hz)，2.55(3H，s)，2.43(3H，s)。
Step 2 phenyl 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethylcarbamate
To a mixture of 3- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } propanoic acid (step 1, 10g, 31.7mmol) in dioxane (200mL) was added diphenylphosphoryl azide (DPPA) (7.54mL, 35mmol) and triethylamine (4.87mL, 35 mmol). The reaction mixture was heated at 120 ℃ for 2 hours. Phenol (6.6g, 70mmol) was added to the reaction mixture and the reaction mixture was heated to reflux. After 3 hours, an additional amount of phenol (3.3g, 35mmol) was added to the reaction mixture. The resulting mixture was heated at reflux temperature overnight. The volatiles were removed and the residue was partitioned between 10% aqueous citric acid (200mL) and ethyl acetate (300 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water (300mL) and brine (300mL), then dried (sodium sulfate) and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) to give 10.3g (77%) of the title compound as an orange yellow solid.
1H-NMR(CDCl3)δ：9.60(1H，s)，7.61(2H，d，J＝8.6Hz)，7.38-7.32(2H，m)，7.24-7.16(3H，m)，7.14-7.09(2H，m)，6.54(1H，s)，5.06(1H，br.s)，3.58-3.50(2H，m)，2.89(2H，t，J＝69Hz)，2.56(3H，s)，2.44(3H，s)。
Step 34, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) -3-nitropyridine
To a mixture of phenyl 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } ethylcarbamate (step 2, 10.0g, 24.6mmol) and p-toluenesulfonamide (6.3g, 36.8mmol) in DMF (100mL) was added sodium hydride (2.0g, 50 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (300mL) and extracted with ethyl acetate/toluene (v/v, 2: 1, 2X 300 mL). The organic extract was washed with water (100mL) and brine (200mL) and then dried (sodium sulfate). The solvent was removed to obtain a crude product. Recrystallization from ethyl acetate gave 9.6g (81%) of the title compound as a brown solid. The mother liquor was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) to give 1.9g (16%) of the title compound as a brown solid.
1H-NMR(CDCl3)δ：9.75(1H，s)，7.62(2H，d，J＝8.4Hz)，7.59(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，7.15(2H，d，J＝8.4Hz)，6.62-6.50(2H，m)，3.55-3.42(2H，m)，2.80(2H，t，J＝6.9Hz)，2.56(3H，s)，2.43(3H，s)，2.39(3H，s)。
Step 43-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) pyridine
To 4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl group)]Amino } carbonyl) amino]Ethyl } anilino) -3-nitropyridine (step 3, 11.4g, 23.6mmol) in methanol (250mL) was added 10% Pd-C (2.0 g). The resulting mixture was subjected to moderate hydrogen pressure (4.0 kgf/cm) 2) Stirred for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to yield 9.0g (85%) of the title compound as a white solid.
1H-NMR(CDCl3)δ：7.69(2H，d，J＝8.0Hz)，7.26(2H，d，J＝8.0Hz)，7.00-6.95(4H，m)，6.61(1H，s)，6.24(1H，br.s)，3.44-3.38(2H，m)，2.70(2H，t，J＝6.7Hz)，2.39(3H，s)，2.33(3H，s)，2.19(3H，s)。
Example 162
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [ 3-oxo-3- (2-thienyl) propyl ] -3H-imidazo [4, 5-b ] pyridine, formate
MS(ESI)m/z 602.48(M+H)+，
Example 163
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (phenyloxymethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 570.5(M+H)+。
Example 164
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (3-pyridyl) ethyl ] -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 569.49(M+H)+。
Example 165
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (3-oxo-3-phenylpropyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 596.28(M+H)+。
Example 166
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (3-phenylpropyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 582.52(M+H)+。
Example 167
2- (ethoxymethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 522.46(M+H)+。
Example 168
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [ (phenylsulfide) methyl ] -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 586.49(M+H)+。
Example 169
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-pentyl-3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 534.51(M+H)+。
Example 170
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (2-phenylethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 568.51(M+H)+。
Example 171
2- (3-butynyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 516.45(M+H)+。
Example 172
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (3-thienylmethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 560.44(M+H)″。
Example 173
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl { phenyl) -2- (4-pentynyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 530.46(M+H)+。
Example 174
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (2-thienylmethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 560.44(M+H)+。
Example 175
5, 7-dimethyl-3- (4- {2- [ { [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (3-pyridylmethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(E SI)m/z 555.48(M+H)+。
Example 176
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [ (2E) -2-pentenyl ] -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 532.48(M+H)+。
Example 177
2-benzyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 554.48(M+H)+。
Example 178
2- (cyanomethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 503.41(M+H)+。
Example 179
2- (methoxymethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 508.44(M+H)+。
Example 180
2-heptyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 562.33(M+H)+。
Example 181
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-octyl-3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 576.37(M+H)+。
Example 182
5, 7-dimethyl-2- (4-methylpentyl) -3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 548.53(M+H)+。
Example 183
2- [ (benzyloxy) methyl ] -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 584.52(M+H)+。
Example 184
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (2-phenyloxyethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 584.33(M+H)+。
Example 185
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino) ethyl } phenyl) -2- [3- (2-thienyl) propyl ] -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 588.5(M+H)+。
Example 186
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl)) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (2-naphthylmethyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 604.37(M+H)+。
Example 187
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (4-phenylbutyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 596.42(M+H)+。
Example 188
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (5-phenylpentyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 610.45(M+H)+。
Example 189
2- (2-ethoxyethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 536.38(M+H)+。
Example 190
2- (2, 3-dihydro-1H-inden-2-ylmethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) 3-H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 594.45(M+H)+。
Example 191
2- (cyclopropylmethyl) -5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 518.45(M+H)+。
Example 192
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- [2- (methylthio) ethyl ] -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 538.44(M+H)+。
Example 193
2-hexyl-57-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine. Formate salt
MS(ESI)m/z 548.44(M+H)+。
Example 194
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (4-pentenyl) -3H-imidazo [4, 5-b ] pyridine, formate salt
MS(ESI)m/z 532.42(M+H)+。
Example 195
6-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 16-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carbonitrile
The reaction was carried out according to the procedure described in example 1, step 7, from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carbonitrile (example 111, step 4).
1H-NMR(CDCl3)δ：8.07(1H，s)，7.50(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.19(1H，s)，3.83(2H，t，J＝7.1Hz)，3.22(2H，t，J＝7.1Hz)，2.79(2H，q，J＝7.5Hz)，1.37(3H，t，J＝7.5Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile
The reaction was carried out according to the procedure described in step 8 of example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carbonitrile (step 1).
1H-NMR(CDCl3)δ：8.07(1H，s)，7.49(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.18(1H，s)，3.64(2H，t，J＝7.0Hz)，3.04(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 31- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile
The reaction was carried out according to the procedure described in example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (step 2).
1H-NMR(CDCl3)δ：8.06(1H，s)，7.46(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.1Hz)，7.19(1H，s)，3.09(2H，t，J＝7.1Hz)，2.89(2H，t，J＝7.1Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 46-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-1H-benzimidazole
The reaction was carried out according to the procedure described in step 10 of example 1 from 1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (step 3).
mp 219-224℃；
IR(KBr)v：3388，2229，1708，1618，1514，1466，1344，1161，1089cm-1.
MS(ESI)m/z 522(M+H)+，520(M-H)-；
1H-NMR(DMSO-d6)δ8.38(1H，s)，7.77(2H，d，J＝8.2Hz)，7.31-7.49(6H，m)，7.32(1H，s)，6.53(1H，br.s)，3.26-3.28(2H，m)，2.69-2.81(4H，m)，2.35(3H，s)，1.25(3H，t，J＝7.6Hz)。
Example 196-Synthesis procedure of example 197
The following compounds were prepared according to the following procedure:
to the desired commercial mixture of carbonic acid and Dichloromethane (DCM) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.05mmol, 0.5mL) at room temperature followed by a solution of 3-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) pyridine (0.038mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for three days and then at 40C for another day. The solvent was removed, the residue dissolved in MeOH (1mL), and the solution filtered through a membrane filter. The filtrate was purified by preparative LC/MS (Shiseido cap cell pack UG 80C 18 (20X 50mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the title compound.
Example 196
N- { [ (2- {4- [5, 7-dimethyl-2- (4-methylpentyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 548.53(M+H)+。
Example 197
N- { [ (2- {4- [5, 7-dimethyl-2- (3-oxo-3-phenylpropyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 596.28(M+H)+。
EXAMPLE 198-Synthesis procedure for example 216
The following compounds were prepared according to the following procedure:
the carboxylic acid (0.06mmol) was dissolved in N, N Diisopropylethylamine (DIEA) (0.106mmol) and Dichloromethane (DCM) (0.3 mL). To the mixture was added a solution of 1-hydroxybenzotriazole Hydrate (HOBT) (0.06mmol) in N, N-Dimethylformamide (DMF) (0.02 mL). To the reaction was added a solution of 3-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } anilino) pyridine (0.044mmol) in DCM (0.3mL) and DMF (0.08mL), followed by a solution of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) (0.13mmol) in DMF (0.25 mL). The reaction solution was stirred at room temperature for 6 hours and then heated at 40 ℃ overnight. The solvent was removed and the residue dissolved in MeOH (0.8 mL). The solution was loaded onto a Varian BondElute SCX cartridge (500mg/3mL) that had been preconditioned with 2mL of LEOH. The solid phase matrix was washed with 5mL MeOH, then eluted with 2N aqueous ammonia/MeOH (3 mL). After removal of the solvent, the product was used for the next reaction.
The first step intermediate was dissolved in EtOH (2mL) and then excess 2N aqueous NaOH solution (1mL) was added to the reaction solution. The reaction mixture was stirred at 40 ℃ to 70 ℃ overnight. After the reaction was completed, the solvent was removed. To the residue was added 2N aqueous HCl (1mL, pH 7.0 adjusted). The aqueous layer was extracted with DCM (1 mL. times.3). The organic layer was concentrated to give a residue. The crude product was purified by preparative LC/MS (Shiseido capcell pack UG 80C 18 (20X 50mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the title compound as the formate salt.
Example 198
N- {5- [5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridin-2-yl ] pentyl } acetamide, formate salt
MS(ESI)m/z 591.33(M+H)+。
Example 199
N- { [ (2- {4- [5, 7-dimethyl-2- (5-oxo-5-phenylpentyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 624.37(M+H)+。
Example 200
N- { [ (2- {4- [2- (2-cyclopenten-1-ylmethyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 544.40(M+H)+。
Example 201
N- { [ (2- {4- [2- (1-cyclopenten-1-ylmethyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 544.40(M+H)+。
Example 202
(2Z) -3- [5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridin-2-yl ] -N-propyl-2-propenamide, formate salt
MS(ESI)m/z 575.44(M+H)+。
Example 203
N- { [ (2- {4- [5, 7-dimethyl-2- (1-methyl-3-oxo-3-phenylpropyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 610.49(M+H)+。
Example 204
N- { [2- {4- [5, 7-dimethyl-2- (3, 3, 3-trifluoro-2-methylpropyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 574.43(M+H)+。
Example 205
N- ({ [2- (4- {2- [2- (diethylamino) ethyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 563.49(M+H)+。
Example 206
N- { [2- (4- {2- [2- (4-fluorophenyl) ethyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 586.46(M+H)+。
Example 207
3- [5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridin-2-yl ] -N, N-diethylpropionamide, formate salt
MS(ESI)m/z 591.50(M+H)+。
Example 208
N- [ ({2- [4- (5, 7-dimethyl-2-tetrahydro-3-furanyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 534.41(M+H)+。
Example 209
N- { [ (2- {4- [5, 7-dimethyl-2- (1-methylbutyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 534.45(M+H)+。
Example 210
N- { [ (2- {4- [2- (cyclopentylmethyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 546.46(M+H)+。
Example 211
N- { [ (2- {4- [5, 7-dimethyl-2- (2-methylcyclopropyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 518.41(M+H)+。
Example 212
N- [ ({2- [4- (5, 7-dimethyl-2- {3- [4- (methoxy) phenyl ] -3-oxopropyl } -3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 626.45(M+H)+。
Example 213
N- ({ [2- (4- {2- [3- (3, 4-dimethylphenyl) propyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 610.28(M+H)+。
Example 214
N- ({ [2- (4- {2- [ (Z) -2- (4-fluorophenyl) ethenyl ] -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 584.41(M+H)+。
Example 215
N- [ ({2- [4- (5, 7-dimethyl-2- { (Z) -2- [2- (methoxy) phenyl ] vinyl } -3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 596.29(M+H)+。
Example 216
N- { [ (2- {4- [2- (5-hexynyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 544.33(M+H)+。
Example 217 example 220 Synthesis procedure
The following compounds were synthesized according to the following process steps: to 3-amino-4, 6-dimethyl-2- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl) at room temperature]Amino } carbonyl) amino]Ethyl } anilino) pyridine (0.044mmol) in Dichloromethane (DCM) (0.2mL) and DMF (0.05mL) was added pyridine (0.103mmol) in DCM (0.2mL), and excess acid chloride (0.066mmol-0.088 mmol). The reaction mixture was stirred at room temperature until the starting compound disappeared (4-6 hours). After the reaction was stopped, MeOH (0.2mL) was added to the reaction mixture, which was then stirred for 1 hour. The solvent was removed by centrifugation in vacuo the residue was dissolved in MeOH (0.8mL) and then loaded with Varian preconditioned with 2mL MeOHSCX cartridge (500mg/3 mL). The solid phase matrix was washed with 5mL MeOH, then eluted with 2N aqueous ammonia/MeO H (3 mL). The eluate is concentrated in vacuo to give an intermediate product.
The intermediate product of the first step was dissolved in EtOH (2mL), and then an excess of 2N NaOH aqueous solution (1mL) was added to the reaction solution. The reaction mixture was stirred at 70 ℃ overnight. After removing the solvent, the residue was neutralized by adding 2n hcl aqueous solution. The aqueous layer was extracted with DCM (1 mL. times.5). The organic layer was dried over sodium sulfate and then concentrated. Purification of the crude product by preparative LC/MS (Shiseido capcellpackUG 80C 18 (20X 50mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) afforded the title compound as the formate salt.
Example 217
4-methyl-N- [ ({2- [4- (2, 5, 7-trimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] benzenesulfonamide, formate salt
MS(ESI)m/z 478.31(M+H)+。
Example 218
N- { [ (2- {4- [2- (2, 2-dimethylpropyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 534.40(M+H)+。
Example 219
N- [ ({2- [4- (2-cyclobutyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 518.38(M+H)+。
Example 220
N- [ ({2- [4- (2-cyclopentyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide, formate salt
MS(ESI)m/z 532.44(M+H)+。
Example 221
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate p-toluenesulfonate
A mixture of 4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonyl carbamate (example 106, 150mg, 0.265mmol), p-toluenesulfonic acid (50.5mg, 0.265mmol) in acetone (3% H20, 0.3ml) was stirred at room temperature for 16H. The precipitated crystalline solid was filtered off, washed with acetone (0.05 ml. times.5), and then dried under vacuum at 40 ℃ for 2 hours to give 158mg (81%) of the title compound as a white solid.
m.p.：234.8℃
1H-NMR(CDCl3)δ：8.66(1H，br.s)，8.35(1H，s)，7.85(2H，d，J＝8.1Hz)，7.81(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.39-7.35(3H，m)，7.29(2H，d，J＝7.9Hz)，7.19(2H，d，J＝7.9Hz)，4.35(2H，t，J＝6.2Hz)，3.13(2H，q，J＝7.6Hz)，3.04(2H，t，J＝6.3Hz)，2.42(3H，s)，2.36(3H，s)，1.43(3H，t，J＝7.4Hz)。
Example 222
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate benzenesulfonate
The title compound was prepared according to the procedure described for example 221 from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonyl carbamate (example 106).
m.p.：194.9℃
1H-NMR(CDCl3)δ：8.83(1H，br.s)，8.39(1H，s)，7.99-7.95(2H，m)，7.81(2H，d，J＝8.4Hz)，7.54(2H，d，J＝8.4Hz)，7.41-7.36(6H，m)，7.29(2H，d，J＝8.4Hz)，4.34(2H，t，J＝6.1Hz)，3.14(2H，q，J＝7.6Hz)，3.03(2H，t，J＝6.1Hz)，2.41(3H，s)，1.42(3H，t，J＝7.4Hz)。
Example 223
4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate methanesulfonate
The title compound was prepared according to the procedure described for example 221 from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonyl carbamate (example 106).
m.p.：172.2℃
1H-NMR(CDCl3)δ：9.03(1H，br.s)，8.52(1H，s)，7.81(2H，d，J＝8.2Hz)，7.56(2H，d，J＝8.2Hz)，7.40(2H，d，J＝8.1Hz)，7.39(1H，s)，7.29(2H，d，J＝8.1Hz)，4.35(2H，t，J＝6.3Hz)，3.16(2H，q，J＝7.6Hz)，3.06(2H，t，J＝6.3Hz)，2.94(3H，s)，2.41(3H，s)，1.45(3H，t，J＝7.6Hz)。
Example 224
5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole p-toluenesulfonate
A mixture of 5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole (example 78, 43mg, 0.085mmol), p-toluenesulfonic acid (16.2mg, 0.085mmol) in ethanol (0.1ml) was stirred at room temperature for 16 h. The precipitated crystalline solid was filtered off, washed with ethanol (0.05 ml. times.5), and then dried under vacuum at 40 ℃ for 2 hours to give 54mg (91%) of the title compound as a white solid.
m.p.：166.7℃
1H-NMR(CDCl3)δ：9.85(1H，br.s)，8.50(1H，s)，8.02(1H，d，J＝8.9Hz)，7.86(2H，d，J＝8.1Hz)，768(2H，dd，J＝1.8，8.2Hz)，7.47(2H，d，J＝8.4Hz)，7.36-7.31(3H，m)，7.22(2H，d，J＝8.4Hz)，7.17(2H，d，J＝8.4Hz)，7.00(1H，br.s)，3.47-3.39(2H，m)3.14(2H，q，J＝7.3Hz)，2.88(2H，t，J＝6.3Hz)，2.58(3H，s)，2.35(3H，s)，2.34(3H，s)，1.45(3H，t，J＝7.6Hz)。
Example 225
5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole benzenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 224 from 5-acetyl-2-ethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) benzimidazole (example 78).
m.p.：117.7℃
1H-NMR(CDCl3)δ：9.62(1H，br.s)，8.52(1H，s)，8.05-7.96(3H，m)，7.67(2H，d，J＝8.2Hz)，7.49-7.43(5H，m)，7.37-7.32(3H，m)，7.19(2H，d，J＝8.2Hz)，6.92-6.88(1H，m)，3.48-3.42(2H，m)3.17(2H，q，J＝7.6Hz)，2.89(2H，t，J＝6.1Hz)，261(3H，s)，2.35(3H，s)，1.49(3H，t，J＝7.6Hz)。
Example 226
4-chloro-2-ethyl-6-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine
Step 1 tert-butyl 2- (4- [ (2-chloro-6-methyl-3-nitro-4-pyridyl) amino ] phenyl } ethylcarbamate
A mixture of 2, 4-dichloro-6-methyl-3-nitro-pyridine (Chorvat, Robert J. et al, J.Med.chem., 1999, 42, 833., 7.5g, 36.2mmol), [2- (4-amino-phenyl) -ethyl ] -carbamic acid tert-butyl ester (Stark, Peter A. et al, J.Med.chem., 1992, 35, 4264., 1.14g, 4.83mmol) in N, N-diisopropylethylamine (50ml) was heated at reflux for 16 hours. After cooling, the mixture was concentrated. The residue was diluted with dichloromethane (200ml) and washed with saturated aqueous sodium bicarbonate (50 ml. times.2). The organic layer was dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (1: 1) gave 310mg (16%) of the title compound as an orange-yellow solid.
1H-NMR(CDCl3)δ：8.19(1H，s)，7.28(2H，d，J＝8.4Hz)，7.16(2H，d，J＝8.3Hz)，6.69(1H，s)，4.62(1H，br s)，3.43-337(2H，m)，2.84(2H，t，J＝7.0Hz)，2.37(3H，s)，1.44(9H，s)。
Step 2 tert-butyl 2- {4- [ (3-amino-2-chloro-6-methyl-4-pyridinyl) amino ] phenyl) ethylcarbamate
The title compound was prepared according to the procedure described in example 6, step 1, from tert-butyl 2- {4- [ (2-chloro-6-methyl-3-nitro-4-pyridyl) amino ] phenyl } ethylcarbamate.
1H-NMR(CDCl3)δ：7.18(2H，d，J＝8.3Hz)，7.03(2H，d，J＝8.2Hz)，676(1H，s)，6.02(1H，br.s)，4.61(1H，br.s)，3.40-3.37(4H，m)，2.78(2H，t，J＝7.0Hz)，2.33(3H，s)，1.44(9H，s)。
Step 3 tert-butyl 2- [4- (4-chloro-2-ethyl-6-methyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylcarbamate
A mixture of tert-butyl 2- {4- [ (3-amino-2-chloro-6-methyl-4-pyridinyl) amino ] phenyl } ethylcarbamate (step 2, 238mg, 0.63mmol), propionyl chloride (70mg, 0.76mmol) in toluene (4.6ml) and dichloromethane (0.6ml) was heated at reflux for 1 hour. After cooling, the mixture was diluted with ethyl acetate (100ml), which was washed with 1N aqueous sodium hydroxide (30 ml. times.2) and brine (30 ml). The organic layer was dried (magnesium sulfate) and concentrated. The residue and p-toluenesulfonic acid monohydrate (5mg, 0.026mmol) were heated at reflux in toluene (5.0ml) for 16 h. After cooling, the mixture was diluted with dichloromethane (100ml) and washed with saturated aqueous sodium bicarbonate (30ml) and brine (30 ml). The organic layer was dried (magnesium sulfate) and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1: 1) gave 90mg (34%) of the title compound as a brown oil.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，6.81(1H，s)，4.75(1H，br s)，3.52-3.44(2H，m)，2.94(2H，t，J＝7.1Hz)，2.82(2H，q，J＝7.6Hz)，2.55(3H，s)，1.46(9H，s)，1.32(3H，t，J＝7.6Hz)。
Step 42- [4- (4-chloro-2-ethyl-6-methyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine
To a stirred solution of tert-butyl 2- [4- (4-chloro-2-ethyl-6-methyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylcarbamate (step 3, 90mg, 0.22mmol) in dichloromethane (8.5ml) at 0 ℃ was added trifluoroacetic acid (1.0ml, 13.0 mmol). The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 5 hours. The mixture was concentrated, diluted with dichloromethane (50ml), washed with saturated aqueous sodium bicarbonate (10ml) and brine (10 ml). The organic layer was dried (magnesium sulfate) and concentrated. Purification by PTLC eluting with ethyl acetate gave 50mg (73%) of the title compound as a brown oil.
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，6.81(1H，s)，3.09(2H，t，J＝6.9Hz)，2.89(2H，t，J＝6.8Hz)，2.83(2H，q，J＝7.4Hz)，2.55(3H，s)，1.31(3H，t，J＝7.4Hz)。
Step 54-chloro-2-ethyl-6-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (4-chloro-2-ethyl-6-methyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine (step 4).
m.p.：163℃
MS(ESI)m/z：512[(M+H)+]，510[(M-H)-]。
1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.2Hz)，7.38-7.21(6H，m)，6.78(1H，s)，3.53-3.51(2H，m)，2.91-2.89(2H，m)，2.79(2H，q，J＝7.2Hz)，2.52(3H，s)，2.37(3H，s)，1.29(3H，t，J＝7.2Hz)。
Example 227
2- [4- (2-Ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (example 42 step 4).
m.p.：158℃
MS(ESI)m/z：493[(MH)+]，491[(M-H)-]。
1H-NMR(DMSO-d6)δ：772(2H，d，J＝8.2Hz)，7.47(2H，d，J＝8.6Hz)，7.43(2H，d，J＝8.6Hz)，7.34(2H，d，J＝8.0Hz)，6.96(1H，s)，4.18(2H，t，J＝6.6Hz)，2.94(2H，t，J＝6.4Hz)，2.76(3H，s)，2.74(2H，q，J＝7.3Hz)，2.50(3H，s)，2.35(3H，s)，1.23(3H，t，J＝7.3Hz)。
Example 228
2- [4- (8-Ethyl-2, 6-dimethyl-9H-purin-9-yl) -phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ (6-chloro-2-methyl-5-nitro-4-pyrimidinyl) amino ] phenyl } ethanol
To a mixture of 4, 6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al, J.chem Soc., 1954, 3832, 7.5g, 36.1mmol) in THF (150ml) was added 4-aminophenylethyl alcohol (2.47g, 18.0mmol), triethylamine (3.65g, 36.1 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 ml). The mixture was extracted with ethyl acetate (100 ml. times.3). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient from 1: 1 to 1: 2) gave 4.0g (72%) of the title compound as a yellow solid.
1H-NMR(CDCl3)δ：9.34(1H，s)，7.50(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.8Hz)，3.89(2H，t，J＝6.6Hz)，2.90(2H，t，J＝6.4Hz)，2.57(3H，s)。
Step 2 diethyl (6- { [4- (2-hydroxyethyl) phenyl ] amino } -2-methyl-5-nitro-4-pyrimidinyl) malonate
To a mixture of 2- {4- [ (6-chloro-2-methyl-5-nitro-4-pyrimidinyl) amino ] phenyl } ethanol (step 1, 2.0g, 6.48mmol) in acetone (61ml) at 0 ℃ was added diethyl malonate (1.53g, 9.54mmol), and then aqueous sodium hydroxide solution (11N, 2ml, 22mmol) was added dropwise over 20 minutes. After the addition, the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (120ml) and adjusted to pH 8.0 by the addition of acetic acid. The whole reaction was extracted with ethyl acetate (100 ml. times.3). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated. The excess diethylmalonate was removed by azeotropic distillation in toluene to give 3.26g (72%) of the title compound as a brown oil.
MS(EI)m/z：432(M+)。
1H-NMR(CDCl3)δ：10.15(1H，s)，7.55(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，5.36(1H，s)，4.31(4H，q，J＝7.1Hz)，3.90(2H，t，J＝6.6Hz)，2.90(2H，t，J＝6.4Hz)，2.56(3H，s)，1.32(6H，t，J＝7.1Hz)。
Step 32- {4- [ (2, 6-dimethyl-5-nitro-4-pyrimidinyl) amino ] phenyl } ethanol
A mixture of diethyl 2- (6- { [4- (2-hydroxyethyl) phenyl ] amino } -2-methyl-5-nitro-4-pyrimidinyl) malonate (step 2, 2.0g, 6.48mmol) in 2N aqueous HCl (15ml) was heated at reflux for 5 hours. After cooling, the reaction was quenched with saturated aqueous sodium bicarbonate (100 ml). The whole was extracted with ethyl acetate (100 ml. times.3). The organic layer was washed with brine (50mL), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient from 1: 1 to 0: 100) gave 1.33g (71%) of the title compound as a yellow solid.
MS(EI)m/z：288(M+)。
1H-NMR(CDCl3)δ：9.81(1H，s)，7.56(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，3.92-3.86(2H，m)，2.89(2H，t，J＝6.4Hz)，2.76(3H，s)，2.56(3H，s)。
Step 42- {4- [ (5-amino-2, 6-dimethyl-4-pyrimidinyl) amino ] phenyl } ethanol
The title compound was prepared from 2- {4- [ (2, 6-dimethyl-5-nitro-4-pyrimidinyl) amino ] phenyl } ethanol (step 3) according to the procedure described in example 6, step 1.
MS(EI)m/z：258(mu 1H-NMR(DMSO-d6)δ：8.14(1H，s)，7.63(2H，d，J＝8.6Hz)，7.12(2H，d，J＝8.4Hz)，4.67(2H，br.s)，3.58(2H，t，J＝7.3Hz)，2.67(2H，t，J＝7.2Hz)，2.28(3H，s)，2.20(3H，s)。
Step 52- [4- (8-Ethyl-2, 6-dimethyl-9H-purin-9-yl) phenyl ] propionate
The title compound was prepared from 2- {4- [ (5-amino-2, 6-dimethyl-4-pyrimidinyl) amino ] phenyl } ethanol (step 4) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.2Hz)，4.37(2H，t，J＝6.9Hz)，3.06(2H，t，J＝6.8Hz)，2.84(3H，s)，2.82(2H，q，J＝7.4Hz)，2.70(3H，s)，2.35(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)，1.15(3H，t，J＝7.6Hz)。
Step 62- [4- (8-Ethyl-2, 6-dimethyl-9H-purin-9-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (8-ethyl-2, 6-dimethyl-9H-purin-9-yl) phenyl ] ethylpropionate (step 5).
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.3Hz)，3.99-3.92(2H，m)，2.99(2H，t，J＝6.4Hz)，2.85(3H，s)，2.83(2H，q，J＝7.5Hz)，2.70(3H，s)，1.32(3H，t，J＝7.3Hz)。
Step 72- [4- (8-Ethyl-2, 6-dimethyl-9H-purin-9-ylphenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (8-ethyl-2, 6-dimethyl-9H-purin-9-yl) phenyl ] ethanol (step 6).
m.p.：162℃
MS(ESI)m/z：494[(M+H)+]，492[(M-H)-]。
1H-NMR(CDCl3)δ：7.94(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.1Hz)，7.24(2H，d，J＝8.6Hz)，7.18(2H，d J＝8.4Hz)，4.36(2H，t，J＝6.4Hz)，2.97(2H，t，J＝6.2Hz)，2.86(3H，s)，2.79(2H，q，J＝7.6Hz)，2.64(3H，s)，2.44(3H，s)，1.28(3H，t，J＝7.6Hz)。
Example 229
2- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl benzoate
A mixture of 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2, 500mg, 1.94mmol), benzoic acid (4.45g, 36.4mmol), benzoic anhydride (4.8g, 21.2mmol) was heated at 120 ℃ for 4 h. After cooling, the mixture was diluted with dichloromethane (100 ml). The solution was washed with saturated aqueous sodium bicarbonate (50ml), brine (50ml), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with ethyl acetate gave 813mg (94%) of the title compound as a white solid.
MS(EI)m/z：447(M+)。
1H-NMR(CDCl3)δ：8.02-7.21(14H，m)，6.87(1H，s)，4.61(2H，t，J＝7.0Hz)，3.18(2H，t，J＝6.8Hz)，2.96(3H，s)，2.61(3H，s)。
Step 22- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl benzoate (step 1).
1H-NMR(CDCl3)δ：7.57-7.18(9H，m)，6.87(1H，s)，3.95(2H，t，J＝6.6Hz)，2.96(2H，t，J＝6.6Hz)，2.94(3H，s)，2.59(3H，s)。
Step 32- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (4, 6-dimethyl-2-phenyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (step 2).
m.p.：194℃
MS(ESI)m/z：541[(M+H)+]，539[(M-H)-]。
1H-NMR(CDCl3)δ：7.89(2H，d，J＝8.2Hz)，7.46-6.95(11H，m)，6.77(1H，s)，4.35(2H，t，J＝6.0Hz)，3.03(3H，s)，2.96(2H，t，J＝6.0Hz)，2.56(3H，s)，2.42(3H，s)。
Example 230
2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylvalerate
The title compound was prepared from 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2) according to the procedure described in example 229, step 1.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.2Hz)，6.71(1H，s)，4.38(2H，t，J＝6.9Hz)，3.07(2H，t，J＝6.9Hz)，2.88(3H，s)，2.78(2H，t，J＝7.6Hz)，2.56(3H，s)，2.33(2H，t，J＝7.4Hz)，1.74-1.55(4H，m)，1.41-1.24(4H，m)，0.91(3H，t，J＝7.2Hz)，0.84(3H，t，J＝7.2Hz)。
Step 22- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl valerate (step 1).
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.2Hz)，6.72(1H，s)，4.00(2H，t，J＝6.6Hz)，3.02(2H，t，J＝6.4Hz)，2.88(3H，s)，2.78(2H，t，J＝7.6Hz)，2.54(3H，s)，1.76-1.64(2H，m)，1.39-1.25(2H，m)，0.85(3H，t，J＝7.4Hz)。
Step 32- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl ] sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (step 2).
m.p.：162℃
MS(ESI)m/z：521[(M+H)+]，519[(M-H)-]。
1H-NMR(CD3OD)δ：7.97(2H，d，J＝8.3Hz)，7.31(2H，d，J＝7.9Hz)，7.18(2H，d，J＝8.4Hz)，6.84(2H，d，J＝8.4Hz)，6.60(1H，s)，4.34(2H，t，J＝5.5Hz)，3.03(3H，s)，2.96(2H，t，J＝5.5Hz)，2.71(2H，t，J＝7.5Hz)，2.52(3H，s)，2.43(3H，s)，1.72-1.62(2H，m)，1.36-1.24(2H，m)，0.84(3H，t，J＝7.3Hz)。
Example 231
2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate p-toluenesulfonate
To a solution of 2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate (example 230) in methanol was added TsOH (1.0 eq). The resulting mixture was stirred at room temperature for 5 minutes and concentrated. The residual solid was collected and dried at 50 ℃ under reduced pressure to give the title compound as a white solid:
1H-NMR(CDCl3)δ：7.89-7.86(4H，m)，7.49(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.1Hz)，7.24(2H，d，J＝8.3Hz)，7.18(2H，d，J＝7.9Hz)，7.03(1H，s)，4.34(2H，t，J＝6.2Hz)，3.12(3H，s)，3.02(2H，t，J＝6.2Hz)，2.80(3H，s)，2.77(2H，t，J＝8.1Hz)，2.42(3H，s)，2.34(3H，s)，1.78-1.68(2H，m)，1.39-1.27(2H，m)，0.86(3H，t，J＝7.3Hz)。
example 232
2- [4- (4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl 2-methylpropionate
The title compound was prepared from 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2) according to the procedure described in example 229, step 1.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，6.66(1H，s)，4.38(2H，t，J＝7.0Hz)，3.08(2H，t，J＝6.8Hz)，3.12-3.02(1H，m)，2.89(3H，s)，2.55(3H，s)，2.61-2.48(1H，m)，1.33(6H，d，J＝7.0Hz)，1.15(6H，d，J＝7.0Hz)。
Step 22- {4- [4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [45-c ] pyridin-1-yl ] phenyl } ethanol
The title compound was prepared from 2- {4- [4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl 2-methylpropionate (step 1) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.3Hz)，6.68(1H，s)，4.00(2H，t，J＝6.6Hz)，3.13-3.04(1H，m)，3.02(2H，t，J＝6.6Hz)，2.88(3H，s)，2.53(3H，s)，1.33(6H，d，J＝7.0Hz)。
Step 32- {4- [4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [4, 6-dimethyl-2- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethanol (step 2).
m.p.：213℃。
MS(ESI)m/z：507[(M+H)+]，505[(M-H)-]。
1H-NMR(CD3OD)δ：7.80(2H，d，J＝8.4Hz)，7.51(2H，d，J＝8.6Hz)，7.34(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.1Hz)，7.01(1H，s)，4.26(2H，t，J＝6.6Hz)，3.15-3.09(1H，m)，3.00(2H，t，J＝6.4Hz)，2.90(3H，s)，2.58(3H，s)，2.36(3H，s)，1.33(6H，d，J＝6.8Hz)。
Example 233
2- {4- [2- (1, 1-Dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [2- (1, 1-Dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl-2, 2-dimethylpropionate
The title compound was prepared from 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2) according to the procedure described in example 229, step 1.
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，6.35(1H，s)，4.38(2H，t，J＝6.6Hz)，3.08(2H，t，J＝6.6Hz)，2.87(3H，s)，2.50(3H，s)，1.34(9H，s)，1.17(9H，s)。
Step 22- {4- [2- (1, 1-dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethanol
The title compound was prepared from 2- {4- [2- (1, 1-dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl 2, 2-dimethylpropionate (step 1) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.6Hz)，6.38(1H，s)，4.00(2H，t，J＝6.4Hz)，3.01(2H，t，J＝6.6Hz)，2.87(3H，s)，2.50(3H，s)，1.34(9H，s)。
Step 32- {4- [2- (1, 1-Dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [2- (1, 1-dimethylethyl) -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethanol (step 2).
m.p.：226℃
MS(ESI)m/z：521[(MH)+]，519[(M-H)-]。
1H-NMR(DMSO-d6)δ：7.71(2H，d，J＝8.3Hz)，7.46(2H，d，J＝8.6Hz)，7.41(2H，d，J＝8.6Hz)，7.35(2H，d，J＝8.1Hz)，6.55(1H，s)，4.20(2H，t，J＝7.0Hz)，2.95(2H，t，J＝7.0Hz)，2.74(3H，s)，2.44(3H，s)，2.36(3H，s)，1.27(9H，s)。
Example 234
2- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylcyclohexanecarboxylate
The title compound was prepared from 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2) according to the procedure described in example 229, step 1.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，6.65(1H，s)，4.39(2H，t，J＝6.8Hz)，3.08(2H，t，J＝6.8Hz)，2.88(3H，s)，2.54(3H，s)，2.71-1.21(22H，m)。
Step 22- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylcyclohexanecarboxylate (step 1).
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.2Hz)，6.68(1H，s)，4.01(2H，t，J＝6.4Hz)，3.02(2H，t，J＝6.4Hz)，2.88(3H，s)，2.72-2.70(1H，m)，2.54(3H，s)，2.30-1.15(10H，m)。
Step 32- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-cyclohexyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (step 2).
m.p.：168℃
MS(ESI)m/z：547[(MH)+]，545[(M-H)-]。
1H-NMR(CD3OD)δ：7.97(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.1Hz)，7.19(2H，d，J＝8.3Hz)，6.77(2H，d，J＝8.2Hz)，6.53(1H，s)，4.33(2H，t，J＝5.3Hz)，3.09(3H，s)，2.97(2H，t，J＝5.5Hz)，2.65-2.55(1H，m)，2.50(3H，s)，2.42(3H，s)，1.77-1.18(10H，m)。
Example 235
2- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl 4-phenylbutyrate
The title compound was prepared from 2- {4- [ (3-amino-2, 6-dimethyl-4-pyridinyl) amino ] phenyl } ethanol (example 42, step 2) according to the procedure described in example 229, step 1.
1H-NMR(CDCl3)δ：7.39(2H，d，J＝8.2Hz)，7.30-7.15(10H，m)，7.06(2H，d，J＝6.4Hz)，6.70(1H，s)，4.37(2H，t，J＝7.1Hz)，3.06(2H，t，J＝6.9Hz)，2.88(3H，s)，2.80(2H，t，J＝7.6Hz)，2.68-2.60(4H，m)，2.54(3H，s)，2.36(2H，t，J＝7.4Hz)，2.09-1.91(4H，m)。
Step 22- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethanol
The title compound was prepared from 2- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl 4-phenylbutyrate (step 1) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.2Hz)，7.25-7.15(5H，m)，7.07(2H，d，J＝6.8Hz)，6.72(1H，s)，3.99(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.3Hz)，2.88(3H，s)，2.81(2H，t，J＝7.6Hz)，2.64(2H，d，J＝7.6Hz)，2.55(3H，s)，2.11-2.00(2H，m)。
Step 32- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [4, 6-dimethyl-2- (3-phenylpropyl) -1H-imidazo [4, 5-c ] pyridin-1-yl ] phenyl } ethanol (step 2).
m.p.：175℃
MS(ESI)m/z：583[(MH)+]，581[(M-H)-]。
1H-NMR(CDCl3)δ：7.95(2H，d，J＝8.3Hz)，7.30-7.14(7H，m)，7.03(2H，d，J＝8.1Hz)，6.81(2H，d，J＝8.0Hz)，6.64(1H，s)，4.33(2H，t，J＝5.7Hz)，3.00(3H，s)，295(2H，t，J＝5.7Hz)，2.72(2H，t，J＝7.5Hz)，2.62(2H，t，J＝7.4Hz)，2.51(3H，s)，2.41(3H，s)，2.07-1.97(2H，m)。
Example 236
4-methyl-N- { [ (2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } benzenesulfonamide-tosylate
Step 12- {4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethanol
A mixture of 2- (4- { [ 2-amino-4- (methoxy) phenyl ] amino } phenyl) ethanol (example 71, step 2, 1.95g, 7.56mmol), pyrazole-3-carbaldehyde (726mg, 7.56mmol) in ethanol (45ml) was heated at reflux for 2 h. After cooling, the mixture was concentrated. A mixture of the residue and lead tetraacetate (4.61g, 8.32mmol) in benzene (50ml) was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous sodium bicarbonate (150 ml). The whole was extracted with ethyl acetate (150 ml. times.4). The organic layer was washed with water (100 ml. times.5), brine (50ml), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with methylene chloride/methanol (gradient from 20: 1 to 10: 1) gave 408mg (16%) of the title compound as an amber solid.
MS(EI)m/z：334(M+)。
1H-NMR(DMSO-d6)δ：7.6(1H，br.s)，7.43(2H，d，J＝7.7Hz)，7.29-7.23(3H，m)，7.04(1H，d，J＝8.8Hz)，6.90(1H，d，J＝8.8Hz)，6.34(1H，br.s)，3.85-3.81(5H，m)，2.92(2H，t，J＝6.6Hz)。
Step 21- [4- (2-chloroethyl) phenyl ] -5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 1).
MS(EI)m/z：352(M+)。
1H-NMR(CDCl3)δ：8.96(0.5H，s)，8.11(0.5H，d，J＝2.9Hz)，7.50(0.5H，d，J＝2.0Hz)，7.46-7.34(5H，m)，7.05(1H，dd，J＝16.5，8.8Hz)，6.93(1H，ddd，J＝1.4，9.0，2.4Hz)，6.71(0.5H，dd，J＝2.9，1.1Hz)，5.81(1H，s)，3.85(3H，s)，3.82(2H，t，J＝7.0Hz)，3.22(2H，t，J＝7.0Hz)。
Step 31- [4- (2-azidoethyl) phenyl-5- (methoxy) -2-1H-pyrazol-3-yl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazole (step 2).
MS(EI)m/z：359(M+)；1H-NMR(CDCl3)δ：14.05(1H，br.s)，7.53-7.50(2H，m)，7.45(2H，d，J＝8.4Hz)，7.37(2H，d，J＝8.4Hz)，7.01(1H，d，J＝8.7Hz)，6.89(1H，dd，J＝8.7，2.4Hz)，5.81(1H，s)，3.85(3H，s)，3.61(2H，t，J＝6.9Hz)，3.03(2H，t，J＝6.9Hz)。
Step 42- (4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazole (step 3).
MS(EI)m/z：333(M+)。
1H-NMR(CDCl3)δ：7.47(1H，d，J＝2.0Hz)，7.43-7.29(5H，m)，7.00(1H，d，J＝8.8Hz)，6.88(1H，dd，J＝9.0，2.4Hz)，5.81(1H，s)，3.80(3H，s)，3.09(2H，t，J＝7.1Hz)，2.90(2H，t，J＝6.8Hz)。
Step 54-methyl-N- { [ (2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } benzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzoimidazol-1-yl ] phenyl } ethylamine (step 4).
MS(ESI)m/z：531[(MH)+]，529[(M-H)-]。
1H-NMR(CDCl3)δ：7.77(2H，d，J＝8.3Hz)，7.44(1H，s)，7.24(2H，d，J＝7.5Hz)，7.14-7.07(5H，m)，6.98(1H，d，J＝9.0Hz)，6.88(1H，d，J＝9.0Hz)，6.10(1H，s)，3.83(3H，s)，3.57-3.55(2H，m)，2.88-2.84(2H，m)，2.35(3H，s)。
Step 64-methyl-N- { [ (2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } benzenesulfonamide p-toluenesulfonamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 4-methyl-N- { [ (2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzoimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } benzenesulfonamide (step 5).
1H-NMR(CDCl3)δ：12.65(1H，s)，9.99(1H，s)，7.87(2H，d，J＝8.1Hz)，7.78(2H，d，J＝8.3Hz)，7.50(2H，d，J＝9.0Hz)，7.39(2H，d，J＝8.4Hz)，7.20(2H，d，J＝7.9Hz)，7.18(2H，d，J＝8.1Hz)，7.08-6.93(5H，m)，6.44(1H，s)，3.76(3H，s)，3.42-3.40(2H，m)，2.92-2.88(2H，m)，2.86(6H，s)。
Example 237
2- {4- [ 5-Methyloxy-2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate P-tosylate
Step 12- {4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [5- (methyloxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethanol (example 236, step 1).
MS(ESI)m/z：532[(M+H)+]，530[(M-H)-]。
1H-NMR(DMSO-d6)δ：7.75(2H，d，J＝8.1Hz)，7.58(2H，d，J＝8.1Hz)，7.38(2H，d，J＝7.8Hz)，7.33-7.21(3H，m)，7.22(2H，d，J＝8.1Hz)，6.96(1H，d，J＝8.1Hz)，6.88(1H，d，J＝8.1Hz)，4.26-4.24(2H，m)，3.82(3H，s)，2.95-2.93(2H，m)，2.34(3H，s)。
Step 22- {4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [5- (methoxy) -2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (step 1).
1H-NMR(CDCl3)δ：7.88(2H，d，J＝8.2Hz)，7.80-7.65(6H，m)，7.44(2H，d，J＝8.1Hz)，7.38-7.26(3H，m)，7.17(2H，d，J＝8.1Hz)，7.10(2H，d，J＝7.6Hz)，4.37-4.33(2H，m)，3.03-2.99(2H，m)，2.39(3H，s)，2.35(3H，s)，2.31(3H，s)。
Example 238
2- {4- [ 6-chloro-2- (1, 5-dimethyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulfonylcarbamate
To a mixture of 2- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol (example 104, step 2, 1.0g, 2.77mmol) in dichloromethane (45ml) was added p-toluenesulfonyl isocyanate (574mg, 2.91 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 ml). The organic layer was separated. The aqueous layer was extracted with dichloromethane (100 ml. times.3). The combined organic layers were washed with brine (50ml), dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 2: 1 to 1: 1) gave 1.51g (98%) of the title compound as an orange yellow solid.
1H-NMR(CDCl3)δ：9.68(1H，s)，8.58(1H，s)，7.91(2H，d，J＝8.4Hz)，7.34(2H，d，J＝7.9Hz)，7.27(2H，d，J＝7.9Hz)，7.20(2H，d，J＝8.4Hz)，7.17(1H，s)，4.33(2H，t，J＝7.0Hz)，2.96(2H，t，J＝6.8Hz)，2.45(3H，s)。
Step 22- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulfonylcarbamate
To a mixture of 2- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulphonylcarbamate (step 1, 1.51g, 2.71mmol) in methanol (250ml) was added 5% platinum sulphide on charcoal (600 mg). The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere (4 atm). The palladium catalyst was removed by filtration and washed with dichloromethane (100 ml). The filtrate was concentrated under reduced pressure to give 1.46g (99%) of the title compound as a brown oil.
1H-NMR(CDCl3)δ：7.90(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.2Hz)，7.16(1H，s)，7.07(2H，d，J＝8.2Hz)，7.06(1H，s)，6.86(2H，d，J＝8.2Hz)，5.40(2H，s)，4.26(2H，t，J＝6.9Hz)，2.85(2H，t，J＝7.2Hz)，2.44(3H，s)。
Step 32- (4- { [ 5-chloro-2- { [ (1, 5-dimethyl-1H-pyrazol-3-yl) carbonyl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
To a mixture of 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate (step 2, 200mg, 0.379mmol) in dichloromethane (1.7ml) was added a solution of 1, 5-dimethyl-1H-pyrazole-3-carboxylic acid (63.8mg, 0.455mmol) and N, N diisopropylethylamine (118mg, 0.909mmol) in dichloromethane (1.7ml), and to the mixture was added a solution of HOBt (61.5mg, 0.455mmol) and HBTU (431mg, 1.14mmol) in DMF (2.5 ml). The mixture was stirred at room temperature for 20 hours.
The mixture was quenched with water (100 ml). The whole was extracted with ethyl acetate (100 ml. times.3). The combined organic layers were washed with water (100 ml. times.3), brine (50ml), dried (magnesium sulfate) and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1: 1) gave 145mg (59%) of the title compound as a red solid.
1H-NMR(CDCl3)δ：8.70(1H，s)，7.87(2H，d，J＝8.1Hz)，7.79(1H，s)，7.28(2H，d，J＝8.1Hz)，7.04(2H，d，J＝8.3Hz)，6.95(2H，d，J＝8.3Hz)，6.72(1H，s)，6.60(1H，s)，4.22(2H，t，J＝6.8Hz)，3.78(3H，s)，2.84-2.80(2H，m)，2.40(3H，s)，2.30(3H，s)。
Step 42- {4- [ 6-chloro-2- (1, 5-dimethyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
A mixture of 2- (4- { [ 5-chloro-2- { [ (1, 5-dimethyl-1H-pyrazol-3-yl) carbonyl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl (4-methylphenyl) sulphonylcarbamate (step 3, 145mg, 0.223mmol) in 2N sodium hydroxide (1ml) and ethanol (2ml) was stirred at 50 ℃ for 85 hours. After cooling, 2N HCI was added and the pH was adjusted to 4.0. The mixture was diluted with water (80ml) and extracted with dichloromethane (80 ml. times.3). The combined organic layers were washed with brine (50ml), dried (magnesium sulfate) and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1: 3) gave 30mg (21%) of the title compound as a red solid.
MS(ESD m/z：632[(MH)+]，630[(M-H)-]。
1H-NMR(CDCl3)δ：8.15(1H，s)，790(2H，d，J＝8.4Hz)，7.34-7.24(6H，m)，7.19(1H，s)，5.81(1H，s)，4.40(2H，t，J＝6.8Hz)，3.76(3H，s)，3.04(2H，t，J＝6.4Hz)，2.41(3H，s)，2.20(3H，s)。
Example 239
N- [ ({2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide
Step 12-butyl-1- [4- (2-chloroethyl) phenyl ] -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethanol (example 230, step 2).
MS(EI)m/z：341(M+)。
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，6.73(1H，s)，3.82(2H，t，J＝7.1Hz)，3.22(2H，t，J＝7.1Hz)，2.89(3H，s)，2.79(2H，t，J＝8.2Hz)，2.58(3H，s)，1.76-1.64(2H，m)，1.39-1.25(2H，m)，0.84(3H，t，J＝7.2Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 2-butyl-1- [4- (2-chloroethyl) phenyl ] -4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine (step 1).
MS(EI)m/z：348(M+)。
1H-NMR(CDCl3)δ：7.46(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.6Hz)，6.72(1H，s)，3.62(2H，t，J＝6.8Hz)，3.03(2H，t，J＝6.8Hz)，2.88(3H，s)，2.78(2H，t，J＝7.6Hz)，2.55(3H，s)，1.74-1.63(2H，m)，1.38-1.24(2H，m)，0.84(3H，t，J＝7.3Hz)。
Step 32- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridine (step 2).
MS(EI)m/z：322(M+)。
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.3Hz)，7.26(2H，d，J＝8.1Hz)，6.72(1H，s)，3.10-3.04(2H，m)，2.90-2.86(5H，m)，2.78(2H，t，J＝7.7Hz)，2.55(3H，s)，1.74-1.64(2H，m)，1.35-1.25(2H，m)，0.84(3H，t，J＝7.3Hz)。
Step 4N- [ ({2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethylamine (step 3).
MS(ESI)m/z：520[(MH+)]，518[(M-H)-]。
1H-NMR(CDCl3)δ：7.77(2H，d，J＝8.1Hz)，7.37(2H，d，J＝7.9Hz)，7.27(2H，d，J＝7.8Hz)，7.19(2H，d，J＝7.5Hz)，6.76(1H，s)，3.57-3.51(2H，m)，2.92(2H，t，J＝6.6Hz)，2.88(3H，s)，2.76(2H，t，J＝7.5Hz)，2.52(3H，s)，2.38(3H，s)，1.73-1.62(2H，m)，1.36-1.23(2H，m)，0.82(3H，t，J＝7.3Hz)。
Step 5N- [ ({2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for example 231 from N- [ ({2- [4- (2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide (step 4).
1H-NMR(CDCl3)δ：9.85(1H，br.s)，7.78(4H，d，J＝8.1Hz)，7.45(2H，d，J＝7.9Hz)，7.27-7.13(6H，m)，7.01(1H，s)，3.45-3.43(2H，m)，3.03(3H，s)，2.89-2.87(2H，m)，2.79-2.73(5H，m)，2.36(3H，s)，2.34(3H，s)，1.74-1.65(2H，m)，1.35-1.23(2H，m)，0.84(3H，t，J＝7.2Hz)。
Example 240
2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate mono-hydrochloride
To a solution of 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulphonylcarbamate (example 7, 694mg, 1.37mmol) in methanol (4ml) was added a solution of 10% HCl in methanol (2ml) at room temperature. The mixture was concentrated and treated with diethyl ether to give 624mg (90%) of the title compound as a pale yellow solid.
1H-NMR(DMSO-d6)δ：11.92(1H，br.s)，7.76(2H，d，J＝7.9Hz)，7.49-7.39(6H，m)，7.26(1H，br.s)，4.98-4.88(1H，m)，2.94-2.83(4H，m)，2.63(3H，s)，2.46(3H，s)，2.34(3H，s)，1.23(3H，t，J＝7.5Hz)，1.12(3H，d，J＝6.1Hz)。
MS(ESI)m/z：507[(MH)+]，505[(M-H)-]。
Example 241
N- { [ (2- {4- [5, 7-dimethyl-2- (3-phenylpropyl) -3H-imidazo [4, 5-b ] pyridin-3-ylphenyl } ethyl ] amino ] carbonyl } -4-methylbenzenesulfonamide
A mixture of n- { [ (2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 162, step 4, 86mg, 0.19mmol), 4-phenylbutyric acid (37mg, 0.23mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (40mg, 0.21mmol) was stirred at room temperature for five days. And concentrating the mixture to obtain orange paste. This material was dissolved in toluene (8ml), and p-toluenesulfonic acid mono-hydrate (3mg, 0.02mol) was added, followed by stirring at reflux temperature for 5 hours. The mixture was diluted with dichloromethane and washed with dilute hydrochloric acid. The organic layer was concentrated. Purification by TLC and development with hexane/ethyl acetate (1: 3) gave 32mg (29%) of the title compound as a colorless solid.
1H-NMR(CDCl3)：7.85(2H，d，J＝8.4Hz)，7.31-7.01(11H，m)，6.91(1H，s)，3.52-3.45(2H，m)，2.83(2H，t，J＝6.4Hz)，2.71-2.65(2H，m)，2.64(3H，s)，2.58-2.53(2H，m)，2.41(3H，s)，2.39(3H，s)，2.00-1.90(2H，m)。
MS(ESI)m/z：582[(MH)+]，580[(M-H)-]。
Example 242
N- { [ (2- {4- [5, 7-dimethyl-2- (3-oxo-3-phenylpropyl) -3H-imidazo [4, 5-B ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for example 241 from N- { [ (2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 146, step 2) and 3-benzoylpropionic acid.
1H-NMR(CDCl3)δ：8.04-7.14(11H，m)，6.90(1H，s)，6.20-6.15(1H，m)，3.50-3.38(4H，m)，3.03-2.81(4H，m)，2.56(3H，s)，2.44(3H，s)，2.41(3H，s)。
MS(ESI)m/z：596[(MH)+]，594[(M-H)-]。
Example 243
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl 3-pyridylsulfonyl carbamate
Step 12- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate
To a mixture of 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenyl ] ethanol (example 104, step 4, 3.90g, 10.6mmol) in dichloromethane (20mL) and pyridine (2mL) was added phenyl chloroformate (1.6mL, 12.7mmol) dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography eluting with hexane/ethyl acetate (3: 1) gave 4.2g (82%) of the title compound as a colorless syrup.
1H NMR(CDCl3)δ：8.12(1H，s)，7.53-7.15(10H，m)，4.56(2H，t，J＝6.8Hz)，3.20(2H，t，J＝6.8Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
MS(EI)m/z：488(M+)。
Step 22- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl 3-pyridylsulfonyl carbamate
To a mixture of 3-pyridinesulfonamide (Rafik, Karaman; et al, J.am.chem.Soc., 1992, 114, 4889, 120mg, 0.76mmol) in DMF (3mL) at room temperature was added NaH (60% oil dispersion, 27mg, 0.68 mmol). After 10 min, phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (step 1, 313mg, 0.64mmol) was added. The mixture was stirred at 80 ℃ for 9 hours. The mixture was diluted with ethyl acetate (50 mL). Washed with water and brine. The organic layer was dried (sodium sulfate) and concentrated. Purification by TLC with dichloromethane/methanol (6: 1) and TLC with dichloromethane/methanol (10: 1) gave 67mg (19%) of the title compound as a colorless solid.
1H-NMR(CDCl3)δ：9.18(1H，s)，8.73-8.72(1H，m)，8.32-8.29(1H，m)，8.09(1H，s)，7.40-7.15(6H，m)，4.33-4.29(2H，m)，2.99-2.94(2H，m)，2.78-2.71(2H，m)，1.35-1.32(3H，m)。
MS(ESI)m/z：553(MH+)，551([M-H]-)
Example 244
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl 2-pyridylsulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2-pyridinesulfonamide (Naito, t.; et al, chem. phase. ball., 1955, 3, 38) and 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 243, step 1).
m.p.：127.0-130.0℃
1H-NMR(CDCl3)δ：8.76-8.73(1H，m)，8.24-8.21(2H，m)，8.16(1H，s)，8.03-7.97(1H，m)，7.62-7.56(1H，m)，7.37(2H，d，J＝8.2Hz)，7.23(2H，d，J＝8.2Hz)，7.17(1H，s)，4.37(2H，t，J＝6.8Hz)，3.01(2H，t，J＝6.8Hz)，2.77(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
MS(ESI)m/z：553(MH+)，551([M-H]-)。
Example 245
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl }) ethyl 4-pyridylsulfonylcarbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 4-pyridinesulfonamide (Commie, A.M.; et al, J.chem.Soc., 1958, 3514) and 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 243, step 1).
1H-NMR(CDCl3)δ：8.82(2H，d，J＝5.2Hz)，8.10(1H，s)，7.87(2H，d，J＝4.9Hz)，7.44(2H，d，J＝7.9Hz)，7.27(2H，d，J＝7.9Hz)，7.20(1H，s)，4.34(2H，t，J＝7.3Hz)，3.04(2H，t，J＝7.3Hz)，2.78(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
MS(ESI)m/z：553(MH+)，551([M-H]-)。
Example 246
2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 11- (4- { [4- (2-hydroxypropyl) phenyl ] amino } -3-nitrophenyl) ethanone
The title compound was prepared according to the procedure described in example 162 step 1 from 1- (4-chloro-3-nitrophenyl) ethanone and 1- (4-aminophenyl) -2-propanol (example 6 step 1).
1H-NMR(CDCl3)δ：9.85(1H，br.s)，8.83-8.82(1H，m)，7.99-7.95(1H，m)，7.33(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.18(1H，d，J＝9.0Hz)，4.13-4.04(1H，m)，2.87-2.72(2H，m)，2.58(3H，s)，1.29(3H，d，J＝6.2Hz)。
Step 21- (3-amino-4- { [4- (2-hydroxypropyl) phenyl ] amino } phenyl) ethanone
The title compound was prepared from 1- (4- { [4- (2-hydroxypropyl) phenyl ] amino } -3-nitrophenyl) ethanone (step 1) according to the procedure described in example 1, step 4.
MS(EI)m/z：284(M+)。
Step 32- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethylpropionate
The title compound was prepared from 1- (3-amino-4- { [4- (2-hydroxypropyl) phenyl ] amino } phenyl) ethanone (step 2) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：8.41-8.40(1H，m)，8.83-8.82(1H，m)，7.92-7.89(1H，m)，7.43(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.12-7.09(1H，m)，5.25-5.18(1H，m)，3.07-2.88(2H，m)，2.80(2H，q，J＝7.3Hz)，2.68(3H，s)，2.34-2.26(2H，m)，1.37(3H，q，J＝7.5Hz)，1.32(3H，d，J＝6.2Hz)，1.10(3H，t，J＝7.5Hz)。
Step 41- { 2-Ethyl-1- [4- (2-hydroxypropyl) phenyl ] -1H-benzimidazol-5-yl } ethanone
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethylpropionate (step 3).
1H-NMR(CDCl3)δ：8.39(1H，s)，7.89-7.86(1H，m)，7.47(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.13-7.10(1H，m)，4.23-4.13(1H，m)，2.94-2.86(2H，m)，2.80(2H，q，J＝7.5Hz)，2.66(3H，s)，1.39-1.33(6H，m)。
Step 52- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- { 2-ethyl-1- [4- (2-hydroxypropyl) phenyl ] -1H-benzimidazol-5-yl } ethanone (step 4).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.1Hz)，7.91-7.86(3H，m)，7.32-7.24(4H，m)，7.17(2H，d，J＝7.9Hz)，7.07(1H，d，J＝8.4Hz)，5.09-5.03(1H，m)，2.99-2.75(2H，m)，2.77(2H，q，J＝7.5Hz)，2.67(3H，s)，2.37(3H，s)，1.33(3H，t，J＝7.5Hz)，1.21(3H，d，J＝6.1Hz)。
MS(ESI)m/z：520(MH+)，518([M-H]-)。
Example 247
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 11- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared according to the procedure described in example 162 step 1 from 2, 4-dichloro-5-nitrobenzotrifluoride and 1- (4-aminophenyl) -2-propanol (example 6 step 1).
1H-NMR(CDCl3)δ：9.69(1H，br.s)，8.58(1H，s)，7.36(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.20(1H，s)，4.13-4.06(1H，m)，2.88-2.73(2H，m)，1.48(1H，d，J＝4.2Hz)，1.30(3H，d，J＝6.2Hz)。
Step 21- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared from 1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 1) according to the procedure described in example 28, step 2.
1H-NMR(CDCl3)δ：7.17(1H，s)，7.15(2H，d，J＝8.4Hz)，7.06(1H，s)，6.90(2H，d，J＝8.4Hz)，4.05-3.98(1H，m)，2.79-2.61(2H，m)，1.26(3H，d，J＝6.3Hz)。
Step 32- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl propionate
The title compound was prepared from 1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 2) according to the procedure described in example 1, step 5.
MS(EI)m/z：438(M+)。
Step 41- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol
The title compound was prepared from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylpropionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.47(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.21(1H，s)，4.20-4.10(1H，m)，2.95-2.83(2H，m)，2.79(2H，q，J＝7.5Hz)，1.56(1H，d，J＝4.2Hz)，1.36(3H，t，J＝7.5Hz)，1.34(3H，d，J＝6.2Hz)。
Step 52- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol (step 4).
1H-NMR(CDCl3)δ：8.09(1H，s)，7.87(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.21(1H，s)，5.06-5.00(1H，m)，3.04-2.74(4H，m)，2.40(3H，s)，1.36(3H，t，J＝7.5Hz)，1.23(3H，d，J＝6.2Hz)。
MS(ESI)m/z：580(MH+)，578([M-H]-)。
Example 248
(1S) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 1 (2S) -1- (4-Nitrophenyl) -2-propanol and (1R) -1-methyl-2- (4-Nitrophenyl) ethylpropionate
To a mixture of 1- (4-nitrophenyl) -2-propanol (Schadt, F.L. et al, J.Am.chem.Soc., 1978, 100, 228., 2.5g, 13.8mmol) and propionic anhydride (1.8g, 13.8mmol) in benzene (34ml) was added Lipase PS/Celite (0.5g, Bianichi, D. et al, J.Org.chem.1988, 53, 5531). The resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (4: 1 to 1: 1) gave 1.91g (58%) of (1R) -1-methyl-2- (4-nitrophenyl) ethyl propionate as a pale yellow oil and 1.14g (46%) of (2S) -1- (4-nitrophenyl) -2-propanol as a colorless solid (93% e.e.). 1.14g of (2S) -1- (4-nitrophenyl) -2-propanol were recrystallized from hexane/diethyl ether to give 617mg of colorless needles (99% e.e.).
(1R) -1-methyl-2- (4-nitrophenyl) ethyl propionate
1H-NMR(CDCl3)δ：8.16(2H，d，J＝8.8Hz)，7.37(2H，d，J＝8.8Hz)，5.22-5.11(1H，m)，3.04-2.87(2H，m)，2.30-2.19(2H，m)，1.26(3H，d，J＝6.1Hz)，1.07(3H，t，J＝7.5Hz)。
(2S) -1- (4-Nitrophenyl) -2-propanol
1H-NMR(CDCl3)δ：8.18(2H，d，J＝8.8Hz)，7.39(2H，d，J＝8.8Hz)，4.14-4.04(1H，m)，2.92-2.79(2H，m)，1.49(1H，d，J＝4.0Hz)，1.28(3H，d，J＝6.1Hz)。
[α]D 23+31.0 ° (c1.00, diethyl ether)
Step 2 (2S) -1- (4-aminophenyl) -2-propanol
The title compound was prepared according to the procedure described in example 1, step 4, from (2S) -1- (4-nitrophenyl) -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.00(2H，d，J＝8.4Hz)，6.65(2H，d，J＝8.4Hz)，3.99-3.89(1H，m)，3.60(2H，br.s)2.73-2.52(2H，m)，1.22(3H，d，J＝6.2Hz)。
Step 31- [4- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -3-nitrophenyl ] ethanone
The title compound was prepared according to the procedure described in example 162, step 1, from 1- (4-chloro-3-nitrophenyl) ethanone and (2S) -1- (4-aminophenyl) -2-propanol (step 2).
1H-NMR(CDCl3)δ：9.85(1H，br.s)，8.83-8.82(1H，m)，7.99-7.95(1H，m)，7.33(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.18(1H，d，J＝9.0Hz)，4.13-4.04(1H，m)，2.87-2.72(2H，m)，2.58(3H，s)，1.29(3H，d，J＝6.2Hz)。
Step 41- [ 3-amino-4- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) phenyl ] ethanone
The title compound was prepared from 1- [4- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -3-nitrophenyl ] ethanone (step 3) according to the procedure described in example 1, step 4.
MS(EI)m/z：284(M+)。
Step 5 (1S) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared from 1- [ 3-amino-4- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) phenyl ] ethanone (step 4) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：8.41-8.40(1H，m)，8.83-8.82(1H，m)，7.92-7.89(1H，m)，7.43(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.12-7.09(1H，m)，5.25-5.18(1H，m)，3.07-2.88(2H，m)，2.80(2H，q，J＝7.3Hz)，2.68(3H，s)，2.34-2.26(2H，m)，1.37(3H，q，J＝7.5Hz)，1.32(3H，d，J＝6.2Hz)，1.10(3H，t，J＝7.5Hz)。
Step 61- (2-Ethyl-1- {4- [ (2S) -2-hydroxypropyl ] phenyl } -1H-benzimidazol-5-yl) ethanone
The title compound was prepared according to the procedure described in example 1, step 6, from (1S) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethylpropionate (step 5).
1H-NMR(CDCl3)δ：8.39(1H，d，J＝1.1Hz)，7.87(1H，dd，J＝8.6，1.1Hz)，7.48(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.12(1H，d，J＝8.6Hz)，4.22-4.12(1H，m)，2.94-2.89(2H，m)，2.80(2H，q，J＝7.5Hz)，2.69(3H，s)，2.42(1H，br.s)，1.37(3H，t，J＝7.5Hz)，1.33(3H，d，J＝6.2Hz)。
Step 7 (1S) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- (2-ethyl-1- {4- [ (2S) -2-hydroxypropyl ] phenyl } -1H-benzimidazol-5-yl) ethanone (step 6).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.1Hz)，7.91-7.86(3H，m)，7.32-7.24(4H，m)，7.17(2H，d，J＝7.9Hz)，7.07(1H，d，J＝8.4Hz)，5.09-5.03(1H，m)，2.99-2.75(2H，m)，2.77(2H，q，J＝7.5Hz)，2.67(3H，s)，2.37(3H，s)，1.33(3H，t，J＝7.5Hz)，1.21(3H，d，J＝6.1Hz)。
MS(ESI)m/z：520(MH+)，518([M-H]-)。
[α]D 24309 ° (c0.120, methanol)
Example 249
(1R) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 1 (2R) -1- (4-Nitrophenyl) -2-propanol
To a solution of (1R) -1-methyl-2- (4-nitrophenyl) ethyl propionate (example 248, step 1, 1.91g, 8.05mmol) in ethanol (20ml) was added aqueous 2N sodium hydroxide (5ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether (2X 50 ml). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (1: 1) gave 1.16g (80%) of the title compound as a colorless solid (79% e.e.). Recrystallization from hexane/diethyl ether yielded 717mg of colorless needles (99% e.e.).
1H-NMR(CDCl3)δ：8.18(2H，d，J＝8.8Hz)，7.39(2H，d，J＝8.8Hz)，4.14-4.04(1H，m)，2.92-2.79(2H，m)，1.49(1H，d，J＝4.0Hz)，1.28(3H，d，J＝6.1Hz)。
[α]D 2332.6 ° (c1.00, diethyl ether)
Step 2 (2R) -1- (4-aminophenyl) -2-propanol
The title compound was prepared according to the procedure described in example 1, step 4, from (2R) -1- (4-nitrophenyl) -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.00(2H，d，J＝8.4Hz)，6.65(2H，d，J＝8.4Hz)，3.99-3.89(1H，m)，3.60(2H，br.s)2.73-2.52(2H，m)，1.22(3H，d，J＝6.2Hz)。
Step 31- [4- ({4- [ (2R) -2-hydroxypropyl ] phenyl } amino) -3-nitrophenyl ] ethanone
The title compound was prepared according to the procedure described in example 162, step 1, from 1- (4-chloro-3-nitrophenyl) ethanone and (2R) -1- (4-aminophenyl) -2-propanol (step 2).
1H-NMR(CDCl3)δ：9.85(1H，br.s)，8.83-8.82(1H，m)，7.99-7.95(1H，m)，7.33(2H，d，J＝8.4Hz)，724(2H，d，J＝8.4Hz)，7.18(1H，d，J＝9.0Hz)，4.13-4.04(1H，m)，2.87-2.72(2H，m)，2.58(3H，s)，1.29(3H，d，J＝6.2Hz)。
Step 41- [ 3-amino-4- ({4- [ (2R) -2-hydroxypropyl ] phenyl } amino) phenyl ] ethanone
The title compound was prepared from 1- [4- ({4- [ (2R) -2-hydroxypropyl ] phenyl } amino) -3-nitrophenyl ] ethanone (step 3) according to the procedure described in example 1, step 4.
MS(EI)m/z：284(M+)。
Step 5 (1R) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared from 1- [ 3-amino-4- ({4- [ (2R) -2-hydroxypropyl ] phenyl } amino) phenyl ] ethanone (step 4) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：8.41-8.40(1H，m)，8.83-8.82(1H，m)，7.92-7.89(1H，m)，7.43(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.12-7.09(1H，m)，5.25-5.18(1H，m)，3.07-2.88(2H，m)，2.80(2H，q，J＝7.3Hz)，2.68(3H，s)，2.34-2.26(2H，m)，1.37(3H，q，J＝7.5Hz)，1.32(3H，d，J＝6.2Hz)，1.10(3H，t，J＝7.5Hz)。
Step 61- (2-Ethyl-1- {4- [ (2R) -2-hydroxypropyl ] phenyl } -1H-benzimidazol-5-yl) ethanone
The title compound was prepared according to the procedure described in example 1, step 6, from (1R) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethylpropionate (step 5).
1H-NMR(CDCl3)δ：8.39(1H，d，J＝1.1Hz)，7.87(1H，dd，J＝8.6，1.1Hz)，7.48(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.12(1H，d，J＝8.6Hz)，4.22-4.12(1H，m)，2.94-2.89(2H，m)，2.80(2H，q，J＝7.5Hz)，2.69(3H，s)，2.42(1H，br.s)，1.37(3H，t，J＝7.5Hz)，1.33(3H，d，J＝6.2Hz)。
Step 7 (1R) -2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- (2-ethyl-1- {4- [ (2R) -2-hydroxypropyl ] phenyl } -1H-benzimidazol-5-yl) ethanone (step 6).
1H-NMR(CDCl3)δ：8.40(1H，d，J＝1.1Hz)，7.91-7.86(3H，m)，7.32-7.24(4H，m)，7.17(2H，d，J＝7.9Hz)，7.07(1H，d，J＝8.4Hz)，5.09-5.03(1H，m)，2.99-2.75(2H，m)，2.77(2H，q，J＝7.5Hz)，2.67(3H，s)，2.37(3H，s)，1.33(3H，t，J＝7.5Hz)，1.21(3H，d，J＝6.1Hz)。
MS(ESI)m/z：520(MH+)，518([M-H]-)。
[α]D 24+6.05 ° (c0.118, methanol).
Example 250
(1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulphonylcarbamate
Step 1(2S) -1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared according to the procedure described in example 162 step 1 from 2, 4-dichloro-5-nitrobenzotrifluoride and (2S) -1- (4-aminophenyl) -2-propanol (example 248 step 2).
1H-NMR(CDCl3)δ：9.69(1H，br.s)，8.58(1H，s)，7.36(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.20(1H，s)，4.13-4.06(1H，m)，2.88-2.73(2H，m)，1.48(1H，d，J＝4.2Hz)，1.30(3H，d，J＝6.2Hz)。
Step 2 (2S) -1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared according to the procedure described for example 248 step 2 from (2S) -1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.17(1H，s)，7.15(2H，d，J＝8.4Hz)，7.06(1H，s)，6.90(2H，d，J＝84Hz)，4.05-3.98(1H，m)，2.79-2.61(2H，m)，1.26(3H，d，J＝6.3Hz)。
Step 3 (1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from (2S) -1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 2).
MS(EI)m/z：438(M+)。
Step 4 (2S) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol
The title compound was prepared from (1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.47(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.21(1H，s)，4.20-4.10(1H，m)，2.95-2.83(2H，m)，2.79(2H，q，J＝7.5Hz)，1.56(1H，d，J＝4.2Hz)，1.36(3H，t，J＝7.5Hz)，1.34(3H，d，J＝6.2Hz)。
Step 5 (S) - {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from (2S) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol (step 4).
m.p.：200.3℃；1H-NMR(CDCl3)δ：8.09(1H，s)，7.87(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.21(1H，s)，5.06-5.00(1H，m)，3.04-2.74(4H，m)，2.40(3H，s)，1.36(3H，t，J＝7.5Hz)，1.23(3H，d，J＝6.2Hz)。
MS(ESI)m/z：580(MH+)，578([M-H]-)。
[α]D 24+1.31 ° (c0.398, methanol)
ee：98％。
Example 251
(1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate mono-P-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from (1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate (example 250, step 5).
1H-NMR(DMSO-d6)δ：11.91(1H，br.s)，8.23(1H，s)，7.75(2H，d，J＝8.3Hz)，7.50-7.37(9H，m)，7.11(2H，d，J＝8.1Hz)，4.97-4.91(1H，m)，2.92-2.76(4H，m)，2.30(3H，s)，2.27(3H，s)，1.24(3H，t，J＝7.3Hz)，1.14(3H，d，J＝6.2Hz)。
MS(ESI)m/z：580(MH+)，578([M-H]-)。
Example 252
(1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulphonylcarbamate
Step 1 (2R) -1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared according to the procedure described in example 162, step 1, from 2, 4-dichloro-5-nitrobenzotrifluoride and (2R) -1- (4-aminophenyl) -2-propanol (step 2, example 249).
1H-NMR(CDCl3)δ：9.69(1H，br.s)，8.58(1H，s)，7.36(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.20(1H，s)，4.13-4.06(1H，m)，2.88-2.73(2H，m)，1.48(1H，d，J＝4.2Hz)，1.30(3H，d，J＝6.2Hz)。
Step 2 (2R) -1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol
The title compound was prepared according to the procedure described in example 28, step 2, from (2R) -1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.17(1H，s)，7.15(2H，d，J＝8.4Hz)，7.06(1H，s)，6.90(2H，d，J＝8.4Hz)，4.05-3.98(1H，m)，2.79-2.61(2H，m)，1.26(3H，d，J＝6.3Hz)。
Step 3 (1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl propionate
The title compound was prepared according to the procedure described in example 1, step 5, from (2R) -1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-propanol (step 2).
MS(EI)m/z：438(M+)。
Step 4 (2R) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -propanol
The title compound was prepared from (1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：812(1H，s)，7.47(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.21(1H，s)，4.20-4.10(1H，m)，2.95-2.83(2H，m)，2.79(2H，q，J＝7.5Hz)，1.56(1H，d，J＝4.2Hz)，1.36(3H，t，J＝7.5Hz)，1.34(3H，d，J＝6.2Hz)。
Step 5 (1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from (2R) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol (step 4).
m.p.：199.9℃
1H-NMR(CDCl3)δ：10.70(1H，br.s)，8.10(1H，s)，7.89(2H，d，J＝8.3Hz)，7.40(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.22(2H，d，J＝8.3Hz)，7.20(1H，s)，5.32-5.00(1H，m)，3.04-2.82(2H，m)，2.78(2H，q，J＝7.5Hz)，2.40(3H，s)，1.36(3H，t，J＝7.5Hz)，1.23(3H，d，J＝6.2Hz)。
MS(ESI)m/z：580(MH+)，578([M-H]-)。
[α]D 242.19 ° (c0.402, methanol)
ee：97％.
Example 253
N- { [ (2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl) -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 11- [4- (2-azidopropyl) phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole
To a mixture of 1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-propanol (step 8, 1.96g, 5.12mmol, example 247), triphenylphosphine (1.75g, 6.66mmol) and diphenylphosphorylazide (1.83mg, 6.66mmol) in tetrahydrofuran (15ml) was added diethyl azocarboxylate (1.16mg, 6.66mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, then at reflux temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (sodium sulfate) and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (2: 1) and TLC purification using hexane/ethyl acetate (1: 1) gave 769mg (37%) of the title compound as a pale yellow paste.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.47(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.21(1H，s)，3.85-3.77(1H，m)，2.92-2.89(2H，m)，2.80(2H，q，J＝7.5Hz)，1.37(3H，d，J＝6.6Hz)，1.36(3H，t，J＝7.5Hz)。
MS(ESI)m/z：408(MH+)。
Step 22- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylamino
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2-azidopropyl) phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole (step 1).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.44(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.21(1H，s)，3.49-3.26(1H，m)，2.86-2.95(2H，m)，2.79(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)，1.20(3H，d，J＝6.2Hz)。
Step 3N- { [ (2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylamine (step 2) according to the procedure described in example 1, step 10.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.73(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.3Hz)，7.29-7.23(4H，m)，7.17(1H，s)，4.20-4.11(1H，m)，2.99-2.82(2H，m)，2.78(2H，q，J＝7.3Hz)，2.38(3H，s)，1.35(3H，t，J＝7.3Hz)，1.24(3H，d，J＝6.6Hz)。
MS(ESI)m/z：579(MH+)，577([M-H]-)。
Example 254
N- { [ ((1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 11- [4- [ (2s) -2-azidopropyl) phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 253, step 1, from (2R) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -2-propanol (example 252, step 4).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.46(2H，d，J＝7.9Hz)，7.29(2H，d，J＝7.9Hz)，7.21(1H，s)，3.84-3.77(1H，m)，2.92-2.89(2H，m)，2.79(2H，q，J＝7.6Hz)，1.39-1.33(6H，m)。
Step 2 (1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- [ (2s) -2-azidopropyl) phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole (step 1).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.44(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.21(1H，s)，3.49-3.26(1H，m)，2.86-2.65(2H，m)，2.79(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)，1.20(3H，d，J＝6.2Hz)。
Step 3N- { [ ((1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from (1S) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethylamine (step 2).
m.p.：141.0-143.0℃
1H-NMR(CDCl3)δ：8.12(1H，s)，7.73(2H，d，J＝8.3Hz)，7.41(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.17(1H，s)，6.58(1H，d，J＝7.7Hz)，4.22-4.14(1H，m)，2.82-2.30(2H，m)，2.78(2H，q，J＝7.6Hz)，2.39(3H，s)，1.35(3H，t，J＝7.5Hz)，1.24(3H，d，J＝6.6Hz)。
MS(ESJ)m/z：579(MH+)，691([M+CF3COOH-H]-)。
[α]D 245.08 ° (c0.394, methanol)
ee：99％。
Example 255
N- { [ ((1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 11- [4- [ (2R) -2-azidopropyl ] phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 253, step 1, from (2S) -1- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -2-propanol (example 250, step 4).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.46(2H，d，J＝7.9Hz)，7.29(2H，d，J＝7.9Hz)，7.21(1H，s)，3.84-3.77(1H，m)，2.92-2.89(2H，m)，2.79(2H，q，J＝7.6Hz)，1.39-1.33(6H，m)。
Step 2 (1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- [ (2R) -2-azidopropyl) phenyl ] -6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole (step 1).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.44(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.21(1H，s)，3.49-3.26(1H，m)，2.86-2.65(2H，m)，2.79(2H，q，J＝7.5Hz)，1.36(3H，t，J＝7.5Hz)，1.20(3H，d，J＝6.2Hz)。
Step 3N- { [ ((R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-methylethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from (1R) -2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } -1-methylethylamine (step 2).
m.p.：138.0-141.0℃
1H-NMR(CDCl3)δ：8.12(1H，s)，7.73(2H，d，J＝8.3Hz)，7.41(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.17(1H，s)，6.58(1H，d，J＝7.7Hz)，4.22-4.14(1H，m)，2.82-2.30(2H，m)，2.78(2H，q，J＝7.6Hz)，2.39(3H，s)，1.35(3H，t，J＝7.5Hz)，1.24(3H，d，J＝6.6Hz)。
MS(ESI)m/z：579(MH+)，691([M+CF3COOH-H]-)。
[α]D 24+3.43 ° (c0.408, methanol)
ee：99％。
Example 256
2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
A mixture of 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol (example 104 step 2, 2.28g, 5.85mmol) and 1H-pyrazole-3-carbaldehyde (562mg, 2.85mmol) in ethanol (35ml) was stirred at reflux temperature for 1H. The mixture was concentrated and dissolved in benzene (40 ml). To this solution was added lead tetraacetate (2.85g, 6.44mmol) at room temperature.
After stirring at room temperature for 18 hours, a saturated aqueous sodium hydrogencarbonate solution (50ml) and ethyl acetate were added to the mixture. The organic layer was separated. Washed with brine, dried (sodium sulfate) and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (20: 1 to 10: 1) followed by dichloromethane/2-propanol (5: 1) gave 979mg (41%) of the title compound as a light brown solid.
1H-NMR(CDCl3/CD3OD＝4/1)δ：8.12(1H，br.s)，7.74(1H，s)，7.59(1H，br.s)，7.47(2H，d，J＝7.9Hz)，7.34-7.30(3H，m)，6.36(1H，br.s)，3.87(2H，br.t，J＝6.8Hz)，2.95(2H，t，J＝6.8Hz)。
MS(ESI)m/z：407(MH+)，405([M-H]-)。
Step 22- [4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：8.18(1H，s)，7.91(2H，d，J＝8.3Hz)，7.54-7.53(1H，m)，7.34-7.23(8H，m)，6.31(1H，br.s)，4.40(2H，t，J＝6.4Hz)，3.01(2H，t，J＝6.4Hz)，2.42(3H，s)。
MS(ESI)m/z：604(MH+)，602([M-H]-)。
Example 257
2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate mono-P-tosylate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (example 256 step 2).
1H-NMR(DMSO-d6)δ：8.24(1H，s)，7.77-7.74(2H，m)，7.48-7.38(10H，m)，7.26(1H，s)，7.11(2H，d，J＝7.9Hz)，6.44(1H，br.s)，4.30-4.20(2H，m)，2.98-2.93(2H，m)，2.33(3H，s)，2.27(3H，s)。
MS(ESI)m/z：604(MH+)，602([M-H]-)。
Example 258
(1S) -2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) -sulfonylcarbamate monohydrochloride
Step 1 (2S) -1- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-propanol
The title compound was prepared according to the procedure described in example 162 step 1 from 2-chloro-4, 6-dimethyl-3-nitropyridine (example 1 step 2) and (2S) -1- (4-aminophenyl) -2-propanol (example 248 step 2).
1H-NMR(CDCl3)δ：9.58(1H，br.s)，7.59(2H，d，J＝8.6Hz)，7.19(2H，d，J＝8.6Hz)，6.53(1H，s)，4.05-3.98(1H，m)，2.82-2.63(2H，m)，2.55(3H，s)，2.43(3H，s)，1.26(3H，d，J＝6.3Hz)。
Step 2 (2S) -1- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-propanol
The title compound was prepared according to the procedure described in example 28, step 2, from (2S) -1- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.13-707(4H，m)，6.60(1H，s)，6.21(1H，br.s)，4.02-3.91(1H，m)，3.26(2H，br s)，2.77-2.57(2H，m)，2.37(3H，s)，2.20(3H，s)，1.24(3H，d，J＝6.1Hz)。
Step 3 (1S) -2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared from (2S) -1- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-propanol (step 2) according to the procedure described in example 1, step 5.
MS(EI)m/z：365(M+)。
Step 4 (2S) -1- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propanol
The title compound was prepared from (1S) -2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，6.91(1H，s)，4.18-4.05(1H，m)，2.92-2.75(4H，m)，2.66(3H，s)，2.52(3H，s)，1.34-1.25(6H，m)。
Step 5 (1S) -2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from (2S) -1- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-propanol (step 4).
1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.2Hz)，7.33(2H，d，J＝8.2Hz)，7.30-7.26(4H，m)，5.14-5.02(1H，m)，2.99-2.77(4H，m)，2.66(3H，s)，2.51(3H，s)，2.42(3H，s)，1.29-1.23(6H，m)。
MS(ESI)m/z：507(MH+)，505([M-H]-)。
Step 62- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate mono-hydrochloride
The title compound was prepared according to the procedure described for the preparation of example 240 from (1S) -2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate (step 5).
1H-NMR(DMSO-d6)δ：11.92(1H，br.s)，7.76(2H，d，J＝7.9Hz)，7.49-7.39(6H，m)，7.26(1H，br.s)，4.98-4.88(1H，m)，2.94-2.83(4H，m)，2.63(3H，s)，2.46(3H，s)，2.34(3H，s)，1.23(3H，t，J＝7.5Hz)，1.12(3H，d，J＝6.1Hz)。
MS(ESI)m/z：507[(M+H)+]，505[(M-H)-]。
[α]D 2412.49 ° (c1.014, methanol)
Example 259
2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 11- [6- ({4- [ 2-hydroxypropyl ] phenyl } amino) -5-nitro-3-pyridinyl ] ethanone
The title compound was prepared according to the procedure described in example 162, step 1, from 1- (6-chloro-5-nitro-3-pyridinyl) ethanone (Paul, b. et al j.med.chem., 1990, 33, 2231-.
1H-NMR(CDCl3)δ：10.37(1H，br.s)，9.06-9.03(2H，m)，7.60(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，4.10-4.00(1H，m)，2.86-2.69(2H，m)，2.60(3H，s)，1.53(1H，d，J＝4.0Hz)，1.28(3H，d，J＝6.2Hz)。
MS(EI)m/z：315(M+)。
Step 21- [ 5-amino-6- ({4- [ (2-hydroxypropyl ] phenyl } amino) -2-pyridinyl ] ethanone
To a solution of 1- [6- ({4- [ 2-hydroxypropyl ] phenyl } amino) -5-nitro-3-pyridinyl ] ethanone (step 1, 1.54g, 4.88mmol) in tetrahydrofuran (10ml) and ethanol (30ml) was added 10% palladium on carbon (150 mg). The resulting mixture was stirred under hydrogen atmosphere for 19 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give 1.74g (100%) of the title compound as a green syrup.
1H-NMR(CDCl3)δ：8.46(1H，d，J＝1.8Hz)，7.56(1H，d，J＝1.8Hz)，7.50(2H，d，J＝8.3Hz)，7.20(2H，d，J＝8.3Hz)，6.85(1H，br.s)，3.76-3.67(1H，m)，3.38(2H，br.s)，2.81-2.62(2H，m)，2.53(3H，s)，1.26(3H，d，J＝6.1Hz)。
Step 32- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared from 1- [ 5-amino-6- ({4- [ (2-hydroxypropyl ] phenyl } amino) -3-pyridyl ] ethanone (step 2) according to the procedure described in example 1, step 5.
MS(EI)m/z：379(M+)。
Step 41- (2-Ethyl-3- {4- [ 2-hydroxypropyl ] phenyl } -3H-imidazo [4, 5-b ] pyridin-6-yl) ethanone
The title compound was prepared from 2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethylpropionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.93(1H，d，J＝1.8Hz)，8.59(1H，d，J＝1.8Hz)，7.48(2H，d，J＝8.3Hz)，7.36(2H，d，J＝8.3Hz)，4.18-4.08(1H，m)，2.94-2.80(2H，m)，2.68(3H，s)，1.39(3H，t，J＝7.5Hz)，1.33(3H，d，J＝6.2Hz)。
Step 52- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- (2-ethyl-3- {4- [ 2-hydroxypropyl ] phenyl } -3H-imidazo [4, 5-b ] pyridin-6-yl) ethanone (step 4).
1H-NMR(CDCl3)δ：8.93(1H，d，J＝1.8Hz)，8.60(1H，d，J＝1.8Hz)，7.92(2H，d，J＝8.4Hz)，7.38-7.29(6H，m)，5.12-5.03(1H，m)，3.03-2.82(4H，m)，2.69(3H，s)，2.43(3H，s)，1.28-1.24(6H，m)。
MS(ESI)m/z：521[(MH)+]，519[(M-H)-]
Example 260
(1S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate
Step 11- [6- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -5-nitro-3-pyridinyl ] ethanone
The title compound was prepared according to the procedure described in example 162, step 1, from 1- (6-chloro-5-nitro-3-pyridinyl) ethanone (Paul, b. et al j.med.chem., 1990, 33, 2231-.
1H-NMR(CDCl3)δ：10.37(1H，br.s)，9.06-9.03(2H，m)，7.60(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，4.10-4.00(1H，m)，2.86-2.69(2H，m)，2.60(3H，s)，1.53(1H，d，J＝4.0Hz)，1.28(3H，d，J＝6.2Hz)。
Step 21- [ 5-amino-6- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -3-pyridinyl ] ethanone
The title compound was prepared according to the procedure described in example 259 step 2 from 1- [6- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -5-nitro-3-pyridinyl ] ethanone (step 1).
1H-NMR(CDCl3)δ：8.46(1H，d，J＝1.8Hz)，7.56(1H，d，J＝1.8Hz)，7.50(2H，d，J＝8.3Hz)，7.20(2H，d，J＝8.3Hz)，6.85(1H，br.s)，3.76-3.67(1H，m)，3.38(2H，br.s)，2.81-2.62(2H，m)，2.53(3H，s)，1.26(3H，d，J＝6.1Hz)。
Step 3 (1S) -2- [4- (6-acetyl-2-ethyl-2H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate
The title compound was prepared according to the procedure described in example 1, step 5, from 1- [ 5-amino-6- ({4- [ (2S) -2-hydroxypropyl ] phenyl } amino) -3-pyridyl ] ethanone (step 2).
MS(EI)m/z：379(M+)。
Step 41- (2-Ethyl-3- {4- [ (2S) -2-hydroxypropyl ] phenyl } -3H-imidazo [4, 5-b ] pyridin-6-yl) ethanone
The title compound was prepared from (1S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.93(1H，d，J＝1.8Hz)，8.59(1H，d，J＝1.8Hz)，7.48(2H，d，J＝8.3Hz)，7.36(2H，d，J＝8.3Hz)，4.18-4.08(1H，m)，2.94-2.80(2H，m)，2.68(3H，s)，1.39(3H，t，J＝7.5Hz)，1.33(3H，d，J＝6.2Hz)。
Step 5.(1S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 1- (2-ethyl-3- {4- [ (2S) -2-hydroxypropyl ] phenyl } -3H-imidazo [4, 5-b ] pyridin-6-yl) ethanone (step 4).
1H-NMR(CDCl3)δ：8.93(1H，d，J＝1.8Hz)，8.60(1H，d，J＝1.8Hz)，7.92(2H，d，J＝8.4Hz)，7.38-7.29(6H，m)，5.12-5.03(1H，m)，3.03-2.82(4H，m)，2.69(3H，s)，2.43(3H，s)，1.28-1.24(6H，m)。
MS(ESI)m/z：521[(MH)+]，519[(M-H)-]。
Example 261
(1S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate mono-P-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from (1S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-methylethyl (4-methylphenyl) sulfonylcarbamate (example 260, step 5).
1H-NMR(DMSO-d6)δ：11.93(1H，br.s)，8.90(1H，d，J＝1.8Hz)，8.63(1H，d，J＝1.8Hz)，7.76(2H，d，J＝8.4Hz)，7.38-7.29(8H，m)，7.11(2H，d，J＝8.4Hz)，4.96-4.87(1H，m)，2.90-2.79(4H，m)，2.32(3H，s)，2.27(3H，s)，1.26(3H，t，J＝7.5Hz)，1.12(3H，d，J＝6.2Hz)。
MS(ESI)m/z：521[(MH+)]，519[(M-H)-]。
[α]D 248.17 ° (c1.020, methanol)
Example 262
2- {4- [ 6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate mono-P-tosylate
Step 12- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl]Amino } phenyl) ethanol (1.83g, 5.54mmol), 2-pyridinecarboxaldehyde (0.53ml, 5.54mmol), and EtOH (40ml) were refluxed for 1 hour. Cooled to room temperature and the solvent removed. The residue was dissolved in benzene (50ml), washed with Pb (OAc) 4(3.38g, 6.10mmol) was treated at room temperature for 1 hour. The mixture was diluted with ethyl acetate and the solution was washed with saturated aqueous sodium bicarbonate and brine. The organic portion was dried over magnesium sulfate and then filtered. After evaporation in vacuo, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate 5/2 to give 1.20g (52%) of the title compound.
1H-NMR(CDCl3)δ：8.42-8.39(1H，m)，8.23(1H，s)，8.10-8.07(1H，m)，7.79-7.75(1H，m)，7.40-7.23(6H，m)，3.97(2H，t，J＝6.6Hz)，2.99(2H，t，J＝6.6Hz)。
MS(ESI)m/z：418([M+H]+)，476([M+CF3CO2]-)。
Step 22- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol.
1H-NMR(CDCl3)δ：8.39-8.37(1H，m)，8.23(1H，s)，8.10-8.06(1H，m)，7.92-7.87(2H，m)，7.81-7.76(1H，m)，7.33-7.18(8H，m)，4.35(2H，t，J＝6.8Hz)，2.98(2H，t，J＝6.8Hz)，2.41(3H，s)；MS(ESI)m/z：615([M+H]+)，613([M-H]-)]
Example 263
2- {4- [ 6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate mono-P-tosylate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate.
MS(ESI)m/z：615([M+H]+)
Example 264
N- { [ (2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono-P-toluenesulfonate
Step 16-chloro-1- [4- (2-chloroethyl) phenyl ] -2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (example 262, step 1).
1H-NMR(CDCl3)δ：8.41-8.39(1H，m)，8.24(1H，s)，8.11(1H，d，J＝8.8Hz)，7.82-7.76(1H，m)，7.38(2H，d，J＝8.4Hz)，7.35(1H，s)，7.30-7.25(3H，m)，3.31(2H，t，J＝7.2Hz)，3.19(2H，t，J＝7.2Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole (step 1).
1H-NMR(CDCl3)δ：8.40-8.39(1H，m)，8.24(1H，s)，8.10(1H，d，J＝7.9Hz)，7.81-7.75(1H，m)，7.39(2H，d，J＝8.4Hz)，7.34(1H，s)，7.29-7.25(3H，m)，3.61(2H，t，J＝6.8Hz)，3.01(2H，t，J＝6.8Hz)。
Step 32- {4- [ 6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole (step 2).
1H-NMR(CDCl3)δ：8.37-8.36(1H，m)，8.19(1H，s)，8.03-8.00(1H，m)，7.78-7.71(1H，m)，7.32-7.18(6H，m)，3.02(2H，t，J＝6.8Hz)，2.82(2H，t，J＝6.8Hz)，2.17(2H，br.s)。
Step 4N- { [ (2- {4- [ 6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine (step 3).
1H-NMR(CDCl3)δ：8.42-8.39(1H，m)，8.24(1H，s)，8.10(1H，d，J＝8.1Hz)，7.81-7.75(1H，m)，7.69(2H，d，J＝8.3Hz)，7.33-7.24(8H，m)，6.72-6.69(1H，m)，3.63-3.56(2H，m)，2.93(2H，t，J＝6.8Hz)，2.38(3H，s)。
MS(ESI)m/z：614[(MH)+]，612[(M-H)-]。
Step 5N- { [ (2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 4).
1H-NMR(DMSO-d6)δ：10.63(1H，br.s)，8.41-8.39(1H，m)，8.35(1H，s)，8.08-7.95(2H，m)，7.75(2H，d，J＝8.3Hz)，7.49(2H，d，J＝8.3Hz)，7.44-7.27(8H，m)，7.10(2H，d，J＝7.7Hz)，6.61-6.57(1H，m)，3.30-3.23(2H，m)，2.74(2H，t，J＝7.0Hz)，2.31(3H，s)，2.27(3H，s)。
MS(ESI)m/z：614[(MH)+]，612[(M-H)-]。
Example 265
N- { [ (2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono-P-toluenesulfonate
Step 16-chloro-1- [4- (2-chloroethyl) phenyl ] -2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethanol (example 255, step 1).
1H-NMR(DMSO-d6)δ：13.29(1H，s)，8.25(1H，s)，7.83-7.81(1H，m)，7.52-7.43(4H，m)，7.23(1H，s)，6.67-6.65(1H，m)，3.95(2H，t，J＝7.0Hz)，3.16(2H，t，J＝7.0Hz)。
Step 21- [4- (2-azidoethyl) phenyl-6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazole (step 1).
1H-NMR(DMSO-d6)δ：13.27(1H，s)，8.25(1H，s)，7.82(1H，s)，7.52-7.43(4H，m)，7.21(1H，s)，6.65(1H，s)，3.67(2H，t，J＝7.0Hz)，2.99(2H，t，J＝7.0Hz)。
Step 32- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylamine
The title compound was prepared according to the procedure described for example 37 step 7 from 1- [4- (2-azidoethyl) phenyl-6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazole (step 2).
MS(EI)m/z：405(M+)。
Step 4N- { [ (2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, 2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethylamine (step 3).
1H-NMR(CDCl3)δ：8.17(1H，s)，7.69(2H，d，J＝8.4Hz)，7.57(1H，d，J＝2.2Hz)，7.30-7.18(8H，m)，6.82-6.77(1H，m)，6.60(1H，d，J＝2.2Hz)，3.64-3.58(2H，m)，2.91(2H，t，J＝6.4Hz)，2.39(3H，s)。
Step 5N- { [ (2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 6-chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 4).
1H-NMR(DMSO-d6)δ：10.64(1H，br.s)，8.24(1H，s)，8.35(1H，s)，7.78-7.75(3H，m)，7.49-7.80(8H，m)，7.11(2H，d，J＝7.9Hz)，6.60-6.57(1H，m)，6.38-6.37(1H，m)，3.33-3.26(2H，m)，2.78(2H，t，J＝7.2Hz)，2.32(3H，s)，2.28(3H，s)。
MS(ESI)m/z：603[(MH)+]，601[(M-H)-]。
Example 266
3- (3-chloro-4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
Step 1 diethyl 2- (2-chloro-4-nitrophenyl) malonate
To a suspension of NaH (1.4g, 34.2mmol) in 80ml of 1, 4-dioxane was added diethyl malonate (5.2ml, 34.2mmol) followed by successive additions of CuBr (4.9g, 34.2mmol) and 3-chloro-4-fluoronitrobenzene (5.0g, 28.5 mmol). The mixture was stirred at room temperature for 0.5 hour and at reflux temperature for 12 hours. The mixture was poured into water and the precipitate was filtered through a celite pad. The filtrate was extracted with ethyl acetate (2X 50 ml). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated to give a green oil. The mixture was purified by column chromatography on silica eluting with hexane/ethyl acetate (10/1) to give 7.6g (85%) of the title compound as a yellow oil
1H-NMR(CDCl3)δ：8.30(1H，d，J＝2.4Hz)，8.16(1H，dd，J＝2.2，8.6Hz)，7.74(1H，d，J＝8.6Hz)，5.27(1H，s)，4.28(2H，q，J＝7.2Hz)，4.27(2H，q，J＝7.2Hz)，1.29(6H，t，J＝7.2Hz)。
Step 22- (2-chloro-4-nitrophenyl) acetic acid
To a solution of diethyl 2- (2-chloro-4-nitrophenyl) malonate (step 1, 7.6g, 24.2mmol) in methanol (18ml) was added 6M-NaOH (12 ml). Stirred at 50 ℃ for 1 hour. The reaction was quenched by addition of saturated aqueous citric acid (16ml) and water. The organic layer was extracted with ethyl acetate (2X 50ml), washed with brine, dried (magnesium sulfate) and concentrated to give 4.52g (87%) of the title compound as a pale yellow solid.
1H-NMR(CDCl3)δ：12.6(1H，br.s)，8.30(1H，d，J＝2.6Hz)，8.18(1H，dd，J＝2.4，8.4Hz)，7.73(1H，d，J＝8.6Hz)，3.90(2H，s)。
Step 3 methyl 2- (2-chloro-4-nitrophenyl) acetate
To a solution of 2- (2-chloro-4-nitrophenyl) acetic acid (step 2, 4.5g, 21mmol) in dimethyl acetate/methanol (4/1), trimethylsilyl chloride (0.3ml) was added and stirred at room temperature for 7 hours. The solvent was removed and the residue was purified by column chromatography on silica, eluting with hexane/ethyl acetate (10/1) to give 3.6g (74%) of the title compound as a yellow oil.
1H-NMR(CDCl3)δ：8.28(1H，d，J＝2.3Hz)，8.11(1H，dd，J＝2.3，8.6Hz)，7.50(1H，d，J＝8.6Hz)，3.88(2H，s)，3.74(3H，s)。
Step 4 methyl 2- (4-amino-2-chlorophenyl) acetate
To a solution of methyl 2- (2-chloro-4-nitrophenyl) acetate (step 3, 3.6g, 15.6mmol) in ethanol/water (4/1) was added Fe (4.4g, 78.0mmol) and ammonium chloride (409mg, 7.8 mmol). The mixture was stirred at reflux temperature for 1 hour. The solvent was removed and the residue was diluted with dichloromethane. The mixture was washed with brine and concentrated to dryness (magnesium sulfate) to give 2.59g (83%) of the title compound as an orange oil.
The title compound was prepared according to the procedure described for example 28, step 2, from methyl 2- (2-chloro-4-nitrophenyl) acetate (step 3).
1H-NMR(CDCl3)δ：7.04(1H，d，J＝8.2Hz)，6.72(1H，d，J＝2.3Hz)，6.54(1H，dd，J＝2.5，8.2Hz)，3.70(3H，s)，3.66(2H，s)
Step 5 methyl { 2-chloro-4- [ (4, 6-dimethyl-3-nitro-2-pyridine) amino ] phenyl } acetate
To a mixture of methyl 2- (4-amino-2-chlorophenyl) acetate (step 4, 2.6g, 13.0mmol) and 4, 6-dimethyl-3-nitro-2-pyridine (example 1, step 2, 2.4g, 13.0mmol) in DMSO, diisopropylethylamine was added. The resulting mixture was stirred at 50 ℃ for 9 hours. The mixture was poured into water and extracted with ethyl acetate (3 × 30 ml). The organic layer was washed with brine and concentrated to a brown oil on drying (magnesium sulfate). Purification of the oil by column chromatography on silica eluting with hexane/ethyl acetate (10/1) gave 1.4g (29%) of the title compound as a yellow solid.
1H-NMR(CDCl3)δ：9.55(1H，br.s)，7.90(1H，d，J＝2.2Hz)，7.43(1H，dd，J＝2.2，8.3Hz)，7.24(1H，d，J＝8.3Hz)，6.59(1H，s)，3.76(2H，s)，3.72(3H，s)，2.56(3H，s)，2.46(3H，s)。
MS(EI)m/z：349(M+)。
Step 6 methyl 2-chloro- {4- [ (3-amino-4.6-dimethyl-2-pyridyl) amino ] phenyl } acetate
The title compound was prepared according to the procedure described in example 28, step 2, from methyl { 2-chloro-4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } acetate (step 5).
1H-NMR(CDCl3)δ：7.26(1H，d，J＝2.2Hz)，7.20(1H，d，J＝8.3Hz)，7.00(1H，dd，J＝2.2，8.3Hz)，6.64(1H，s)，6.37(1H，br.s)，3.70(3H，s)，3.27(1H，br.s)，2.68(3H，s)，2.38(3H，s)，2.20(3H，s)。
Step 7 methyl 2- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ethyl acetate
The title compound was prepared from methyl 2-chloro- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } acetate (step 6) according to the procedure described in example 1, step 5
1H-NMR(CDCl3)δ：7.50(1H，d，8.3Hz)，7.47(1H，d，J＝2.2Hz)，7.31(1H，dd，J＝2.2，8.3Hz)，6.92(1H，s)，3.87(2H，s)，3.77(3H，s)，2.85(2H，q，J＝7.5Hz)，2.65(3H，s)，2.53(3H，s)，1.31(3H，t，J＝7.5Hz)。
MS(EI)m/z：357(M+)。
Step 82- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine-3) phenylethanol
To a solution of methyl 2- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ethyl acetate (step 7, 1.13g, 3.15mmol) was added LAH carefully and stirred at room temperature for 1 hour. The reaction was quenched with water and the mixture was diluted with ethyl acetate (50 ml). To the mixture was added a saturated aqueous solution (50ml) of sodium potassium tartrate, and the mixture was stirred for 2.5 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2X 20 ml). The combined organic layers were washed with brine and concentrated to dryness (Mg2SO4) to give 1.0g of the title compound as a white solid.
1H-NMR(CDCl3)δ：7.41-7.53(2H，m)，7.25-7.29(1H，m)，6.92(1H，s)，3.96(2H，m)，3.11(3H，t，J＝7.4Hz)，2.82(2H，m)，2.65(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.4Hz)。
MS(EI)m/z：329(M+)。
Step 93- [ 3-chloro-4- (2-chloroethyl) phenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4.5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from methyl 2- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenylethanol (step 8)
1H-NMR(CDCl3)δ：7.45-7.52(2H，m)，7.23-7.31(1H，m)，6.92(1H，s)，3.82(2H，t，J＝7.3Hz)，3.29(2H，t，J＝7.3Hz)，2.83(2H，q，J＝7.6Hz)，2.65(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.6Hz)。
Step 103- (4- (2-azidoethyl-3-chlorophenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [ 3-chloro-4- (2-chloroethyl) phenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 9)
1H-NMR(CDCl3)δ：7.45-7.48(2H，m)，7.29(1H，dd，J＝2.1，7.9Hz)，6.92(1H，s)，3.62(1H，t，J＝7.1Hz)，3.12(1H，t，J＝7.3Hz)，2.83(2H，q，J＝7.4Hz)，2.65(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.4Hz)。
Step 112- [ 2-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [45-b ] pyridin-3-yl) phenyl ] ethylamine
To a solution of methyl 3- [4- (2-azidoethyl) -3-chlorophenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 10, 430mg, 1.2mmol) in ethanol/water (4/1) was added Fe (335mg, 6.0mmol) and ammonium chloride (409mg, 7.8 mmol). The mixture was stirred at reflux temperature for 1 hour. The solvent was removed and the residue was diluted with dichloromethane. The mixture was washed with brine and concentrated to give 390mg of the title compound as an orange oil.
1H-NMR(CDCl3)δ：7.44(2H，d，J＝7.4Hz)，7.25(1H，m)，6.92(1H，s)，2.92-3.15(6H，m)，2.83(2H，q，J＝7.4Hz)，2.65(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.4Hz)。
Step 12
2- [ 2-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) ethylamine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [ 2-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 11)
1H-NMR(CDCl3)δ：7.83(2H，d，J＝8.4Hz)，7.28-7.36(4H，m)，7.14(1H，d，J＝7.7Hz)，6.92(1H，s)，6.28(1H，br.s)，3.58(2H，dt，J＝6.3Hz)，3.02(2H，t，J＝6.4Hz)，2.74(2H，q，J＝7.6Hz)，2.66(3H，s)，2.45(3H，s)，2.41(3H，s)，1.25(3H，t，J＝7.6Hz)。
MS(ESI)m/z：526(M+)。
Example 267
3- (2-chloro-4- [2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
Step 12- { 3-chloro-4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 4, 6-dimethyl-3-nitro-2-pyridine (0.66g, 3.8mmol, example 1, step 2) and 4-amino-2-chloro-phenylethanol (0.72g, 3.8mmol, eur.j.med.chem., 1996, 31, 133.).
1H-NMR(CDCl3)δ：9.85(1H，s)，8.37(1H，d，J＝8.4Hz)，7.31(1H，d，J＝2.0Hz)，7.14(1H，dd，J＝2.0，8.3Hz)，6.60(1H，s)，3.87(2H，dt，J＝6.2，6.4Hz)，2.84(2H，t，J＝6.4Hz)，256(3H，s)，2.46(3H，s)，1.40(1H，t，J＝6.2Hz)。
MS(EI)m/z：321(M+)。
Step 2 methyl 3-chloro- (4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- { 3-chloro-4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.26(1H，d，J＝2.2Hz)，7.20(1H，d，J＝8.3Hz)，7.00(1H，dd，J＝2.2，8.3Hz)，6.64(1H，s)，6.37(1H，br.s)，3.70(3H，s)，3.27(1H，br.s)，2.68(3H，s)，2.38(3H，s)，2.20(3H，s)。
Step 32- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenylethyl propionate
The title compound was prepared from 3-chloro- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl propionate (step 2) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：7.50(1H，d，8.3Hz)，7.47(1H，d，J＝2.2Hz)，7.31(1H，dd，J＝2.2，8.3Hz)，6.92(1H，s)，3.87(2H，s)，3.77(3H，s)，2.85(2H，q，J＝7.5Hz)，2.65(3H，s)，2.53(3H，s)，1.31(3H，t，J＝7.5Hz)。
MS(EI)m/z：357(M+)。
Step 42- [ 3-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenylethanol
The title compound was prepared from methyl 2- [ 2-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenylethylpropionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.51(1H，s)，7.34(2H，s)，6.91(1H，s)，3.96(2H，dd，J＝6.2，12.0Hz)，2.96(2H，t，J＝7.4Hz)，2.70(2H，m)，2.66(3H，s)，2.51(3H，s)，1.67(1H，br.t，J＝6.2Hz)，1.28(3H，t，J＝7.4Hz)。
MS(ESI)m/z：329(M+)。
Step 53- [ 2-chloro-4- (2-chloroethyl) phenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [ 3-chloro-4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenylethanol (step 4).
1H-NMR(CDCl3)δ：7.49(1H，d，J＝1.3Hz)，7.34-7.49(2H，m)，6.91(1H，s)，3.80(2H，t，J＝7.2Hz)，3.17(2H，t，J＝7.0Hz)，2.60-2.85(2H，m)，2.66(3H，s)，2.51(3H，s)，1.28(3H，t，J＝7.5Hz)。
MS(EI)m/z：347[(M-H)-]。
Step 63- [4- (2-azidoethyl) -3-chlorophenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [ 2-chloro-4- (2-chloroethyl) phenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 5).
1H-NMR(CDCl3)δ：7.49(1H，m，J＝1.8Hz)，7.31-7.38(2H，m)，6.91(1H，s)，3.62(2H，t，J＝7.0Hz)，2.98(2H，t，J＝7.3Hz)，2.60-2.80(2H，m)，2.66(3H，s)，2.51(3H，s)，1.27(3H，t，J＝7.5Hz)。
MS(EI)m/z：354(M+)。
Step 72- [ 3-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
To a stirred solution of 3- [4- (2-azidoethyl) -3-chlorophenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 6, 149mg, 0.4mmol) in THF (4ml) at room temperature was added triphenylphosphine (116mg, 0.4 mmol). After the addition was complete, stirring was continued at the same temperature for another 2.5 hours and at reflux temperature for 3.5 hours. To the resulting mixture was added water (1.0ml) at room temperature, and the solvent was removed the mixture was dissolved in dichloromethane (100ml) and washed with brine. The organic layer was dried (magnesium sulfate) and concentrated to give a yellow oil.
MS(EI)m/z：328(M+)。
Step 82- [ 3-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [ 3-chloro-4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 7).
1H-NMR(CDCl3)δ：7.88(1H，s)，7.85(1H，s)，7.19-7.34(5H，m)，6.92(1H，s)，6.94(1H，s)，6.13(1H，br.s)，3.54(2H，m)，2.78(2H，t，J＝6.4Hz)，2.67(3H，s)，2.63(3H，m)，2.42(3H，s)，2.40(3H，s)，1.25(3H，t，J＝7.5Hz)。
MS(EI)m/z：526(M+)。
Example 268
2-ethyl-3- (3-methoxy-4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
Step 1 diethyl 2- (2-methoxy-4-nitrophenyl) malonate
The title compound was prepared from 4-bromo-3-methoxynitrobenzene according to the procedure described in example 266, step 1.
1H-NMR(CDCl3)δ：7.78(1H，dd，J＝2.2，8.4Hz)，7.75(1H，d，J＝2.2Hz)，7.54(1H，d，J＝8.4Hz)，5.15(1H，s)，4.25(2H，q，J＝7.2Hz)，4.25(2H，q，J＝7.2Hz)，3.94(3H，s)，1.28(6H，t，J＝7.2Hz)。
Step 22- (2-methoxy-4-nitrophenyl) acetic acid
The title compound was prepared according to the procedure described for example 266 step 2 from diethyl 2- (2-methoxy-4-nitrophenyl) malonate (step 1).
1H-NMR(CDCl3)δ：12.4(1H，br.s)，7.82(1H，dd，J＝2.2，8.4Hz)，7.75(1H，dd，J＝2.2Hz)，7.50(1H，d，J＝8.4Hz)，3.90(3H，s)，3.66(2H，s)。
Step 3 methyl 2- (2-methoxy-4-nitrophenyl) acetate
To a solution of 2- (2-methoxy-4-nitrophenyl) acetic acid (step 2, 1.2g, 5.5mmol) in methanol/dichloromethane (11ml, 1/1) was added trimethylsilyldiazomethane (2M, 5.6ml, 11.8 mmol). Stir at room temperature for 10 minutes. The mixture was quenched with saturated aqueous citric acid and extracted with ethyl acetate (3X 20 ml). The organic layer was washed with brine and concentrated to dryness (magnesium sulfate) to give 1.2g of the title compound as an orange yellow solid.
1H-NMR(CDCl3)δ：7.83(1H，dd，J＝2.2，8.3Hz)，7.73(1H，dd，J＝2.2Hz)，7.34(1H，d，J＝8.1Hz)，3.93(3H，s)，3.71(2H，s)，3.71(3H，s)。
Step 4 methyl 2- (4-amino-2-methoxyphenyl) acetate
To a solution of methyl 2- (2-methoxy-4-nitrophenyl) acetate (step 3, 1.2g, 5.5mmol) in methanol (10ml) was added 10% Pd/C (130mg, 0.12 mmol). Stirred at room temperature for 3 hours under hydrogen atmosphere. The catalyst was filtered through a celite pad, washing and ethyl acetate ethanol. The filtrate was concentrated to give 1.1g of the title compound as a violet oil.
1H-NMR(CDCl3)δ：6.94(1H，d，J＝7.7Hz)，6.26(1H，d，J＝2.0Hz)，6.23(1H，s)，3.70(3H，s)，3.76(3H，s)，367(3H，s)，3.52(2H，s)。
Step 5 methyl {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] -2-methoxyphenyl } acetate
The title compound was prepared according to the procedure described in example 1, step 3, from methyl 2- (4-amino-2-methoxyphenyl) acetate (step 4).
1H-NMR(CDCl3)δ：9.60(1H，s)，7.47(1H，d，J＝1.7Hz)，7.06-7.15(2H，m)，6.55(1H，s)，3.84(3H，s)，3.69(3H，s)，3.62(2H，s)，2.56(3H，s)，2.44(3H，s)。
MS(EI)m/z：345(M+)。
Step 6 methyl {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino ] -2-methoxyphenyl } acetate
The title compound was prepared according to the procedure described in example 28, step 2, from methyl {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] -2-methoxyphenyl } acetate (step 5).
1H-NMR(CDCl3)δ：7.03(1H，d，J＝5.1Hz)，7.02(1H，s)，6.60(1H，s)，6.57(1H，dd，J＝2.2，8.3Hz)，3.79(3H，s)，3.68(3H，s)，3.56(2H，s)，3.25-3.35(br.s，2H)，2.38(3H，s)，2.20(3H，s)。
MS(EI)m/z：315(M+)。
Step 7 methyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methoxyphenylethyl acetate
The title compound was prepared according to the procedure described in example 1, step 5, from methyl {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] -2-methoxyphenyl } acetate (step 6).
1H-NMR(CDCl3)δ：7.36(1H，d，J＝7.9Hz)，6.89-6.99(3H，m)，3.84(2H，s)，3.74(3H，s)，3.71(2H，s)，2.85(2H，q，J＝7.5Hz)，2.66(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.5Hz)。
MS(EI)m/z：353(M+)。
Step 82- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methoxyphenyl ethanol
The title compound was prepared according to the procedure described in example 266, step 8, from methyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methoxyphenylethyl acetate (step 7).
1H-NMR(CDCl3)δ：7.33(1H，d，J＝7.7Hz)，6.87-6.95(3H，m)，3.90(2H，dt，J＝6.0，6.2Hz)，3.84(3H，s)，2.98(2H，t，J＝6.4Hz)，2.84(2H，q，J＝7.5Hz)，2.66(3H，s)，2.53(3H，s)，1.76(1H，br.t)，1.30(3H，t，J＝7.5Hz)。
MS(EI)m/z：324[(M-H)-]。
Step 93- [4- (2-chloroethyl) -3-methoxyphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4.5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methoxyphenylethanol (step 8).
1H-NMR(CDCl3)δ：7.33(1H，d，J＝7.7Hz)，6.87-6.94(3H，m)，3.84(3H，s)，3.77(3H，t，J＝7.6Hz)，3.16(2H，t，J＝7.3Hz)，2.84(2H，q，J＝7.6Hz)，2.66(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.6Hz)。
Step 103- [4- (2-azidoethyl) -3-methoxyphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) -3-methoxyphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 9).
1H-NMR(CDCl3)δ：7.45-7.48(2H，m)，7.29(1H，dd，J＝2.1，7.9Hz)，6.92(1H，s)，3.62(1H，t，J＝7.1Hz)，3.12(1H，t，J＝7.3Hz)，2.83(2H，q，J＝7.4Hz)，2.65(3H，s)，2.53(3H，s)，1.30(3H，t，J＝7.4Hz)。
Step 112- [4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl-2-methoxy) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 3- [4- (2-azidoethyl) -3-methoxyphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 10).
1H-NMR(CDCl3)δ：7.30(1H，d，J＝7.7Hz)，6.92(1H，dd，J＝2.0，7.9Hz)，6.91(1H，br.s)，6.86(1H，d，J＝2.0Hz)，3.83(3H，s)，2.65(3H，s)，2.99(2H，br.t，J＝4.5Hz)，2.85(2H，q，J＝8.3Hz)，2.84(2H，q，J＝7.7Hz)，2.66(3H，s)，2.53(3H，s)，1.29(3H，t，J＝7.7Hz)。
Step 122-Ethyl- (3-methoxy-4- {2- [ ({ [ (4-methylphenyl ] sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl-2-methoxy) phenyl ] ethylamine (step 11).
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.3Hz)，7.30(4H，m)，7.14(1H，d，J＝81Hz)，7.01(1H，d，J＝7.9Hz)，6.92(1H，s)，6.79(1H，d，J＝2.0Hz)，6.63(1H，dd，J＝1.8，7.7Hz)，6.04(1H，br.t，J＝5.1Hz)，3.74(3H，s)，3.51(2H，dt，J＝6.0Hz)，2.85(2H，t，J＝6.2Hz)，2.70(2H，q，J＝7.5Hz)，2.66(3H，s)，2.44(3H，s)，2.41(3H，s)，1.23(3H，t，J＝7.5Hz)。
MS(ESI)m/z：522[(M+H)+]，520[(M-H)-]。
Example 269
2-ethyl-3- (3-methyl-4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
Step 1 diethyl 2- (2-methyl-4-nitrophenyl) malonate
The title compound was prepared from 4-bromo-3-methylnitrobenzene according to the procedure described in example 268, step 1.
1H-NMR(CDCl3)δ：8.10(1H，s)，8.05-8.10(1H，m)，7.62(1H，d，J＝9.2Hz)，4.93(1H，s)，4.26(2H，q，J＝7.3Hz)，4.25(2H，q，J＝7.3Hz)，2.46(3H，s)，1.28(6H，t，J＝7.3Hz)。
Step 22- (2-methyl-4-nitrophenyl) acetic acid
The title compound was prepared according to the procedure described for the preparation of example 266 step 2 from diethyl 2- (2-methyl-4-nitrophenyl) malonate (step 1)
1H-NMR(CDCl3)δ：8.08(1H，br.s)，8.02(1H，dd，J＝8.6Hz)，7.49(1H，d，J＝8.4Hz)，3.77(2H，s)，2.35(3H，s)。
Step 3 methyl 2- (2-methyl-4-nitrophenyl) acetate
The title compound was prepared according to the procedure described for example 266 step 3 from 2- (2-methyl-4-nitrophenyl) acetic acid (step 2).
1H-NMR(CDCl3)δ：8.07(1H，d，J＝2.1Hz)，8.02(1H，dd，J＝2.3，5.9Hz)，7.36(1H，d，J＝8.4Hz)，3.74(2H，s)，3.71(3H，s)，2.42(3H，s)。
Step 4 methyl 2- (4-amino-2-methylphenyl) acetate
The title compound was prepared from methyl 2- (2-methyl-4-nitrophenyl) acetate (step 3) according to the procedure described in example 268, step 4
1H-NMR(CDCl3)δ：6.97(1H，d，J＝7.9Hz)，6.48-6.52(2H，m)，3.67(3H，s)，3.57(2H，br.s)，3.53(3H，s)，2.22(3H，s)。
Step 5 methyl {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] -2-methylphenyl } acetate
The title compound was prepared according to the procedure described in example 1, step 3, from methyl 2- (4-amino-2-methylphenyl) acetate (step 4).
1H-NMR(CDCl3)δ：7.54(1H，br.d，J＝8.3Hz)，7.38(1H，br.s)，7.17(1H，d，J＝8.39Hz)，6.52(1H，s)，3.69(3H，s)，3.63(2H，s)，2.55(3H，s)，2.43(3H，s)，2.32(3H，s)。
MS(EI)m/z：345(M+)。
Step 6 methyl {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino ] -2-methylphenyl } acetate
The title compound was prepared according to the procedure described in example 28, step 2, from methyl {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] -2-methylphenyl } acetate (step 5).
1H-NMR(CDCl3)δ：7.07(1H，d，J＝9.0Hz)，6.91-6.93(2H，m)，6.62(1H，s)，6.36(1H，br.s)，3.79(3H，s)，3.67(3H，s)，3.57(2H，s)，3.30(br.s，2H)，2.37(3H，s)，2.26(3H，s)，2.2(3H，s)。
Step 7 Ethyl methyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methylphenylacetate
The title compound was prepared according to the procedure described in example 1, step 5, from methyl {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] -2-methylphenyl } acetate (step 6).
1H-NMR(CDCl3)δ：7.39(1H，d，J＝7.6Hz)，7.17-7.25(2H，m)，6.90(1H，s)，3.74(3H，s)，3.72(2H，s)，2.82(2H，q，J＝7.4Hz)，2.65(3H，s)，2.52(3H，s)，2.40(3H，s)，1.28(3H，t，J＝7.6Hz)。
MS(EI)m/z：337(M+)。
Step 82- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methylphenyl ] ethanol
The title compound was prepared according to the procedure described in example 266, step 8, from methyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methylphenylethyl acetate (step 7).
1H-NMR(CDCl3)δ：7.35(1H，d，J＝7.9Hz)，7.17(1H，s)，7.16(1H，d，J＝7.9Hz)，6.90(1H，s)，3.84(2H，dt，J＝6.8Hz)，2.96(2H，t，J＝7.0Hz)，2.81(2H，q，J＝7.5Hz)，2.66(3H，s)，2.52(3H，s)，2.40(s，3H)，1.91(1H，br.t)，1.28(3H，t，J＝7.5Hz)。
MS(EI)m/z：324[(M-H)-]。
Step 93- [4- (2-chloroethyl) -3-methylphenyl ] -2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) -2-methylphenylethanol (step 8).
1H-NMR(CDCl3)δ：7.35(1H，d，J＝8.4Hz)，7.17-7.19(2H，m)，6.90(1H，s)，3.75(2H，t，J＝7.6Hz)，3.17(2H，t，J＝7.6Hz)，2.81(2H，q，J＝7.5Hz)，2.65(3H，s)，2.41(3H，s)，2.36(3H，s)，1.28(3H，t，J＝7.5Hz)。
Step 103- [4- (2-azidoethyl) -3-methylphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 8, from 3- [4- (2-chloroethyl) -3-methylphenyl-2-ethyl-5, 7-dimethyl-3H imidazo [4, 5-b ] pyridine (step 9).
1H-NMR(CDCl3)δ：7.34(1H，d，J＝8.7Hz)，7.19-7.26(2H，m)，6.90(1H，s)，3.62(1H，t，J＝7.1Hz)，3.56(2H，t，J＝7.6Hz)，2.99(2H，t，J＝7.6Hz)，2.81(2H，q，J＝7.6Hz)，2.65(3H，s)，2.52(3H，s)，2.41(3H，s)，1.27(3H，t，J＝7.6Hz)。
Step 112- [4- (-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl-2-methyl) phenyl ] ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 3- [4- (2-azidoethyl) -3-methylphenyl-2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 10).
1H-NMR(CDCl3)δ：7.32(1H，d，J＝7.7Hz)，7.14-7.16(2H，m)，6.91(1H，br.s)，6.90(1H，s)，3.02(2H，br.t，J＝7.3Hz)，2.77-2.87(4H，m)，2.65(3H，s)，2.53(3H，s)，2.40(3H，s)，1.28(3H，t，J＝7.5Hz)。
Step 122-Ethyl- (3-methyl-4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl-2-methyl) phenyl ] ethylamine (step 11).
1H-NMR(CDCl3)δ：7.86(1H，d，J＝8.0Hz)，7.31(1H，d，J＝8.0Hz)，7.03(1H，d，J＝7.9Hz)，6.91(1H，s)，6.85(1H，d，J＝8.4Hz)，6.07-6.11(1H，m)，3.51(2H，q，J＝6.4Hz)，2.85(2H，t，J＝6.4Hz)，261-2.69(2H，m)，2.69(3H，s)，2.44(3H，s)，2.28(3H，s)，1.23(3H，t，J＝7.5Hz)。
MS(ESI)m/z：506[(M+H)+]，504[(M-H)-]。
Example 270
6-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
Step 1 (4-amino-2-pyridyl) acetonitrile
The title compound was prepared according to the procedure described in example 28, step 2, from (4-nitro-2-pyridinyl) acetonitrile (8.6g, 52.9mmol, Katz; R.B.; Voyle, M., Synthesis, 1989, 4, 314.).
1H-NMR(CDCl3)δ：8.04(1H，d，J＝2.8Hz)，7.17(1H，d，J＝8.2Hz)，6.99(1H，dd，J＝2.8，8.4Hz)，3.81(2H，s)，3.76(2H，br.s)。
Step 2 {5- [ 5-chloro-2-nitro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetonitrile
The title compound was prepared according to the procedure described for example 1 step 3 from (5-aminopyridin-2-yl) acetonitrile (step 1).
1H-NMR(CDCl3)δ：9.66(1H，s)，8.60(2H，m)，7.71(1H，dd，J＝2.6，8.4Hz)，7.60(1H，d，J＝8.3Hz)，7.13(1H，s)，4.03(2H，s)
MS(EI)m/z：356(M+)。
Step 3 {5- [ 2-amino-5-chloro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetonitrile
The title compound was prepared according to the procedure described in example 28, step 2, from {5- [ 5-chloro-2-nitro 4- (trifluoromethyl) anilino ] -2-pyridinyl } acetonitrile (step 2).
1H-NMR(CDCl3)δ：8.25(1H，d，J＝2.1Hz)，7.12-7.34(3H，m)，5.47(1H，br.s)，3.89(2H，s)，3.78(2H，br.s)。
Step 4 {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl) -2-pyridinyl } acetonitrile
The title compound was prepared according to the procedure described in example 1, step 5, from {5- [ 2-amino-5-chloro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetonitrile (step 3).
1H-NMR(CDCl3)δ：8.66(1H，s)，8.15(1H，s)，7.73-7.83(2H，m)，7.12(1H，s)，4.12(2H，s)，2.79(2H，q，J＝7.6Hz)，1.40(3H，t，J＝7.6Hz)。
Step 52- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethanamine
To {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl](step 4, 1.0g, 2.8mmol) in aqueous ammonia-ethanol (30ml), Raney-Ni was added, and the mixture was stirred under hydrogen atmosphere for 8 hours (3.0 kgf/cm)2). The catalyst was filtered and the solvent was removed. The residue was diluted with ethyl acetate, washed with brine, dried (magnesium sulfate), and concentrated to give 813mg of the title compound as a black solid.
MS(EI)m/z：368(M+)。
Step 66-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- [5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethanamine (step 5).
1H-NMR(CDCl3)δ：8.63(1H，d，J＝2.2Hz)，8.14(1H，s)，7.77(2H，d，J＝8.3Hz)，7.66(1H，dd，J＝2.6，8.3Hz)，7.45(1H，d，J＝8.3Hz)，7.30(2H，d，J＝8.4Hz)，7.21(1H，s)，3.73-3.80(2H，m)，3.17(2H，t，J＝6.2Hz)，2.79(2H，q，J＝7.5Hz)，2.42(3H，s)，1.38(3H，t，J＝7.5Hz)。
MS(ESI)m/z：566[(M+H)]，564[(M-H)-]。
Example 271
6-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole (example 270).
1H-NMR(DMSO-d6)δ：8.71(1H，br.s)，8.20(1H，br.s)7.95(1H，m)，7.43-7.64(4H，m)，7.12(2H，br.s)，6.09(1H，br.s)，3.39(2H，br.s)，2.92(2H，br.s)，2.73(2H，br.s)，2.28(3H，br.s)，1.27(3H，br.s)。
MS(ESI)m/z：566[(M+H)+]，564[(M-H)-]。
Example 272
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 1 Ethyl (5-amino-2-pyridinyl) acetate
To a solution of (5-amino-2-pyridyl) acetic acid (1.46g, 9.6mmol, Daisley; R.W.; Hanbali, J.R., Synthetic communications, 1981, 11(9), 743.) in ethanol was added concentrated sulfuric acid, and the mixture was stirred under hydrogen atmosphere at room temperature for 16.5 hours. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, the solvent was removed, the mixture was diluted with water and extracted with ethyl acetate (5X 20 ml). The organic layer was washed with brine and concentrated to dryness (magnesium sulfate) to give 1.2g of the title compound as a brown oil.
1H-NMR(CDCl3)δ：8.04(1H，d，J＝2.8Hz)，7.07(1H，d，J＝8.2Hz)，6.96(1H，dd，J＝2.6，8.2Hz)，4.71(2H，q，J＝7.1Hz)，3.72(2H，s)，3.66(2H，br.s)，1.25(3H，t，J＝7.1Hz)。
Step 2 Ethyl {5- [ 5-chloro-2-nitro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetate
The title compound was prepared according to the procedure described in example 1, step 3, from ethyl (5-amino-2-pyridyl) acetate (step 1).
1H-NMR(CDCl3)δ：9.66(1H，s)，8.60(2H，m)，7.71(1H，dd，J＝2.6，8.4Hz)，7.60(1H，d，J＝8.3Hz)，7.13(1H，s)，4.03(2H，s)
MS(EI)m/z：356(M+)。
Step 3 Ethyl {5- [ 2-amino-5-chloro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetate
The title compound was prepared according to the procedure described in example 28, step 2, from ethyl {5- [ 5-chloro-2-nitro 4- (trifluoromethyl) anilino ] -2-pyridinyl } acetate (step 2).
1H-NMR(CDCl3)δ：7.25(1H，d，J＝1.5Hz)，7.21(1H，m)，7.16(1H，s)，7.09(1H，s)，7.47(1H，d，J＝8.2Hz)，5.47(1H，s)，4.20(2H，q，J＝7.2Hz)，3.80(2H，s)，3.77(2H，br.s)，1.28(3H，t，J＝7.2Hz)。
Step 4 Ethyl {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } acetate
The title compound was prepared from ethyl {5- [ 2-amino-5-chloro-4- (trifluoromethyl) anilino ] -2-pyridinyl } acetate (step 3) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：8.61(1H，d，J＝2.0Hz)，8.14(1H，s)，7.71(1H，dd，J＝2.0，8.2Hz)，7.62(1H，d，J＝8.2Hz)，7.21(1H，s)，4.27(1H，q，J＝7.3Hz)，4.01(2H，s)，2.79(2H，q，J＝7.6Hz)，1.38(3H，t，J＝7.4Hz)，1.33(3H，t，J＝7.1Hz)。
Step 52- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethanol
The title compound was prepared according to the procedure described in example 266, step 8, from ethyl {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } acetate (step 4).
1H-NMR(CDCl3)δ：8.57(1H，d，J＝2.50Hz)，8.13(1H，s)，7.67(1H，dd，J＝2.6，8.2Hz)，7.49(1H，d，J＝8.2Hz)，7.20(1H，s)，4.15(1H，q，J＝5.6Hz)，3.20(2H，t，J＝5.4Hz)，2.79(2H，q，J＝7.4Hz)，1.39(3H，t，J＝7.6Hz)。
Step 62- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } - (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethanol (step 5).
1H-NMR(CDCl3)δ：8.59(1H，d，J＝2.3Hz)，8.13(1H，s)，7.88(2H，d，J＝8.4Hz)，7.65(1H，dd，J＝2.5，8.2Hz)，7.44(1H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.20(1H，s)，4.57(2H，t，J＝6.4Hz)，3.25(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.4Hz)，2.42(3H，s)，1.38(3H，t，J＝7.4Hz)。
MS(ESI)m/z：567[(M+H)+]。
Example 273
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethyl (4-methylphenyl) sulfonylcarbamate hydrochloride
The title compound was prepared according to the procedure described for the preparation of example 240 from 2- [5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethyl- (4-methylphenyl) sulfonyl carbamate (example 273).
1H-NMR(DMSO-d6)δ：11.9(1H，br.s)，8.72(1H，br.s)，8.18(1H，s)，8.03-8.07(1H，m)，7.74(1H，d，J＝7.6Hz)，7.58(1H，d，J＝8.2Hz)，7.43(2H，d，J＝5.1Hz)，7.39(1H，s)，4.45(2H，t，J＝6.2Hz)，3.17(2H，t，J＝6.2Hz)，2.76(2H，q，J＝7.6Hz)，2.35(3H，s)，1.27(3H，t，J＝7.3Hz)。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]。
Example 274
2-ethyl-3- (4- {2- [ ({ [ 4-pyridylsulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18, step 2, from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18, step 1) and pyridyl-4-sulfonamide (Chern, Ji-Wang; Leu, Yu-Ling; et al, j.med chem., 1997, 40, 2276.; Graham, Samuel l.; Shepard, Kenneth l.; et al, j.med.chem., 1989, 32, 2548).
m.p.：227.9-228.7℃
1H-NMR(CDCl3)δ：8.63(2H，d，J＝5.9Hz)，7.65(2H，d，J＝5.9Hz)，7.36(4H，s)，6.96(1H，s)，3.20(2H，br.s)，2.75(br.s，2H)，2.70(2H，q，J＝7.6Hz)，2.53(2H，s)，2.40(3H，s)，1.20(3H，t，J＝7.6Hz)。
MS(ESI)m/z：479[(M+H)+]，477[(M-H)-]。
Example 275
2-ethyl-3- (4- {2- [ ({ [ 2-pyridylsulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 18, step 2, from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18, step 1) and pyridyl-2-sulfonamide (Chern, Ji-Wang; Leu, Yu-Ling; et al, j.med.chem., 1997, 40, 2276.; Graham, Samuel l.; Shepard, Kenneth l.; et al, j.med.chem., 1989, 32, 2548).
1H-NMR(CDCl3)δ：8.51(1H，br.s)，8.08(1H，br.s)，7.94(1H，br.s)，7.29(2H，s)，7.19(1H，br.s)，6.91(1H，s)，2.81(2H，br.s)，2.73(2H，q，J＝7.6Hz)，2.66(3H，s)，2.78(3H，s)，2.49(m，2H)，1.26(3H，t，J＝7.3Hz)。
MS(ESI)m/z：479[(M+H)+]，477[(M-H)-]。
Example 276
2-ethyl-3- (4- {2- [ ({ [ 3-pyridylsulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine
The title compound was prepared from phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate (example 18 step 1) and pyridyl-3-sulfonamide (chern., Ji-Wang; Leu, Yu-Ling; et al, j.med.chem., 1997, 40, 2276; Graham, Samuel l.; Shepard, Kenneth l.; et al, j.med.chem., 1989, 32, 2548) according to the procedure described in example 18 step 2.
1H-NMR(CDCl3) δ: 9.15(1H, d, J ═ 1.9Hz), 8.83(1H, dd, J ═ 1.9, 5.1Hz), 8.34(1H, dd, J ═ 6.5 hr z), 7.50(1H, dd, J ═ 4.9, 8.1Hz), 7.12-7.23(4H, m), 6.93(1H, s), 5.92(1H, br.s), 3.51(2H, q, J ═ 5.9Hz), 2.86(2H, m), 2.69(3H, m), 2.66(3H, s), 2.43(3H, s), 1.27(3H, t, J ═ 7.6 Hz).
MS(ESI)m/z：479[(M+H)+]
Example 277
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-phenyl } ethyl- (2-chlorophenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 2-chlorophenyl sulfonamide.
1H-NMR(CDCl3)δ：8.18(1H，s)，8.07(1H，d，J＝7.8Hz)，7.69(1H，d，J＝3.8Hz)，7.59(1H，dd，J＝4.3，8.1Hz)，7.51(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.4Hz)，7.31(1H，s)，4.29(2H，t，J＝6.2Hz)，2.94(2H，t，J＝6.5Hz)，2.76(2H，q，J＝7.6Hz)，1.26(3H，t，J＝7.3Hz)。
m.p.202.4-202.8℃。
MS(ESI)m/z：586[(M+H)+]，584[(M-H)-]
Example 278
2- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
Step 12-methyl-1- (4-nitrophenyl) -2-propanol
To a solution of 1, 1-dimethyl-2- (4-nitrophenyl) ethyl acetate (52mmol) in MeOH (50ml) was added 4N-LiOH (40 ml). The mixture was stirred at 50 ℃ for 2 hours. After removal of the solvent, the mixture was diluted with water and extracted with ethyl acetate (4X 50 ml). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. The crude product was purified by column chromatography on silica, eluting with hexane/ethyl acetate (5/1) to give the title compound as a yellow oil (3.3g, 33%).
1H-NMR(CDCl3)δ：8.17(2H，d，J＝8.9Hz)，7.40(2H，d，J＝8.6Hz)，2.88(2H，s)，1.63(1H，br.s)，1.25(6H，s)
Step 21- (4-aminophenyl) -2-methyl-2-propanol
The title compound was prepared according to the procedure described for example 28 step 2, from 2-methyl-1- (4-nitrophenyl) -2-propanol (step 1).
1H-NMR(CDCl3)δ：7.00(2H，d，J＝8.4Hz)，6.65(2H，d，J＝8.4Hz)，3.61(2H，br.s)，2.65(2H，s)，1.39(1H，br.s)，1.20(6H，s)
Step 31- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-methyl-2-propanol
The title compound was prepared according to the procedure described for the preparation of example 266 step 5 from 1- (4-aminophenyl) -2-methyl-2-propanol (step 2)
1H-NMR(CDCl3)δ：9.60(1H，s)，7.59(2H，d，J＝8.7Hz)，7.19(2H，d，J＝8.4Hz)，6.52(1H，s)，2.75(2H，s)，2.54(3H，s)，2.43(3H，s)，1.24(6H，s)
Step 41- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-methyl-2-propanol
The title compound was prepared from 1- {4- [ (4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } -2-methyl-2-propanol (step 3) according to the procedure described in example 28, step 2
1H-NMR(CDCl3)δ：7.10(4H，s)，6.61(1H，s)，6.33(2H，s)，3.28(1H，br.s)，2.70(2H，s)，2.37(3H，s)，2.20(3H，s)，1.22(6H，s)
Step 52- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-methyl-2-propanol
The title compound was prepared from 1- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } -2-methyl-2-propanol (step 4) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.47Hz)，6.91(1H，s)，2.87(2H，s)，2.84(2H，q，J＝7.6Hz)，2.66(3H，s)，2.52(3H，s)，1.31(6H，s)，1.28(2H，d，J＝7.6Hz)
Step 62- [4- (2-Ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-methyl-2-propanol (step 5).
1H-NMR(CDCl3)δ：7.94(2H，t，J＝8.6Hz)，7.33(2H，d，J＝8.6Hz)，7.16(4H，m)，6.93(1H，s)，3.10(2H，s)，2.81(2H，q，J＝7.6Hz)，2.67(3H，s)，2.54(3H，s)，2.40(3H，s)，2.42(3H，s)，1.48(6H，s)，1.28(3H，t，J＝7.6Hz)。
m.p.173.5-174.0℃。
MS(ESI)m/z：521[(M+H)+]，519[(M-H)-]。
Example 279
6-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } -3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
Step 1 (6- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl) methanol
The title compound was prepared from 1- (6-amino-3-pyridyl) methanol according to the procedure of example 266, step 5.
1H-NMR(CDCl3)δ：10.51(1H，br.s)，9.26(1H，s)，8.60(1H，s)，8.42(1H，s)，7.79(1H，d，J＝8.1Hz)，7.01(1H，d，J＝8.1Hz)，4.75(2H，s)。
Step 2 (6- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } -3-pyridylcarbinol
The title compound was prepared according to the procedure described in example 28, step 2, from {5- [ 5-chloro-2-nitro-4- (trifluoromethyl) anilino ] -3-pyridinyl } methanol (step 1).
MS(EI)m/z：317(M+)。
Step 3 {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } methylpropionate
The title compound was prepared from (6- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl } methanol (step 2) according to the procedure described in example 1, step 5.
MS(EI)m/z：411(M+)。
Step 4 {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } methanol;
the title compound was prepared from {5- [ 5-chloro-2-nitro 4- (trifluoromethyl) anilino ] -3-pyridinyl } methylpropionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.67(1H，s)，8.19(1H，s)，8.09(1H，d，J＝8.6Hz)，7.79(1H，d，J＝8.4Hz)，7.65(1H，s)，5.54(1H，t，J＝5.6Hz)，4.69(2H，d，J＝5.6Hz)，2.95(2H，q，J＝7.3Hz)，1.27(3H，t，J＝7.2Hz)。
Step 56-chloro-1- [5- (chloromethyl) -2-pyridinyl ] -2-ethyl-5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from {5- [ 5-chloro-2-nitro 4- (trifluoromethyl) anilino ] -3-pyridyl } methanol (step 4).
1H-NMR(CDCl3)δ：8.72(1H，d，J＝2.2Hz)，8.12(1H，s)，8.07(1H，dd，J＝2.2，8.1Hz)，7.45-7.48(2H，m)，4.72(2H，s)，3.01(2H，q，J＝7.6Hz)，1.39(3H，t，J＝7.6Hz)。
Step 66- { 6-chloro-2-ethyl-5-yl-5- (trifluoromethyl) -1H-benzimidazol-yl ] -3-pyridinyl } acetonitrile
To a solution of 6-chloro-1- [5- (chloromethyl) -2-pyridinyl ] -2-ethyl-5- (trifluoromethyl) -1H-benzimidazole (from step 5, 550mg, 1.5mmol) in DMF (5ml) and water (1ml) was added KCN (470g, 7.2mmol) at room temperature, and the reaction mixture was stirred for 2 hours. The mixture was diluted with water and extracted with a solution (3X 30ml) of ethyl acetate/toluene (4/1). The organic layer was washed with water, dried (magnesium sulfate) and concentrated. This material was purified by column chromatography on silica eluting with hexane/ethyl acetate (1/) to give 198mg (37%) of the title compound as an orange oil.
1H-NMR(CDCl3)δ：8.70(1H，d，J＝2.6Hz)，8.13(1H，s)，8.06(1H，dd，J＝2.6，8.0Hz)，7.52(1H，d，J＝8.20Hz)，7.47(1H，s)，3.94(2H，s)，3.01(2H，q，J＝7.5Hz)，C1-40(3H，t，J＝7.5Hz)
Step 7
2- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethanamine
The title compound was prepared according to the procedure described in example 270, step 5, from {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } acetonitrile (step 6).
MS(EI)m/z：368(M+)。
Step 86-chloro-2-ethyl-1- (6- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl) -2-pyridyl) -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethanamine (step 7).
1H-NMR(CDCl3)δ：8.50(1H，s)，8.12(1H，s)，7.817(1H，d，J＝6.0Hz)，7.72(2H，d，J＝8.4Hz)，7.42(1H，s)，7.24-7.37(3H，m)，7.21(1H，s)，6.771，br.s)，3.60(2H，dt，J＝6.2Hz)，2.94-3.01(4H，m)，2.37(3H，s)，1.37(3H，t，J＝7.5Hz)。
MS(ESI)m/z：566[(M+H)+]，564[(M-H)-]。
Example 280
2- {4- (5-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1, 1-dimethylethyl (4-methylphenyl) sulphonylcarbamate
Step 11- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-methyl-2-propanol
The title compound was prepared from 1- (4-aminophenyl) -2-methyl-2-propanol following the procedure of example 266, step 5
1H-NMR(CDCl3)δ：9.70(1H，br.s)，8.58(1H，s)，7.36(2H，d，J＝8.4Hz)，7.21-7.25(3H，m)，2.83(2H，s)，1.28(6H，s)。
MS(EI)m/z：388(M+)。
Step 21- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-methyl-2-propanol
The title compound was prepared according to the procedure described in example 28, step 2, from 1- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-methyl-2-propanol (step 1)
1H-NMR(CDCl3)δ：7.10(4H，s)，6.61(1H，s)，6.33(2H，s)，3.28(1H，br.s)，2.70(2H，s)，2.37(3H，s)，2.20(3H，s)，1.22(6H，s)。
MS(EI)388(M+)。
Step 31- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -2-methyl-2-propanol
The title compound was prepared according to the procedure described in example 1, step 5, from 1- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -2-methyl-2-propanol (step 2).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.48(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.22(1H，s)，2.90(2H，s)，2.80(2H，q，J＝7.3Hz)，1.36(3H，t，J＝7.3Hz)1.32(6H，s)。
MS(EI)m/z：396(M+)。
Step 42- { 4-5-chloro-2-ethyl (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -2-methyl-2-propanol (step 3).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.94(2H，d，J＝8.7Hz)，7.36(2H，d，J＝8.1Hz)，7.15-7.27(5H，m)，3.16(2H，s)，2.78(2H，q，J＝7.6Hz)，2.43(3H，s)，1.47(6H，s)，1.37(3H，t，J＝7.6Hz)。
m.p.174.6-175.3℃。
MS(ESI)m/z：594[(M+H)+]，592[(M-H)-]。
Example 281
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (2, 4-dimethyl-1, 3-thiazol-5-yl) sulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 2, 4-dimethyl-1, 3-thiazol-5-ylsulfonamide.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.41(2H，d，J＝7.9Hz)，7.27(2H，d，J＝7.9Hz)，7.20(1H，s)，4.45(2H，t，J＝6.9Hz)，3.08(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.7Hz)，2.71(3H，s)，2.68(3H，s)，1.36(3H，t，J＝7.7Hz)。
m.p.168.3-169.0℃。
MS(ESI)m/z：587[(M+H)+]，585[(M-H)-]。
Example 282
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl sulfonamide.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.41(2H，d，J＝7.9Hz)，7.27(2H，d，J＝7.9Hz)，7.20(1H，s)，4.45(2H，t，J＝6.9Hz)，3.08(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.7Hz)，2.71(3H，s)，2.68(3H，s)，1.36(3H，t，J＝7.7Hz)。
m.p.192.0-192.7℃。
MS(ESI)m/z：604[(M+H)+]，602[(M-H)-]。
Example 283
2- {4- [ 5-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } propyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4-aminophenyl) -propanol
To a mixture of ethyl 2- (4-amino-phenyl) -propionate (5.0g, 25.9mmol, Takahashi, 1. et al, Heterocycles 1996, 43, 2343-. The reaction mixture was quenched with 25% aqueous ammonia (50ml) under ice-cold bath. The resulting precipitate was filtered and the filtrate was concentrated under reduced pressure to give 3.88g (99%) of the title compound as a brownish paste.
1H-NMR(CDCl3)δ：7.03(2H，d，J＝8.5Hz)，6.66(2H，d，J＝8.5Hz)，3.70-3.57(4H，m)，2.90-2.78(1H，m)，1.34-1.30(1H，m)，1.22(3H，d，J＝7.1Hz)。
MS(EI)m/z：151(M+)。
Step 22- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -1-propanol
The title compound was prepared from 2- (4-aminophenyl) 1-propanol (step 1) according to the procedure for example 266, step 5
1H-NMR(CDCl3)δ：9.69(1H，br.s)，8.58(1H，s)，7.38(2H，d，J＝8.3Hz)，7.21-7.26(3H，m)，3.77(2H，m)，3.03(1H，m)，1.41(1H，t，J＝5.7Hz)，1.33(3H，d，J＝7.1Hz)
Step 32- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -1-propanol
The title compound was prepared according to the procedure described for example 28 step 2 from 2- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) -1-propanol (step 2)
1H-NMR(CDCl3)δ：7.21-7.26(3H，m)，7.07(1H，s)，6.93(2H，d，J＝8.4Hz)，5.41(1H，br.s)，3.68-3.69(2H，br.s)，2.93(1H，m)，1.38(1H，br.s)，1.28(3H，d，J＝7.1Hz)
Step 42- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1-propanol
The title compound was prepared according to the procedure described in example 1, step 5, from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) -propanol (step 3).
1H-NMR(CDCl3)δ：8.12(1H，s)，7.49(2H，d，J＝2.3Hz)，7.30(2H，d，J＝8.4Hz)，7.22(1H，s)，3.83(2H，m)，3.11(1H，m)，2.80(2H，q，J＝7.6Hz)1.57(1H，m)，1.33-1.40(6H，m)。
Step 52- {4- [ 5-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] -1-propanol (step 4).
1H-NMR(CDCl3)δ：8.11(1H，s)，7.904(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.4Hz)，7.27(1H，s)，7.24(1H，s)，7.20(1H，s)，4.19-4.30(2H，m)，3.20(1H，m)，2.78(2H，q，J＝7.5Hz)，2.43(3H，s)，1.53(3H，t，J＝7.56Hz)，1.34(3H，t，J＝6.9Hz)。
m.p.179.9-180.5℃。
MS(ESI)m/z：581[(M+H)+]，579[(M-H)-]。
Example 284
2- (4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
Step 11- (4- { [ 4-hydroxy-2-methylpropyl) phenyl ] amino } -3-nitrophenyl) ethanone
The title compound was prepared from 1- (4-aminophenyl) -2-methyl-2-propanol following the procedure of example 266, step 5
1H-NMR(CDCl3)δ：9.85(1H，br.s)，8.83(1H，s)，7.97(1H，d，J＝9.0Hz)，7.10-7.40(4H，m)，2.82(2H，s)，2.58(3H，s)，1.28(6H，s)
Step 21- (3-amino-4- { [4- (2-hydroxy-2-methylpropyl) phenyl ] amino } phenyl) ethanone
The title compound was prepared according to the procedure described in example 28 step 2 from 1- (4- { [ 4-hydroxy-2-methylpropyl) phenyl ] amino } -3-nitrophenyl) ethanone (step 1)
1H-NMR(CDCl3)δ：7.38-7.46(2H，m)，7.16(2H，dd，J＝8.4Hz)，6.96(2H，d，J＝8.4Hz)，5.62(2H，br.s)，3.60(1H，br.s)，2.73(2H，s)，2.54(3H，s)，1.39(1H，br.s)，1.24(6H，s)
Step 31- { 2-Ethyl-1- [4- (2-hydroxy-2-methylpropyl) phenyl ] -1H-benzimidazol-5-yl } ethanone
The title compound was prepared from 1- (3-amino-4- { [4- (2-hydroxy-2-methylpropyl) phenyl ] amino } phenyl) ethanone (step 2) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：8.40(1H，s)，7.90(1H，d，J＝8.6Hz)，7.46(2H，d，J＝8.1Hz)，7.30(2H，d，J＝8.1Hz)，7.14(1H，d，J＝8.6Hz)，2.96(2H，s)，2.82(2H，q，J＝7.6Hz)，2.68(3H，s)，1.63(1H，br.s)，1.38(3H，t，J＝7.6Hz)，1.32(6H，s)
Step 42- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] -1, 1-dimethylethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- { 2-ethyl-1- [4- (2-hydroxy-2-methylpropyl) phenyl ] -1H-benzimidazol-5-yl } ethanone (step 3).
1H-NMR(CDCl3)δ：8.41(1H，s)，7.88-7.95(3H，m)，7.09-7.35(7H，m)，3.14(2H，s)，2.80(2H，q，J＝7.6Hz)，2.68(3H，s)，2.40(3H，s)，1.45(6H，s)，1.38(3H，t，J＝7.6Hz)。
m.p.103.4-104.2℃。
MS(ESI)m/z：534[(M+H)+]，532[(M-H)-]。
Example 285
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-methyl-2-pyridinyl) sulfonylcarbamate mono-hydrochloride
The title compound was prepared from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate following the procedure described in example 243, step 2.
1H-NMR(CDCl3)δ：8.57(1H，s)，8.15(1H，s)，8.12(1H，d，J＝8.0Hz)，7.77(1H，d，J＝7.9Hz)，7.37(1H，d，J＝7.9Hz)，7.17-7.25(4H，m，)，4.36(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.5Hz)，2.46(3H，s)，1.36(3H，t，J＝7.3Hz)。
m.p.205.8℃。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]。
Example 286
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-methyl-2-pyridinyl) sulfonylcarbamate mono-hydrochloride
The title compound was prepared according to the procedure for example 240 from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (5-methyl-2-pyridinyl) sulfonylcarbamate (example 285).
1H-NMR(CDCl3)δ：8.53(1H，s)，8.49(1H，s)，8.08(1H，d，J＝7.6Hz)，7.78(1H，d，J＝6.8Hz)，7.53(2H，br.s)，7.41(3H，br.s)，4.38(2H，t，J＝5.9Hz)，3.21(2H，br.s)，3.07(2H，t，J＝5.9Hz)，2.47(3H，s)，1.51(3H，br.s)。
m.p.200.2℃。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]。
Example 287
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 1 Benzylethyl 2- (6-nitro-3-pyridinyl) malonate
To a mixture of 5-bromo-2-nitropyridine (8.66g, 42.7mmol) and benzylethylmalonate (9.50g, 42.7mmol) in tetrahydrofuran (160ml) and dimethylformamide (40ml) was added potassium carbonate (5.90g, 42.7 mmol). Stirred at reflux temperature for 20 hours. The mixture was diluted with water (1 l) and extracted with ethyl acetate (3X 200 ml). The organic layer was washed with brine and concentrated to dryness (magnesium sulfate) to give 5.26g of the title compound as an orange oil.
1H-NMR(CDCl3)δ：8.61(1H，d，J＝2.2Hz)，8.26(1H，d，J＝8.4Hz)，8.19(1H，dd，J＝2.1，8.6Hz)，7.29-7.38(5H，m)，5.22(2H，d，J＝3.6Hz)，4.84(1H，s)，4.22(2H，m)，1.23(3H，t，J＝7.1Hz)。
Step 2 Ethyl (6-nitro-3-pyridyl) acetate
To a solution of benzylethyl 2- (6-nitro-3-pyridyl) malonate (5.26g, 15.3 mmol) in ethanol was added palladium on carbon (530 mg). Stirred at room temperature for 6 hours under hydrogen atmosphere. The catalyst was filtered through a celite pad and the filtrate was concentrated to give the title compound as a brown-yellow oil.
1H-NMR(CDCl3)δ：7.95(1H，d，J＝1.8Hz)，7.40(1H，dd，J＝2.4，8.4Hz)，6.48(1H，d，J＝8.4Hz)，4.42(2H，br.s)，4.14(2H，q，J＝7.1Hz)，3.46(2H，s)，1.26(3H，t，J＝7.1Hz)。
Step 32- (6-amino-3-pyridyl) ethanol
To a solution of ethyl (6-nitro-3-pyridyl) acetate (468mg, 2.60mmol) in tetrahydrofuran was added LiAlH4The mixture was stirred at room temperature for 2 hours. Saturated 25% NH for reaction3The aqueous solution was quenched and the precipitate removed. The filtrate was concentrated to give the title compound as a yellow oil.
1H-NMR(CDCl3)δ：7.73(1H，d，J＝2.8Hz)，7.23(1H，dd，J＝8.6Hz)，6.37(1H，d，J＝2.6，8.1Hz)，5.63(2H，br.s)，3.49(2H，t，J＝7.3Hz)，2.51(2H，t，J＝7.3Hz)。
MS(EI)m/z：138(M+)。
Step 4 (6- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl } ethanol
The title compound was prepared according to the procedure described for example 1, step 3, from 2- (6-amino-3-pyridyl) ethanol (step 3).
1H-NMR(CDCl3)δ：8.49(1H，s)，8.32(1H，d，J＝2.2Hz)，7.64(1H，dd，J＝2.4，8.4Hz)，7.36(1Hs)，6.97(1H，d，J＝8.4Hz)，3.91(2H，t，J＝6.5Hz)，2.89(2H，t，J＝6.5Hz)
MS(EI)m/z：361(M+)。
Step 5 (6- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from (6- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl } ethanol (step 4).
MS(EI)m/z：331(M+)。
Step 62- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethyl propionate
To (6- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } -3-pyridinyl } ethanol (787mg, 2.37mmol, from step 5) was added propionic acid and propionic anhydride and stirred at 120 ℃ for 15 h the mixture was quenched with NaOH and extracted with dichloromethane (3X 30ml) the organic layer was washed with brine and concentrated to give 5.26g of the title compound as an orange oil.
1H-NMR(CDCl3)δ：8.58(1H，d，J＝1.9Hz)，8.12(1H，s)，7.83(1H，dd，J＝2.2，8.1Hz)，7.45(1H，s)，7.39(1H，d，J＝8.1Hz)，4.40(2H，t，J＝6.8Hz)，4.12(2H，q，J＝7.3Hz)，3.10(2H，t，J＝6.5Hz)，2.99(2H，q，J＝7.6Hz)，2.29-2.44(2H，m)，1.38(3H，t，J＝7.4Hz)，1.15(3H，t，J＝7.6Hz)。
Step 52- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethanol
The title compound was prepared according to the procedure described in example 266, step 8, from 2- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethyl propionate (step 4).
1H-NMR(CDCl3)δ：8.60(1H，d，J＝2.3Hz)，8.11(1H，s)，7.91(1H，dd，J＝2.5，8.0Hz)，7.45(1H，s)，7.38(1H，d，J＝8.1Hz)，4.01(1H，t，J＝6.2Hz)，3.72-3.77(2H，m)，2.94-3.04(2H，m)，1.38(3H，t，J＝7.4Hz)。
Step 62- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethyl- (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- {6- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-pyridinyl } ethanol (step 5).
1H-NMR(CDCl3)δ：8.33(1H，d，J＝1.9Hz)，8.08(1H，s)，7.91(2H，d，J＝8.4Hz)，7.70(1H，dd，J＝2.4，8.1Hz)，7.29-7.42(4H，m)，7.20(1H，s)，4.39(2H，t，J＝6.2Hz)，3.00(2H，t，J＝6.2Hz)，2.93(2H，t，J＝7.6Hz)，2.43(3H，s)，1.32(3H，t，J＝7.4Hz)。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]。
Example 288
2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethyl (4-methylphenyl) sulfonylcarbamate mono-hydrochloric acid
Step 1
The title compound was prepared according to the procedure described for the preparation of example 240 from 2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -3-pyridinyl } ethyl- (4-methylphenyl) sulfonyl carbamate (example 287).
1H-NMR(CDCl3)δ：8.40(1H，br.s)，8.49(1H，br.s)，8.12(1H，br.s)，7.82(2H，br.s)，7.65(1H，br.s)，7.25-7.28(2H，m)，4.40(2H，br.s)，3.35(1H，s)，3.12(2H，br.s)，2.41(3H，s)，2.43(3H，s)，1.53(3H，br.s)。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]。
Example 289
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl-5-isoquinolinylsulphonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 5-isoquinolinesulfonamide.
1H-NMR(CDCl3)δ：9.39(1H，s)，8.70(2H，t，J＝6.3Hz)，8.43(1H，d，J＝6.2Hz)，8.29(1H，d，J＝8.1Hz)，8.12(1H，s，)，7.78(1H，t，J＝7.6Hz)，7.16-7.33(5H，m)，4.32(2H，t，J＝6.9Hz)，2.97(2H，t，J＝6.8Hz)，2.77(2H，q，J＝7.4Hz)，1.346(3H，t，J＝7.4Hz)。
MS(ESI)m/z：603[(M+H)+]，601[(M-H)-]。
Example 290
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl-5-quinolinylsulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1-benzimidazol-1-yl) phenylethyl- (4-methylphenyl) sulfonyl carbamate and 5-quinolinylsulfonamide
1H-NMR(CDCl3)δ：8.43(1H，d，J＝86Hz)，8.20-8.25(2H，m)，8.13(1H，s)，8.12(1H，s，)，7.81-7.91(2H，m)，7.68-7.72(1H，m)，7.30-7.34(2H，m)，7.12-7.16(3H，m)，4.37(2H，t，J＝6.6Hz)，2.98(2H，t，J＝6.3Hz)，2.74(2H，q，J＝7.4Hz)，1.35(3H，t，J＝7.4Hz)。
MS(ESI)m/z：567[(M+H)+]，565[(M-H)-]
Example 291
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- [5- (dimethylamino) -1-naphthyl ] sulfonylcarbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 5- (dimethylamino) -1-naphthylsulfonamide.
1H-NMR(CDCl3)δ：8.61(1H，d，J＝8.4Hz)，8.46(1H，dd，J＝1.2，7.5Hz)，8.12(1H，s)，87.58(2H，t，J＝8.3Hz)，7.12-7.24(6H，m)，4.30(2H，t，J＝6.8Hz)，2.93(2H，t，J＝6.8Hz)，2.75(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
m.p.203.4℃；
MS(ESI)m/z：645[(M+H)+]，643[(M-H)。
Example 292
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1-methyl-1H-imidazol-4-yl) sulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 1-methyl-1H-imidazol-4-ylsulfonamide.
1H-NMR(CDCl3)δ：8.13(1H，s)，7.72(1H，d，J＝1.5Hz)，7.55(1H，d，J＝1.3Hz)，7.41(2H，d，J＝8.2Hz)，7.26(2H，d，J＝8.2Hz)，7.20(1H，s)，4.38(2H，t，J＝6.6Hz)，3.78(3H，s)，3.04(2H，d，J＝6.8Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
m.p.204.3℃；
MS(ESI)m/z：556[(M+H)+]，554[(M-H)-]。
Example 293
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1-methyl-1H-imidazol-4-yl) sulfonylcarbamate monohydrochloride
The title compound was prepared according to the procedure described for example 240 from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1-methyl-1H-imidazol-4-yl) sulfonyl carbamate (example 292).
MS(ESI)m/z：556[(M+H)+]，554[(M-H)-]
Example 294
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl carbamate
The title compound was prepared according to the procedure described in example 243, step 2, from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethylphenyl carbonate and 1, 2-dimethyl-1H-imidazol-4-ylsulfonamide.
1H-NMR(CDCl3)δ：8.12(1H，s)，7.63(1H，s)，7.41(2H，d，J＝8.2Hz)，7.25(2H，d，J＝8.2Hz)，7.19(1H，s)，4.37(2H，t，J＝6.8Hz)，3.64(3H，s)，3.04(2H，d，J＝6.6Hz)，2.79(2H，q，J＝7.6Hz)，2.42(3H，s)，1.36(3H，t，J＝7.6Hz)m.p.221.2℃。
MS(ESI)m/z：570[(M+H)+]，568[(M-H)-]。
Example 295
2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1, 2-dimethyl-1H-imidazol-4-yl) sulfonylcarbamate dihydrochloride
The title compound was prepared according to the procedure described for example 240 from 2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (1, 2-dimethyl-1H-imidazol-4-yl) sulfonyl carbamate (example 294).
MS(ESI)m/z：570[(M+H)+]，568[(M-H)-]。
Example 296
2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanol
The title compound was prepared from 4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenylethanol according to the procedure described in example 236, step 1.
1H-NMR(DMSO-d6)δ：13.15(1H，br.s)，7.77(3H，s)，7.35(2H，d，J＝7.7Hz)，7.25(2H，d，J＝7.7Hz)，7.02(1H，s)，6.53(1H，s)，4.75(2H，t，J＝4.8Hz)，3.71(2H，q，J＝6.8Hz)，2.81(1H，t，J＝6.6Hz)，258(3H，s)，2.42(3H，s)
Step 22- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanol (step 1).
1H-NMR(DMSO-d6)δ：13.14(1H，br.s)，7.69-7.78(3H，m)，7.21-7.43(6H，m)，7.02(1H，s)，6.52(1H，s)，4.18(2H，t，J＝6.4Hz)，2.89(2H，t，J＝6.4Hz)，2.58(2H，s)，2.41(3H，s)，2.32(3H，s)。
MS(ESI)m/z：531(MH+)，529([M-H]-)。
Example 297
2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl- ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate sodium salt
Step 12- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described for example 2 from 2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) 3H-imidazo [4, 5-b ] pyridin-3-yl- ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (example 296).
1H-NMR(CDCl3)δ：9.85(1H，s)，8.37(1H，d，J＝8.4Hz)，7.31(1H，d，J＝2.0Hz)，7.14(1H，dd，J＝2.0，8.3Hz)，6.60(1H，s)，3.87(2H，dt，J＝6.2，6.4Hz)，2.84(2H，t，J＝6.4Hz)，2.56(3H，s)，2.46(3H，s)，1.40(1H，t，J＝6.2Hz)。
MS(ESI)m/z：531(MH+)，529([M-H]-)。
Example 298
N- { [ (2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 13- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4.5-b ] pyridine
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanol (example 297, step 1).
1H-NMR(CDCl3)δ：13.15(1H，s)，7.77(2H，br.s)，7.43(2H，br.s)，7.20(2H，br.s)，7.04(1H，s)，6.54(1H，br.s)，3.96(2H，t，J＝6.8Hz)，3.15(2H，tm J＝6.8Hz)，2.60(3H，s)，2.30(3H，s)。
Step 23- [4- (2-azidoethyl) phenyl ] -5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridine
The title compound was prepared according to the procedure described in example 1, step 5, from 3- [4- (2-chloroethyl) phenyl ] -5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridine (step 1).
1H-NMR(DMSO-d6)δ：13.15(1H，br.s)，9.85(1H，br.s)，7.76(1H，br.s)，7.41(2H，d，J＝8.1Hz)，7.31(2H，d，J＝8.1Hz)，7.04(1H，s)，6.53(1H，s)，3.69(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.8Hz)，2.58(3H，s)，2.42(3H，s)，MS(EI)m/z：358(M+)。
Step 32- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanamine
The title compound was prepared according to the procedure described in example 1, step 6, from 3- [4- (2-azidoethyl) phenyl ] -5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridine (step 2).
1H-NMR(DMSO-d6)δ：9.83(1H，br.s)，7.68(2H，br.s)，7.23-7.43(5H，m)，7.04(1H，s)，5.75(1H，s)，2.68-2.90(4H，m)，2.59(3H，s)，2.42(3H，s)，MS(EI)m/z：332(M+)。
Step 4N- { [ (2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-ylphenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared from 2- {4- [5, 7-dimethyl-2- (1H-pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethanamine (step 3) according to the procedure described in example 1, step 7
1H-NMR(CDCl3)δ：7.80(2H，d，J＝8.2Hz)，7.58(1H，br.s)，7.20-7.35(6H，m)，7.08(1H，s)，6.20(1H，br.s)，3.42(2H，t，J＝6.8Hz)，2.84(2H，t，J＝6.9Hz)，2.68(2H，s)，2.50(3H，s)，2.34(3H，s)。
MS(ESI)m/z：530(MH+)，528([M-H]-)。
Example 299
2- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 14-chloro-2-methyl-5-nitrobenzonitrile
To a solution of 4-chloro-2-methyl-5-nitrobenzonitrile (10g, 66mmol) in concentrated sulfuric acid at 0 deg.C was added potassium nitrate (7.0g, 69.3mmol) in small portions, and the reaction mixture was stirred at room temperature overnight. Then poured into ice and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated. The resulting precipitate was collected by filtration, washed with ether and dried under reduced pressure to give 5.5g (42%) of the title compound.
1H-NMR(CDCl3)δ：8.19(1H，s)，757(1H，s)，2.64(3H，s)。
Step 24- { [4- (2-hydroxyethyl) phenyl ] amino } -2-methyl-5-nitrobenzonitrile
The title compound was prepared according to the procedure described in example 1, step 3, from 3-bromo-6-chloro-2, 4-dimethyl-5-nitropyridine (step 2).
1H-NMR(CDCl3)δ：9.76(1H，br.s)，8.51(1H，s)，7.36(1H，d，J＝8.4Hz)，7.22(1H，d，J＝8.3Hz)，6.96(1H，s)，3.94(2H，dd，J＝11.7，6.2Hz)，2.94(2H，t，J＝6.4Hz)，2.42(3H，s)
Step 35-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } -2-methylbenzonitrile
The title compound was prepared according to the procedure described in example 1, step 4, from 2- {4- [ (5-bromo-4, 6-dimethyl-3-nitro-2-pyridinyl) amino ] phenyl } ethanol (step 3).
1H-NMR(CDCl3)δ：7.19(1h，d，J＝8.4Hz)，6.94-7.00(4H，m)，5.59(1H，br.s)，3.84-3.90(2H，m)，3.50(2H，br.s)，2.85(2H，t，J＝6.4Hz)，2.37(3H，s)。
Step 52- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ (3-amino-5-bromo-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (step 4).
MS(EI)m/z：361(M+)
Step 62-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -6-methyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl 2-methylpropionate (step 5) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：8.00(1H，s)，7.50(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，6.98(1H，s)，4.01(2H，t，J＝6.4Hz)，3.03(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.5Hz)，2.56(3H，s)，1.35(3H，t，J＝7.5Hz)
Step 72- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -6-methyl-1H-benzimidazole-5-carbonitrile (step 6).
1H-NMR(CDCl3)δ：8.03(1H，s)，7.92(2H，d，J＝8.4Hz)，7.39(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.1Hz)，6.96(1H，s)，4.39(2H，t，J＝6.8Hz)，3.04(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.7Hz)，2.57(3H，s)，2.44(3H，s)，1.35(3H，t，J＝7.5Hz)
Example 300
N- [ ({2- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl ] (4-methylbenzenesulfonamide)
Step 11- [4- (2-chloroethyl) phenyl ] -2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethanol (step 6).
1H-NMR(CDCl3)δ：8.02(1H，s)，7.48(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，6.96-6.98(1H，m)，3.83(2H，t，J＝7.1Hz)，3.21(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.5Hz)，2.58(3H，s)，1.35(3H，t，J＝7.5Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 8, from 6-bromo-3- [4- (2-chloroethyl) phenyl ] -2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridine (step 7).
MS(EI)m/z：412(M+)；1H-NMR(CDCl3)δ：8.02(1H，s)，7.48(2H，d，J＝8.0Hz)，7.30(2H，d，J＝8.2Hz)，6.95(1H，s)，3.63(2H，t，J＝6.8Hz)，3.03(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.5Hz)，2.57(3H，s)，1.35(3H，t，J＝7.3Hz)。
Step 31- [4- (2-aminoethyl) phenyl ] -2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 9, from 2- [4- (6-bromo-2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl azide (step 8).
1H-NMR(CDCl3)δ：7.49(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.93(1H，s)，6.60(2H，br.s)，3.32-3.00(5H，m)，2.65(3H，s)，2.48(3H，s)，1.31(6H，d，J＝6.8Hz)。
Step 4N- [ ({2- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl- (4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from [4- (2-isopropyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylamine (step 9).
1H-NMR(CDCl3)δ：8.00(1H，s)，7.72(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.4Hz)，7.28-7.32(4H，m)，6.95(1H，m)，3.56-3.63(2H，m)，2.96(2H，t，J＝7.1Hz)，2.78(2H，q，J＝7.7Hz)，2.54(3H，s)，2.41(3H，s)，1.34(3H，t，J＝7.5Hz)
Example 301
2-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine di-hydrochloride
Step 12-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-3H-imidazo [45-b ] pyridine
To a mixture of N- { [ (2- {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (300mg, 0.66mmol) in THF (6ml) was added a solution of BrCN (175mg, 1.65mmol) in water (2 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over magnesium sulfate and filtered. After concentration in vacuo, the residue was purified by preparative TLC (dichloromethane/MeOH ═ 10/1) to yield 224mg (71%) of the title compound.
1H-NMR(DMSO-d6)δ：10.82(1H，s)，8.54(2H，s)，7.79(2H，d，J＝8.3Hz)，7.51-7.40(6H，m)，7.06(1H，s)，6.91(1H，t，J＝5.5Hz)，3.29-3.24(2H，m)，2.80-2.76(2H，m)，2.48(3H，s)，2.38(3H，s)，2.36(3H，s)。
MS(ESI)m/z：479([M+H]+)，477([M-H]-)。
Step 22-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine di-hydrochloride
The title compound was prepared according to the procedure described for the preparation of example 240 from 2-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine.
MS(ESI)m/z：479([M+H]+)，477([M-H]-)。
Example 302
5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -2- (methylthio) -3H-imidazo [4, 5-b ] pyridine
N- { [ (2- {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino group was reacted at room temperature]Phenyl } ethyl) amino]A mixture of carbonyl } -4-methylbenzenesulfonamide (110mg, 0.24mmol), bis-2-pyridylthiocarbonate (68mg, 0.29mmol), and THF (5ml) was stirred for three days. The mixture was diluted with dichloromethane and washed with 0.1M hydrochloric acid and brine. The organic portion was dried over magnesium sulfate and filtered. Removing the solvent to obtain N- [ ({2- [4- [ (5, 7-dimethyl-2-thio-3H-imidazo [4, 5-b))]Pyridin-3-yl) phenyl]Ethyl } amino) carbonyl } -4-methylbenzenesulfonamide [ MS (ESI) m/z: 496([ M + H)]+)，494([M-H]-). This material was dissolved in THF (2ml) and a solution of 1M NaOMe in MeOH (0.49ml) and MeI (45, microliters, 0.73mmol) was added to the mixture at room temperature. After 1 h, the mixture was evaporated in vacuo and the residue was purified by preparative TLC (dichloromethane/MeOH ═ 10/1) to give 31mg (25%) of the title compound.
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.1Hz)，7.22-7.16(4H，m)，6.88(1H，s)，6.02(1H，t，J＝5.6Hz)，3.51-3.45(2H，m)，2.83(2h，t，J＝6.2Hz)，2.67(3H，s)，2.62(3H，s)，2.42(3H，s)，2.417(3H，s)。
MS(ESI)m/z：510([M+H]+)，508([M-H]-)
Example 303
5, 7-dimethyl-2- (methylamino) -3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
N- { [ (2- {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino group was reacted at room temperature]Phenyl } ethyl) amino]A mixture of carbonyl } -4-methylbenzenesulfonamide (300mg, 0.66mmol), methyl isothiocyanate (56. mu.l, 0.86mmol), and THF (6ml) was stirredThree days. Removal of the solvent gave N- { [ (2- {4- [ (4, 6-dimethyl- { [ (methylamino) thiocarbonyl)]Amino } -2-pyridyl) amino]Phenyl } ethyl) amino]Carbonyl } -4-methylbenzenesulfonamide [ MS (ES M/z: 527([ M + H) ]]+)，525([M-H]-)]. This material was dissolved in MeCN (4ml) and treated with MeI (54. mu.l) at 0 ℃ for 20 hours. After concentration under reduced pressure, the residue was purified by preparative TLC (ethyl acetate/EtOH ═ 20/1) to give 170mg (52%) of the title compound.
1H-NMR(CD3OD)δ：7.72(2H，d，J＝8.3Hz)，7.24(4H，d，J＝7.9Hz)，7.15(2H，d，J＝8.4Hz)，6.70(1H，s)，3.28(2H，t，J＝7.0Hz)，2.90(3H，s)，2.72(2H，t，J＝7.0Hz)，2.41(3H，s)，2.26(3H，s)，2.24(3H，s)。
MS(ESI)m/z：493([M+H]+)，491([M-H]-)。
Example 304
5, 7-dimethyl-2- (methylamino) -3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine mono-hydrochloride
The title compound was prepared from 5, 7-dimethyl-2- (methylamino) -3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine hydrochloride following the procedure described for example 240.
MS(ESI)m/z：493([M+H]+)，491([M-H]-)
Example 305
N- [5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridin-2-yl ] acetamide
2-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl) was reacted at room temperature]Amino } carbonyl) amino]Ethyl } phenyl) -3H-imidazo [4, 5-b]Pyridine (73mg) with pyridine (1ml) and Ac2O (0.2ml) for 3 hours. After evaporation in vacuo, the residue was used for preparation of TLPurification by C (hexane/acetone ═ 1/1) gave 4mg (5%) of the title compound.
1H-NMR(CDCl3)δ：7.79(2H，d，J＝8.4Hz)，7.34-7.22(7H，m)，7.04(1H，s)，6.30(1H，br.s)，3.51-3.48(2H，m)，2.87-2.83(2H，m)，2：66(3H，s)，2.53(3H，s)，2.42(3H，s)，2.26(3H，s)
MS(ESI)m/z：521([M+H]+)，519([M-H]-)
Example 306
5, 7-dimethyl-2- (dimethylamino) -3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine
To a mixture of 2-amino-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine (70mg) in THF (1ml) at room temperature was added NaH (21mg, 0.88 mmol). After 10 minutes, MeI (27. mu.l) was added to the mixture and stirred at room temperature for two days. The mixture was poured into ice water and extracted with dichloromethane. The organic portion was dried over magnesium sulfate and then filtered. After removal of the solvent by evaporation, the residue was purified by preparative TLC (dichloromethane/MeOH ═ 10/1) to yield 27mg (36%) of the title compound.
1H-NMR(CDCl3)δ：7.86(2H，d，J＝8.4Hz)，7.32-7.24(4H，m)，7.16(2H，d，J＝8.4Hz)，6.77(1H，s)，6.04(1H，t，J＝5，7Hz)，3.50-3.44(2H，m)，2.78(2H，t，J＝6.3Hz)，2.71(6H，s)，2.55(3H，s)，2.41(3H，s)，2.34(3H，s)。
MS(ESI)m/z：507([M+H]+)，505([M-H]-)。
Example 307
2- [4- (2-amino-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethanol according to the procedure described for example 3.
1H-NMR(CDCl3)δ：9.55(1H，s)，789(2H，d，J＝8.3Hz)，7.54(2H，d，J＝8.6Hz)，7.32(2H，d，J＝8.6Hz)，7.11(2H，d，J＝8.4Hz)，6.54(1H，s)，4.28(2H，t，J＝7.0Hz)，2.88(2H，t，J＝7.0Hz)，255(3H，s)，2.43(6H，s)。
MS(ESI)m/z：485([M+H]+)，483([M-H]-)。
Step 22- {4- [ (3-amino-4, 6-dimethyl-2-pyridyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonamidocarbamate
The title compound was prepared from 2- {4- [ (4, 6-dimethyl-3-nitro-2-pyridyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate according to the procedure described in example 1, step 4.
1H-NMR(CDCl3)δ：7.82(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，6.93(2H，d，J＝8.4Hz)，6.84(2H，d，J＝8.4Hz)，6.66(1H，s)，4.22(2H，t，J＝6.6Hz)，2.77(2H，t，J＝6.6Hz)，2.39(3H，s)，2.37(3H，s)，2.22(3H，s)。
MS(ESI)m/z：455([M+H]+)，453([M-H]-)。
Step 32- [4- (2-amino-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate according to the procedure described for example 127.
1H-NMR(DMSO-d6)δ：7.76(2H，d，J＝8.3Hz)，7.42-7.35(6H，m)，6.78(1H，s)，6.61(1H，br.s)，4.22(2H，t，J＝6.6Hz)，2.92(2H，d，J＝6.6Hz)，2.373(3H，s)，2.365(3H，s)，2.32(3H，s)；MS(ESI)m/z：480([M+H]+)，478([M-H]-)。
Example 308
2- {4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for the preparation of example 129 from 2- [4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate.
1H-NMR(DMDO-d6)δ：7.78(2H，d，J＝8.1Hz)，7.43-7.33(7H，m)，6.77(1H，s)，6.43(1H，br.s)，4.25(2H，t，J＝6.6Hz)，2.93(2H，t，J＝6.6Hz)，2.88(3H，s)，2.41(3H，s)，2.37(3H，s)，2.31(3H，s)。
MS(ESI)m/z：494([M+H]+)，492([M-H]-)。
Example 309
2- {4- [5, 7-dimethyl-2- (methylthio) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate according to the procedure described for example 128.
1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.4Hz)，7.36-7.22(6H，m)，6.88(1H，s)，4.32(2H，t，J＝6.6Hz)，2.93(2H，t，J＝6.6Hz)，2.72(3H，s)，2.62(3H，s)，2.48(3H，s)，2.41(3H，s)；MS(ESI)m/z：511([M+H]+)，509([M-H]-)
Example 310
2- {4- [5, 7-dimethyl-2- (methylsulfonyl) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
To a stirred solution of 2- {4- [5, 7-dimethyl-2- (methylthio) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (100mg, 0.20mmol) in AcOH (1ml) at room temperature was added a solution of potassium permanganate (62mg, 0.39mmol) in water (2 ml). After 1 hour, the mixture was poured into saturated aqueous sodium bicarbonate ice and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and filtered. After concentration in vacuo, the residue was purified by preparative TLC (dichloromethane/MeOH ═ 10/1) to yield 70mg (66%) of the title compound.
1H-NMR(CDCl3)δ：7.91(2H，d，J＝8.4Hz)，7.47(2H，d，J＝8.2Hz)，7.34-7.26(4H，m)，7.08(1H，s)，4.35(2H，t，J＝6.7Hz)，3.45(3H，s)，2.96(2H，t，J＝6.7Hz)，2.68(3H，s)，2.55(3H，s)，2.42(3H，s)；MS(ESI)m/z：543([M+H]+)，541([M-H]-)
Example 311
5-acetyl-2- (methylamino) -1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described for example 129 from N- { [ (2- {4- [ (4-acetyl-2-aminophenyl) amino ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide.
1H-NMR(CDCl3) δ: 8.06(1H, s), 7.75-7.66(3H, m), 7.38-7.26(6H, m), 6.89(1H, d, J ═ 8.3Hz), 6.60(1H, br.s), 3.55(2H, dd, J ═ 12.5 and 6.6Hz), 3.08(3H, s), 2.91(2H, t, J ═ 6.6Hz), 2.61(3H, s), 2.38(3H, s)
MS(ESI)m/z：506([M+H]+)，504([M-H]-)
Example 312
2- {4- [ 6-chloro-2- (3-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 6-chloro-2- (3-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol according to the procedure described for example 138.
1H-NMR(CDCl3) δ: 8.70(1H, dd, J ═ 2.2 and 0.7Hz), 8.62(1H, dd, J ═ 4.5 and 1.7Hz), 8.23(1H, s), 8.01-7.97(1H, m), 7.45(2H, dd, J ═ 6.5 and 2.2Hz), 7.37-7.24(7H, m), 3.97(2H, t, J ═ 6.6Hz), 2.99(2H, t, J ═ 6.6 Hz); MS (ESI) m/z: 418([ M + H) ]+)，476([M+CF3CO2]-)
Step 22- {4- [ 6-chloro-2- (3-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- (3-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol.
1H-NMR(CDCl3) δ: 8.73(1H, dd, J ═ 4.9 and 1.8Hz), 8.40-8.36(1H, m), 8.23(1H, s), 7.91(1H, dd, J ═ 2.2 and 0.7Hz), 7.84-7.80(2H, m), 7.49-7.43(2H, m), 7.31-7.17(6H, m), 4.44(2H, t, J ═ 6.2Hz), 3.02(2H, t, J ═ 6.2Hz), 2.41(3H, s); MS (ESI) m/z: 615([ M + H ]]+)，613([M-H]-)
Example 313
2- {4- [ 6-chloro-2- (4-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 6-chloro-2- (4-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol according to the procedure described for example 138.
1H-NMR(CDCl3) δ: 8.60(2H, dd, J ═ 4.6 and 1.7Hz), 8.25(1H, s), 7.49-7.44(4H, m), 7.37(1H, s), 7.27-7.23(2H, m), 4.00(2H, t, J ═ 6.4Hz), 3.02(2H, t, J ═ 6.4 Hz); MS (ESI) m/z: 418([ M + H) ]+)，476([M+CF3CO2]-)
Step 22- {4- [ 6-chloro-2- (4-pyridyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- (4-pyridinyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol.
1H-NMR(CDCl3) δ: 8.60(2H, dd, J ═ 4.8 and 1.5Hz), 8.27(1H, s), 7.89(2H, d, J ═ 8.3Hz), 7.44-7.18(9H, m), 4.39(2H, t, J ═ 6.4Hz), 3.03(2H, t, J ═ 6.4Hz), 2.40(3H, s);
MS(ESI)m/z：615([M+H]+)，613([M-H]-)
example 314
2- {4- [ 6-chloro-2- (2-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-2- (2-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol according to the procedure described for example 138.
1H-NMR(CDCl3)δ：8.22(1H，s)，7.47(1H，s)，7.33-7.10(8H，m)，3.89(2H，t，J＝6.4Hz)，2.89(2H，t，J＝6.4Hz)，2.20(3H，s)；MS(ESI)m/z：431([M+H]+)
Step 22- {4- [ 6-chloro-2- (2-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- (2-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol.
1H-NMR(CDCl3)δ：8.24(1H，s)，7.78(2H，d，J＝8.2Hz)，7.46(1H，s)，7.35-7.09(8H，m)，7.00(2H，d，J＝8.4Hz)，4.27(2H，t，J＝6.8Hz)，2.88(2H，t，J＝6.8Hz)，2.41(3H，s)，2.11(3H，s)；
MS(ESI)m/z：628([M+H]+)，489([M+CH3CO2]-)
Example 315
2- {4- [ 6-chloro-2- (1, 3-thiazol-2-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-2- (1, 3-thiazol-2-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol according to the procedure described for example 138.
1H-NMR(CDCl3)δ：8.23(1H，s)，7.75(1H，d，J＝3.1Hz)，7.47-7.45(3H，m)，7.36-7.27(3H，m)，3.99(2H，t，J＝6.4Hz)，3.03(2H，t，J＝6.4Hz)
MS(ESI)m/z：424([M+H]+)，482([M+CH3CO2]-)
Step 22- {4- [ 6-chloro-2- (1, 3-thiazol-2-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from 2- {4- [ 6-chloro-2- (1, 3-thiazol-2-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol following the procedure described in example 3.
1H-NMR(CDCl3)δ：8.23(1H，s)，7.91(2H，d，J＝8.4Hz)，7.74(1H，d，J＝3.1Hz)，7.46(1H，d，J＝3.1Hz)，7.38-7.26(7H，m)，4.40(2H，t，J＝6.8Hz)，3.04(2H，t，J＝6.8Hz)，2.42(3H，s)
MS(ESI)m/z：621([M+H]+)，619([M-H]-)
Example 316
2- {4- [ 6-chloro-2- (1H-imidazol-4-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-2- (1H-imidazol-4-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol according to the procedure described for example 138.
1H-NMR(CDCl3/CD3OD＝4/1)δ：8.09(1H，s)，7.65(1H，s)，7.50(2H，d，J＝8.7Hz)，7.33(2H，d，J＝8.2Hz)，7.25(1H，s)，6.91(1H，s)，3.93(2H，t，J＝6.4Hz)，3.00(2H，t，J＝6.4Hz)
MS(ESI)m/z：407([M+H]+)，405([M-H]-)
Step 22- {4- [ 6-chloro-2- (1H-imidazol-4-yl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from 2- {4- [ 6-chloro-2- (1H-imidazol-4-yl) -5- (trifluoromethyl) -1H-benzoimidazol-1-yl ] phenyl } ethanol according to the procedure described in example 3.
MS(ESI)m/z：604([M+H]+)，602([M-H]-)
Example 317
2- [4- (5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step.14- (2-hydroxyethyl) phenylboronic acid
To a stirred solution of 4-bromophenylethylalcohol (5.00g, 24.9mmol) in THF (80ml) at-78 deg.C was added 1.5M n-butyllithium in hexane (39.8ml, 59.7mmol) over 30 minutes. After 1 hour, B (O) was slowly added to the mixture at-78 deg.CiPr)3(8.61ml, 37.3mmol) in THF (20 ml). The resulting mixture was warmed to room temperature and treated with 2M hydrochloric acid (100ml) for 1 hour. The reaction was extracted with dichloromethane, then dried over magnesium sulfate, and then filtered. After evaporation in vacuo, the residue was purified by column chromatography on silica gel eluting with dichloromethane/MeOH 20/1 to give 2.61g (63%) of the title compound.
1H-NMR(CD3OD)δ：7.64-7/48(2H，m)，7.19-7.13(2H，m)，3.70(2H，t，J＝7.2Hz)，2.77(2H，t，J＝7.2Hz)
MS(ESI)m/z：165([M-H]-)
Step 24- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) oxy ] ethyl } phenylboronic acid
4- (2-hydroxyethyl) phenylboronic acid (1.00g, 6.02mmol) was treated with pTsNCO (1.01ml, 6.63mmol) and pyridine (90ml) for 2 h at room temperature. The mixture was poured into 2M glacial hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with dichloromethane/MeOH 20/1 to give 2.20g (quant.) of the title compound.
1H-NMR(DMSO-d3)δ：11.95(1H，br.s)，7.97(1H，s)，7.75-7.67(2H，m)，7.40(2H，d，J＝8.6Hz)，7.13(2H，d，J＝7.7Hz)，4.18(2H，t，J＝6.6Hz)，2.81(2H，t，J＝6.6Hz)，2.40(3H，s)
MS(ESI)m/z：381([M+NH4]+)，362([M-H]-)
Step 32- [4- (5, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
A mixture of 4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) oxy ] ethyl } phenylboronic acid (100mg, 0.28mmol), 5, 6-dimethylbenzimidazole (40mg, 0.28mmol), Cu (OAc)2(60mg, 0.33mmol), triethylamine (115. mu.l, 0.83mmol), MS4A (100mg), and dichloromethane (4ml) was stirred at room temperature for 1 week. Filter through celite bed, dilute filtrate with dichloromethane, and wash with water. The organic portion was dried over magnesium sulfate and filtered. After concentration under reduced pressure, the residue was purified by preparative TLC (dichloromethane/MeOH ═ 10/1) to give 28mg (22%) of the title compound.
1H-NMR(CDCl3)δ：7.82(2H，d，J＝8.4Hz)，7.72(1H，s)，7.57(1H，s)，7.33(2H，d，J＝8.1Hz)，7.12(2H，d，J＝8.4Hz)，7.07(1H，s)，7.01(2H，d，J＝8.4Hz)，4.39(2H，t，J＝6.1Hz)，2.94(2H，t，J＝6.1Hz)，2.42(3H，s)，2.39(3H，s)，2.26(3H，s)
MS(ESI)m/z：464([M+H]+)，462([M-H]-)
Example 318
6-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 16-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 7, from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carbonitrile (example 111, step 4).
1H-NMR(CDCl3)δ：8.07(1H，s)，7.50(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.19(1H，s)，3.83(2H，t，J＝7.1Hz)，3.22(2H，t，J＝7.1Hz)，2.79(2H，q，J＝7.5Hz)，1.37(3H，t，J＝7.5Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carbonitrile (step 1).
1H-NMR(CDCl3)δ：8.07(1H，s)，7.49(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.18(1H，s)，3.64(2H，t，J＝7.0Hz)，3.04(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 31- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described for example 37 step 7 from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (step 2).
1H-NMR(CDCl3)δ：8.06(1H，s)，7.46(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.1Hz)，7.19(1H，s)，3.09(2H，t，J＝7.1Hz)，2.89(2H，t，J＝7.1Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 46-chloro-5-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (step 3).
mp 219-224℃
IR(KBr)v：3388，2229，1708，1618，1514，1466，1344，1161，1089cm-1
MS(ESI)m/z 522(M+H)+，520(M-H)-；
1H-NMR(DMSO-d6)δ8.38(1H，s)，7.77(2H，d，J＝8.2Hz)，7.31-7.49(6H，m)，7.32(1H，s)，6.53(1H，br.s)，3.26-3.28(2H，m)，2.69-2.81(4H，m)，2.35(3H，s)，1.25(3H，t，J＝7.6Hz)。
Example 319
6-chloro-5- (dimethylamino) -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 1N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine
To a mixture of 38% formaldehyde (0.5ml, 5.6mmol) and 3M aqueous sulfuric acid (0.4ml, 0.12mmol) at 0 deg.C was added 6-chloro-1- [4- (2-chloroethyl) phenyl]-2-Ethyl-1H-benzimidazol-5-ylamine (example 110, step 6, 100mg, 0.3mmol) and NaBH 4(153mg, 4mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 2) to give 48mg (46%) of the title compound as a white solid.
MS(E1)m/z：361(M+)
1H-NMR(CDCl3)δ：7.54(1H，s)，7.44(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.13(1H，s)，3.82(2H，t，J＝7.0Hz)，3.19(2H，t，J＝7.0Hz)，2.82(6H，s)，2.75(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 2N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine
The title compound was prepared according to the procedure described in example 1, step 8, from N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine (step 1).
1H-NMR(CDCl3)δ：7.54(1H，s)，7.43(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.12(1H，s)，3.62(2H，t，J＝7.0Hz)，3.01(2H，t，J＝7.0Hz)，2.82(6H，s)，2.75(2H，q，J＝7.6Hz)，1.34(2H，t，J＝7.6Hz)。
Step 3N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine
The title compound was prepared according to the procedure described in example 37, step 7, from N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine (step 2).
1H-NMR(CDCl3)δ：7.54(1H，s)，7.41(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，7.13(1H，s)，3.08(2H，t，J＝6.9Hz)，2.87(2H，t，J＝6.9Hz)，2.82(6H，s)，2.75(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 46-chloro-5- (dimethylamino) -2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N, N-dimethylamine (step 3).
m.p.：108-114℃
MS(ESI)m/z：540(MH+)，538([M-H]-)。
1H-NMR(CDCl3)δ：7.73(2H，d，＝8.0Hz)，7.54(1H，s)，7.25-7.39(6H，m)，7.11(1H，s)，6.73(1H，br.s)，3.58(2H，q，J＝6.9Hz)，2.94(2H，t，J＝6.9Hz)，2.71-2.82(8H，m)，2.40(3H，s)，1.33(3H，t，J＝7.6Hz)。
Example 320
6-chloro-2-ethyl-5- (methylamino) -1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 16-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylcarboxamide
Formic acid (0.06ml, 1.65mmol) was added to a solution of acetic anhydride (0.14ml) in THF (5ml) at 0 deg.C under nitrogen. The mixture was stirred at 60 ℃ for 2 hours. The mixture was then cooled again to 0 ℃ and a solution of 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylamine (example 110, step 6, 100mg, 0.3mmol) in THF (2ml) was added. The mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed with 2N aqueous sodium hydroxide (50ml) brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 10) to give 68mg (67%) of the title compound as a pale yellow solid.
MS(EI)m/z：361(M+)
1H-NMR(CDCl3)δ：8.53-8.76(1H，br.s)，7.66(1H，s)，7.44-7.48(2H，m)，7.26-7.31(2H，m)，7.18(1H，s)，3.83(2H，t，J＝6.9Hz)，3.20(2H，t，J＝6.9Hz)，2.78(2H，q，J＝7.4Hz)，1.32-1.39(3H，m)。
Step 2N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -N-methylamine
Under nitrogen atmosphere at room temperature, (6-chloro-1- [4- (2-chloroethyl) phenyl]-2-Ethyl-1H-benzimidazol-5-ylcarboxamide (step 1, 112mg, 0.3mmol) in THF (15ml) Me was added 2S BH3(0.07ml, 0.77 mmol). The mixture is refluxed for 1 hourThen (c) is performed.
The mixture was then cooled to room temperature, and methanol (3ml) and 2N aqueous hydrochloric acid (12ml) were added. The mixture was stirred at 70 ℃ for 30 minutes. The volatile components were removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (50ml), brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 4) to give 93mg (87%) of the title compound as a white solid.
MS(EI)m/z：347(M+)
1H-NMR(CDCl3)δ：742(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.04(1H，s)，7.03(1H，s)，3.81(2H，t，J＝6.9Hz)，3.18(2H，t，J＝6.9Hz)，2.95(3H，s)，2.75(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 3N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N-methylamine
The title compound was prepared according to the procedure described in example 1, step 8, from N- { 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -N-methylamine (step 2).
1H-NMR(CDCl3)δ：7.42(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.04-7.03(2H，m)，4.19(1H，br.s)，3.61(2H，t，J＝7.0Hz)，3.00(2H，t，J＝7.0Hz)，2.95(3H，s)，2.75(2H，q，J＝7.6Hz)，1.33(3H，t，J＝7.6Hz)。
Step 4N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N-methylamines
The title compound was prepared according to the procedure described in example 37, step 7, from N- {1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N-methylamine (step 3).
1H-NMR(CDCl3)δ：7.39(2H，d，J＝8.4Hz)，7.25(2H，d，J＝8.4Hz)，7.06(1H，s)，7.03(1H，s)，3.64(2H，br.s)，3.15(2H，t，J＝7.2Hz)，2.94-2.99(5H，m)，2.73(2H，q，J＝7.5Hz)，1.32(3H，t，J＝7.5Hz)。
Step 56-chloro-2-ethyl-5- (methylamino) -1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from N- {1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-yl } -N-methylamine (step 4).
m.p.：95-100℃
MS(ESI)m/z：526(MH+)，524([M-H]-)。
1H-NMR(CDCl3)δ：7.73(2H，d，J＝8.4Hz)，7.23-7.36(7H，m)，7.03(1H，s)，3.57(2H，t，J＝6.6Hz)，2.89-2.94(5H，m)，2.73(2H，q，J＝7.4Hz)，1.32(3H，t，J＝7.4Hz)。
Example 321
4-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 13-chloro-2-nitrobenzamide
A mixture of 3-chloro-2-nitro-benzoic acid (1g, 4.9mmol) and thionyl chloride (di) chloride (9ml) was stirred at 80 ℃ for 1 hour. Thionyl chloride was removed under reduced pressure and the residue dissolved in dichloromethane (15 ml). The mixture was cooled to 0 ℃ and 30% NH was added dropwise3Ammonia water (2 ml). The mixture was stirred at 0 ℃ for 25 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (100ml), and brine (100 ml). The organic phase is dried (sodium sulphate) and concentrated under reduced pressure to yield 1.2g (quant.) of the title compound as a pale orange yellow solid.
1H-NMR(CDCl3)δ：7.68-7.92(3H，m)。
Step 23-chloro-2-nitrobenzonitrile
To a solution of 3-chloro-2-nitrobenzamide (step 1, 1.2g, 4.9mmol) in DMF (8ml) was added dropwise a solution of thionyl chloride (di) chloride (2ml, 24.8mmol) in DMF (3ml) at room temperature. The mixture was stirred at 120 ℃ for 2.5 hours. The mixture was poured into ice water, and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (100ml), brine (100ml), then dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3: 1/1: 2) to give 1g (quant.) of the title compound as a pale yellow solid.
1H-NMR(CDCl3)δ：7.61-7.68(1H，m)，7.74-7.78(2H，m)。
Step 32- [4- (3-cyano-2-nitroanilino) phenyl ] ethanol
The title compound was prepared according to the procedure described for example 1, step 3, from 3-chloro-2-nitrobenzonitrile (step 2) and 4-aminophenylethyl alcohol.
MS(EI)m/z：283(M+)
1H-NMR(CDCl3)δ：9.37(1H，br.s)，7.15-7.41(7H，m)，3.91(2H，t，J＝6.4Hz)，2.91(2H，t，J＝6.4Hz)。
Step 42-amino-3- [4- (2-hydroxyethyl) anilino ] benzonitrile
The title compound was prepared according to the procedure described in example 40, step 2, from 2- [4- (3-cyano-2-nitroanilino) phenyl ] ethanol (step 3).
MS(EI)m/z：253(M+)
1H-NMR(CDCl3)δ：7.22-7.28(2H，m)，7.10(2H，d，J＝8.4Hz)，6.69-6.75(3H，m)，5.13(1H，br.s)，4.54(2H，br.s)，3.84(2H，t，J＝6.4Hz)，2.80(2H，t，J＝6.4Hz)。
Step 52- [4- (4-cyano-2-ethyl-1-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2-amino-3- [4- (2-hydroxyethyl) anilino ] benzonitrile (step 4).
TLC, Rf 0.6, hexane: ethyl acetate (1: 1).
Step 62-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-4-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (4-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 5).
MS(EI)m/z：291(M+)
1H-NMR(CDCl3)δ：7.58(1H，d，J＝6.3Hz)，7.49(2H，d，J＝8.3Hz)，7.19-7.32(4H，m)，4.01(2H，t，J＝6.4Hz)，3.02(2H，t，J＝6.4Hz)，2.86(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 71- [4- (2-chloroethyl) phenyl-2-ethyl-1H-benzimidazole-4-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 7, from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-4-carbonitrile (step 6).
1H-NMR(DMSO-d6)δ：7.72(1H，dd，J＝1.2Hz，7.4Hz)，7.51-7.60(4H，m)，7.30-7.42(2H，m)，3.97(2H，t，J＝7.0Hz)，3.18(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.6Hz)，1.26(3H，t，J＝7.6Hz)。
Step 81- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carbonitrile (step 7).
1H-NMR(CDCl3)δ：7.59(1H，dd，J＝1.2Hz，7.3Hz)，7.48(2H，d，J＝8.0Hz)，7.19-7.32(4H，m)，3.63(2H，t，J＝6.6Hz)，3.03(2H，t，J＝6.6Hz)，2.84(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz)。
Step 91- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carbonitrile
The title compound was prepared according to the procedure described for example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carbonitrile (step 8).
1H-NMR(CDCl3)δ：7.58(1H，dd，J＝1.3Hz，7.4Hz)，7.44(2H，d，J＝8.2Hz)，7.19-7.32(4H，m)，3.08(2H，t，J＝6.7Hz)，2.81-2.93(4H，m)，1.33(3H，t，J＝7.5Hz)。
Step 104-cyano-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carbonitrile (step 9).
m.p.：95-103℃
IR(KBr)v：2225，1676，1516，1433，1340，1161，1091，794，663cm-1。
MS(ESI)m/z：488(MH+)，486([M-H]-)。
1H-NMR(CDCl3)δ：7.72(2H，d，J＝8.1Hz)，7.59(1H，d，J＝7.0Hz)，7.42(2H，d，J＝8.1Hz)，7.18-7.32(6H，m)，6.72(1H，br.s)，3.57(2H，t，J＝7.1Hz)，2.96(2H，t，J＝7.1Hz)，2.85(2H，q，J＝7.6Hz)，2.41(3H，s)，1.33(3H，t，J＝7.6Hz)。
Example 322
2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-4-carboxamide
Step 12-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-4-carboxamide
To a stirred suspension of 2- {4- [ (3-amino-4, 6-dimethyl-2-pyridinyl) amino ] phenyl } ethanol (step 4, 820mg, 3.3mmol) in toluene (30ml) was added propionyl chloride (630mg, 6.8mmol) dropwise at 0 ℃. The reaction mixture was refluxed for 1.5 hours. After cooling, the mixture was poured into water (50ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous sodium hydroxide (50ml) and brine (50ml), then dried (sodium sulfate). The solvent was removed under reduced pressure and the residue was dissolved in THF (20ml) and methanol (20 ml). The mixture was added to a 4N aqueous LiOH solution (10ml), and stirred at room temperature for 14 hours. The mixture was evaporated. The residue was dissolved in ethyl acetate (100ml), which was washed with water (50 ml). The organic layer was washed with brine (50mL) and dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 2/1: 5/0: 1) to give 260mg (26%) of the title compound as a white solid.
MS(EI)m/z：309(M+)
1H-NMR(CDCl3)δ：9.81(1H，br.s)，8.13(1H，dd，J＝2.0Hz，7.0Hz)，7.47(2H，d，J＝80Hz)，7.25-7.31(4H，m)，5.99(1H，br.s)，4.00(2H，t，J＝6.4Hz)，3.01(2H，t，J＝6.4Hz)，2.82(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 21- [4- { 2-chloroethyl) phenyl ] -2-ethyl-1-benzimidazole-4-carboxamide
The title compound was prepared according to the procedure described in example 1, step 7, from 2- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethanol (step 1).
1H-NMR(DMSO-d6)δ：929(1H，br.s)，7.81-7.91(1H，m)，7.79(1H，br.s)，7.49-7.60(4H，m)，7.24-7.33(2H，m)，3.97(2H，t，J＝6.8Hz)，3.18(2H，t，J＝6.8Hz)，2.80(2H，q，J＝7.5Hz)，1.27(3H，t，J＝7.5Hz)。
Step 31-4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carboxamide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-carboxamide (step 2).
1H-NMR(DMSO-d6)δ：9.29(1H，br.s)，7.89(1H，d，J＝7.3Hz)，7.79(1H，br.s)，751-7.59(4H，m)，7.22-7.33(2H，m)，3.68(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.5Hz)，1.27(3H，t，J＝7.5Hz)。
Step 41- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazole-4-carboxamide
The title compound was prepared according to the procedure described for example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (step 3).
1H-NMR(DMSO-d6)δ：9.30(1H，br.s)，7.89(1H，d，J＝6.5Hz)，7.81(1H，br.s)，7.48-7.49(4H，m)，7.26-7.30(2H，m)，2.77-2.89(6H，m)，1.28(3H，t，J＝6.4Hz)。
Step 52-Ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-4-carboxamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (step 4).
m.p.：208-214℃
IR(KBr)v：3336，1664，1589，1508，1406，1342，1168，976cm-1。
MS(ESI)m/z：506(MH+)，504([M-H]-)。
1H-NMR(DMSO-d6)δ：929(1H，br.s)，7.89(1H，dd，J＝1.3Hz，7.2Hz)，7.75-7.79(3H，m)，7.22-7.49(8H，m)，6.54(1H，br.s)，2.75-2.83(4H，m)，2.35(3H，s)，1.27(3H，t，J＝7.4Hz)。
Example 323
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (methylsulfonyl) -1H-benzimidazole
Step 11, 5-dichloro-2- (methylsulfinyl) -4-nitrobenzene
To a mixture of (2, 4-dichloro-phenyl) -methyl sulfone (Ono Mitsunori, nakamurayoshida, Sato shino, Itoh Isamu, chem.lett, 1988, 395-. The mixture was stirred at 55 ℃ for 1 hour. The mixture was poured into ice water, neutralized with 6N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was washed with brine and dried (sodium sulfate). The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with hexane/ethyl acetate (2: 1/1: 1) to give 3g (74%) of the title compound as a white solid.
1H-NMR(CDCl3)δ：8.45(1H，s)，7.65(1H，s)，2.89(3H，s)。
Step 21, 5-dichloro-2- (methylsulfonyl) -4-nitrobenzene
To a solution of 1, 5-dichloro-2- (methylsulfinyl) -4-nitrobenzene (1.0g, 3.9mmol) in dichloromethane (50ml) was added 3-chloroperoxybenzoic acid (1.7g, 9.8 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The mixture was added to a saturated aqueous solution of sodium hydrogencarbonate (20ml) and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50mL) and dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (2: 1) to give 1g (100%) of the title compound as a white solid.
MS(EI)m/z：269(M+)。
1H-NMR(CDCl3)δ：8.68(1H，s)，7.81(1H，s)，3.30(3H，s)。
Step 32- {4- [ 5-chloro-4- (methylsulfonyl) -2-nitroanilino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 3, from 1, 5-dichloro-2- (methylsulfonyl) -4-nitrobenzene and 4-aminophenylethyl alcohol (step 2).
MS(EI)m/z：370(M+)
1H-NMR(CDCl3)δ：9.81(1H，br.s)，8.99(1H，s)，7.39(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.18(1H，s)，3.94(2H，t，J＝6.2Hz)，3.25(3H，s)，2.95(2H，t，J＝6.2Hz)。
Step 42- {4- [ 2-amino-5-chloro-4- (methylsulfonyl) anilino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 40, step 2, from 2- {4- [ 5-chloro-4- (methylsulfonyl) -2-nitroanilino ] phenyl ] ethanol (step 3).
MS(EI)m/z：340(M+)
1H-NMR(CDCl3)δ：7.50(1H，s)，7.22(2H，d，J＝8.4Hz)，7.15(1H，s)，7.00(2H，d，J＝8.4Hz)，5.71(1H，br.s)，3.88(2H，t，J＝6.4Hz)，3.67(2H，br.s)，3.22(3H，s)，2.86(2H，t，J＝6.4Hz)。
Step 52- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- {4- [ 2-amino-5-chloro-4- (methylsulfonyl) anilino ] phenyl } ethanol (step 4).
TLC, Rf 0.7, hexane: ethyl acetate (1: 2).
Step 62- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 5).
MS(EI)m/z：378(M+)
1H-NMR(CDCl3)δ：8.60(1H，s)，7.52(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.10(1H，s)，397-4.04(2H，m)，3.29(3H，s)，303(2H，t，J＝6.5Hz)，2.80(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 76-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl sulfone
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 6).
1H-NMR(CDCl3)δ：8.62(1H，s)，7.50(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.24(1H，s)，3.83(2H，t，J＝7.1Hz)，3.29(3H，s)，3.22(2H，t，J＝7.1Hz)，2.80(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 81- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-ylmethyl sulfone
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-ylmethyl sulfone (step 7).
1H-NMR(CDCl3)δ：8.62(1H，s)，7.50(2H，d，J＝8.4Hz)，7.25(2H，d，J＝8.4Hz)，7.23(1H，s)，3.64(2H，t，J＝6.9Hz)，3.29(3H，s)，3.04(2H，t，J＝6.9Hz)，2.80(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 92- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-1H-benzimidazol-5-ylmethyl sulfone (step 8).
1H-NMR(CDCl3)δ：8.61(1H，s)，7.47(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.24(1H，s)，3.29(3H，s)，3.10(2H，t，J＝7.1Hz)，2.90(2H，t，J＝7.1Hz)，2.80(2H，q，J＝7.5Hz)，1.37(3H，t，J＝7.5Hz)。
Step 106-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (methylsulfonyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanamine (step 9).
m.p.：105-118℃
IR(KBr)v：2879，1676，1518，1458，1309，1142，1089，993cm-1。
MS(ESI)m/z：575(MH+)，573([M-H]-)。
1H-NMR(CDCl3)δ：8.59(1H，s)，7.75(2H，d，J＝8.4Hz)，7.43(2H，d，J＝8.4Hz)，7.29-7.33(4H，m)，7.21(1H，s)，6.69(1H，br.s)，3.55-3.62(2H，m)，3.29(3H，s)，2.96(2H，t，J＝6.9Hz)，2.80(3H，q，J＝7.5Hz)，2.41(3H，s)，1.34(3H，t，J＝7.5Hz)。
Example 324
6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (methylsulfonyl) -1H-benzimidazole sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (methylsulfonyl) -1H-benzimidazole (example 323)
m.p.：175-183℃
IR(KBr)v：3375，1604，1516，1458，1139，1083，993cm-1。
Example 325
2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2-ethyl-5- (methylsulfonyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (example 323, step 6).
m.p.：105-110℃
IR(KBr)v：1751，1517，1458，1309，1163，1141，1089cm-1。
MS(ESI)m/z：576(MH+)，574([M-H]-)。
1H-NMR(CDCl3)δ：8.60(1H，s)，7.91-7.94(2H，m)，7.21-7.43(7H，m)，4.40(2H，br.s)，3.31(3H，s)，3.05(2H，br.s)，2.78-2.81(2H，m)，2.44(3H，s)，1.33(3H，t，J＝7.6Hz)。
Example 326
5- (aminosulfonyl) -6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
Step 12.4-dichloro-5-nitrobenzenesulfonyl chloride
Under an ice-water bath, 2, 4-dichloronitrobenzene (10g, 52mmol) was added dropwise to ClSO3H (8ml, 120 mmol). The mixture was stirred at 130 ℃ for 26 hours. The mixture was cooled to room temperature and poured into ice water. The resulting precipitate was collected by filtration and dried under reduced pressure to give 9g (60%) of the title compound as a brown solid.
MS(EI)m/z：290(M+)
1H-NMR(CDCl3)δ：8.70(1H，s)，7.90(1H，s)。
Step 2N- (tert-butyl) -2, 4-dichloro-5-nitrobenzenesulfonamide
The title compound was prepared according to the procedure for example 87, step 1, from 2, 4-dichloro-5-nitrobenzenesulfonyl chloride and tert-butylamine (step 1).
1H-NMR(CDCl3)δ：8.65(1H，s)，7.74(1H，s)，5.01(1H，br.s)，1.27(9H，s)。
Step 3N- (tert-butyl) -2-chloro-4- [4- (2-hydroxyethyl) anilino ] -5-nitrobenzenesulfonamide
The title compound was prepared according to the procedure described for example 162 step 1 from N- (tert-butyl) -2, 4-dichloro-5-nitrobenzenesulfonamide and 4-aminophenylethyl alcohol (step 2).
1H-NMR(CDCl3)δ：9.72(1H，br.s)，8.95(1H，s)，7.37(2H，d，J＝8.3Hz)，7.24(2H，d，J＝8.3Hz)，7.17(1H，s)，4.79(1H，br.s)，3.90-3.96(2H，m)，2.94(2H，t，J＝6.4Hz)，1.26(9H，s)。
Step 45-amino-N (tert-butyl) -2-chloro-4- [4- (2-hydroxyethyl) anilino ] benzenesulfonamide
The title compound was prepared according to the procedure described in example 40, step 2, from N- (tert-butyl) -2-chloro-4- [4- (2-hydroxyethyl) anilino ] -5-nitrobenzenesulfonamide (step 3).
MS(EI)m/z：397(M+)
1H-NMR(CDCl3)δ：7.51(1H，s)，7.20(2H，d，J＝8.4Hz)，7.14(1H，s)，6.95(2H，d，J＝8.4Hz)，5.22(1H，br.s)，4.89(1H，br.s)，3.87(2H，t，J＝6.4Hz)，2.85(2H，t，J＝6.4Hz)，1.23(9H，s)。
Step 52- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared according to the procedure described in example 1, step 5, from 5-amino-N- (tert-butyl) -2-chloro-4- [4- (2-hydroxyethyl) anilino ] benzenesulfonamide (step 4).
TLC, Rf 0.8, hexane: ethyl acetate (1: 2).
Step 6N- (tert-butyl) -6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 5).
1H-NMR(CDCl3)δ：8.57(1H，s)，7.49(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.20(1H，s)，4.98(1H，br.s)，4.00(2H，br.s)，3.02(2H，t，J＝6.4Hz)，2.79(2H，q，J＝7.5Hz)，1.37(3H，t，J＝7.5Hz)，1.21(9H，s)。
Step 7N- (tert-butyl) -6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 7, from N- (tert-butyl) -6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-sulfonamide (step 6).
1H-NMR(CDCl3)δ：8.58(1H，s)，7.49(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.19(1H，s)，4.96(1H，br.s)，3.83(2H，t，J＝7.0Hz)，3.21(2H，t，J＝7.0Hz)，2.80(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)，1.22(9H，s)。
Step 81- [4- (2-azidoethyl) phenyl ] -N- (tert-butyl) -6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 1, step 8, from N- (tert-butyl) -6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazole-5-sulfonamide (step 7).
1H-NMR(CDCl3)δ：8.57(1H，s)，7.48(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，7.19(1H，s)，4.96(1H，br.s)，3.63(2H，t，J＝6.9Hz)，3.03(2H，t，J＝6.9Hz)，2.79(2H，q，J＝7.4Hz)，1.37(3H，t，J＝7.4Hz)，1.21(9H，s)。
Step 91- [4- (2-aminoethyl) phenyl ] -N- (tert-butyl) -6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2-azidoethyl) phenyl ] -N- (tert-butyl) -6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide (step 8).
1H-NMR(CDCl3)δ：8.57(1H，s)，7.44(2H，d，J＝8.5Hz)，7.29(2H，d，J＝8.5Hz)，7.20(1H，s)，5.03(1H，br.s)，3.09(2H，t，J＝6.9Hz)，2.89(2H，t，J＝6.9Hz)，2.79(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)，1.22(9H，s)。
Step 105- [ (tert-butylamino) sulfonyl ] -6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -N- (tert-butyl) -6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide (step 9).
1H-NMR(CDCl3)δ：8.54(1H，s)，7.78(2H，d，J＝8.3Hz)，7.41(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.2Hz)，7.23(2H，d，J＝8.2Hz)，7.16(1H，s)，6.61(1H，br.s)，5.21(1H，br.s)，3.54-3.60(2H，m)，2.95(2H，t，J＝6.9Hz)，2.78(2H，q，J＝7.5Hz)，2.41(3H，s)，1.35(3H，t，J＝7.5Hz)，1.21(9H，s)。
Step 115- (aminosulfonyl) -6-chloro-2-ethyl-1-4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 88, step 1, from 5- [ (tert-butylamino) sulfonyl ] -6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole (step 9).
m.p.：163-170℃
IR(KBr)v：1676，1517，1400，1340，1159，1089，995cm-1。
MS(ESI)m/z：576(MH+)，574([M-H]-)。
1H-NMR(DMSO-d6)δ：8.25(1H，s)，7.77(2H，d，J＝8.3Hz)，7.55(2H，br.s)，7.37-7.48(6H，m)，7.20(1H，s)，6.54(1H，br.s)，3.27(2H，br.s)，2.71-2.81(4H，m)，2.34(3H，s)，1.23(3H，t，J＝7.6Hz)。
Example 327
2- {4- [5- (aminosulfonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4- [ (tert-butylamino) sulfonyl ] -6-chloro-2-ethyl-1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from N- (tert-butyl) -6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-sulfonamide (example 326, step 6).
1H-NMR(CDCl3)δ：8.58(1H，s)，7.93(2H，d，J＝8.2Hz)，7.33-7.39(4H，m)，7.20(2H，d，J＝～8.2Hz)，7.16(1H，s)，5.07(1H，br.s)，4.38(2H，t，J＝6.2Hz)，3.03(2H，t，J＝6.2Hz)，2.78(2H，q，J＝7.5Hz)，2.44(3H，s)，1.35(3H，t，J＝7.5Hz)，1.21(9H，s)。
Step 22- {4- [5- (aminosulfonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared from 2- (4- {5- [ (tert-butylamino) sulfonyl ] -6-chloro-2-ethyl-1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate (step 1) according to the procedure described in example 88, step 1.
m.p.：110-115℃
IR(KBr)v：1676，1517，1400，1340，1159，1089，995cm-1
MS(ESI)m/z：576(MH+)，574([M-H]-)。
1H-NMR(DMSO-d6)δ：8.25(1H，s)，7.76(2H，d，J＝8.4Hz)，7.55(2H，br.s)，7.47(4H，s)，7.41(2H，d，J＝8.4Hz)，7.20(1H，s)，4.29(2H，t，L＝6.6Hz)，2.96(2H，t，J＝6.6Hz)，2.75(2H，q，J＝7.5Hz)，2.35(3H，s)，1.24(3H，t，J＝7.5Hz)。
Example 328
2- [4- (6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- [4- (6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl ] sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carbonitrile (example 111, step 4).
m.p.：85-98℃
IR(KBr)v：1747，1618，1517，1465，1348，1290，1163，1089cm-1
MS(ESI)m/z：523(MH+)，521([M-H]-)
1H-NMR(CDCl3)δ：8.07(1H，s)，7.92(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.1Hz)，7.25(2H，d，J＝8.1Hz)，7.17(1H，s)，4.39(2H，t，J＝6.8Hz)，3.04(2H，t，J＝6.8Hz)，2.78(2H，q，J＝7.6Hz)，2.44(3H，s)，1.35(3H，t，J＝7.6Hz)。
Example 329
N- [ ({2- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide
Step 14-cyano-3, 5-dimethyl-2-nitrophenyl trifluoromethanesulfonate
To a solution of 4-hydroxy-2, 6-dimethyl-3-nitro-benzonitrile (v.auwers; Saurwein; fortsch.ch.phys.; 18; Heft 2, s.23; 2.6g, 13.4mmol) in dichloromethane (150ml) was added triflic anhydride (3.4ml, 20mmol) and pyridine (1.5ml, 20mmol) at 0 ℃. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2: 1) to give 3g (69%) of the title compound as a pale yellow solid.
MS(EI)m/z：324(M+)
1H-NMR(CDCl3)δ：7.34(1H，s)，2.68(3H，s)，2.61(3H，s)。
Step 22- {4- [ (4-cyano-3, 5-dimethyl-2-nitrophenyl) amino ] phenyl } acetic acid ethyl ester
The title compound was prepared according to the procedure described in example 1, step 3, from 4-cyano-3, 5-dimethyl-2-nitrophenyl trifluoromethanesulfonate (step 1).
1H-NMR(CDCl3)δ：8.08(1H，br.s)，7.27(2H，d，J＝8.4Hz)，7.15(2H，d，J＝8.4Hz)，4.30(2H，t，J＝7.0Hz)，2.96(2H，t，J＝7.0Hz)，2.65(3H，s)，2.41(3H，s)，2.05(3H，s)。
Step 32- {4- [ (4-cyano-3, 5-dimethyl-2-nitrophenyl) amino ] phenyl } acetic acid ethyl ester
The title compound was prepared according to the procedure described in example 6, step 3, from ethyl 2- {4- [ (4-cyano-3, 5-dimethyl-2-nitrophenyl) amino ] phenyl } acetate (step 2).
1H-NMR(CDCl3)δ：7.14(2H，d，J＝8.4Hz)，6.85-6.89(3H，m)，5.50(1H，br.s)，4.26(2H，t，J＝7.1Hz)，3.54(2H，br.s)，2.89(2H，t，J＝7.1Hz)，2.41(3H，s)，2.37(3H，s)，2.05(3H，s)。
Step 42- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] acetic acid ethyl ester
The title compound was prepared according to the procedure described in example 1, step 5, from ethyl 2- {4- [ (4-cyano-3, 5-dimethyl-2-nitrophenyl) amino ] phenyl } acetate (step 3).
1H-NMR(CDCl3)δ：7.45-7.47(2H，m)，7.26-7.29(2H，m)，6.79(1H，br.s)，4.37(2H，t，J＝7.0Hz)，3.08(2H，t，J＝7.0Hz)，2.83-2.89(5H，m)，2.56(3H，s)，2.09(3H，s)，1.28(3H，br.s)。
Step 52-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -4, 6-dimethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 6, from ethyl 2- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] acetate (step 4).
MS(EI)m/z：319(M+)
1H-NMR(CDCl3)δ：7.40-7.51(4H，m)，6.93(1H，s)，3.68-3.75(2H，m)，2.85(2H，t，J＝6.7Hz)，2.68-2.76(5H，m)，2.50(3H，s)，1.22(3H，t，J＝7.4Hz)。
Step 61- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 7, from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (step 5).
1H-NMR(CDCl3)δ：7.45(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，6.79(1H，s)，3.83(2H，t，J＝7.1Hz)，3.21(2H，t，J＝7.1Hz)，2.88(3H，s)，2.81(2H，q，J＝7.6Hz)，2.55(3H，s)，1.29(3H，t，J＝7.6Hz)。
Step 71- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (step 6).
MS(EI)m/z：412(M+)
1H-NMR(CDCl3)δ：7.47(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，6.78(1H，s)，3.63(2H，t，J＝6.8Hz)，3.03(2H，t，J＝6.8Hz)，2.87(3H，s)，2.80(2H，q，J＝7.6Hz)，2.55(3H，s)，1.29(3H，t，J＝7.6Hz)。
Step 81- [4- (2-aminoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile
The title compound was prepared according to the procedure described for example 37 step 7 from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (step 7).
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.6Hz)，7.25(2H，d，J＝8.6Hz)，6.79(1H，s)，3.08(2H，t，J＝7.0Hz)，2.63-2.91(7H，m)，2.55(3H，s)，1.29(3H，t，J＝7.6Hz)。
Step 9N- [ ({2- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (step 8).
m.p.：140-145℃
IR(KBr)v：3340，2214，1664，1517，1338，1166，1091cm-1
MS(ESI)m/z：516(MH+)，514([M-H]-)
1H-NMR(CDCl3)δ：7.71(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，7.25-7.31(4H，m)，6.77(1H，s)，6.73(1H，br.s)，3.55-3.62(2H，m)，2.95(2H，t，J＝7.0Hz)，2.87(3H，s)，2.80(2H，q，J＝7.6Hz)，2.52(3H，s)，2.41(3H，s)，1.28(3H，t，J＝7.6Hz)。
Example 330
2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide (example 111, step 5)
m.p.：170-175℃
IR(KBr)v：3463，3342，1747，1685，1593，1161，1080，881cm-1
MS(ESI)m/z：541(MH+)，539([M-H]-)
1H-NMR(CDCl3)δ：8.13(1H，s)，7.96(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.36(2H，d，J＝8.1Hz)，7.01(2H，d，J＝8.1Hz)，6.94(1H，s)，6.55(1H，br.s)，4.38(2H，t，J＝6.1Hz)，3.01(2H，t，J＝6.1Hz)，2.70(2H，q，J＝7.5Hz)，2.45(3H，s)，1.29(3H，t，J＝7.5Hz)。
Example 331
2- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- [4- (5-cyano-2-ethyl-4, 6-dimethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (example 329, step 5)
m.p.：208-213℃
IR(KBr)v：1747，1517，1230，1161，1089cm-1
MS(ESI)m/z：517(MH+)，515([M-H]-)
1H-NMR(DMSO-d6)δ：7.76(2H，d，J＝8.4Hz)，7.40-7.48(6H，m)，6.91(1H，s)，4.27(2H，t，J＝67Hz)，2.96(2H，t，J＝6.7Hz)，2.67-2.73(5H，m)，2.48(3H，s)，2.36(3H，s)，1.21(3H，t，J＝7.6Hz)。
Example 332
2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } ethanone (example 78, step 4)
m.p.：188-190℃
IR(KBr)v：1743，1683，1606，1515，1348，1163，1076cm-1
MS(ESI)m/z：506(MH+)，504([M-H]-)
1H-NMR(DMSO-d6)δ：8.33(1H，d，J＝1.4Hz)，7.82(1H，dd，J＝1.4Hz，8.4Hz)，7.76(2H，d，J＝8.4Hz)，7.45(4H，s)，7.40(2H，d，J＝8.4Hz)，7.14(1H，d，J＝8.4Hz)，4.28(2H，t，J＝6.5Hz)，2.97(2H，t，J＝6.5Hz)，2.75(2H，q，J＝7.4Hz)，2.64(3H，s)，2.35(3H，s)，1.25(3H，t，J＝7.4Hz)。
Example 333
6-chloro-2-ethyl-N-methyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
Step 12, 4-dichloro-N-methyl-5-nitrobenzamide
To a solution of 2, 4-dichloro-5-nitrobenzoic acid (8g, 33.9mmol) in toluene (200ml) was added thionyl chloride (12.4ml, 169mmol) at room temperature. The mixture was stirred at 80 ℃ for 5 hours. The solvent was removed and the residue was dissolved in tetrahydrofuran (60 ml). 40% methylamine (1.4ml, 33.9mmol) was added to the mixture at 0 ℃ and the mixture was stirred at room temperature for 2.5 hours. The volatile components were removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100ml), brine (100ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2: 1/1: 1/1: 2) to give 5.3g (63%) of the title compound as a pale yellow solid.
1H-NMR(CDCl3)δ：8.27(1H，s)，7.65(1H，s)，3.15(3H，s)。
Step 22-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N-methyl-5-nitrobenzamide
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-dichloro-N-methyl-5-nitrobenzamide (step 1).
1H-NMR(CDCl3)δ：9.62(1H，s)，8.22(1H，s)，7.24-7.35(4H，m)，6.95(1H，s)，3.60-3.67(2H，m)，2.73-2.79(5H，m)。
Step 35-amino-2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N-methylbenzamide
The title compound was prepared according to the procedure described in example 28, step 2, from 2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N-methyl-5-nitrobenzamide (step 2).
1H-NMR(CDCl3)δ：7.28(1H，s)，7.15(2H，d，J＝8.4Hz)，7.08(1H，s)，6.89(2H，d，J＝8.4Hz)，6.53(1H，br.s)，5.41(1H，br.s)，3.84-3.86(2H，m)，3.66(2H，br.s)，3.00(3H，d，J＝5.0Hz)，2.83(2H，t，J＝6.6Hz)。
Step 46-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -N-methyl-1H-benzimidazole-5-carboxamide
The title compound was prepared from 5-amino-2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N-methylbenzamide (step 3) according to the procedure described in example 1, step 5.
MS(EI)m/z：357(M+)
1H-NMR(CDCl3)δ：7.98(1H，s)，7.47(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，7.09(1H，s)，6.23(1H，br.s)，3.96-4.02(2H，m)，3.05(3H，d，J＝4.9Hz)，3.00(2H，t，J＝6.4Hz)，2.77(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 56-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 7, from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -N-methyl-1H-benzimidazole-5-carboxamide (step 4).
1H-NMR(CDCl3)δ：7.98(1H，s)，7.47(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz)，7.10(1H，s)，6.35(1H，br.s)，3.83(2H，t，J＝6.9Hz)，3.21(2H，t，J＝6.9Hz)，3.05(3H，d，J＝4.9Hz)，2.82(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 61- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 5).
MS(El)m/z：382(M+)
1H-NMR(CDCl3)δ：7.94(1H，s)，7.46(2H，d，J＝8.0Hz)，7.27(2H，d，J＝8.0Hz)，7.06(1H，s)，363(2H，t，J＝7.0Hz)，2.98-3.06(5H，m)，2.77(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.6Hz)。
Step 71- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described for example 37 step 7 from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 6).
1H-NMR(CDCl3)δ：7.91(1H，s)，7.42(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.06(1H，s)，6.55(1H，br.s)，3.03-3.10(SH，m)，2.72-2.83(2H，m)，1.33(3H，t，J＝7.6Hz)。
Step 86-chloro-2-ethyl-N-methyl-1- (4- {2- [ ({ [ (4-methylphenylsulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 7).
m.p.：122-135℃
IR(KBr)v：2877，1637，1519，1400，1340，1161，1091cm-1
MS(ESI)m/z：554(MH+)，552([M-H]-)
1H-NMR(CDCl3)δ：779-7.84(3H，m)，7.28-7.33(4H，m)，7.12(2H，d，J＝8.2Hz)，6.96(1H，s)，6.80(1H，br.s)，6.70(1H，br.s)，3.48-3.54(2H，m)，3.08(3H，d，J＝4.8Hz)，2.89(2H，t，J＝6.9Hz)，2.72(2H，q，J＝7.5Hz)，2.41(3H，s)，1.30(3H，t，J＝7.5Hz)。
Example 334
2- (4- { 6-chloro-2-ethyl-5- [ (methylamino) carbonyl ] -1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- { 6-chloro-2-ethyl-5- [ (methylamino) carbonyl ] -1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -N-methyl-1H-benzimidazole-5-carboxamide (example 333, step 4).
m.p.：201-204℃
MS(ESI)m/z：555(MH+)，553([M-H]-)
1H-NMR(DMSO-d6)δ：8.27-8.29(1H，m)，7.76(2H，d，J＝8.1Hz)，7.69(1H，s)，7.40-7.48(6H，m)，7.06(1H，s)，4.28(2H，t，J＝6.3Hz)，2.96(2H，t，J＝6.3Hz)，2.69-2.78(5H，m)，2.36(3H，s)，1.23(3H，t，J＝7.5Hz)。
Example 335
2- {4- [ 6-chloro-5- [ (dimethylamino) carbonyl ] -2- (1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12, 4-dichloro-N, N-dimethyl-5-nitrobenzamide
To a solution of 2, 4-dichloro-5-nitrobenzoic acid (4g, 17mmol) in toluene (50ml) was added thionyl chloride (6ml, 84mmol) at room temperature. The mixture was stirred at 80 ℃ for two days. The solvent was removed and the residue was dissolved in tetrahydrofuran (30 ml). 50% dimethylamine (760mg) was added to the mixture at 0 ℃ and the mixture was stirred at room temperature overnight. The volatile components were removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50ml), brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1.1) to give 3.6g (82%) of the title compound as a pale yellow solid.
1H-NMR(CDCl3)δ：7.90(1H，s)，7.65(1H，s)，3.15(3H，s)，2.91(3H，s)。
Step 22-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N, N-dimethyl-5-nitrobenzamide
The title compound was prepared according to the procedure described in example 1, step 3, from 2, 4-dichloro-N, N-dimethyl-5-nitrobenzamide (step 1).
MS(EI)m/z：363(M+)
1H-NMR(CDCl3)δ：9.52(1H，br.s)，8.20(1H，s)，7.34(2H，d，J＝8.2Hz)，7.22(2H，d，J＝8.2Hz)，7.16(1H，s)，3.92(2H，m)，3.13(3H，s)，2.89-2.94(5H，m)。
Step 35-amino-2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N, N-dimethylbenzamide
The title compound was prepared according to the procedure described in example 28, step 2, from 2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N, N-dimethyl-5-nitrobenzamide (step 2).
1H-NMR(CDCl3)δ：7.05-7.11(3H，m)，6.79(2H，d，J＝8.5Hz)，6.63(1H，s)，5.59(1H，s)，3.79-3.83(4H，m)，3.11(3H，s)，2.92(3H，s)，2.79(2H，t，J＝6.4Hz)。
Step 42- {4- [ 6-chloro-5- [ (dimethylamino) carbonyl ] -2- (1-methylethyl) -1H-benzimidazol-1-ylphenyl } ethyl propionate
The title compound was prepared from 5-amino-2-chloro-4- { [4- (2-hydroxyethyl) phenyl ] amino } -N, N-dimethylbenzamide (step 3) according to the procedure described in example 1, step 5.
Step 56-chloro-1- [4- (2-hydroxyethyl) phenyl ] -N, N-dimethyl-2- (1-methylethyl) -1H-benzimidazole-5-carboxamide
The title compound was prepared from 2- {4- [ 6-chloro-5- [ (dimethylamino) carbonyl ] -2- (1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 4) according to the procedure described in example 1, step 6.
MS(EI)m/z：371(M+)
1H-NMR(CDCl3)δ：766(1H，s)，7.46(2H，d，J＝8.5Hz)，7.27(2H，d，J＝8.5Hz)，7.12(1H，s)，395-4.00(2H，m)，3.17(3H，s)，3.00(2H，d，J＝6.6Hz)，2.87(3H，s)，2.78(2H，q，J＝7.5Hz)，1.34(3H，t，J＝7.5Hz)。
Step 62- [ 6-chloro-5- [ (dimethylamino) carbonyl ] -2- (1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -N, N-dimethyl-2- (1-methylethyl) -1H-benzimidazole-5-carboxamide (step 5).
m.p.：173-176℃
IR(KBr)v：1741，1637，1519，1398，1344，1159，1078，904cm-1
MS(ESI)m/z：569(MH+)，567([M-H]-)
1H-NMR(CDCl3)δ：7.93(2H，d，J＝8.4Hz)，7.70(1H，s)，7.27-7.34(4H，m)，7.09-7.12(3H，m)，4.35(2H，t，J＝6.6Hz)，3.19(3H，s)，2.98(2H，t，J＝66Hz)，2.88(3H，s)，2.74(2H，q，J＝7.5Hz)，2.42(3H，s)，1.29(3H，t，J＝7.5Hz)。
Example 336
2- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
Step 11, 5-dichloro-2- [ (methyloxy) methyl ] -4-nitrobenzene
Sodium methoxide (44ml, 66mmol) was added to a solution of 1, 5-dichloro-2- (chloromethyl) -4-nitrobenzene (Hagmann, William k.; Dorn, Conrad p.; frankshu, Robert a.; O' Grady, Laura a.; Bailey, Philip j.; et al; JMCMAR; j.med.chem.; EN; 29; 8; 1986; 1436-. The mixture was stirred at 80 ℃ for 21 hours. The volatile components were removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50ml), brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (6: 1/4: 1) to give 2.8g (27%) of the title compound as a pale yellow oil.
1H-NMR(CDCl3)δ：8.01(1H，s)，7.09(1H，s)，4.49(2H，s)，3.96(3H，s)。
Step 22- [4- ({ 5-chloro-4- [ (methoxy) methyl ] -2-nitrophenyl } amino) phenyl ] ethanol
The title compound was prepared from 1, 5-dichloro-2- [ (methyloxy) methyl ] -4-nitrobenzene (step 1) according to the procedure described in example 1, step 3.
1H-NMR(CDCl3)δ：9.45(1H，br.s)，8.28(1H，s)，7.17-7.33(5H，m)，4.44(2H，s)，3.91(1H，br.s)，3.45(3H，s)，2.91(2H，t，J＝6.6Hz)。
Step 32- [4- ({ 2-amino-5-chloro-4- [ (methyloxy) methyl ] phenyl } amino) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- [4- ({ 5-chloro-4- [ (methyloxy) methyl ] -2-nitrophenyl } amino) phenyl ] ethanol (step 2).
1H-NMR(CDCl3)δ：7.07-7.01(3H，m)，6.88(1H，s)，6.74(2H，d，J＝8.4Hz)，5.16(1H，br.s)，4.47(2H，s)，3.82(2H，t，J＝6.6Hz)，3.71(2H，br.s)，3.46(3H，s)，2.79(2H，t，J＝6.6Hz)。
Step 42- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethanol
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- ({ 2-amino-5-chloro-4- [ (methyloxy) methyl ] phenyl } amino) phenyl ] ethanol (step 3).
MS(EI)m/z：344(M+)
1H-NMR(CDCl3)δ：7.82(1H，s)，7.46(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.2Hz)，7.12(1H，s)，4.65(1H，s)，3.99(2H，br.s)，3.45(3H，s)，3.00(3H，t，J＝7.6Hz)，2.78(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 52- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- (4- { 6-chloro-2-ethyl-5- [ (methoxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethanol (step 4).
m.p.：174.5℃
IR(KBr)v：3377，2813，1718，1519，1398，1342，1159，1093，1062cm-1
MS(ESI)m/z：542(MH+)，540([M-H]-)
1H-NMR(CDCl3)δ：7.94(2H，d，J＝8.2Hz)，7.83(1H，s)，7.08-7.33(7H，m)，4.64(s，2H)，4.37(2H，t，J＝6.4Hz)，3.46(3H，s)，2.97(2H，t，J＝6.4Hz)，2.73(2H，q，J＝7.5Hz)，2.42(3H，s)，1.26(3H，t，J＝7.5Hz)。
Example 337
2- {4- [ 6-chloro-2-ethyl-5- (hydroxymethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 6-chloro-5- (chloromethyl) -2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 5, from 2- [4- ({ 2-amino-5-chloro-4- [ (methyloxy) methyl ] phenyl } amino) phenyl ] ethanol (example 336, step 3).
MS(EI)m/z：348(M+)
1H-NMR(CDCl3)δ：7.83(1H，s)，7.46(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，7.15(1H，s)，4.84(2H，s)，3.96-4.02(2H，m)，3.00(2H，t，J＝6.4Hz)，2.77(2H，q，J＝7.5Hz)，1.34(2H，t，J＝7.5Hz)。
Step 26-chloro-5- (chloromethyl) -1- [4- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl ] oxy } ethyl) phenyl ] -2-ethyl-1H-benzimidazole
The title compound was prepared according to the procedure described in example 90, step 2, from 2- {4- [ 6-chloro-5- (chloromethyl) -2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethanol (step 1).
MS(EI)m/z：405(M+)
1H-NMR(CDCl3)δ：7.83(1H，s)，7.43(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，7.11(1H，s)，4.85(2H，s)，3.91(2H，t，J＝6.4Hz)，2.94(2H，t，J＝6.4Hz)，2.76(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)，0.87(9H，s)，0.00(6H，s)。
Step 3 { 6-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl ] oxy } ethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methylpropionate
To a solution of 6-chloro-5- (chloromethyl) -1- [4- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl ] oxy } ethyl) phenyl ] -2-ethyl-1H-benzimidazole (step 2, 403mg, 0.86mmol) in N, N-dimethylformamide (10ml) at room temperature were added propionic acid (0.06ml, 0.86mmol) and sodium bicarbonate (144mg, 1.72 mmol). The mixture was stirred at 60 ℃ for 7 hours. Water (50ml) was added to the mixture and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (8: 1/4: 1) to give 235mg (53%) of the title compound as a pale yellow oil.
1H-NMR(CDCl3)δ：7.81(1H，s)，7.43(2H，d，J＝8.5Hz)，7.24(2H，d，J＝8.5Hz)，7.11(1H，s)，5.33(2H，s)，3.91(2H，t，J＝6.6Hz)，2.93(2H，t，J＝6.6Hz)，2.77(2H，q，J＝7.5Hz)，2.42(2H，q，J＝7.5Hz)，1.33(3H，t，J＝7.5Hz)，1.18(3H，t，J＝7.5Hz)，0.87(9H，s)，0.00(6H，s)。
Step 4 { 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } methylpropionate
The title compound was prepared according to the procedure described in example 90, step 6, from { 6-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl ] oxy } ethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } methylpropionate (step 3).
MS(EI)m/z：386(M+)
1H-NMR(CDCl3)δ：7.70(1H，s)，7.37(2H，d，J＝8.3Hz)，7.17(2H，d，J＝8.3Hz)，7.04(1H，s)，5.21(2H，s)，3.88(2H，d，J＝6.6Hz)，2.91(2H，t，J＝6.6Hz)，2.67(2H，q，J＝7.5Hz)，2.32(2H，q，J＝7.5Hz)，1.24(3H，t，J＝7.5Hz)，1.08(3H，t，J＝7.5Hz)。
Step 5[ 6-chloro-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) oxy ] ethyl } phenyl) -1H-benzimidazol-5-yl ] methylpropionate
The title compound was prepared according to the procedure described for example 3 from { 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } methylpropionate (step 4).
1H-NMR(CDCl3)δ：7.92(2H，d，J＝8.3Hz)，7.81(1H，s)，7.32-7.36(4H，m)，7.21-7.25(2H，m)，7.10(1H，s)，5.32(2H，s)，4.38(2H，t，J＝6.7Hz)，3.02(2H，t，J＝6.7Hz)，2.76(2H，q，J＝7.6Hz)，2.37-2.49(5H，m)，1.33(3H，t，J＝7.6Hz)，1.18(3H，t，J＝7.6Hz)。
Step 62- (4- [ 6-chloro-2-ethyl-5- (hydroxymethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from [ 6-chloro-2-ethyl-1- (4- {2- [ ([ (4-methylphenyl) sulfonyl ] amino } carbonyl) oxy ] ethyl } phenyl) -1H-benzimidazol-5-yl ] methylpropionate (step 5) according to the procedure described in example 1, step 6.
m.p.：172.7℃
IR(KBr)v：1745，1519，1240，1160，1089，1058cm-1
MS(ESI)m/z：528(MH+)，526([M-H]-)
1H-NMR(DMSO-d6)δ：7.74-7.77(3H，m)，7.39-7.46(6H，m)，7.03(1H，s)，4.63(2H，s)，4.27(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.6Hz)，2.72(2H，q，J＝7.5Hz)，2.34(3H，s)，1.23(3H，t，J＝7.5Hz)。
Example 338
N- ({ [2- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide
Step 11- [4- (2-azidoethyl) phenyl-6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazole
The title compound was prepared according to the procedure for example 26 step 5 from 2- (4- { 6-chloro-2-ethyl-5- [ (methoxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethanol (example 336, step 4).
MS(EI)m/z：369(M+)
1H-NMR(CDCl3)δ：7.82(1H，s)，7.45(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.11(1H，s)，4.65(2H，s)，3.62(2H，t，J＝7.0Hz)，3.45(3H，s)，3.02(2H，t，J＝J＝7.0Hz)，2.77(2H，q，J＝7.7Hz)，1.34(3H，t，J＝7.7Hz)。
Step 22- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethylamine
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazole (step 1).
1H-NMR(CDCl3)δ：7.82(1H，s)，7.42(2H，d，J＝8.4Hz)，7.24-7.29(2H，m)，7.12(1H，s)，4.65(1H，s)，3.45(3H，ds)，3.08(2H，t，J＝6.7Hz)，2.88(2H，t，J＝6.7Hz)，2.77(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 3N- ({ [2- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 2- (4- { 6-chloro-2-ethyl-5- [ (methyloxy) methyl ] -1H-benzimidazol-1-yl } phenyl) ethanamine (step 2).
m.p.：134.6℃
IR(KBr)v：3377，2813，1718，1519，1398，1342，1159，1093，1062cm-1
MS(ESI)m/z：541(MH+)，539([M-H]-)
1H-NMR(CDCl3)δ：7.82(1H，s)，7.72(2H，d，J＝8.4Hz)，7.24-7.39(4H，m)，7.09(1H，s)，6.72(1H，br.s)，4.65(2H，s)，3.57(2H，m)，3.45(3H，s)，2.93(2H，d，J＝6.8Hz)，2.77(2H，q，J＝7.5Hz)，2.40(3H，s)，1.32(3H，t，J＝7.5Hz)。
Example 339
2- {4- [ 6-chloro-2- [3- (4-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12 Ethyl 4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate
To a mixture of 2- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethanol (example 104, step 1, 8.1g, 22.4mmol) and pyridine (1.8ml, 22.45mmol) in dichloromethane (200ml) was added acetyl chloride (1.6ml, 22.4mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 45 minutes. Water (50ml) was added to the mixture and extracted with dichloromethane (300 ml). The organic layer was washed with brine (100ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2: 1) to give 8.6g (95%) of the title compound as a yellow solid.
1H-NMR(CDCl3)δ：9.68(1H，br.s)，8.57(1H，s)，7.35(2H，d，J＝8.4Hz)，7.22(2H，d，J＝8.4Hz)，7.17(1H，s)，4.33(2H，t，J＝7.0Hz)，3.00(2H，t，J＝7.0Hz)，2.06(3H，s)。
Step 22 Ethyl- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate
The title compound was prepared according to the procedure described in example 28, step 2, from ethyl 2- (4- { [ 5-chloro-2-nitro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (step 1).
1H-NMR(CDCl3)δ：7.13-7.16(3H，m)，7.06(1H，s)，6.89(2H，d，J＝8.4Hz)，5.43(1H，br.s)，4.26(2H，t，J＝7.2Hz)，3.69(2H，br.s)，2.89(2H，d，J＝7.2Hz)，2.04(3H，s)。
Step 32- (4- { [ 5-chloro-2- { [4- (4-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) acetic acid ethyl ester
A mixture of ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (step 2, 250mg, 0.67mmol), 4- (4-pyridinyl) butanoic acid (200mg, 1mmol), and WSC (191mg, 1mmol) in dichloromethane (7ml) was stirred at room temperature for 1.5 h. Water (5ml) was added to the mixture, and the mixture was extracted with methylene chloride (30 ml). The organic layer was washed with brine (5ml) and then dried (sodium sulfate). The solvent was removed under reduced pressure to give the title compound as a pale brown amorphous form.
MS(EI)m/z：519(M+)
Step 42- {4- [ 6-chloro-2- [3- (4-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
A mixture of ethyl 2- (4- { [ 5-chloro-2- { [4- (4-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (step 3, 220mg, 0.42mmol) and 2N sodium hydroxide (15ml) in ethanol (20ml) was stirred at 40 ℃ for 7 hours. The solvent was removed and water (50ml) was added to the residue. The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with dichloromethane: methanol (20: 1) to yield 105mg (54%) of the title compound as a light brown oil.
1H-NMR(CDCl3)δ：8.40-8.42(2H，m)，8.10(1H，s)，7.43(2H，d，J＝8.3Hz)，7.16-7.19(3H，m)，7.02(2H，d，J＝6.0Hz)，4.00(2H，t，J＝6.2Hz)，3.00(2H，t，J＝6.2Hz)，2.75(2H，t，J＝7.3Hz)，2.68(2H，t，J＝7.3Hz)，2.11-2.19(2H，m)。
Step 52- {4- [ 6-chloro-2- [3- (4-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 1 from 2- {4- [ 6-chloro-2- [3- (4-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 4).
m.p.：80-87℃
IR(KBr)v：1743，1610，1517，1431，1346，1161cm-1
MS(ESt)m/z：657(MH+)，655([M-H]-)；
1H-NMR(CDCl3)δ：8.32(2H，d，J＝6.0Hz)，8.09(1H，s)，7.99(2H，d，J＝8.2Hz)，7.34(2H，d，J＝8.2Hz)，7.22(2H，d，J＝8.2Hz)，7.15(1H，s)，6.94-7.02(4H，m)，4.48(2H，t，J＝5.4Hz)，3.01(2H，t，J＝5.4Hz)，2.74(2H，t，J＝6.0Hz)，2.54(2H，t，J＝7.9Hz)，2.44(3H，s)，2.16-2.21(2H，m)。
Example 340
2- {4- [ 6-chloro-2- [3- (3-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4- { [ 5-chloro-2- { [4- (3-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) acetic acid ethyl ester
The title compound was prepared according to the procedure described in example 339, step 3, from ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2).
1H-NMR(CDCl3)δ：8.43(2H，br.s)，7.50-7.71(2H，m)，7.15-7.28(6H，m)，6.96(2H，d，J＝8.3Hz)，6.43(1H，br.s)，4.26(2H，t，J＝7.0Hz)，2.90(2H，t，J＝7.0Hz)，2.70(2H，t，J＝7.3Hz)，2.41(2H，t，J＝7.3Hz)，2.03-2.08(5H，m)。
Step 22- {4- [ 6-chloro-2- [3- (3-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 339, step 4, from ethyl 2- (4- { [ 5-chloro-2- { [4- (3-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (step 1).
MS(EI)m/z：459(M+)
1H-NMR(CDCl3)δ：8.33(1H，d，J＝4.4Hz)，8.09(1H，s)，7.62(1H，s)，7.43-7.50(3H，m)，7.16-7.22(4H，m)，4.02(2H，t，J＝5.6Hz)，2.99(2H，t，J＝5.6Hz)，2.74(2H，t，J＝7.5Hz)，2.64(2H，t，J＝6.6Hz)，2.04-2.13(2H，m)。
Step 32- {4- [ 6-chloro-2- [3- (3-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- [3- (3-pyridyl) isopropyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 2).
m.p.：90-95℃
IR(KBr)v：1743，1517，1431，1346，1301，1161，1130，1085cm-1
MS(ESI)m/z：657(MH+)，655([M-H]-)
1H-NMR(CDCl3)δ：8.59(1H，dd，J＝1.7Hz，5.1Hz)，8.08(1H，s)，7.95(2H，d，J＝8.3Hz)，7.86(1H，d，J＝1.7Hz)，7.54-7.58(1H，m)，7.27-7.34(5H，m)，7.20(1H，s)，7.12(2H，d，J＝8.4Hz)，4.46(2H，t，J＝5.1Hz)，3.00(2H，t，J＝5.1Hz)，2.77-2.82(2H，m)，2.62(2H，t，J＝7.0Hz)，2.43(3H，s)，1.85-1.91(2H，m)。
Example 341
2- {4- [ 6-chloro-2- [ 3-oxo-3- (3-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4- { [ 5-chloro-2- { [ 4-oxo-4- (3-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (example 339, step 2) according to the procedure described in example 339, step 3.
1H-NMR(CDCl3)δ：9.19(1H，d，J＝2.2Hz)，8.80(1H，dd，J＝1.8Hz.3.9Hz)，8.20(1H，d，J＝7.9Hz)，7.64(2H，br.s)，7.44(1H，dd，J＝5.8Hz，7.9Hz)，7.28(1H，s)，7.19(2H，d，J＝8.3Hz)，7.05(2H，d，J＝8.3Hz)，6.70(1H，br.s)，4.27(2H，t，J＝7.1Hz)，3.49(2H，t，J＝5.5Hz)，2.92(2H，t，J＝7.1Hz)，2.78(2H，t，J＝5.8Hz)，2.05(3H，s)。
Step 23- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl 1-1- (3-pyridine) -1-propanone
The title compound was prepared according to the procedure described in example 339, step 4, from 2- (4- { [ 5-chloro-2- { [ 4-oxo-4- (3-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (step 1).
1H-NMR(CDCl3)δ：9.05-9.06(1H，m)，8.77-8.79(1H，m)，8.24-8.28(1H，m)，8.06(1H，s)，7.54(2H，d，J＝8.5Hz)，7.40-7.46(3H，m)，3.97-4.04(2H，m)，3.66(2H，t，J＝7.0Hz)，3.19(2H，t，J＝7.0Hz)，3.02(2H，t，J＝6.4Hz)。
Step 32- {4- [ 6-chloro-2- [ 3-oxo-3- (3-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 3- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -1- (3-pyridyl) -1-propanone (step 2).
m.p.：89-95℃
IR(KBr)v：2972，1747，1693，1517，1346，1230，1161，1085cm-1
MS(ESI)m/z：671(MH+)，669([M-H]-)
1H-NMR(CDCl3)δ：8.91(1H，s)，8.83-8.85(1H，m)，8.23-8.27(1H，m)，8.05(1H，s)，7.92(2H，d，J＝8.2Hz)，7.33-7.48(7H，m)，7.21(1H，s)，4.43(2H，t，J＝6.3Hz)，3.47(2H，t，J＝7.1Hz)，3.25(2H，t，J＝7.1Hz)，3.04(2H，t，J＝6.3Hz)，2.43(3H，s)。
Example 342
2- {4- [ 6-chloro-2- [ 3-oxo-3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- (4- { [ 5-chloro-2- { [ 4-oxo-4- (2-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (example 339, step 2) according to the procedure described in example 339, step 3.
MS(EI)m/z：533(M+)
Step 23- { 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -1- (2-pyridyl) -1-propanone
The title compound was prepared according to the procedure described in example 339, step 4, from 2- (4- { [ 5-chloro-2- { [ 4-oxo-4- (2-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (step 1).
1H-NMR(CDCl3)δ：8.67-8.69(1H，m)，7.84(1H，s)，7.96-7.99(1H，m)，7.81-7.84(1H，m)，7.39-7.51(5H，m)，7.23(1H，s)，3.96-4.02(2H，m)，3.91(2H，t，J＝6.9Hz)，3.15(2H，t，J＝6.9Hz)，3.01(2H，t，J＝6.4Hz)。
Step 32- {4- [ 6-chloro-2- [ 3-oxo-3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 3- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -1- (2-pyridyl) -1-propanone (step 2).
m.p.：233.6℃
IR(KBr)v：1743，1703，1515，1481，1336，1203，1120，1087，995cm-1
MS(ESI)m/z：671(MH+)，669([M-H]-)
1H-NMR(DMSO-d6)δ：8.74-8.76(1H，m)，8.13(1H，S)，7.90-8.03(2H，m)，7.77(2H，d，J＝8.1Hz)，7.66-7.70(1H，m)，7.49-7.58(4H，m)，7.42(2H，d，J＝8.1Hz)，7.34(1H，s)，4.30(2H，t，J＝6.4Hz)，3.83(2H，t，J＝6.4Hz)，3.09(2H，t，J＝6.4Hz)，2.98(2H，t，J＝6.4Hz)，2.50(3H，s)。
Example 343
2- {4- [ 6-chloro-2- [3- (2-pyridinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl- (4-methylphenyl) sulfonyl carbamate
Step 12- (4- { [ 5-chloro-2- { [4- (2-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (example 339, step 2) according to the procedure described in example 339, step 3.
1H-NMR(CDCl3)δ：9.26(1H，br.s)，8.39-8.41(1H，m)，7.86(1H，s)，7.69-7.72(1H，m)，7.49(1H，s)，7.25-7.28(1H，m)，7.15-7.21(3H，m)，7.00(2H，d，J＝8.4Hz)，4.27(2H，t，J＝7.1Hz)，2.98(2H，t，J＝6.3Hz)，2.91(2H，t，J＝7.1Hz)，2.33(2H，t，J＝5.9Hz)，2.05(3H，s)。
Step 22- {4- [ 6-chloro-2- [3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2- (4- { [ 5-chloro-2- { [4- (2-pyridinyl) butyryl ] amino } -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (step 1) according to the procedure described in example 339, step 4.
1H-NMR(CDCl3)δ：8.43-8.45(1H，m)，8.09(1H，s)，7.53-7.59(1H，m)，7.45(2H，d，J＝8.2Hz)，7.22-7.25(3H，m)，7.05-7.13(2H，m)，3.98(2H，t，J＝6.3Hz)，3.00(2H，t，J＝6.3Hz)，2.84(4H，t，J＝7.5Hz)，2.18-2.22(2H，m)，1.81-1.90(2H，m)。
Step 32- {4- [ 6-chloro-2- [3- (2-pyridine) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-tolyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 6-chloro-2- [3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 2).
m.p.：193℃
IR(KBr)v：1747，1626，1517，1433，1350，1159，1120，1085cm-1
MS(ESI)m/z：657(MH+)，655([M-H]-)
1H-NMR(CDCl3)δ：8.47-8.49(1H，m)，8.08(1H，s)，7.90(2H，d，J＝8.4Hz)，7.60-7.66(1H，m)，7.36(2H，d，J＝8.4Hz)，7.11-7.22(7H，m)，4.44(2H，t，J＝6.0Hz)，3.01(2H，t，J＝6.0Hz)，2.82-2.88(4H，m)，2.45(3H，s)，1.84-1.94(2H，m)。
Example 344
2- {4- [ 6-chloro-2- [3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] ethyl (4-methylphenyl) sulfonylcarbamate P-tosylate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 6-chloro-2- [3- (2-pyridyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (example 343).
m.p.：108-110℃
IR(KBr)v：3062，1745，1456，1232，1163，1010cm-1
Example 345
N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 1N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino) carbonyl } -4-methylbenzenesulfonamide
To N- [ ({2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl) at room temperature]Ethyl } amino) carbonyl]A mixture of 4-methylbenzenesulfonamide (example 78, 238mg, 0.47mmol) and 2N sodium hydroxide (0.1ml) in ethanol (10ml) was added NaBH4(178mg, 0.47mmol) and 2N sodium hydroxide (0.1ml) in ethanol (4 ml). The mixture was stirred at room temperature for 4 hours. Water (10ml) was added to the mixture, followed by NH4And CI neutralization. The mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 4/1: 6)/dichloromethane: methanol (10: 1) to give 198mg (83%) of the title compound as a white solid.
m.p.：190℃
IR(KBr)v：3384，2979，1716，1514，1404，1159，1087cm-1
MS(ESI)m/z：507(MH+)，505([M-H]-)
1H-NMR(CDCl3)δ：7.73-7.76(3H，m)，7.21-7.34(7H，m)，7.20(1H，d，J＝8.5Hz)，6.66(1H，br.s)，5.02(1H，q，J＝6.4Hz)，3.52-3.59(2H，m)，2.91(2H，t，J＝7.0Hz)，2.75(2H，q，J＝7.5Hz)，2.39(3H，s)，1.54(3H，d，J＝6.4Hz)，1.30(3H，t，J＝7.5Hz)。
Example 346
N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } 4-methylbenzenesulfonamide P-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from/\\/- { [ (2- {4- [ 2-ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 345).
m.p.：110-115℃
IR(KBr)v：3062，1708，1519，1340，1163cm-1
Example 347
N- ({ [2- (4- { 2-Ethyl-5- [1- (methyloxy) ethyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide
Step 1N- ({ [2- (4- { 2-Ethyl-5- [1- (methoxy) ethyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide
To a solution of N- { [ (2- {4- [ 2-ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 345, 151mg, 0.3mmol) in dichloromethane (15ml) was added thionyl chloride (0.1ml, 1.5mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue dissolved in methanol (15 ml). Triethylamine (0.08ml, 0.6mmol) was added to the mixture and stirred at room temperature for 5 hours. The solvent was removed and the residue was extracted with dichloromethane (50 ml). The organic layer was washed with water (10ml), brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1: 6)/dichloromethane: methanol (10: 1) to give 139mg (89%) of the title compound as a white solid.
MS(ESI)m/z：521(MH+)，519([M-H]-)
1H-NMR(CDCl3)δ：7.65-7.75(3H，m)，7.27-7.37(6H，m)，7.16-7.20(1H，m)，7.07(1H，d，J＝8.3Hz)，669(1H，br.s)，4.42(1H，q，J＝6.5Hz)，3.54-3.62(2H，m)，3.22(3H，s)，2.93(2H，t，J＝7.0Hz)，2.93(2H，t，J＝7.0Hz)，2.78(2H，q，J＝7.6Hz)，2.39(3H，s)，1.49(3H，d，J＝6.5Hz)，1.32(3H，t，J＝7.6Hz)。
Example 348
N- ({ [2- (4- { 2-Ethyl-5- [1- (methyloxy) ethyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide P-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- ({ [2- (4- { 2-ethyl-5- [1- (methyloxy) ethyl ] -1H-benzimidazol-1-yl } phenyl) ethyl ] amino } carbonyl) -4-methylbenzenesulfonamide (example 347)
m.p.：110-115℃
IR(KBr)v：3064，1710，1519，1452，1340，1163，1033cm-1
Example 349
N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide P-toluenesulfonate
Step 1N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
To a solution of N- [ ({2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl } amino) carbonyl ] -4-methylbenzenesulfonamide (example 78, 100mg, 0.19mmol) in tetrahydrofuran (15ml) was added dropwise MeMgI (1.2ml, 0.99mmol) at 0 ℃ under nitrogen. The mixture was stirred at 0 ℃ for 1 hour and then at room temperature for 30 minutes. Water (10ml) was added to the mixture, and the mixture was extracted with methylene chloride (50 ml). The organic layer was washed with brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with methylene chloride: methanol (30: 1/20: 1/10: 1) to give 100mg (97%) of the title compound as a white solid.
MS(ESI)m/z：521(MH+)，519([M-H]-)
1H-NMR(CDCl3)δ：7.87(1H，s)，7.76(2H，d，J＝7.9Hz)，7.17-7.38(7H，m)，7.00(1H，d，J＝8.5Hz)，6.69(1H，br.s)，3.52(2H，br.s)，2.88(2H，br.s)，2.73(2H，br.s)，2.36(3H，s)，1.62(6H，s)，1.27(3H，m)。
Step 2N- { [ (2- {4- [ 2-Ethyl-5- (1-hydroxy-1-methyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 2-ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 1).
m.p.：146-150℃
IR(KBr)v：2871，1685，1519，1448，1340，1124cm-1
Example 350
2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
Step 11- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1-benzimidazole-5-carboxamide
A solution of 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carbonitrile (example 329, step 6, 997mg, 2.95mmol) in concentrated sulfuric acid (50ml) was stirred at 80 ℃ for 15H. The mixture was poured into ice and neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300ml) and then dried (sodium sulfate). The solvent was removed to give 871mg (83%) of the title compound as a white solid.
MS(EI)m/z：355(M+)
1H-NMR(CDCl3)δ：7.43(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，6.73(1H，s)，6.56(1H，br.s)，5.88(1H，br.s)，3.82(2H，t，J＝7.0Hz)，3.19(2H，t，J＝7.0Hz)，2.82(2H，q，J＝7.6Hz)，2.72(3H，s)，2.41(3H，s)，1.26(3H，t，J＝7.6Hz)。
Step 21- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 8, from 1- [4- (2-chloroethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carboxamide (step 1).
1H-NMR(CDCl3)δ：7.44(2H，d，J＝8.4Hz)，7.27-7.30(2H，m)，6.73(1H，s)，5.97(1H，br.s)，5.72(1H，br.s)，3.62(2H，t，J＝7.1Hz)，3.02(2H，t，J＝7.1Hz)，2.80(2H，q，J＝7.5Hz)，2.73(3H，s)，2.42(3H，s)，1.26(3H，t，J＝7.5Hz)。
Step 31- [4- (2-aminoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 9, from 1- [4- (2-azidoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carboxamide (step 2).
1H-NMR(CDCl3)δ：7.41(2H，d，J＝8.2Hz)，7.26(2H，d，J＝8.2Hz)，6.74(1H，s)，6.00(1H，br.s)，5.76(1H，br.s)，3.07(2H，t，J＝7.1Hz)，2.87(2H，t，J＝7.1Hz)，2.81(2H，q，J＝7.5Hz)，2.74(3H，s)，2.43(3H，s)，1.26(3H，t，J＝7.5Hz)。
Step 42-Ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- [4- (2-aminoethyl) phenyl ] -2-ethyl-4, 6-dimethyl-1H-benzimidazole-5-carboxamide (step 3).
MS(ESI)m/z：534(MH+)，532([M-H]-)
1H-NMR(CD3OD)δ：7.88(1H，s)，7.80(2H，d，J＝8.3Hz)，7.25-7.42(6H，m)，6.74(1H，br.s)，3.42(2H，t，J＝6.8Hz)，2.86(2H，t，J＝6.8Hz)，2.79(2H，q，J＝7.6Hz)，2.65(3H，s)，2.37(3H，s)，2.34(3H，s)，1.21(3H，t，J＝7.6Hz)。
Step 52-Ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide (step 4).
Example 351
N- { [ (2- {4- [ 2-Ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide P-toluenesulfonate
Step 12, 2, 2-trifluoro-1- (4- { [4- (2-hydroxyethyl) phenyl ] amino } -3-nitrophenyl) ethanone
The title compound was prepared from 1- (4-amino-3-nitrophenyl) -2, 2, 2-trifluoroacetone according to the procedure described in example 45, step 1.
1H-NMR(CDCl3)δ：9.47(1H，br.s)，8.10(1H，d，J＝2.6Hz)，7.16-7.33(6H，m)，3.87-3.94(2H，m)，2.91(2H，t，J＝6.4Hz)，1.43(1H，t，J＝5.6Hz)。
Step 21- (3-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } phenyl) -2, 2, 2-trifluoroacetone
The title compound was prepared according to the procedure described in example 1, step 4, from 2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxyethyl) phenyl ] amino } -3-nitrophenyl) ethanone (step 1).
1H-NMR(CDCl3)δ：7.05-7.09(3H，m)，6.57-6.70(4H，m)，3.82(2H，t，J＝6.6Hz)，2.78(2H，t，J＝6.6Hz)。
Step 32- {4- [ 2-Ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate
The title compound was prepared from 1- (3-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } phenyl) -2, 2, 2-trifluoroacetone (step 2) according to the procedure described in example 1, step 5.
1H-NMR(CDCl3)δ：7.65(1H，s)，7.45(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.06(2H，s)，4.38(2H，t，J＝6.9Hz)，3.07(2H，t，J＝6.9Hz)，2.79(2H，q，J＝7.4Hz)，2.35(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.4Hz)，1.14(3H，t，J＝7.5Hz)。
Step 41- { 2-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone
The title compound was prepared from 2- {4- [ 2-ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 3) according to the procedure described in example 1, step 6.
1H-NMR(CDCl3)δ：7.65(1H，s)，7.47(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.06(2H，s)，3.96-4.03(2H，m)，3.01(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 51- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone
The title compound was prepared according to the procedure described in example 1, step 7, from 1- { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone (step 4).
1H-NMR(CDCl3)δ：7.66(1H，s)，7.45(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.07(2H，s)，3.82(2H，t，J＝7.0Hz)，3.20(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 61- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone
The title compound was prepared according to the procedure described in example 1, step 8, from 1- {1- [4- (2-chloroethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone (step 5).
1H-NMR(CDCl3)δ：7.65(1H，s)，7.46(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.06(1H，s)，3.62(2H，t，J＝7.0Hz)，3.02(2H，t，J＝7.0Hz)，2.79(2H，q，J＝7.5Hz)，1.35(3H，t，J＝7.5Hz)。
Step 71- {1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone
The title compound was prepared from 1- {1- [4- (2-azidoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone (step 6) according to the procedure described in example 1, step 9.
1H-NMR(CDCl3)δ：7.65(1H，s)，7.43(2H，d，J＝8.5Hz)，7.28(2H，d，J＝8.5Hz)，7.07(2H，s)，3.09(2H，t，J＝6.7Hz)，2.89(2H，t，J＝6.7Hz)，2.79(2H，q，J＝7.4Hz)，1.35(3H，t，J＝7.4Hz)。
Step 8N- { [ (2- {4- [ 2-Ethyl-5- (trifluoroacetyl) -1-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 1- {1- [4- (2-aminoethyl) phenyl ] -2-ethyl-1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone (step 7).
MS(ESI)m/z：547(MH+)，545([M-H]-)
1H-NMR(CDCl3)δ：7.72(2H，d，J＝8.4Hz)，7.64(1H，s)，7.39(2H，d，J＝8.4Hz)，7.27-7.29(4H，m)，7.02-7.04(2H，m)，6.75(1H，br.s)，3.55-3.62(2H，m)，2.94(2H，t，J＝6.9Hz)，2.79(2H，q，J＝7.5Hz)，2.39(3H，s)，1.33(3H，t，J＝7.5Hz)。
Step 9N- { [ (2{4- [ 2-Ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 2-ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 8)
m.p.：194.1℃
IR(KBr)v：3589，1701，1627，1521，1458，1330，1091cm-1
Example 352
2- {4- [ 2-Ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate P-tosylate
Step 12- {4- [ 2-Ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 1- { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } -2, 2, 2-trifluoroacetone (example 351, step 4).
MS(ESI)m/z：548(MH+)，546([M-H]-)
1H-NMR(CDCl3)δ：7.93(2H，d，J＝8.4Hz)，7.64(1H，s)，7.28-7.35(4H，m)，7.20(2H，d，J＝8.4Hz)，7.05-7.07(2H，m)，4.37(2H，t，J＝6.6Hz)，3.00(2H，t，J＝6.6Hz)，2.76(2H，q，J＝7.6Hz)，2.43(3H，s)，1.31(3H，t，J＝7.6Hz)。
Step 22- {4- [ 2-Ethyl-5- (trifluoroacetyl)) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 2-ethyl-5- (trifluoroacetyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (step 1)
m.p.：92-97℃
IR(KBr)v：1745，1519，1458，1350，1222，1163，1122cm-1
Example 353
2- {4- [ 5-acetyl-2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate P-tosylate
Step 11- [1- [4- (2-hydroxyethyl) phenyl ] -2- (1H-pyrazol-3-yl) -1H-benzimidazol-5-yl ] ethanone
The title compound was prepared from 1- (3-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } phenyl) ethanone (example 78, step 2) according to the procedure described in example 236, step 1.
MS(EI)m/z：345(M+)
1H-NMR(CDCl3)δ：8.53(1H，s)，7.94(1H，d，J＝8.4Hz)，7.48-7.53(3H，m)，7.37(2H，d，J＝8.2Hz)，7.27(1H，s)，7.18(1H，d，J＝8.4Hz)，6.03(1H，br.s)，4.02(2H，t，J＝6.6Hz)，3.05(2H，t，J＝6.6Hz)，2.69(3H，s)。
Step 22- {4- [ 5-acetyl-2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 1- [1- [4- (2-hydroxyethyl) phenyl ] -2- (1H-pyrazol-3-yl) -1H-benzimidazol-5-yl ] ethanone (step 1).
MS(ESI)m/z：544(MH+)，542([M-H]-)
1H-NMR(DMSO-d6)δ：8.41(1H，s)，7.77-7.89(4H，m)，7.38-7.42(7H，m)，7.12(1H，d，J＝8.5Hz)，6.65(1H，br.s)，4.29(2H，t，J＝6.6Hz)，2.96(2H，t，J＝6.6Hz)，2.66(3H，s)，2.35(3H，s)。
Step 32- {4- [ 5-acetyl-2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 5-acetyl-2- (1H-pyrazol-3-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (step 2)
m.p.：204℃
IR(KBr)v：3249，1755，1676，1595，1517，1440，1332，1207，1161，1008cm-1
Example 354
N- { [ (2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide P-toluenesulfonate
Step 12- (4- { [ 5-chloro-2- [ (2-hydroxypropionyl) amino ] -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate
The title compound was prepared from 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (example 339, step 2) according to the procedure described in example 339, step 3.
MS(EI)m/z：444(M+)
Step 22- {4- [ 6-chloro-2- (1-hydroxyethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate
The title compound was prepared according to the procedure described in example 339, step 4, from 2- (4- { [ 5-chloro-2- [ (2-hydroxypropionyl) amino ] -4- (trifluoromethyl) phenyl ] amino } phenyl) ethyl acetate (step 1)
1H-NMR(CDCl3)δ：8.14(1H，s)，7.48(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.4Hz)，724(1H，s)，4.88-4.98(1H，m)，4.38(2H，t，J＝7.0Hz)，3.66(1H，d，J＝8.1Hz)，3.08(2H，t，J＝7.0Hz)，2.09(3H，s)，1.57(3H，d，J＝6.6Hz)。
Step 31- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- {4- [ 6-chloro-2- (1-hydroxyethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (step 2)
MS(ESI)m/z：384(M+)
1H-NMR(CDCl3)δ：8.14(1H，s)，7.49(2H，d，J＝8.6Hz)，7.34(2H，d，J＝8.6Hz)，7.25(1H，s)，4.89-4.96(1H，m)，3.98(2H，t，J＝6.2Hz)，3.36(1H，d，J＝5.5Hz)，3.01(2H，t，J＝6.2Hz)，1.54(3H，m)。
Step 41- [ 6-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (diphenyl) silyl ] oxy } ethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol
A mixture of 1- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol (step 3, 461mg, 1.19mmol), tert-butyldiphenylsilyl chloride (0.35ml, 1.3mmol), triethylamine (0.2ml, 1.4mmol) and N, N-dimethylaminopyridine (6mg, 0.05mmol) in dichloromethane (11ml) was stirred at room temperature under nitrogen for 4 hours. Water (50ml) was added and extracted with dichloromethane (100 ml). The organic layer was washed with water (50ml), brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1/1: 1) to give 590mg (80%) of the title compound as white amorphous form.
1H-NMR(CDCl3)δ：8.14(1H，s)，7.59-7.63(4H，m)，7.34-7.46(8H，m)，7.22-7.30(3H，m)，4.87-4.96(1H，m)，3.94(2H，t，J＝6.4Hz)，3.29(1H，d，J＝8.1Hz)，2.97(2H，t，J＝6.4Hz)，1.52(3H，d，J＝6.6Hz)，1.03(9H，s)。
Step 56-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (diphenyl) silyl ] oxy } ethyl) phenyl ] -2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole
To a solution of 1- [ 6-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (diphenyl) silyl ] oxy } ethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol (step 4, 590mg, 0.95mmol) in DMF (10ml) was added NaH (45mg, 1.13 mmol). MeI (0.08ml, 1.23mmol) was then added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Water (30ml) was added to the mixture, which was subjected to extraction with ethyl acetate (100 ml). The organic layer was washed with water (50ml), brine (50ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1) to give 550mg (91%) of the title compound as a colorless oil.
1H-NMR(CDCl3)δ：8.17(1H，s)，7.20-7.70(15H，m)，4.54(1H，q，J＝6.6Hz)，3.95(2H，t，J＝6.6Hz)，3.22(3H，s)，2.97(2H，t，J＝6.6Hz)，1.55(3H，d，J＝6.6Hz)，1.03(9H，s)。
Step 62- {4- [ 6-chloro-2- [1- (methoxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 90, step 6, from 6-chloro-1- [4- (2- { [ (1, 1-dimethylethyl) (diphenyl) silyl ] oxy } ethyl) phenyl ] -2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole (step 5).
MS(ESI)m/z：398(M+)
1H-NMR(CDCl3)δ：8.18(1H，s)，7.49(2H，d，J＝8.4Hz)，7.33(2H，d，J＝8.4Hz)，7.24(1H，s)，4.58(1H，q，J＝6.6Hz)，4.00(2H，br.s)，3.24(3H，s)，3.02(2H，t，J＝6.5Hz)，1.55-1.60(3H，m)。
Step 76-chloro-1- [4- (2-chloroethyl) phenyl ] -2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 7, from 2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 6).
MS(ESI)m/z：416(M+)
1H-NMR(CDCl3)δ：8.18(1H，s)，7.48(2H，d，J＝8.5Hz)，7.35(2H，d，J＝8.5Hz)，7.23(1H，s)，5.57(1H，q，J＝6.6Hz)，3.83(2H，t，J＝7.1Hz)，3.19-3.24(5H，m)，1.57(3H，d，J＝6.6Hz)。
Step 81- [4- (2-azidoethyl) phenyl ] -6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole
The title compound was prepared according to the procedure described in example 1, step 8, from 6-chloro-1- [4- (2-chloroethyl) phenyl ] -2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole (step 7).
MS(ESI)m/z：423(M+)
1H-NMR(CDCl3)δ：8.18(1H，s)，7.48(2H，d，J＝8.2Hz)，7.35(2H，d，J＝8.2Hz)，7.22(1H，s)，4.57(1H，q，＝6.6Hz)，3.63(2H，t，J＝6.9Hz)，3.23(3H，s)，3.04(2H，t，J＝6.9Hz)，1.56(3H，d，J＝6.6Hz)。
Step 92- {4- [ 6-chloro-2- [1- (methoxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanamine
The title compound was prepared according to the procedure described in example 37, step 7, from 1- [4- (2 azidoethyl) phenyl ] -6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazole (step 8).
1H-NMR(CDCl3)δ：8.18(1H，s)，7.45(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.24(1H，s)，4.57(1H，q，J＝6.6Hz)，3.23(3H，s)，3.10(2H，br.s)，2.90(2H，t，J＝6.6Hz)，1.57(3H，d，J＝6.6Hz)。
Step 10N- { [ (2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described in example 1, step 10, from 2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethanamine (step 9).
MS(ESI)m/z：595(MH+)，593([M-H]-)；
1H-NMR(CDCl3)δ：8.18(1H，s)，7.73(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.6Hz)，7.27-7.34(4H，m)，7.21(1H，s)，6.76(1H，br.s)，457(1H，q，J＝6.6Hz)，3.56-3.63(2H，m)，3.23(3H，s)，2.96(2H，t，J＝7.1Hz)，2.41(3H，s)，1.56(3H，d，J＝6.6Hz)。
Step 11N- { [ (2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 10)
IR(KBr)v：2873，1712，1517，1454，1342，1122，1033，1010cm-1
Example 355
2- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate P-tosylate
Step 12- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for the preparation of example 345 from 2- [4- (5-acetyl-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate (example 332)
MS(ESI)m/z：508(MH+)，506([M-H]-)
1H-NMR(CDCl3)δ：7.94(2H，d，J＝8.3Hz)，7.77(1H，s)，7.03-7.35(8H，m)，5.04(1H，q，J＝6.4Hz)，4.36(2H，t，J＝6.6Hz)，2.97(2H，t，J＝6.6Hz)，2.74(2H，q，J＝7.5Hz)，2.43(3H，s)，1.56(3H，d，J＝6.4Hz)，1.28(3H，t，J＝7.5Hz)。
Step 22- {4- [ 2-Ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 2-ethyl-5- (1-hydroxyethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (step 1)
m.p.：96-110℃
IR(KBr)v：1743，1519，1456，1163，1033，1010cm-1
Example 356
2- {4- [ 2-Ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate P-tosylate
Step 12- (4- { [ 3-methyl-4- (methyloxy) -2-nitrophenyl ] amino } phenyl) ethanol
The title compound was prepared from 1-chloro-3-methyl-4- (methyloxy) -2-nitrobenzene according to the procedure described in example 1, step 3
MS(EI)m/z：302(M+)
1H-NMR(CDCl3)δ：7.11-7.20(3H，m)，6.89-6.96(3H，m)，6.53(1H，br.s)，3.83(5H，br.s)，2.81(2H，t，J＝6.4Hz)，2.25(3H，s)。
Step 22- (4- { [ 2-amino-3-methyl-4- (methyloxy) phenyl ] amino } phenyl) ethanol
The title compound was prepared according to the procedure described in example 1, step 4, from 2- (4- { [ 3-methyl-4- (methyloxy) -2-nitrophenyl ] amino } phenyl) ethanol (step 1).
MS(EI)m/z：272(M+)
1H-NMR(CDCl3)δ：7.03(2H，d，J＝8.6Hz)，6.92(1H，d，J＝8.6Hz)，6.57(2H，d，J＝8.6Hz)，6.32(2H，d，J＝8.6Hz)，5.01(1H，br.s)，3.77-3.90(7H，m)，2.76(2H，t，J＝6.4Hz)，2.09(3H，s)。
Step 32- {4- [ 2-Ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate
The title compound was prepared according to the procedure described in example 1, step 5, from 2- (4- { [ 2-amino-3-methyl-4- (methyloxy) phenyl ] amino } phenyl) ethanol (step 2).
MS(EI)m/z：366(M+)。
Step 42- {4- [ 2-Ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- {4- [ 2-ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.42(2H，d，＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，6.84(2H，s)，3.97(2H，t，J＝6.4Hz)，3.86(3H，s)，2.99(2H，t，J＝6.4Hz)，2.81(2H，q，J＝7.7Hz)，2.58(3H，s)，1.26(3H，t，J＝7.7Hz)。
Step 52- {4- [ 2-Ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 4).
MS(ESI)m/z：508(MH+)，506([M-H]-)
1H-NMR(CDCl3)δ：7.98(2H，d，J＝8.3Hz)，7.33(2H，d，J＝8.9Hz)，6.88-6.91(6H，m)，4.28(2H，t，J＝6.0Hz)，3.89(3H，s)，2.84(2H，t，J＝6.0Hz)，2.74(2H，q，J＝7.5Hz)，2.56(3H，s)，2.43(3H，s)，1.05(3H，t，J＝7.5Hz)。
Step 62- {4- [ 2-Ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonamide carbamate p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 2-ethyl-4-methyl-5- (methyloxy) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (step 5)
m.p.：94-103℃
IR(KBr)v：1747，1458，1232，1163，1120cm-1
Example 357
2- [4- (2-Ethyl-5-phenyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 4-bromo-2-nitrophenyl) amino ] phenyl } ethanol
The title compound was prepared from 2, 5-dibromonitrobenzene according to the procedure described in example 162, step 1.
1H-NMR(CDCl3)δ：9.43(1H，br.s)，8.34(1H，d，J＝2.4Hz)，7.43-7.39(1H，m)，7.30(2H，d，J＝8.3Hz)，7.20(2H，d，J＝8.3Hz)，7.08(1H，d，J＝9.2Hz)，3.94-3.88(2H，m)，2.90(2H，d，J＝6.4Hz)，1.43(1H，t，J＝5.7Hz)。
Step 22- {4- [ (2-amino-4-bromophenyl) amino ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 28, step 2, from 2- {4- [ (4-bromo-2-nitrophenyl) amino ] phenyl } ethanol (step 1).
1H-NMR(CDCl3)δ：7.08(2H，d，J＝8.4Hz)，6.97-6.93(2H，m)，6.84(1H，dd，J＝8.3，2.2Hz)，6.69(2H，d，J＝8.6Hz)，5.04(1H，br.s)，3.80(2H，br.s)，3.82(2H，t，J＝6.4Hz)，2.79(2H，t，J＝6.4Hz)。
Step 32- [4- (5-bromo-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethylpropionate
The title compound was prepared from 2- {4- [ (2-amino-4-bromophenyl) amino ] phenyl } ethanol (step 2) according to the procedure described in example 1, step 5.
MS(EI)m/z 401(M+)
Step 42- [4- (5-bromo-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethanol
The title compound was prepared according to the procedure described in example 1, step 6, from 2- [4- (5-bromo-2-ethyl-1H-benzimidazol-1-yl) phenyl ] ethyl propionate (step 3).
1H-NMR(CDCl3)δ：7.90(1H，s)，7.45(2H，d，J＝8.1Hz)，7.26-7.30(3H，m)，6.96(1H，d，J＝8.4Hz)，3.98(2H，m)，3.00(2H，t，J＝6.4Hz)，2.78(2H，q，J＝7.6Hz)，1.34(3H，t，J＝7.6Hz)。
Step 52- [4- (2-ethyl-5-phenyl-1H-benzimidazol-1-yl) phenyl ] ethanol
To 2- [4- (5-bromo-2-ethyl-1H-benzimidazol-1-yl) phenyl]To a solution of ethanol (step 4, 116mg, 0.57mmol) in 1, 2-dimethoxyethane (DME, 6ml) was added PhB (OH)2(141mg, 1.16mmol), potassium carbonate (240mg, 1.75mmol) and Pd (PPh)3)4(67mg, 0.06 mmol). The mixture was stirred at 95 ℃ for 11 hours. The reaction mixture was diluted with water and extracted with dichloromethane (4X 10 ml). The organic layer was dried (magnesium sulfate) and concentrated to give a brown oil. The mixture was purified by silica prep TLC (hexane/ethyl acetate 1/5) to give 52mg (27%) of the title compound.
MS(EI)m/z 342(M+)
1H-NMR(CDCl3)δ：8.00(1H，d，J＝1.6Hz)，7.65(2H，dd，J＝1.6，8.4Hz)，7.42-7.48(5H，m)，7.32-7.35(3H，m)，7.15(2H，d，J＝8.4Hz)，4.00(2H，brt)，3.01(2H，t，J＝6.5Hz)，2.82(2H，q，J＝7.6Hz)，1.37(3H，t，J＝7.6Hz)。
Step 62- [4- (2-Ethyl-5-phenyl-1H-benzimidazol-1-yl) phenyl ] ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- [4- (2-ethyl-5-phenyl-1H-benzimidazol-1-yl) phenyl ] ethanol (step 5).
MS(ESI)m/z 540[M+H]+，538[M-H]-.
1H-NMR(CDCl3)δ：8.00(1H，s)，7.94(2H，d，J＝8.2Hz)，7.65(2H，d，J＝8.6Hz)，7.43-7.48(3H，m)，7.29-7.36(7H，m)，7.15(2H，d，J＝8.4Hz)，4.39(2H，t，J＝6.8Hz)，3.01(2H，t，J＝6.4Hz)，2.70(2H，q，J＝7.4Hz)，2.43(s，3H)，1.35(3H，t，J＝7.6Hz)。
Example 358
2- {4- [ 2-Ethyl-5- (5-pyrimidinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 12- {4- [ 2-Ethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzimidazol-1-yl ] phenyl } ethanol
To 2- [4- (5-bromo-2-ethyl-1H-benzimidazol-1-yl) phenyl]Ethanol (example 357, step 4, 2.5g, 7.24mmol) and bis (3, 3-dimethyl-2-butanone) diboron (1.84g, 7.24mmol) in DMSO was added potassium acetate (2.13g, 21.7mmol), 1, 1' -bis (diphenylphosphino) ferrochrome (241.mg, 043mmol) and Pd (dppf) Cl2-CH2Cl2(362mg, 0.44 mmol). The mixture was stirred at 80 ℃ for 7 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3X 80 ml). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated to give a black oil. The mixture was chromatographed on neutral silica, eluting with hexane/ethyl acetate (1: 4) to give 1.38g (35%) of the title compound as a purple solid.
MS(EI)m/z 391[M-H]+
1H-NMR(CDCl3)δ：8.25(1H，s)，7.64(2H，dd，J＝0.8，8.1Hz)，7.45(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.08(1H，d，J＝8.1Hz)，3.99(2H，t，J＝6.5Hz)，3.00(2H，t，J＝6.5Hz)，2.81(2H，q，J＝7.6Hz)，1.36(12H，s)，1.32(3H，t，J＝7.8Hz)。
Step 22- {4- [ 2-Ethyl-5- (5-pyrimidinyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
To 2- {4- [ 2-ethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzimidazol-1-yl]Phenyl } ethanol (step 1, 100mg, 0.26mmol) and 5-bromopyrimidine (45mg, 0.28mmol) in 1, 2-dimethoxyethane (3.5ml) was added saturated aqueous sodium bicarbonate (1.2ml) and Pd (PPh)3)4(60mg, 0.05 mmol). The mixture was stirred at 70 ℃ for 17 hours. The reaction mixture was diluted with water and extracted with dichloromethane (3X 10 ml). The organic layer was dried (magnesium sulfate) and concentrated to give a light brown oil. The mixture was purified by preparative TLC on silica (dichloromethane/methanol ═ 10/1) to yield 45mg (50%) of the title compound.
MS(EI)m/z 344(M+)
1H-NMR(CDCl3)δ：9.19(1H，s)，9.00(2H，s)，7.99(1H，s)，7.49(2H，d，J＝8.2Hz)，7.31-7.42(3H，m)，7.23(1H，d，J＝8.4Hz)，4.00(2H，q，J＝6.1Hz)，3.02(2H，t，J＝6.4Hz)，2.83(2H，q，J＝7.6Hz)，1.39(3H，t，J＝7.6Hz)。
Step 32- {4- [ 2-Ethyl-5- (5-pyrimidinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-5- (5-pyrimidinyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 2).
MS(ESI)m/z 542[M+H]+，540[M-H]-.
1H-NMR(CDCl3)δ：9.20(1H，s)，8.97(2H，s)，7.30-7.42(4H，m)，7.24(2H，d，J＝8.2Hz)，7.14(2H，d，J＝8.2Hz)，4.41(2H，t，J＝6.4Hz)，3.03(2H，t，J＝6.1Hz)，2.89(2H，q，J＝7.4Hz)，2.43(3H，s)，1.34(3H，t，J＝7.4Hz)。
Example 359
2- {4- [ 2-Ethyl-5- (4-pyridinyl) -1H-benzimidazol-1-yl ] phenyl) ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 2-Ethyl-5- (4-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 4-bromopyridine hydrochloride (step 2) according to the procedure described in example 358, step 1.
MS(EI)m/z 343(M)+。
1H-NMR(CDCl3)δ：8.66(2H，d，J＝6.1Hz)，8.07(1H，d，J＝1.2Hz)，7.57(2H，d，J＝6.1Hz)，7.45-7.52(3H，m)，7.34(2H，d，J＝8.4Hz)，7.20(1H，d，J＝8.4Hz)，4.00(2H，br.s)，3.03(2H，t，J＝6.6Hz)，2.83(2H，q，J＝7.4Hz)，1.39(3H，t，J＝7.4Hz)。
Step 22- {4- [ 2-Ethyl-5- (4-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-5- (4-pyridyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 1).
MS(ESI)m/z 541[M+H]+，539[M-H]-.
1H-NMR(CDCl3)δ：8.52(2H，d，J＝5.8Hz)，8.00(1H，s)，7.94(2H，d，J＝8.1Hz)，7.48(2H，d，J＝5.8Hz)，7.23-7.40(5H，m)，7.20(2H，d，J＝8.1Hz)，7.00(2H，d，J＝8.2Hz)，4.41(2H，t，J＝5.8Hz)，3.02(2H，t，J＝5.8Hz)，2.76(2H，q，J＝7.4Hz)，2.39(3H，s)，1.32(3H，t，J＝7.4Hz)。
Example 360
2- {4- [ 2-Ethyl-5- (3-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 2-Ethyl-5- (3-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 3-bromopyridine according to the procedure described in example 358, step 1.
MS(EI)m/z 343(M)+。
1H-NMR(CDCl3)δ：8.91(1H，d，J＝1.8Hz)，8.55-8.61(1H，m)，8.00(1H，s)，7.90-7.97(1H，m)，7.48(2H，d，J＝8.2Hz)，7.42(1H，d，J＝8.7Hz)，7.35(2H，d，J＝8.2Hz)，7.21(1H，d，J＝8.4Hz)，4.00(2H，m)，3.02(2H，t，J＝6.5Hz)，2.83(2H，q，J＝7.6Hz)，1.92(1H，s)，1.39(3H，t，J＝7.6Hz)。
Step 22- {4- [ 2-Ethyl-5- (3-pyridin) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-5- (3-pyridyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 1).
MS(ESI)m/z 541[M+H]+，539[M-H]-.
1H-NMR(CDCl3)δ：8.76(1H，s)，8.63(1H，m)，7.87-8.01(4H，m)，7.22-7.50(6H，m)，7.23-7.40(5H，m)，7.16(2H，d，J＝8.2Hz)，7.00(1H，d，J＝8.2Hz)，4.42(2H，br.s)，3.01(2H，br.s)，2.74(2H，q，J＝7.4Hz)，2.43(3H，s)，1.31(3H，t，J＝7.4Hz)。
Example 361
2- {4- [ 2-Ethyl-5- (2-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 2-Ethyl-5- (2-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared from 2-bromopyridine according to the procedure described in example 358, step 1.
MS(EI)m/z 343(M)+。
1H-NMR(CDCl3)δ：8.70(1H，dd，J＝1.5，5.3Hz)，8.32(1H，d，J＝1.5Hz)，8.00(1H，dd，J＝1.5，8.4Hz)，7.76-7.80(2H，m)，7.48(2H，d，J＝8.2Hz)，7.35(2H，d，J＝8.2Hz)，7.16-7.23(2H，m)，3.93-4.05(2H，m)，3.01(2H，t，J＝6.6Hz)，2.83(2H，q，J＝7.6Hz)，1.91(1H，s)，1.38(3H，t，J＝7.6Hz)。
Step 22- {4- [ 2-Ethyl-5- (2-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-5- (2-pyridyl) -1H-benzimidazol-1-yl ] phenyl } ethanol (step 1).
MS(ESI)m/z 541[M+H]+，539[M-H]-。
1H-NMR(CDCl3)δ：8.68(1H，d，J＝4.6Hz)，8.31(1H，s)，7.88-7.98(3H，m)，7.73-7.82(2H，m)，7.17-7.26(5H，m)，7.07-7.17(3H，m)，4.29(2H，t，J＝6.3Hz)，2.90(2H，t，J＝6.4Hz)，2.73(2H，q，J＝7.6Hz)，2.36(3H，s)，1.28(3H，t，J＝7.6Hz)。
Example 362
2- {4- [ 2-Ethyl-5- (4-pyridinyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
Step 12- {4- [ 2-Ethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-1-yl ] phenyl } ethanol
The title compound was prepared according to the procedure described in example 358, step 1, from 4-bromo-1-methyl-1H-pyrazole (Huettel et al, liebig ann. chem., 1955, 593, 179).
MS(EI)m/z 343(M+)
1H-NMR(CDCl3)δ：7.86(1H，s)，7.78(1H，s)，7.46(2H，d，J＝8.4Hz)，7.28-7.35(3H，m)，7.09(2H，d，J＝8.2Hz)，3.99(2H，m)，3.01(2H，t，J＝6.4Hz)，2.81(2H，q，J＝7.6Hz)，1.36(3H，t，J＝7.6Hz)。
Step 22- {4- [ 2-Ethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared according to the procedure described for example 3 from 2- {4- [ 2-ethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-benzoimidazol-1-yl ] phenyl } ethanol (step 1).
MS(ESI)m/z 544[M+H]+，542[M-H]-.
1H-NMR(CDCl3)δ：7.95(1H，s)，7.92(1H，s)，7.86(4H，m)，7.77(1H，s)，7.62(1H，s)，7.24-7.40(7H，m)，7.06(21H，d，J＝7.7Hz)，4.39(2H，t，J＝6.0Hz)，397(3H，s)，3.02(2H，q，J＝6.3Hz)，2.78(2H，q，J＝7.4Hz)，2.44(3H.s)，1.35(3H，t，J＝7.4Hz)。
Example 363
2- {4- [ 6-chloro-2- [ 3-oxo-3- (1-pyrrolidinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2) and 4-oxo-4- (1-pyrrolidinyl) butanoic acid (mccaland; proshow, j.org.chem., 1957, 22, 122.) following the procedure described for example 339.
m.p.：98-105℃
IR(KBr)v：2875，1747，1624，1517，1400，1346，1130，1085cm-1
MS(ESI)m/z：663(MH+)，661([M-H]-)
1H-NMR(CDCl3)δ：8.08(1H，s)，7.92(2H，d，J＝8.2Hz)，7.22-7.36(7H，m)，4.38(2H，t，J＝6.6Hz)，3.49(2H，t，J＝6.8Hz)，3.43(2H，t，J＝6.8Hz)，2.97-3.07(4H，m)，2.88(2H，m)，2.44(3H，s)，1.94-1.98(2H，m)，1.82-1.86(2H，m)。
Example 364
2- {4- [ 6-chloro-2- [ 3-oxo-3- (1-piperidinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared from ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2) and 4-oxo-4- (1-piperidinyl) butanoic acid (Becker, Frederick f.; Banik, Bimal k., bioorg.med.chem.lett., 1998, 20, 2877) following the procedure described for example 339.
m.p.：210℃
IR(KBr)v：1753，1649，1515，1433，1406，1366，1161，1118，1091cm-1
MS(ESI)m/z：677(MH+)，675([M-H]-)
1H-NMR(CDCl3)δ：8.14(1H，s)，7.78(2H，d，J＝8.4Hz)，7.47-7.56(4H，m)，7.42(2H，d，J＝8.4Hz)，7.31(1H，s)，4.29(2H，t，J＝6.6Hz)，3.37-3.40(4H，m)，2.92-2.99(6H，m)，2.36(3H，s)，1.50-1.56(4H，m)，1.35-1.36(2H，m)。
Example 365
2- {4- [ 6-chloro-2- [3- (2-oxo-1-pyrrolidinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
The title compound was prepared from ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2) and 4- (2-oxo-1-pyrrolidinyl) butyric acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, j.hetrocycl.chem., 1982, 19, 1465) according to the procedure described for example 339.
m.p.：85-90℃
IR(KBr)v：1745，1624，1517，1433，1348，1299，1161，1130，1085cm-1
MS(ESI)m/z：663(MH+)，661([M-H]-)
1H-NMR(CDCl3)δ：8.09(1H，s)，7.91(2H，d，J＝8.5Hz)，7.19-7.33(7H，m)，4.42(2H，t，J＝6.0Hz)，3.38(2H，t，J＝7.0Hz)，3.27(2H，t，J＝7.0Hz)，3.00(2H，t，J＝6.0Hz)，2.70-2.75(2H，m)，2.42(3H，s)，2.37-2.40(2H，m)，1.93-2.04(4H，m)。
Example 366
2- {4- [ 6-chloro-2- [3- (2-oxo-1-piperidinyl) propyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared from ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2) and 4- (2-oxo-1-piperidinyl) butanoic acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, j.heterocyclic. chem., 1982, 19, 1465) following the procedure described for example 339.
m.p.：98-105℃
IR(KBr)v：1745，1618，1433，1348，1301，1230，1161，1130，1085cm-1
MS(ESI)m/z：677(MH+)，675([M-H]-)
1H-NMR(CDCl3)δ：8.08(1H，s)，7.89(2H，d，J＝8.0Hz)，7.16-7.29(7H，m)，4.40(2H，t，J＝5.9Hz)，3.35(2H，t，J＝7.2Hz)，3.25-3.27(2H，m)，2.98(2H，t，J＝5.9Hz)，2.73(2H，t，J＝7.2Hz)，2.35-2.40(5H，m)，1.92-1.99(2H，m)，1.73-1.76(4H，m)。
Example 367
N- { [ (2- {4- [ 6-chloro-2- (1-hydroxyethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 11- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol
From 4-chloro-N according to the procedures described in example 339, step 3 and example 1, step 52- [4- (2-chloroethyl) phenyl group]-5- (trifluoromethyl) -1, 2-phenylenediamine and lactic acid.
1H-NMR(CDCl3)δ：8.14(1H，s)，7.49(2H，d，J＝8.2Hz)，7.37(2H，d，J＝8.2Hz)，4.90-4.96(1H，m)，3.83(2H，t，J＝6.8Hz)，3.75(1H，d，H＝8.1Hz)，3.22(2H，t，J＝6.8Hz)，1.57(3H，d，J＝6.9Hz)。
Step 2N- { [ (2- {4- [ 6-chloro-2- (1-hydroxyethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for example 1 from 1- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol (step 1).
m.p.：220℃
IR(KBr)v：3348，1706，1533，1519，1434，1344，1328，1126cm-1
MS(ESI)m/z：581(MH+)，579([M-H]-)
1H-NMR(CDCl3)δ：8.23(1H，s)，7.78(2H，d，J＝8.1Hz)，7.32-7.50(7H，m)，6.58(1H，br.s)，5.66(1H，br.s)，4.78(1H，br.s)，3.30-3.32(2H，m)，2.79-2.82(2H，m)，2.34(3H，s)，1.51(3H，d，J＝6.8Hz)。
Example 368
N- { [ (2- {4- [ 2-acetyl-6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino) carbonyl ] -4-methylbenzenesulfonamide
Step 11- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanone
A solution of 1- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanol (example 367, step 1, 400mg, 1mmol) in dichloromethane was added manganese dioxide (2.7g, 32 mmol). The mixture was stirred at room temperature for 24 hours. Purification by flash column chromatography directly eluting with hexane/ethyl acetate (4: 1) gave 350mg (88%) of the title compound as a white solid.
1H-NMR(CDCl3)δ：8.31(1H，s)，7.44(2H，d，J＝8.1Hz)，7.23-7.28(3H，m)，3.82(2H，t，J＝7.3Hz)，3.21(2H，t，J＝7.3Hz)，2.80(3H，s)。
Step 2N- { [ (2- {4- [ 2-acetyl-6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for example 1 from 1- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethanone (step 1)
m.p.：225℃
IR(KBr)v：3350，1697，1519，1326，1294，1134，1083cm-1
MS(ESI)m/z：579(MH+)，577([M-H]-)
1H-NMR(CDCl3)δ：8.31(1H，s)，7.74(2H，d，J＝8.4Hz)，7.21-7.39(7H，m)，6.70(1H，br.s)，3.55-3.62(2H，m)，2.94(2H，t，J＝7.2Hz)，2.81(3H，s)，2.40(3H，s)。
Example 369
N- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 12- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -2-propanol
From 2-Hydroxyisobutyric acid and 4-chloro-N according to the procedure described in example 339, step 3 and example 1, step 52- [4- (2-chloroethyl) phenyl group]-5- (trifluoromethyl) -1, 2-phenylenediamine the title compound is prepared.
1H-NMR(CDCl3)δ：8.13(1H，s)，7.46(2H，d，J＝8.2Hz)，7.34(2H，d，J＝8.2Hz)，7.00(1H，s)，3.84(2H，t，J＝7.0Hz)，3.38(1H，s)，3.22(2H，t，J＝7.00Hz)，1.53(6H，s)。
Step 2N- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for example 1 from 2- [ 6-chloro-1- [4- (2-chloroethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -2-propanol (step 1).
1H-NMR(CDCl3)δ：8.13(1H，s)，7.73(2H，d，J＝8.2Hz)，7.30-7.39(6H，m)，6.99(1H，s)，6.68(1H，br.s)，3.55-3.66(2H，m)，2.95(2H，t，J＝6.6Hz)，2.42(3H，s)，1.13(6H，d，J＝6.2Hz)。
Example 370
N- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono P-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 369).
m.p.：146-150℃
IR(KBr)v：1685，1515，1448，1340，1124，1089，1010cm-1
Example 371
N- {1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl-5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethyl } acetamide
Step 11, 1-Dimethylethyl 1- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethylcarbamate
The title compound was prepared according to the procedure described in example 339, step 3 and example 1, step 5, from N- (tert-butoxycarbonyl) -alanine and ethyl 2- (4- { [ 2-amino-5-chloro-4- (trifluoromethyl) phenyl ] amino } phenyl) acetate (example 339, step 2).
MS(EI)m/z：483(M+)
1H-NMR(CDCl3)δ：8.12(1H，s)，7.50(2H，d，J＝8.6Hz)，7.35-7.37(2H，m)，7.24(1H，s)，5.46(1H，br.s)，4.92-4.98(1H，m)，3.95-4.02(2H，m)，3.00(2H，t，J＝6.5Hz)，1.43(3H，s)，1.40(9H，s)。
Step 21, 1-Dimethylethyl 1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethylcarbamate
The title compound was prepared according to the procedure described for example 1 from 1, 1-dimethylethyl 1- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethylcarbamate (step 1)
1H-NMR(CDCl3)δ：8.13(1H，s)，7.79(2H，d，J＝8.2Hz)，7.15-7.35(7H，m)，6.50(1H，br.s)，5.55(1H，d，J＝8.6Hz)，4.88-4.93(1H，m)，3.46-3.52(2H，m)，2.87-2.96(2H，m)，2.41(3H，s)，1.40(12H，s)。
Step 3N- { [2- {4- [2- (1-aminoethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
To a solution of 1, 1-dimethylethyl 1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethylcarbamate (step 2, 190mg, 0.28mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1ml) and stirred at room temperature for 2 hours. Water (10ml) was added to the mixture and extracted with dichloromethane (20 ml). The organic layer was washed with brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with methylene chloride/methanol (10: 1/5: 1) to give 160mg (99%) of the title compound as a white solid.
MS(ESI)m/z：580(MH+)，578([M-H]-)
Step 4N- {1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethyl } acetamide
To a mixture of N- { [ (2- {4- [2- (1-aminoethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (step 3, 100mg, 0.17mmol) in dichloromethane (12ml) was added acetyl chloride (0.01ml, 0.18mmol) and stirred at room temperature for 5 hours. Water (10ml) was added to the mixture, and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with methylene chloride/MeOH (10: 1) to give 59mg (53%) of the title compound as a white solid.
MS(ESI)m/z：622(MH+)，620([M-H]-)
1H-NMR(CDCl3)δ：8.14(1H，s)，7.80(2H，d，J＝8.2Hz)，7.25-7.40(7H，m)，7.00(1H，br.s)，6.03(1H，br.s)，5.15-5.20(1H，m)，3.43-3.68(2H，m)，2.88-2.98(2H，m)，2.39(3H，s)，1.96(3H，s)，1.51(3H，d，J＝6.9Hz)。
Example 372
N- {1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethyl } acetamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- {1- [ 6-chloro-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] ethyl } acetamide (example 371).
m.p.：135-142℃
IR(KBr)v：3267，1676，1517，1456，1236，1163，1122，1010cm-1
Example 373
2- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate
Step 1 (3-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } phenyl) (phenyl) methanone
The title compound was prepared from (4-chloro-3-nitrophenyl) (phenyl) methanone according to the procedure described for example 78.
1H-NMR(CDCl3)δ：7.77(2H，d，J＝6.9Hz)，7.42-7.55(3H，m)，7.36(1H，s)，7.14-7.25(4H，m)，6.97(2H，d，J＝8.5Hz)，5.64(1H，s)，3.83-3.89(2H，m)，3.64(2H，br.s)，2.84(2H，t，J＝6.6Hz)，1.47(1H，br.s)。
Step 2 { 2-Ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } (phenyl) methanone
The title compound was prepared from (3-amino-4- { [4- (2-hydroxyethyl) phenyl ] amino } phenyl) (phenyl) methanone (step 1) according to the procedure described for example 1.
1H-NMR(CDCl3)δ：8.21(1H，s)，7.80-7.84(3H，m)，7.44-7.57(5H，m)，7.27-7.34(2H，m)，7.18(1H，d，J＝8.4Hz)，3.98-4.03(2H，m)，3.02(2H，t，＝6.3Hz)，2.81(2H，q，J＝7.6Hz)，1.89(1H，t，J＝5.4Hz)，1.37(3H，t，J＝7.6Hz)。
Step 32- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } (phenyl) methanone (step 2).
MS(ESI)m/z：568(MH+)，566([M-H]-)
1H-NMR(CDCl3)δ：8.21(1H，s)，7.92(2H，d，J＝8.4Hz)，7.79-7.84(3H，m)，7.44-7.58(3H，m)，7.23-7.36(6H，m)，7.15(1H，d，J＝8.6Hz)，4.37(2H，t，J＝6.6Hz)，3.01(2H，t，J＝6.6Hz)，2.79(2H，q，J＝7.6Hz)，2.42(3H，s)，1.34(3H，t，J＝7.6Hz)。
Example 374
2- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from 2- {4- [ 2-ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonyl carbamate (example 373).
m.p.：102-107℃
IR(KBr)v：1747，1654，1517，1448，1033，1008cm-1
Example 375
N- { [ (2- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
Step 1N- { [ (2- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for the preparation of example 78 from { 2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazol-5-yl } (phenyl) methanone (example 373, step 2).
MS(ESI)m/z：567(MH+)，565([M-H]-)
1H-NMR(CDCl3)δ：8.20(1H，s)，7.72-7.83(5H，m)，7.28-7.60(9H，m)，7.15(1H，d，J＝8.6Hz)，6.74(1H，br.s)，3.59(2H，m)，2.94(2H，t，J＝7.1Hz)，2.82(2H，q，J＝7.4Hz)，2.39(3H，s)，1.35(3H，t，J＝7.4Hz)。
Example 376
N- { [ (2- {4- [ 2-Ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide mono-p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from/\\/- { [ (2- {4- [ 2-ethyl-5- (phenylcarbonyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 375).
m.p.：198℃
IR(KBr)v：1697，1660，1596，1519，1446，1319，1035cm-1
Example 377
2- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulphonylcarbamate
Step 12- {4- [ 6-chloro-2- (1-chloro-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate
To a solution of 2- {4- [ 6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (300mg, 0.68mmol) in dichloromethane (15ml) was added thionyl chloride (0.07ml, 1.02mmol) and the reaction mixture was refluxed overnight. The reaction mixture was poured into water (10ml), and the mixture was extracted with dichloromethane (30 ml). The organic layer was washed with brine (10ml) and then dried (sodium sulfate). Removal of the solvent gave 273mg (87%) of the title compound as white amorphous form.
MS(EI)m/z：458(M+)。
Step 22- {4- [2- (1-azido-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate
A mixture of 2- {4- [ 6-chloro-2- (1-chloro-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (step 1, 273mg, 0.68mmol), sodium azide (88mg, 1.36mmol), KI (112mg, 0.68mmol) in DMF (8ml) was stirred at room temperature under nitrogen for 5.5 hours. The reaction mixture was poured into water (5ml), and the aqueous mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water (5ml) and brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give 133mg (42%) of the title compound as a yellow oil.
MS(EI)m/z：465(M+)
1H-NMR(CDCl3)δ：8.17(1H，s)，7.46(2H，d，J＝8.4Hz)，7.35(2H，d，J＝8.4Hz)，7.02(1H，s)，4.39(2H，t，J＝7.0Hz)，3.09(2H，t，J＝7.0Hz)，2.08(3H，s)，1.70(6H，s)。
Step 32- {4- [2- (1-amino-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate
A mixture of 2- {4- [2- (1-azido-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (step 2, 133mg, 0.28mmol) and Lindlar catalyst (13mg) in methanol (5ml) was stirred under hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration through a celite pad, and the filtrate was concentrated to give the title compound as a yellow oil (121mg, 98%).
MS(EI)m/z：439(M+)
Step 42- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate
To a solution of 2- {4- [2- (1-amino-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (step 3, 121mg, 0.27mmol) in dichloromethane (5ml) was added acetyl chloride (0.02ml, 0.3 mmol). The reaction mixture was stirred at room temperature for 7 hours. Water (5ml) was added to the reaction mixture, and the aqueous mixture was extracted with methylene chloride (30 ml). The organic layer was washed with water (5ml) and brine (10ml) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with methylene chloride/methanol (10/1) to give 76mg (57%) of the title compound as a white amorphous form.
MS(EI)m/z：481(M+)
1H-NMR(CDCl3)δ：8.14(1H，s)，7.42(2H，d，J＝8.2Hz)，7.28(2H，d，J＝8.4Hz)，6.91(1H，s)，4.38(2H，t，J＝6.6Hz)，3.07(2H，t，J＝6.6Hz)，2.06(3H，s)，1.75(6H，s)，1.68(3H，s)。
Step 5N- {1- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -1-methylethyl } acetamide
The title compound was prepared according to the procedure described in example 1, step 6, 2- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl acetate (step 4).
1H-NMR(CDCl3)δ：8.13(1H，s)，7.44(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，6.92(1H，s)，5.95(1H，br.s)，3.98(2H，t，J＝6.4Hz)，2.99(2H，t，J＝6.4Hz)，1.68-1.75(9H，m)。
Step 62- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate
The title compound was prepared according to the procedure described for example 3 from N- {1- [ 6-chloro-1- [4- (2-hydroxyethyl) phenyl ] -5- (trifluoromethyl) -1H-benzimidazol-2-yl ] -1-methylethyl } acetamide (step 5).
MS(ESI)m/z：637(M+)，635([M-H]-)
1H-NMR(CD3OD)δ：8.04(1H，s)，7.83(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，7.34(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，6.93(1H，s)，4.32(2H，t，J＝6.4Hz)，3.02(2H，t，J＝6.4Hz)，2.37(3H，s)，1.75(6H，s)，1.53(3H，s)。
Example 378
2- {4- [2- [1- (acetylamino) -1-methylethyl ] -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl (4-methylphenyl) sulfonylcarbamate p-toluenesulfonate
The title compound was prepared according to the procedure described for the preparation of example 231 from N- { [ (2- {4- [ 6-chloro-2- [1- (methyloxy) ethyl ] -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] phenyl } ethyl) amino ] carbonyl } -4-methylbenzenesulfonamide (example 377)
IR(KBr)v：1751，1508，1450，1340，1161，1122cm-1
Example 379
6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
Step 12- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethylmethane sulfonate
A mixture of 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl ] -1H-benzimidazole-5-carboxamide (example 111, step 4, 500mg, 1.45mmol), triethylamine (293mg, 2.90mmol) and methanesulfonyl chloride (322mg, 2.9mmol) in dichloromethane (20ml) was stirred at room temperature for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50mL) and then dried (sodium sulfate). After removal of the solvent, the crude product was purified by TLC [ hexane/ethyl acetate (1: 1) ] to yield 304mg (50%) of the title compound as a white solid.
MS(ESI)m/z：422([M+H]+)。
1H-NMR(CDCl3)δ：7.54(1H，s)，7.44(2H，d，J＝8.3Hz)，7.29(2H，d，J＝8.3Hz)，7.13(1H，s)，3.82(2H，t，J＝7.0Hz)，3.19(2H，t，J＝7.0Hz)，2.82(6H，s)，2.75(2H，q，J＝7.6Hz)，1.35(3H，t，J＝7.6Hz)。
Step 26-chloro-2-ethyl-1- {4- [2- (methylamino) ethyl ] phenyl } -1H-benzimidazole-5-carboxamide
A mixture of 2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl ] phenyl } ethyl methanesulfonate (step 1, 304mg, 0.72mmol) and a solution of methylamine (40% in methanol, 10ml) and water (5ml) was heated overnight at 100 ℃ in a sealed tube. The reaction mixture was partitioned between dichloromethane (30ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (50ml) and dried (sodium sulphate). After removal of the solvent, the crude product was purified by TLC [ dichloromethane/methanol (10: 1) ] to yield 154mg (60%) of the title compound as a yellow solid.
1H-NMR(CDCl3)δ：7.54(1H，s)，7.43(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.12(1H，s)，3.62(2H，t，J＝7.0Hz)，3.01(2H，t，J＝7.0Hz)，2.82(6H，s)，275(2H，q，J＝7.6Hz)，1.34(2H，t，J＝7.6Hz)。
Step 36-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide
The reaction was carried out according to the procedure described in step 10 of example 1 from 6-chloro-2-ethyl-1- {4- [2- (methylamino) ethyl ] phenyl } -1H-benzimidazole-5-carboxamide (step 2).
MS(ESI)m/z：554(MH+)，552([M-H]-)。
1H-NMR(CDCl3)δ：8.09(1H，s)，7.97-7.94(2H，d，J＝8.4Hz)，7.40-7.31(4H，m)，7.16-7.13(2H，d，J＝8.4Hz)，7.07(1H，s)，6.36(1H，br)，3.52(2H，br)，2.98(2H，br)，2.93(3H，s)，2.78-2.69(2H，d，J＝7.6Hz)，2.42(3H，s)，1.34-1.28(3H，t，J＝7.6Hz)。
Example 380
6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide sodium salt
The title compound was prepared according to the procedure described for example 2 from 6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole-5-carboxamide (example 379).
MS(ESI)m/z：554(MH+)，552([M-H]-)。
EP4 antagonists: pyrrole of the formula II
Preferred pyrrole compounds (II) are the following:
R1is lower alkyl substituted by carboxyl; a carboxyl group; a protected carboxyl group; a carbamoyl group; a heterocyclic group; lower alkoxy substituted with carbamoyl; aryl substituted with carboxyl, carbamoyl or heterocyclic group; or amino optionally substituted with lower alkylsulfonyl (more preferably, lower alkyl substituted with carboxy, carbamoyl, tetrazolyl, lower alkoxy substituted with carbamoyl, aryl substituted with carboxy or carbamoyl), R2Is hydrogen or a lower alkyl group,
q is
[ wherein-A)1-is a single bond or lower alkylene (more preferably methylene),
is a ring (C)5-C9) Alk-enes, cyclo C3-C9) Alkane or bicyclo (C)6-C9) Alkalene, bicyclo (C)5-C9) Alkane (more preferably, cyclo (C)5-C7) Alk-ene, cyclo (C)5-C7) Alkane, bicyclo [2.2.1 ]]Heptene or bicyclo [2.2.1]Heptane) was added,
-A3is a single bond or lower alkylene (more preferably a single bond)]And are and
x is O.
Test analysis of the invention
Several lines of evidence suggest that the interaction of cytokines and prostaglandins is critical for the development of atherosclerotic conditions. However, the precise mechanism of formation of atherosclerotic plaques and the relationship between plaque formation and prostaglandins and cytokines has not been determined. Up to now, cytokine production and PGE2The relationship of (A) was investigated in vitro using isolated cells or cell lines, e.g., macrophages, monocytes and T-cells (Zeng, L.I. et al, J.Pharmacol. Exp. Ther., 1998, 286, 1420-. For example, PGE2 enhances IL-6 production by hsb.2 culture line human leukemia T cells. Hsb.2 cells co-express the EP2, EP3 and EP4 subtypes of PGE2 receptor. In these cells, the EP4/EP2/EP3 receptor-selective agonist colloidal bismuth subcitrate (misoprostol), but not the EP3 receptor-selective agonist M&B28767, induces an increase in IL-6 production (Zeng, et al, 1998). Enhancement of IL-6 production by PGE2 induced by dibutanoylCyclic adenosine monophosphate mimics and is inhibited by protein kinase a inhibitors, suggesting that EP4 and/or EP2 receptors appear to mediate PGE 2-induced increases in IL-6 production by hsb.2T cells through a cAMP-dependent mechanism. In contrast, EP4 and EP2 agonists inhibited IL-1-induced IL-6 production in lymphocytes from arthritic mouse synovial fluid (Kurihara, Y et al, Clin. exp. Immunol. Vol.123, 323-containing 330, 2001).
Thus, the modulation of cytokine production by PGE2 in peripheral monocytes appears to be different for various diseases. Macrophages and T cells are detected in plaques in atherosclerotic lesions (van der Wal, A.C. et al, Circulation, 1994, 89, 36-44). However, the interaction of cytokines and PGs in atherosclerotic plaque lesions is unclear. Thus, there is a need for a more specific therapeutic target system to control monocyte and T-cell activation.
In the present invention, we have newly found that human whole blood cells can greatly enhance IL-6 production using PGE2 alone. The present invention is a more specific therapeutic target system for controlling IL-6 production. In addition, the system is an effective method for detecting molecular targets of atherosclerosis and IL-6 related disorders.
The test reagents for the screening assays of the invention can each be selected or obtained from a library of compounds. These agents include peptides, combinatorial chemically derived molecular libraries formed from D-and/or L-configured amino acids, phosphopeptides, anti-EP 4 antibodies, EP4 antisense nucleotides (EP4 antisense nucleotides), and small organic and inorganic compounds. Libraries include biological libraries, libraries of natural compounds, peptide-like libraries (libraries of molecules with peptide function, but which have a novel non-peptide backbone and remain biologically active against enzymatic degradation) (see, e.g., Zuckermann, J.Med.chem.37: 2678-85, 1994), spatially addressable parallel solid or liquid phase libraries, synthetic library methods using the overlap method, "one-bead-compound" library methods, "and synthetic library methods using affinity chromatography selection.
Examples of synthetic molecular library methods are found in the prior art, e.g., DeWitt et al, Proc.Natl.Acad.Sci.90: 6909, 1993; erd et al, proc.natl.acad.sci.91: 11422, 1994; zuckermann et al, j.med.chem.37: 2678, 1994; cho et al, Science, 261: 1303, 1995; carrell et al, angelw.chem.int. english version 33: 2061, 1994; and Gallop et al, j.med.chem.37: 1233, 1994.
Libraries of compounds may be present in solution (e.g., Houghten, Biotechniques, 13: 412. 421, 1992), or on beads (Lam, Nature 354: 82-84, 1991), on chips (chip) (Fodor, Nature 364: 555. sup. + 556, 1993), bacteria or spores (Ladner, U.S. patent No.5,223,409), plasmids (Cull et al, Proc. Natl. Acad. Sci. USA.89: 1865. 1869, 1992) or phages (Scott et al, Science 249: 386. 390, 1990; Devilin, Science 249: 404. 406. 1990; Cwirla et al, Proc. Natl. Acad. Sci. (USA) 87: 6378. 6382, 1990; Felici, J.mol. mol. 310. Biol. 301: 1991; Lalich et al, 1991).

Claims (4)

  1. Use of an EP4 receptor antagonist for the manufacture of a medicament for the treatment of atherosclerosis in IL-6 related diseases, wherein said EP4 receptor antagonist is
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
    2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine; or
    5-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
    or a pharmaceutically acceptable salt thereof.
  2. 2. Use of an EP4 receptor antagonist according to claim 1, wherein the EP4 receptor antagonist is
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine sodium salt; or
    2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine.
  3. 3. Pharmaceutical composition comprising an EP4 receptor antagonist for the treatment of atherosclerosis in IL-6 related diseases, wherein said EP4 receptor antagonist is
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
    2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine; or
    5-acetyl-2-ethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-benzimidazole;
    or a pharmaceutically acceptable salt thereof.
  4. 4. The pharmaceutical composition according to claim 3 wherein said EP4 receptor antagonist is
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine;
    2-ethyl-5, 7-dimethyl-3- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -3H-imidazo [4, 5-b ] pyridine sodium salt; or
    2-ethyl-4, 6-dimethyl-1- (4- {2- [ ({ [ (4-methylphenyl) sulfonyl ] amino } carbonyl) amino ] ethyl } phenyl) -1H-imidazo [4, 5-c ] pyridine.
HK05108862.3A 2002-04-12 2003-04-03 Use of ep4 receptor ligands in the manufacture of a medicament for the treatment of il-6 involved diseases HK1076737B (en)

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