BR122012015772B1 - IMIDAZOLE COMPOUNDS Fused TO ATILA OR HETEROARIL - Google Patents

Abstract

imidazole compounds fused to atyl or heteroaryl. The present invention relates to compounds having the formulas, or pharmaceutically acceptable salts thereof, wherein y y, y², y³ and ^4 ~, r¹, s, b, w and p are as defined in the claims.

Description

(54) Title: IMIDAZOLE COMPOUNDS MELTED WITH ATYLUM AND HETEROARYL (51) Int.CI .: C07D 471/04; A61K 31/4178; A61K 31/437; A61P 29/00; C07D 235/08; C07D 491/04; C07D 473/00; C07D 521/00; C07D 401/06; C07D 401/04; C07D 417/12; C07D 403/12; C07D 401/12; C07D 235/30; C07D 417/04; C07D 403/04; C07D 403/06 (30) Unionist Priority: 19/10/2000 US 60 / 241,825 (73) Holder (s): ASKAT INC.

(72) Inventor (s): KAZUNARI NAKAO; YOSHIYUKI OKUMURA; MIYAKO MATSUMIZU; NAOMI UNEO; YOSHINOBU HASHIZUME; TOMOKI KATO; AKIYOSHI KAWAI; YORIKO MIYAKE; SEIJI NUKUI; KATSUHIRO SHINJYO; ΚΑΝΑ TANIGUCHI

1/451

Invention Patent Descriptive Report for IMIDAZOLE COMPOUNDS FUSED WITH ARYL OR HETEROARYL.

Split order from PI0114704-8, filed on 10.15.2001. Technical Field

This invention relates to imidazole compounds fused to aryl or heteroaryl, or their pharmaceutically acceptable salts, to the pharmaceutical compositions containing them, and to their medicinal uses. The compounds of this invention have activity as prostaglandin E ₂ receptor antagonists, and these are useful in treating or alleviating pain and inflammation and other disorders associated with inflammation, such as arthritis, to treat or prevent disorders or disease states selected from pain, inflammatory and similar diseases.

Prior Art

Prostaglandins are meters of pain, fever and other symptoms associated with inflammation. In particular, prostaglandin E ₂ (PGE ₂ ) is the predominant eicosanoid detected in inflammatory states. In addition, he is also involved in several physiological, and / or pathological states, such as hyperalgesia, uterine contraction, digestive peristalsism, in the awake state, in the suppression of gastric acid secretion, in blood pressure, in the function of platelets, bone metabolism, angiogenesis and the like.

Four PGE ₂ receptor subtypes (EP !, EP ₂ , EP ₃ and EP ₄ ) have been cloned that show distinct pharmacological properties, the EP ₄ subtype, a Gs-coupled receptor, stimulates cAMP production, and is distributed by a wide variety of tissues, suggesting that it should play a very important role in biological events mediated by PGE ₂ .

WO99 / 47497 describes carboxylic acid and acylsulfonamide compounds as prostaglandin receptor antagonists.

Brief Description of the Invention

The present invention provides a compound with the following formula:

2/451 γ ³ -γΛ / - R ¹

Λ

WyO r ^{2 N} 'S' ^ZR o% (D or its pharmaceutically acceptable salts, where

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N, CH or C (L);

R ¹ is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted alkoxy, Cv8-S (O) m- alkyl, Q ¹ , pyrrolidinyl, piperidyl, oxypyrrolidinyl, oxopiperidyl, amino, mono- or di- (C18 alkyl) amino, C1-4-C (= O) -N (R ³ ) alkyl - or C1-8-S (O) mN (R ³ ) - alkyl, in that said C 1 -alkyl, C 2 alkenyl. ₈ and C ₂ alkynyl. ₈ are optionally substituted with halo, C1.3 alkyl, hydroxy, oxo, C4 alkoxy, C1-6 alkyl (O) _m- , C3-7 cycloalkyl, cyano, indanyl, 1,2,3,4-tetrahydronaftila, 1,2-dihydronaftila, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ S (O) m-, Q ¹ -C1- alkyl- , Q ¹ -CM-S (0) m- alkyl, Q ¹ -C1-4 alkyl (C) -N (R ³ ) -, Q ¹ -CU-N alkyl (R ³ ) - or CW-C alkyl (O) -N (R ³ ) -;

Q ¹ is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halo, Cm alkyl, C-μ alkyl substituted with halo, hydroxy, C-1-4 alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (C4 amino alkyl, cyano, HO C1-4 alkyl, C ^ alkoxy C ^ alkoxy, C-alkylsulfonyl, aminosulfonyl, alkyl CM-C (= O) -, HO (O =) C-, C4 -O (O =) C-, R ³ N (R ⁴ ) C (= O) -, alkylsulfonylamino CM | C ₃ cycloalkyl. ₇ , R ³ -C (= O) N (R ⁴ ) - or NH2 (HN =) C-;

A is a 5- or 6-membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5- to 6-membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from among

3/451 halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cu alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (Cm alkyl) amino, cyan, HO-Cm alkyl, CM alkoxy-Cm alkyl, CM-sulfonyl alkyl, aminosulfonyl, acetyl, R ³ N (R ⁴ ) C (= O) -, HO (O =) C-, Cm-O (O =) C- alkyl, Cm sulfonylamino Cm , C3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - and NH ₂ (HN =) C-;

B is an alkylene group Cm, C 3-7 cycloalkylene, _C2 -6 alkenylene, alkynylene C ^ _2, -O-C1-5 alkylene, alkylene-O-alkylene Cv ₂ CI_ _2, all substituted with halo, substituted or alkylene Cm optionally with an oxo group or an Cm alkyl group;

W is NH, N-alkyl Cm, O, S, N-OR ⁵ or a covalent bond;

R ² is H, Cm alkyl, OH or Cm alkoxy;

Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, in which said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, alkyl Cm, Cm halo substituted with halo, C ₂ -4 alkenyl, C ₂ ^ alkynyl, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di (CM alkyl) amino, cyan, HO -Alkyl Cm, CM alkoxy-Cm alkyl, Cm alkylsulfonyl, Aminosulfonyl, Cm-C (= 0) -,, R ³ N (R ⁴ ) C (= O) -, HO (O =) C-, Cm- O (O =) C-, alkylsulfonylamino Cm, C3.7 cycloalkyl, NH2 (HN =) C-, Q ² -S (O) m-, Q ² -O-, Q ² -N (R ³ ) - or Q ² -;

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (CM alkyl) amino, cyano, HO-Cm alkyl, alkoxy Cm-CM alkyl, CM-alkyl sulfonyl, aminossulfonila, Cm alkyl - C (= O) -, HO (O =) C-, alkyl CI_ ₄ -O (O =) C-, alkylsulfonylamino m, C ₃ cycloalkyl. ₇ , R ³ -C (= O) N (R ⁴ ) -,

NH ₂ (HN =) C-, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) _m -, Q ² -, Q ² -C (= O) - , Q ² -O-, Q ² Cm-0- alkyl, or two adjacent L groups optionally bond to each other forming an alkylene chain having 3 or 4 members, in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;

4/451 m is 0, 1 or 2;

R ³ and R ⁴ are selected, independently, from H and Cm alkyl;

R ⁵ is H, Cm alkyl, Cm- (0 =) C- alkyl or Cm-O alkyl - (= O) C ~;

Q ² is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, or a tricyclic ring with 6 to 12 members, optionally containing up to 3 heteroatoms selected from O, N and S, in which said monocyclic or bicyclic aromatic ring with 5 to 12 members optionally be substituted with halo, alkyl Ci. ₄ alkyl substituted with halo Cm, Cm alcenila, C alcinila m _2, hydroxy, alkoxy Cy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (C4 alkyl, cyano, HO C ₁₄ alkyl ₎ CM alkoxy Cm alkyl, CM alkyl sulfonyl, aminosulfonyl, C _M alkyl-C (= O) -, R ^ K ^ CÍOJN-, HO (O =) C-, alkyl C _M -O (O =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, alkyl C-C (= O) NH-, or NH ₂ (HN =) C-.

The imidazole compounds fused to aryl or heteroaryl of this invention have an antagonistic action in relation to prostaglandin and are therefore useful in therapy, especially for the treatment of a dysfunction or condition selected from the group consisting of pain, fever or inflammation associated with fever rheumatic, flu or other viral infections, common cold, pain in the neck or lower back, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine, toothache, sprains and muscle aches on exertion, myositis , neuralgia, fibromyalgia, synovitis, arthritis including rheumatoid arthritis, degenerative diseases of the joints (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including those from radiation and corrosive chemicals, sunburn, pain after surgical or dental interventions or bone fracture, immune or autoimmune diseases such as systemic lupus erythematosus; AIDS (acquired immunodeficiency syndrome), intestinal cancers such as colon cancer; neoplastic cell transformations or growth of metastatic tumors; diabetic retinopathy, tumor angiogenesis; prostanoid-induced contraction of smooth muscles and associated with dysmenorrhea, premature labor, a5 / 451 rhinitis, atopic dermatitis, asthma or eosinophil-related disorders, hyperimmunoglobulinemia, Castleman's disease, myeloma; Alzheimer's disease, sleep disorders, endocrine disorders; glaucoma; bone loss; osteoporosis; promoting bone formation; Paget's disease: cycloprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; bleeding in the GI tract and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, hemophilia and other bleeding problems; kidney disease; thrombosis; vascular occlusive disease; pre-surgery; and anti-coagulation, or the like in mammals, especially in humans.

The present invention provides a pharmaceutical composition for the treatment of a prostaglandin-mediated disorder or condition, in a mammal including a human, which includes administering to the said subject a therapeutically effective amount of a compound of formula (I).

In addition, the present invention provides a pharmaceutical composition for the treatment of a disorder or condition selected from the group consisting of pain, fever or inflammation associated with rheumatic fever, flu or other viral infections, the common cold, pain in the neck or in the lower back, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine, toothache, sprains and muscle pain on exertion, myositis, neuralgia, fibromyalgia, synovitis, arthritis including rheumatoid arthritis, degenerative diseases of joints (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including those from radiation and corrosive chemicals, sunburn, pain after surgical or dental interventions or bone fracture, immune or autoimmune diseases such as systemic lupus erythematosus; AIDS (acquired immunodeficiency syndrome), intestinal cancers such as colon cancer; neoplastic cell transformations or growth of metastatic tumors; diabetic retinopathy, tumor angiogenesis; contraction of smooth muscles induced by prostanoids and associated with

6/451 dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil-related disorders, hyperimmunoglobulinemia, Castleman's disease, myeloma; Alzheimer's disease, sleep disorders, endocrine disorders; glaucoma; bone loss; osteoporosis; promoting bone formation; Paget's disease: cycloprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; bleeding in the GI tract and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, hemophilia and other bleeding problems; kidney disease; thrombosis; vascular occlusive disease; pre-surgery; and anti-coagulation, or the like, which includes a therapeutically effective amount of an imidazzoic compound fused to an aryl or heteroaryl of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Furthermore, the present invention provides a method for the treatment of a prostaglandin-mediated disorder or condition, in a mammal including a human, which includes administering to the said subject a therapeutically effective amount of a compound of formula ( I).

In addition, the present invention provides a method for the treatment of pain, fever or inflammation associated with rheumatic fever, flu or other viral infections, the common cold, pain in the neck or lower back, skeletal pain, post-pain childbirth, dysmenorrhea, headache, migraine, toothache, sprains and muscle aches on exertion, myositis, neuralgia, fibromyalgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemicals, sunburn, pain after surgical or dental interventions or bone fracture, immune or autoimmune diseases such as systemic lupus erythematosus; AIDS (acquired immunodeficiency syndrome), intestinal cancers such as colon cancer; neoplastic transformations of cells or growth of metastatic tumors; diabetic retinopathy, tumor angiogenesis; contraction of smooth muscles induced by prostanoids and associated with dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil-related disorders, hyperimmunoglobulinemia, Castleman's disease, myeloma; Alzheimer's disease, sleep disorders, endocrine disorders; glaucoma; bone loss; osteoporosis; promoting bone formation; Paget's disease: cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; bleeding in the GI tract and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, hemophilia and other bleeding problems; kidney disease; thrombosis; vascular occlusive disease; pre-surgery; and anti-coagulation, or the like, which includes administering to said subject a therapeutically effective amount of a compound of formula (I).

The present invention also provides a pharmaceutical formulation that includes a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more pharmacologically active agents.

The present invention also provides a pharmaceutical formulation that includes a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more pharmacologically active agents, selected from a NSAID (non-steroidal anti-inflammatory agent) selective for COX- 2, either selective for COX-1, or non-selective, opioids, anticonvulsants, antidepressants, local anesthetics, disease-modifying anti-rheumatoid drugs, or steroids.

The following invention also provides a compound with the following formula:

(ID

8/451 or its salts, in which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N, CH or C (L);

R ¹ is H, C1 alkyl, C2.8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C4 alkoxy, halo-substituted Cqg alkoxy, C-sS (O) m-, Q ¹ alkyl, amino, mono- or di- (C4 alkyl), Cm-C (= O) -N (R ³ ) alkyl - or C1-4-S (O) mN (R ³ ) alkyl - wherein said Cm alkyl, C2-8 alkenyl and C2.8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, Cm alkoxy, C1-4 alkyl (S) m-, C3-7 cycloalkyl, cyano, indanyl, 1,2,3,4- tetrahydronaftila, 1,2 dihydronaftila, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ -S (O) m-, Q ¹ -C1.4-O- alkyl, Q ¹ -C ¹ alkyl ^ -S (O) _m -, Q ¹ -Cm-C (O) alkyl -N (R ³ ) -, Q ¹ -Cm-N alkyl (R ³ ) - or CmC (O) -N alkyl (R ³⁾ ) -;

Q ¹ is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy , Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (C4 amino alkyl, cyano, HOalkyl Cm, CM alkoxy Cm, alkylsulfonyl Cm, aminosulfonyl, alkyl CM-C (= O) - , HO (O =) C-, alkyl CU-O (O =) C-, R ³ N (R ⁴ ) C (= O) -, C, 4 alkylsulfonylamino, Cj.7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - or NH ₂ (HN =) C-;

A is a benzene ring optionally substituted with up to 3 substituents, or a pyridine ring optionally substituted with up to 3 substituents, wherein said substituents are selected from halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, alkoxy Cm substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (alkyl Cm) amino, cyano, HO-alkyl Cm, alkoxy CM-alkyl Cm, alkyl CM-sulfonyl, aminosulfonyl, acetyl, R ³ N (R ⁴ ) C (= O) -, HO (O =) C-, alkyl Cm-O (O =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - and NH ₂ (HN =) C-;

B is an alkylene group _C2 _6, cicfoalquileno 3-7 alkenylene, C ₂ alkynylene or _C2 _6 _6 optionally substituted with a C1-3 alkyl group;

W is NH or O;

P is H, a protecting group, or Q ³ -OC (= O);

9/451

Q ³ is a 6 to 10-membered monocyclic or bicyclic aromatic ring, optionally substituted with halo, Cm alkyl, Cm alkoxy, Cm alkylthio, nitro, cyano, alkyl CM-sulfonyl, alkyl C _M -C (= O) -, HO (O =) C- or C1-4 alkyl (O =) C-;

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (CM alkyl) amino, cyano, HO-Cm alkyl, alkoxy CM-alkyl Cm, alkyl CM-sulfonyl, aminosulfonyl, HO (O =) C-, alkyl Cm-O (O =) C-, alkylsulfonylamino C _M , cycloalkyl C3.7, R ³ -C (= O) N ( R ⁴ ) -, NH2 (HN =) C-, R ³ N (R ⁴ ) C (= O) or R ³ N (R ⁴ ) S (O) m-, or two adjacent L groups optionally bond to each other another forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms;

m is 0, 1 or 2; and

R ³ and R ⁴ are selected independently from H and Cm alkyl. The following invention also provides a compound with the following formula:

(III) or its salts, in which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N, CH or C (L);

R ¹ is H, Cm alkyl, C2-8 alkenyl, C2-8 alkynyl, C3.7 cycloalkyl, Cm alkoxy, Cm alkoxy substituted with halo, C1-8-S (O) alkyl m-, Q ¹ , amino, mono- or di- (C 1 -s) alkyl amino, Cm-C (= O) -N (R ³ ) alkyl - or CM-S (O) mN (R ³ ) alkyl - wherein said Cm alkyl, C ₂ alkenyl if C2-8 alkynyl are optionally substituted with halo, Cm alkyl, Cm alkoxy, Cm10 / 451 alkyl

S (O) _m -, C3-7 cycloalkyl, cyano, indanyl, 1,2,3,4-tetrahydronaphthyl, 1,2dihydronaphthyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ -S (0) m-, Q ¹ -Cm-O- alkyl, Q ¹ -C1-4-S alkyl (O) _m- , Q ¹ -Cm-C alkyl (O) -N (R ³ ) - or Q ¹ - Cm-N alkyl (R ³ ) -;

Q ¹ is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy , Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (CM alkyl) amino, cyano, HOalkyl Cm, CM alkoxy Cm, alkyl CM-sulfonyl, aminosulfonyl, CH-C alkyl (= O ) -, HO (O =) C-, CW-O (O =) C-, R ³ N (R ⁴ ) C (= O) -, C1J alkylsulfonylamino, C3-7 cycloalkyl, R ³ -C ( = O) N (R ⁴ ) - or NH2 (HN =) C-;

A is a benzene ring optionally substituted with up to 3 substituents, or a pyridine ring optionally substituted with up to 3 substitutes, wherein said substitutes are selected from halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, atoxy Cm , Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (Cm alkyl) amino, cyano, HO-alkyl Cm, CM alkoxy Cm, alkyl CM-sulfonyl, aminosulfonyl, acetyl, R ³ N (R ⁴ ) C (= O) -, HO (O =) C-, alkyl Cm-O (O =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - and NH ₂ (HN =) C-;

B is an alkylene group of C ₂ -e, C3-7 cycloalkylene, alkenylene or _C2 .6 _C2 -6 alkynylene, substituted C1-3 opcionalmentecom an alkyl group;

W is NH or O;

P is H, a protecting group, or ZS (O) ₂ -N (R ² ) -C (= O);

Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, in which said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, alkyl Cm, Cm alkyl substituted with halo, Cm alkenyl, C2-4 alkynyl, hydroxy, alkoxy Cm, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di (CM alkyl) amino, cyan, HO-Cm alkyl , CM-alkyl-Cm alkyl, CM-sulfonyl alkyl, aminosulfonyl, Cm-C (= O) -, R ³ -C (= O) N (R ⁴ ) -, HO (O =) C-, Cm-0 alkyl ( 0 =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, NH ₂ (HN =) C-,

11/451

Q ² -S (O) _m -, Q ² -O-, Q ² -N (R ³ ) - or Q ² -;

L is halo, Cm alkyl, C1-4 alkyl substituted with halo, hydroxy, C1- alkoxy, C1-4 alkoxy substituted with halo, C1-6 alkylthio, nitro, amino, mono- or di- (C4-alkyl, cyano, HO-Cm-alkyl, alkoxy C1- alkyl Cm, C1- alkyl alkyl, aminosulfonyl, C ^ alkyl C (= O), HO (O =) C-, C Cmyl (O =) C-, C1-7 alkylsulfonylamino, C3-7 cycloalkyl, R ³ - C (= O) N (R ⁴ ) -,

NH ₂ (HN =) C-, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) _m -, or two adjacent L groups optionally link to each other forming a alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms;

m is 0, 1 or 2; and

R ² , R ³ and R ⁴ are selected independently from H and C 1-4 alkyl ·

Detailed Description of the Invention

The term alkyl, as used herein, means a monovalent saturated hirocarbon group, with a straight or branched chain, including but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, neopentyl, and the like.

The term alkenyl, as used herein, means a monovalent group of hirocarbon having at least one double bond, including but not limited to, ethenyl, propenyl, 1-butenyl, 2butenyl, and the like.

The term alkynyl, as used herein, means a monovalent group of hirocarbon having at least one triple bond, including but not limited to, ethynyl, propynyl, 1-butynyl, 2butynyl, and the like.

The term halo, as used herein, refers to F, Cl, Br or I, preferably F or Cl.

The term cycloalkyl, as used herein, means a saturated carbocyclic group that includes, but is not limited to, cyclopropyl, cyclobuyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like.

12/451

The term alkoxy, as used herein, means an O-alkyl group, where alkyl has been defined above.

The term aromatic monocyclic ring, as used herein, means a monocyclic, carbocyclic or heterocyclic aromatic ring (and containing 0-4 heteroatoms selected from O, N and S), including, but not imitating, phenyl, pyrazolyl , furyl, thienyl, oxazolyl, tetrazolyl, thiasolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, iso-oxazolyl, isothiazolyl, triazolyl, furazanil and the like.

The term aromatic bicyclic ring, as used in this document, means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring (and containing 0-4 heteroatoms selected from O, N and S), including, but not imitating, naphthyl , benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinolyl, phthalazinyl, quinazolyl, quinoxalyl and the like.

The term alkylene, as used herein, means a saturated hydrocarbon (with a straight or branched chain) in which a hydrogen atom is removed from each of the terminal carbons, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

The term cycloalkylene, as used herein, means a divalent cycloalkyl group, including but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene, and the like.

The term alkenylene, as used herein, means a straight or branched chain hydrocarbon chain spacer group having at least one double bond, including but not limited to, -CH = CH-, -CH = CHCH ₂ -, -CH = CHCH (CH ₃ ) -, and the like.

The term alkynylene, as used herein, means a straight or branched chain hydrocarbon chain spacer group having at least one triple bond, including but not limited to, -C = C-, CC = CCH2- , -C = CCH (CH ₃ ) -, and the like.

13/451

The term tricyclic ring, as used in this document, means a saturated carbocyclic group that includes, but is not limited to, adamantyl, tricycle [5.2.1.0. ^2.6 ] dean, and the like.

The expression two adjacent L groups that optionally bond to each other forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms, as used in this document means, but is not limited to, -O-CH ₂ -O-, -CH2-O-CH2-, -0-CH2CH2-, -ch2CH2 “O -, - o-ch ₂ ch2-o-, - ch2Ch ₂ ch ₂ -o-, -o-ch ₂ ch ₂ ch ₂ -,

-CH2-O-CH2CH2-, -CH2CH2-O-CH2-, and the like.

The term aryl, as used herein, means aromatic groups including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, and the like.

The term protecting group, as used in this document, means a hydroxy or amino protecting group, which is selected from typical hydroxy or amino protecting groups, described in Protective Groups in Organic Synthseis, edited by TW Greene, et al.

(John Wiley & Sons, 1991.).

The term treat, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing, the disorder or condition to which that term applies, or one or more symptoms of that disorder or condition. The term treatment, as used in this document, refers to the act of treating, as defined immediately above.

In compounds with formula (I),

Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from N, CH and C (L);

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, alkoxy Cm, mono- or di- (CM alkyl) amino, Cm alkoxy substituted with halo, cyano, HO-alkyl Cm, alkoxy CM-alchemia Cm, alkylsulfonyl Cm , sulfonyl aminos30, Cm-C alkyl (= O) -, alkylsulfonylamino Cm, C3-7 cycloalkyl, R ³ C (= O) N (R ⁴ ) -, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) _m -, Q ² -, Q ² -C (= O) -, Q ² -O-, Q ² Cm-0- alkyl, or two adjacent L groups optionally bond one to

14/451 another forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms;

m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and Cm alkyl; and

Q ² is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, or a tricyclic ring with 8 to 12 members, optionally containing up to 3 heteroatoms selected from O, N and S, in which said monocyclic or bicyclic aromatic ring with 5 to 12 members is optionally substituted with halo, C1.4 alkyl, Cm halo substituted, C24 alkenyl, C2-4 alkynyl, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, mono- or di- (alkyl CM) amino, cyano, HO-Cm alkyl, CM alkoxy Cm, alkyl CM-sulfonyl, aminosulfonyl, Cm-C (= 0) -, R ³ (R ⁴ ) C (= O) N-, HO ( O =) C-, Cm-0 alkyl (0 =) C-, C-alkylsulfonylamino, C3.7 cycloalkyl or Cm-C alkyl (= O) NH-, or more preferably, Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from N, CH and C (L); L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, mono- or di- (CMylamino alkyl, Cm alkoxy substituted with halo, cyano, HO-alkyl Cm, alkyl CM-sulfonyl, aminosulfonyl, alkyl Cm- (0 =) C-, HO (O =) C-, alkyl Cm-O (O =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, R ³ C (= O) N (R ⁴ ) -, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) m-, Q ² -, Q ² -C (= O) -, Q ² -O-, Q ² alkyl Cm -O-, or two adjacent L groups optionally bond to each other forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms;

m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and C _M alkyl; and

Q ² is a monocyclic aromatic ring, with 5 or 6 members, or a tricyclic ring with 8 to 12 members containing up to 3 heteroatoms selected from N or S, where said aromatic monocyclic ring is

15/451 optionally substituted with halo, more preferably Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from N, CH and C (L); m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and Cm alkyl; and

Q ² is a 5- or 6-membered monocyclic aromatic ring or an 8 to 12-membered tricyclic ring optionally containing 1 sulfur atom, wherein said 5 or 6-membered aromatic monocyclic ring is optionally substituted with halo, more preferably Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from N, CH and C (L);

L is halo, C1-4 alkyl, C1-4 alkyl substituted with halo, hydroxy, C1-4 alkoxy, halo-substituted alkoxy, cyano, HO-C1-4 alkyl, acetyl, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) _m -, Q ² -, Q ² -C (= O) -, Q ² -O-, Q ² -C ^ -O- alkyl, or two adjacent L groups bond together to each other forming a methylenedioxy group;

R ³ and R ⁴ are selected, independently, from H and Cm alkyl; and

Q ² is a 5- or 6-membered monocyclic aromatic ring, more preferably Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from N, CH and C (L);

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (= O) NH ₂ , trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other another to form a methylenedioxy group, more preferably Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from the group consisting of

a) Y ¹ and Y ³ are C (L), Y ² is CH and Y ⁴ is N;

b) Y ¹ is CH, Y ² and Y ³ are C (L) and Y ⁴ is N;

c) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is N;

d) Y ¹ and Y ³ are C (L), Y ² is N and Y ⁴ is CH;

e) Y ¹ is C (L), Y ² , Y ³ and Y ⁴ are CH;

f) Y ¹ , Y ³ and Y ⁴ are CH and Y ² is C (L);

g) Y ¹ , Y ² and Y ³ are CH and Y ⁴ is C (L);

16/451

h) Y ¹ and Y ² are C (L), and Y ³ and Y ⁴ are CH;

i) Y ¹ and Y ³ are C (L), and Y ² and Y ⁴ are CH;

j) Y ¹ and Y ⁴ are CH and Y ² and Y ³ are C (L);

k) Y ¹ and Y ² are CH, Y ³ is C (L) and Y ⁴ is N;

l) Y ¹ and Y ³ are CH, Y ² is C (L) and Y ⁴ is N;

m) Y ¹ , Y ² , Y ³ and Y ^{4 are} CH;

η) Y ¹ and Y ² are C (L), Y ³ is CH, and Y ⁴ is N;

o) Y ¹ , Y ² and Y ⁴ are CH and Y ³ is C (L);

p) Y ¹ and Y ² are C (L), Y ³ is N and Y ⁴ is CH;

q) Y ¹ and Y ³ are C (L), and Y ² and Y ⁴ are N;

r) Y ¹ is C (L), Y ² and Y ³ are CH, and Y ⁴ is N;

s) Y ² is C (L), Y ¹ and Y ³ are CH and Y ⁴ is N; and

t) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is CH;

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (= O) NH ₂ , trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other another to form a methylenedioxy group, more preferably Y ¹ , Y ² , Y ³ , and Y ⁴ are preferably selected independently from the group consisting of

a) Y ^{1 and} Y ^{3 are} C (L), Y ^{2 is} CHeY ⁴ isN;

b) Y ¹ is CH, Y ² and Y ³ are C (L) and Y ⁴ is N;

c) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is N;

d) Y ¹ and Y ³ are C (L), Y ² is N and Y ⁴ is CH;

e) Y ¹ is C (L), Y ² , Y ³ and Y ⁴ are CH;

f) Y ¹ , Y ³ and Y ⁴ are CH and Y ² is C (L);

g) Y ', Y ² and Y ³ are CH and Y ⁴ is C (L);

h) Y ¹ and Y ² are C (L), and Y ³ and Y ⁴ are CH;

i) Y ¹ and Y ³ are C (L) and Y ² and Y ⁴ are CH;

j) Y ¹ and Y ⁴ are CH and Y ² and Y ² are C (L); and

k) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is CH;

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C (= O) NH ₂ , trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other another to form a group

17/451 methylenedioxy.

In compounds with formula (I),

R ¹ is preferably H, Cvg alkyl, C2.8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C.8 alkoxy, halo-substituted C.8s alkoxy (O) m-, Q ¹ , pyrrolidinyl , piperidyl, oxipyrrolidinyl, oxopiperidyl, amino, mono- or di- (C4 alkyl), C1-4 alkyl (= O) -N (R ³ ) - or C1-6 alkyl (R) mN (R ³ ) -, in that said C1-8 alkyl, C2-alkenyl and C2.8 alkynyl are optionally substituted with halo, C1.3 alkyl, hydroxy, oxo, Cm alkoxy, Cv4S (O) m-) alkyl C3.7, cyano, indanyl, 1,2,3,4-tetrahydronaphthia, 1,2-dihydronaphthyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , Q ¹ C (O) -, Q ¹ -O-, Q ¹ -S (O) m-, Q ¹ -alkyl 0, .8-0-, Q ¹ -alkyl C, ^ -S (O) m-, Q ¹ -alkyl C ,. 4-C (O) -N (R ³ ) -, Q ¹ -CW-N alkyl (R ³ ) - or C, ^ -C (O) -N (R ³ ) - alkyl;

Q ¹ is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halo, CX alkyl, C1.4 alkyl substituted with halo, hydroxy, C4 alkoxy, C1-4 alkoxy substituted with halo, C14 alkylthio, nitro, amino, mono- or di- (C4 amino alkyl, cyano, HO C1-4 alkyl, C ^ alkoxy Cm, CX sulfonyl alkyl, aminosulfonyl, alkyl 0, ., - 0 (= 0) -, HO (O =) C-, alkyl 0,., - 0 (0 =) 0-, R ³ N (R ⁴ ) C (= O) -, alkylsulfonylamino C, ^ , C3.7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - or NH2 (HN =) C-;

m is 0 or 2; and

R ³ is H, Cy alkyl, more preferably R ¹ is H, C1-8 alkyl, C2-8 alkenyl, C2.8 alkynyl, C3.7 cycloalkyl, Q ¹ , pyrrolidinyl, piperidyl, oxipyrrolidinyl, oxopiperidyl, amino, mono- or di - (Ci_8 alkyl) amino, wherein said alkyl CI_ ₈ is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, alkoxy C _1-4 alkyl, Ci ^ -S (O) _m -, C3-7 cycloalkyl, cyano , indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ -S or Q ¹ C 1 -O- alkyl, or C-C alkyl (O ) -N (R ³ ) -; em is 0 or 2, more preferably R ¹ is H, C1-8 alkyl, C2-8 alkenyl, C2.8 alkynyl, C3-7 cycloalkyl, Q ¹ or mono- or di- (C1-8 alkyl) amino, wherein said alkyl CI ₈ is optionally substituted with halo, alkyl C - [_ 3, hydroxy, oxo, alkoxy Cm alkyl, Ci_4-S (O) _m -, cycloalkyl C ₃ - _7, cyano, inda18 / 451 nila, pyrrolidinyl, piperidila, oxopirrolidinila , oxopiperidyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O, Q ¹ -S or Q ¹ -Cyl-Cm-0- alkyl, or Cm-C (O) -N (H) - alkyl;

Q ¹ is a monocyclic aromatic ring, with 5 or 6 members, optionally containing up to 4 heteroatoms selected from N and S; em is 0 or 2, more preferably

R ¹ is Cm alkyl, C3-7 cycloalkyl, or Q ¹ , mono- or di- (Cmyl alkyl) amino, wherein said C- | _5 alkyl is optionally substituted with C1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , or CM-C (O) -N (R ³ ) - alkyl; and

Q ¹ is a monocyclic aromatic ring, with 5 to 12 members, optionally containing up to 2 heteroatoms selected from N and S; more preferably R ¹ is C 1-5 alkyl, mono- or di- (C 1 amino alkyl, pyrrolidinyl or pyridyl optionally substituted with C 1 -.3 alkyl, hydroxy, oxo, a 5- or 6-membered aromatic monocyclic ring, wherein said aromatic monocyclic ring with 5 or 6 members contains 1 or 2 atoms selected from N and S, or alkyl Cm-C (O) -N (H) -, more preferably R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl.

In the compounds of formula (l),

In the compounds of formula (I),

R ² is preferably H or Cm alkyl, more preferably H.

A is preferably a 5- or 6-membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N and S, wherein said 5- to 6-membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo , Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, C14 alkoxy substituted with halo, more preferably a 5- or 6-membered aromatic monocyclic ring optionally substituted with halo, Cm alkyl, or Cm alkoxy, more preferably a monocyclic aromatic ring with 5 or 6 members optionally substituted with halo or Cm alkyl, more preferably a 5- or 6-membered monocyclic aromatic ring, most preferably phenyl or pyridyl.

19/451

In compounds with formula (I)

B is preferably a cycloalkylene or C3-7 alkylene optionally substituted ₆ CI_ with an oxo group or a C1-3 alkyl group, more preferably a C1-3 alkylene group optionally substituted with a C1-3 alkyl group, more preferably a Cv2 alkylene optionally substituted with methyl, and most preferably ethylene or propylene.

In compounds with formula (I),

W is preferably NH, N-alkyl Cm, O, or N-OH, more preferably NH, N-alkyl or O, and most preferably NH, N-CH ₃ , or O.

In compounds with formula (I),

Z is preferably a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 3 heteroatoms selected from N, O and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo , C1-4 alkyl, C1-4 halo-substituted alkyl, C1-4 alkenyl, hydroxy, C1-4 alkoxy, nitro, amino, cyano, C1-4-HO alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-C (= O) alkyl -, R ³ N (R ⁴ ) C (= O) -, HO (O =) C-, alkyl CM-O (O =) C-, alkylsulfonylamino CH | alkyl CM-C (= O) NH-, Q ² -S (O) m-, Q ² -O-, Q ² -N (R ³ ) - or Q ² -;

m is 0 or 2;

Q ² is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, or a tricyclic ring with 8 to 12 members, optionally containing up to 3 heteroatoms selected from O, N and S, the said monocyclic or bicyclic aromatic ring, with 5 to 12 members, is optionally substituted with halo, C1-C4 alkyl, C1-C4 alkyl substituted with halo, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with halo, C1 -C4 alkylthio, mono- or di- (C1-C4 alkyl) amino, cyano, HOC1-4 alkyl, C1-C4 alkoxy- C1-C4 alkyl, C1-C4 alkylsulfonyl, aminosulfonyl, C, -C4 alkyl- (O =) C-, R ³ (R ⁴ ) C (= O) N-, HO (O =) C-, C, -C4 alkyl-O (O =) C-, C _r C ₄ alkylsulfonylamino, C3-C7 cycloalkyl or C1-C4 alkyl-C (= O) NH-, more preferably Z is a monocyclic or bicyclic aromatic ring, with 5 to 12 members optionally containing up to 3 heteroatoms selected from among

20/451

N and S, the said aromatic monocyclic or bicyclic aromatic ring, with 5 to 12 members being optionally substituted with halo, C1-C4 alkyl, Ci-C ₄ alkyl substituted with halo, C _r C ₄ alkenyl, Ci-C ₄ alkoxy , nitro, amino, cyano, R ³ (R ⁴ ) C (= O) N-, CrC4 alkyl-O (O =) C-, Q ² -S (O) m-, Q ² -O-, Q ² -N (R ³ ) - or Q ² -; m is 0 or 2;

R ³ and R ⁴ are independently selected from H and C 1 -C ₄ alkyl; and

Q ² is a monocyclic aromatic ring, with 5 or 6 members, or a tricyclic ring with 8 to 12 members, optionally containing up to 3 heteroatoms selected from N and S, and said said monocyclic aromatic ring, with 5 or 6 members is optionally substituted with halo, more preferably Z is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 3 heteroatoms selected from N and S, and said said monocyclic or bicyclic aromatic ring, with 5 to 12 members is optionally substituted with halo, cyano, R ³ C (= O) N (R ⁴ ) -, Cr C4 alkyl-O (O =) C-, Q ² -S (O) m-, Q ² -O-, Q ² - N (R ³ ) - or Q ² -; m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and Ci ^ aiquila; and

Q ² is an aromatic monocyclic ring, with 5 or 6 members, or a tricyclic ring with 8 to 12 members, optionally containing a sulfur atom, in which said aromatic monocyclic or bicyclic ring with 5 or 6 members is optionally substituted with halo , more preferably Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12-membered aromatic monocyclic ring is optionally substituted with halo, C _M alkyl , nitro, R ³ C (= O) N (R ⁴ ) -, or Q ² -;

R ³ and R ⁴ are selected, independently, from H and C 1 alkyl; and

Q ² is a 5- or 6-membered monocyclic aromatic ring, more preferably Z is a 5- to 10-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, wherein said aromatic monocyclic ring with 5 to 10 mem21 / 451 bros is optionally substituted with chlorine, bromine, methyl, nitro, CH ³ C (= O) NH-, tBuC (= O) NH- or phenyl, and most preferably Z is phenyl, pyrazolyl, thiazolyl, thioadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thioadiazolyl and thienyl, optionally substituted with one to three substituents selected independently from chlorine, bromine, methyl, acetylamino, pivaloylamino, nitro and phenyl.

A preferred group of compounds of the present invention include those compounds of formula (I) in which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is H, Cm alkyl, C2.8 alkenyl, C2_8 alkynyl, C3.7 cycloalkyl, Cve alkoxy, C1-8 alkoxy substituted with halo, C1-8-S (O) m- alkyl, Q ¹ , pyrrolidinyl, piperidyl, oxipyrrolidinyl , oxopiperidyl, amine, mono- or di- (C4-alkyl) amino, C1-C-alkyl (= O) -N (R ³ ) - or C1-8-S (O) mN (R ³ ) alkyl - , wherein said Cm alkyl, C2 alkenyl. ₈ and C ₂ alkynyl. . ₈ are optionally substituted with halo, Ci ₃ alkyl, hydroxy, oxo, alkoxy Cm, Cu alkyl-S (0) _m - C ₃ cycloalkyl. ₇ , cyano, indanyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ S (O) m-, Q ¹ -CM-O- alkyl, Q ¹ -CM-S (O) _m alkyl, Q ¹ -Cm-C alkyl (= 0) N (R ³ ) -, or Cm alkyl -C (= O) ~ N (R ³ ) -;

Q ¹ is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, optionally containing up to 4 heteroatoms selected from enter O, N and S, and optionally substituted with halo, C1-4 alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, Cm alkylthio, nitro, amino, mono- or di- (alkyl CM) amino, cyano, HOalkyl Cm, alkoxy CM-alkyl Cm, alkyl CM-sulfonyl, aminosulfonyl, alkyl C _M -C (= O) -, HO (O =) C-, C _M alkyl -O (O =) C-, R ³ N (R ⁴ ) C (= O) -, C ^ alkylsulfonylamino, C3.7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - or NH2 (HN =) C-;

A is a 5- or 6-membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N and S, wherein said 5- to 6-membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, al22 / 451 kilo C _M) Cm alkyl substituted with halo, hydroxy, alkoxy Cm θ alkoxy Cm substituted with halo;

B is a C3-7 cycloalkylene group or Cm alkylene optionally substituted with an oxo group or with a Cm alkyl group;

W is NH, N-alkyl Cm, O, or N-OH;

R ² is H or Cm alkyl;

Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, in which said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, alkyl Cm, Cm alkyl substituted with halo, C ₂ ^ alkenyl, hydroxy, Cm alkoxy, nitro, amino, cyano, HO-alkyl Cm, alkyl CM-sulfonyl, aminosulfonyl, C _M C (= O) -, R ³ N ( R ⁴ ) C (= O) -, HO (O =) C-, Cm-O alkyl (O =) C-, alkylsulfonylamino alkyl CM-C (= O) NH, Q ² -S (O) m-, C ^, Q ² -S (O) _m -, Q ² -O-, Q ² -N (R ³ ) - or Q ² -;

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, mono- or di- (CM alkyl) amino, Cm alkoxy substituted with halo, cyano, HO-alkyl Cm, CM alkoxy Cm, CM alkyl -sulfonyl, aminosulfonyl, Cm-0 alkyl (0 =) C-, HO (O =) C-, Cm-C alkyl (O =) C- alkylsulfonifamino C _H , C3-7 cidoalkyl, R ³ -C (= O ) N (R ⁴ ) -, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) m-, Q ² , Q ² -C (= O) -, Q ² -O-, Q ² -alkyl-O- _t CM or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two carbon atoms (nonadjacent) are optionally replaced by oxygen atoms;

m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and Cm alkyl; θ

Q ² is a monocyclic or bicyclic aromatic ring, with 5 to 12 members, or a tricyclic ring with 8 to 12 members, optionally containing up to 3 heteroatoms selected from O, N and S, in which said monocyclic or bicyclic aromatic ring with is 5 to 12 members optionally substituted with halo, alkyl Cm, Cm alkyl substituted with halo, C alcenila ₂ -4, -4 alcinila C _2, hydroxy, alkoxy Cm, Cm alkoxy substituted with ha23 / 451

Io, Cm alkylthio, amino, mono- or di- (Cv ₄ alkyl) amino, cyano, HO-C 1 alkyl 4, C _M alkoxy Cm, C 4 -sulfonyl alkyl, aminosulfonyl, CmC alkyl (= O) - , R ³ (R ⁴ ) C (= O) N ~, HO (O =) C-, alkyl 0 ^ -0 (0 =) 0-, alkylsulfonylamino Cm, cycloalkyl C3-7 or alkyl CmC (= O) NH .

Another preferred group of compounds of the present invention includes with formula (I) in which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is H, C1-8 alkyl, C2-8 alkenyl, C2.8 alkynyl, 03-7 cycloalkyl, Q ¹ , pyrrolidinyl, piperidyl, oxypyrrolidinyl, oxopiperidyl, amino, mono- or di (C1-8 alkyl) amino, where ₈ CI_ said alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, alkoxy Cm alkyl, Ci ^ -S (O) _m -, C3-7 cycloalkyl, cyano, indanila, pyrrolidinyl, piperidila, oxopirrolidinila, oxopiperidia, Q ¹ , Q ¹ -C (O) -, Q'-O-, Q ¹ -S-, Q'-C ^ -O- alkyl or C, ^ - C (O) -N (R ³ ) -;

Q ¹ is a 5- to 12-membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, Cm alkyl, Cm alkylsulfonyl Cm and Cm-C alkyl (= O) -;

A is a 5- or 6-membered aromatic monocyclic ring optionally optionally substituted with halo, C1-4 alkyl or Cm alkoxy;

B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or an alkyl group CI_ _3;

W is NH, N-alkyl Cm, O, or N-OH;

R ² is H or Cm alkyl;

is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, in which said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, Cm alkyl, alkyl Cm replaced with halo, Cm aylenyl, Cm alkoxy, Nitro, amino, cyano, R ³ C (= O) -N (R ⁴ ), CM-O (O =) C-, Q ² -S (O) m alkyl -, Q ² -O-, Q ² -N (R ³ ) - or Q ² -;

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, mono- or di- (CM alkyl) amino,

24/451 cyano, HO-C ^ alkyl, alkyl CI_ -sulfonila _4, aminossulfonila alkyl, C? -C (= O), HO (O =) C-, C ^ alkyl -O (O =) C-, alkylsulfonylamino Cm, C3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) -, R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) _m -, Q ² -, Q ² -C (= O) -, Q ² -O-, Q ² C1-4-O- alkyl, or two adjacent L groups optionally link to each other forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally replaced by oxygen atoms;

m is 0 or 2;

R ³ and R ⁴ are selected, independently, from H and C 1 alkyl; and

Q ² is a 5- or 6-membered monocyclic aromatic ring, or an 8 to 12-membered tricyclic ring, optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6-membered aromatic ring is optionally substituted with halo.

Another preferred group of compounds of the present invention includes with formula (I) in which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is H, C ₂ s alkyl, C ₂ -s alkenyl or C ₂ -8 alkynyl, cycloalkyl wherein said C ₈ alkyl, θ optionally substituted with halo, hydroxy alkyl, oxo, C 4 alkoxy, C 1-4 alkyl S (O) _m -, C3-7 cycloalkyl, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q ¹ , Q ¹ -C (O) -, Q ¹ -O-, Q ¹ -S-, Q ¹ -C ^-O- alkyl or C ^-CÍOJ-NIR ³ ) alkyl;

Q ¹ is a 5- or 6-membered monocyclic aromatic ring, optionally containing up to 4 heteroatoms selected from N and S;

A is a 5- or 6-membered monocyclic aromatic ring optionally substituted with halo or Cm alkyl;

B is a C 3-7 cycloalkylene group or a C 1-6 alkylene optionally substituted with an oxo group or with a C 1-3 alkyl group;

W is NH, N-C 1-4 alkyl, O, or N-OH;

R ² is H or C 1-6 alkyl;

Z is a monocyclic or bicyclic aromatic ring, with 5 to 12

25/451 members, optionally containing up to 3 heteroatoms selected from N and S, said monocyclic or bicyclic aromatic ring with 5 to 12 - membered is optionally substituted with halo, alkyl Cm, Cm alkyl substituted with halo, C _M alkoxy alcenila Cm, nitro, amino, cyano, R ³ C (= O) -N (R ⁴ ), C alkyl., - 0 (0 =) 0-, Q ² -S (O) _m -, Q ² -O -, Q ² -N (R ³ ) - or Q ² -;

L is halo, Cm alchemy, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, cyano, HO-Cm alkyl, HO (O =) C-, Cm-O (O =) C- alkyl, alkylsulfonylamino Cm, C ₃ cycloalkyl. ₇ , R ³ -C (= O) N (R ⁴ ) -. R ³ N (R ⁴ ) C (= O) -, R ³ N (R ⁴ ) S (O) m-, Q ² -, Q ² -C (= O) -, Q ² -O-, Q ² Cm-O- alkyl, or two adjacent L groups optionally bond to each other forming an alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally substituted by oxygen atoms;

m is 0 or 2;

R ³ and R ⁴ are independently selected from H and Cm alkyl! θ

Q ² is a 5- or 6-membered aromatic ring, or an 8 to 12-membered tricyclic ring, optionally containing up to 1 sulfur atom, wherein said 5- or 6-membered aromatic ring is optionally substituted with a halo.

Another group of preferred compounds of the present invention includes compounds of the formula (!) In which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is Cv ₅ alkyl or C ₃ cycloalkyl. _7, wherein said Ci_5 alkyl is optionally substituted with alkyl CI_ _3, hydroxy, oxo, pyrrolidinyl, piperidila, oxopirrolidinila, oxopiperidila, Q ¹ or Cm alkyl-C (O) -N (H) -;

Q ¹ is a 5-12 membered monocyclic aromatic ring, optionally containing up to 2 heteroatoms selected from N and S;

A is a 5- or 6-membered monocyclic aromatic ring;

B ₃ is alkylene optionally substituted with CI_ CI_ ₃ alkyl;

W is NH, N-alkyl Cm, or O;

26/451

R ^{2 is} H;

Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, in which said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, Cm alkyl, nitro, R ³ C (= O) N (R ⁴ ) - or Q ² -;

L is halo, Cm alkyl, Cm alkyl substituted with halo, hydroxy, Cm alkoxy, Cm alkoxy substituted with halo, cyano, HO-alkyl Cm, acetyl, HO (O =) C-, R ³ N (R ⁴ ) C ( = O) -, R ³ N (R ⁴ ) S (O) _m -, Q ² -, Q ² -C (= O) -, or two adjacent L groups bond to each other to form a methylenedioxy group;

R ³ and R ⁴ are independently selected from H and Cm alkyl! and

Q ² is an aromatic ring with 5 or 6 members.

Another group of preferred compounds of the present invention includes compounds of the formula (!) In which

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is alkyl CI_ ₅ is optionally substituted with alkyl CI_ _3, hydroxy, oxo, monocyclic aromatic ring of 5 or 6 members, wherein the aromatic ring being 5 or 6 members containing 1 or 2 heteroatoms selected from N and S , or Cim-C (O) -N (R ³ ) - alkyl;

A is phenyl;

B is a C ₁ alkylene group optionally substituted with methyl;

WéNH, N-CH ₃ , or O;

R ² is H;

Z is a 5- to 10-membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 10-membered monocyclic aromatic ring is optionally substituted with chlorine, bromine, methyl, nitro , CH ₃ C (= O) NH-, t-BuC (= O) NH- or phenyl;

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl,

27/451

-C (= O) NH2-, trifluoroethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond together to form a methylenedioxy group.

Another group of preferred compounds of the present invention includes compounds of formula (I) wherein

Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N,

CH, and C (L);

R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-acetylamino-1-methyl [ethyl;

A is phenyl;

B is ethylene or propylene;

W is NH, N-CH ₃ , or O;

R * is H;

Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl groups being optionally substituted with one to three substituents selected independently from chlorine, bromine, methyl, acetylamino, pivaloylamino nitric and phenyl; and

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, C (= O) NH ₂ -, trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other another to form a methylenedioxy group.

Another group of preferred compounds of the present invention includes compounds of formula (I) wherein

Y ¹ , Y ² , Y ³ and Y ⁴ are selected from the group consisting of

a) Y ¹ and Y ³ are C (L), Y ² is CH and Y ⁴ is N;

b) Y ¹ is CH, Y ² and Y ³ are C (L) and Y ⁴ is N;

c) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is N;

d) Y ¹ and Y ³ are C (L), Y ² is N and Y ⁴ is CH;

e) Y ¹ is C (L), Y ² , Y ³ and Y ⁴ are CH;

f) Y ¹ , Y ³ and Y ⁴ are CH and Y ² is C (L);

28/451

g) Y ¹ . Y ² and Y ³ are CH and Y ⁴ is C (L); H) Y ¹ and Y ² are C (L), and Y ³ and Y ⁴ are CH; i) Y ¹ and Y ³ are C (L), and Y ² and Y ⁴ are CH; j) Y ¹ and Y ⁴ are CH and Y ² and Y ³ are C (L); k) Y ¹ and Y ² are CH, Y ³ is C (L) and Y ⁴ is N; D Y ¹ and Y ³ are CH, Y ² is C (L) and Y ⁴ is N; m) Y ¹ , Y ² , Y ³ and Y ⁴ are CH; n) Y ¹ and Y ² are C (L), Y ³ is CH, and Y ⁴ is N; O) Y ¹ , Y ² and Y ⁴ are CH and Y ³ is C (L); P) Y ¹ and Y ² are C (L), Y ³ is N and Y ⁴ is CH; q) Y ¹ and Y ³ are C (L), and Y ² and Y ⁴ are N; 0 Y ¹ is C (L), Y ² and Y ³ are CH, and Y ⁴ is N; and s) Y ² is C (L), Y ¹ and Y ³ are CH and Y ⁴ is N; R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopen thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-ace-

thiamino-1-methylethyl;

A is phenyl;

B is ethylene or propylene;

WéNH, N-CH ₃ , or O;

R ^{2 is} H;

Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl groups being optionally substituted with one to three substituents selected independently from chlorine, bromine, methyl, acetylamino, pivaloylamino nitro and phenyl; and

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, C (= O) NH2-, trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other to form a methylenedioxy group.

Another group of preferred compounds of the present invention includes compounds of formula (I) wherein

Y ¹ , Y ² , Y ³ and Y ⁴ are selected from the group consisting of

29/451

a) Y ^{1 and} Y ³ areC (L), Y ² isCKeY ⁴ isN;

b) Y ¹ is CH, Y ² and Y ³ are C (L) and Y ⁴ is N;

c) Y ¹ , Y ² and Y ³ are C (L) and Y ⁴ is N;

d) Y ^{1 and} Y ^{3 are} C (L), Y ^{2 is} Ne and ^{4 is} CH;

e) Y ¹ is C (L), Y ² , Y ³ and Y ⁴ are CH;

f) Y ¹ , Y ³ and Y ⁴ are CH and Y ² is C (L);

g) Y ¹ , Y ² and Y ³ are CH and Y ⁴ is C (L);

h) Y ¹ and Y ² are C (L), and Y ³ and Y ⁴ are CH;

i) Y ¹ and Y ³ are C (L) and Y ² and Y ⁴ are CH; and

j) Y ¹ and Y ⁴ are CH and Y ² and Y ² are C (L);

R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidintla, pyridyl or 1-acetylamino-1-methylethyl;

A is phenyl;

B is ethylene or propylene;

WéNH, N-CH ₃ , or O;

R ^{2 is} H;

Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl groups being optionally substituted with one to three substituents selected independently from chlorine, bromine, methyl, acetylamino, pivaloylamino nitro and phenyl; and

L is chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, C (= O) NH2-, trifluoromethoxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups bond to each other to form a methylenedioxy group.

The preferred individual compounds of this invention are as follows:

3- (4- {2 - [({[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -2-ethyl-5 , 7-dimethyl-3/7-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;

30/451

N- [5 - ({[({2- [4- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-ò] 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) -5 / 7- (1,3) dioxolo [4,5- / | benzimidazole;

6-chloro-5-cyano-2-ethyl-1- (4- {2 - [({[(4 ~ methylphenylsulfonyl] amino} -carboni]) amino] ethyl} phenyl) -1 / - / - benzimidazole;

2-ethyl-5,7-dimethyl-3- (4- {2- [methyl ({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -3 / - / - imidazo [4 , 5-b] pyridine;

2-ethyl-5,7-dimethyl3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-b ] pyridine;

2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazole / 4,5-b] ptridin-3-yl) phenyl] -1-methylethyl (4-methylphenyl) sulfonylcarbamate

5.7- dimethyl-3- (4- {2 - [({[(4-methyl [phenyl) sulfonyl] amino} carbonyl) -amino] ethyl} phenyl) -2-propyl-3H-imidazo [4,5-5 ] pyridine;

2-isopropyl-5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -3 / - / - Ímidazo [4, 5-b] pyridine;

2-butyl-5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5 -b] pyridine;

2-isobutyl-5,7-dimethyl “3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -car20 bonyl) 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-3/7-imidazo [4,5-ò ] pyridine;

5.7- dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) annino] ethyl} phenyl) -3 / 7-imidazo [4,5-ò] pyridine ;

3- {4- [2 - ({[(4-biphenylsulfonyl) amino] carbonyl} amino) ethyl] phenyl} -2-ethyl3H-imidazo [4,5-Z)] pyridine;

2-ethyl-5 ₎ 7-dimethyl-3- {4- [2 - ({[(1-naphthylsulfonyl) amino] carbonyl} amino) ethyl] pheni!} - 3B-imidazo [4,5-Z?] Pyridine ;

2-ethyl-5,7-dimethyl-3- {4- [2 - ({[2 (-naphthylsulfonyl) amino] carbonyl} 30 amino) ethyl] phenyl} -3 / 7-imidazo [4,5-b] pyridine;

2-ethyl-5 _J 7-dimethyl-3- {4- [2 - ({[(2-thienyl) sulfonyl) amino] carbonyl} amino) ethyl] phenyl} -3 / 7-imidazo [4,5-b ] pyridine;

31/451

3- (4- {2 - [({[(5-chloro-2-thienyl) sulfonyl] amino} carbonyl) amino] -ethyl} phenyl) -2 ~ ethyl-5,7-dimethyl ~ 3H-imidazo [ 4,5-ò] pyridine;

3- (4- {2 - [({[(4,5-dichloro-2-thienyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -2-ethyl-5,7-dimethyl-3 / 7- imidazo [4,5-ô] pyridine;

3- {4- [2 - ({[(1-benzothien-2-ylsulfonyl) amino] carbonyl} amino) ethyl] phenyl} -2-ethyl-5,7-dimethyl-3 / - / - imidazo [4, 5-ô] pyridine;

3- (4- {2 - [({[(2-chlorophenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -2ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine;

2-ethyl-5,6-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) 10 amino] ethyl} phenyl) -3H-imidazo [4,5- ó] 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-etif-7-methyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -3 / - / - irnidazo [ 4,5-b] pyridine;

6-cyano-2-ethyl-5,7-dimethyl-3- (4- {2 - [({[(4-nethylphenyl) sulfonyl] -amino} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-ô] pyridine;

2-ethyl-4,6-dimethyl-1 - (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -1/7 “imidazo [4,5 -c] pyridine;

4- methyl-2-ethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) to mino] 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) benzinnidazole;

5-cyano-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) benzimidazole;

2-ethyl-5-hydroxy-1- (4- {2 - [({[(4 "methylphenyl) sulfonyl] amino} carbonyl) 30 amino] ethyl} phenyl) -1 H-benzimidazole;

2-ethyl-4,5-dimethyl-1- (4- {2 - [({[(4-methylphenyl) sulfoni [] amino} -carbonyl) amino] ethyl} phenyl) benzimidazole;

32/451

4.6- dimethyl-2-ethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbO “nyl) amino] ethyl} phenyl) benzimidazole;

5.6- dimethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) -amino] ethyl} phenyl) 1/7-benzimidazole;

5.6- dichloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} ~ carbonyl) amino] ethyl} phenyl) 1/7-benzimidazole;

2- [4- (5,6-dichloro-2-ethyl-1 H-benzimidazol-1-yl) phenethyl (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-1-benzimidazole-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate;

5- chloro-6-methyl-1 ~ (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) 1 / - / - benzimidazole;

6- chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1H-benzimidazole-5-carboxamide;

2- ethyl-3- {4- [2 - ({[({3- [hydroxy (oxide) amino] phenyl} sulfonyl) amino] carbontl} amino) ethyl] -phenyl} -5,7-dimethyl-3H- imidazo [4,5-b] pyridine;

3- (4- {2 - [({[(4 "Chlorophenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -2ethyl-5,7-dimethyl-3H-imidazo [4,5-ò] pyridine;

N- [4 ~ ({[({2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-Z>] pyridin-3-yl) phenyl] ethyl} amino) carbonyl] amino} sulfonyl) phenyl] -2,2-propanamide;

3- (4- {2 - [({[(2-chlorophenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -2ethyl-5,7-dimethyl-3/7-imidazo [4 ₎ 5-jb] pyridine;

3- (4- {2 - [({[(3-chlorophenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -2ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridine;

3- (4- {2 - [({[(5-chloro-2-thienyl) sulfonyl] amino} carbonyl) amino] ethyl} pheni [) - 2-ethyl-5,7-dimethyl-3H-imidazo [4 ₁ 5-b] pyridine;

3- (4- {2 - [({[(5-bromo-2-thienyl) sulfonyl] alkaline} carbonyl) amine] ethyl} phenyl) “2-ethyl-5,7-dimethyl-3/7-imidazo [ 4,5-b] pyridine;

3- (4- {2 - [({[(2-bromophenyl) sulfonyl] amino} carbonyl) amino] ethyl} -phenyl) 2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5 -b] pyridine;

33/451

3- {4- [2 - ({[({4-chloro-3-nitrophenyl} sulfonyl) amino] -carbonyl} amino) ethyl] phenyl} -2-ethyl-5,7-diimethyl-3H-imidazo [4 , 5-o] pyridine;

2- [4- (2-ethyl-4,6-drmetyl-1/7-imidazo [4,5-c] pyridin-1-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [5,7-dimethyl-2- (methylamino) -3H-imidazo [4,5-d] pyridin-3-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate;

N-ff ^ - ^ - t? ^ -Dimethyl ^ -methylaminoJ-SH-imidazoKõ-òJpirrdirn-Sil] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide;

N - {[(2- {4- [2-ethyl-5- (1-hydroxy-1-methylethyl) -1 / 7-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-carboxamide;

2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] phenyl} ethyl pyridinyljetyl (2-chlorophenyl) sulfonylcarbamate;

2- {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] -2-pyridinyl} ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} (5-methyl-2-pyridinyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (1H-pyrazol-3yl) -5- (trifluoromethyl) -1 A / -benzimidazole-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (4-pyridinyl) -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1H-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

N - {[(2- {4- [6-chloro-2-ethyl-5- (methylsulfonyl) -1 / 7-benzimidazol-1-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide;

2- {4- [6-chloro-2-ethyl-5- (methylsulfonyl) -1 / 7-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

Ν - {[({2- [4- (2-βίίί-5,7 ^ ι ^ βΐιΊ-3Η-όθηζιΊΌΐ ^ 3ζο [4,5-ό] ρίη ^ ϊη-3-ι () ίβnil] ethyl} amino ) carbonyl] -2-thiophenesulfonamide;

2- [4- (4,6-dimethyl-2-phenyl-1/7-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

34/451 2- [4- (2-butyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6 chloro-2-ethyl ~ 5- (trifluoromethyl) -1H-benzimidazol-1-yl) phenyl (5-chloro-1,3-dimethyl-1/7-pyrazol-4-yl) phenyl ] ethyl;

2- {4- [4,6-dimethyl-2- (3-phenylpropyl) -1 H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (2-pyridinyl) - (5trifluoromethyl) -1 / 7-benzimidazole-1-yl] phenyl jetyl (4-methylphenyl) sulfonyl carbamate;

(1-S) -2- {4- [6-chloro-2-ethyl- (5-trifluoromethyl) -1 H-benzimidazole-1-ylmethylethyl (4-methylphenyl) sulfonifcarbamate;

2- {6- [6-chloro-2-ethyl- (5-trifluoromethyl) -1 / 7-benzimidazole-1-II] -3-pyridinylpropionate (4-methylphenyl) sulfonylcarbamate;

N - {[(2- {4- [6-chloro-2- (1-hydroxy-1methylethyl) -5- (trifluoromethyl) -1Hbenzimidazol-1-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide; and

N - {[(2- {4- [5,7-dimethi 1-2- (1 H-pyrazol-3-yl) -3 / 7-imidazo [4,5-5] pi ridin3-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide;

2- {4- [2- (1,1-dimethylethyl) -4,6-dimethyl-1/7-imidazo [4,5-c] pyridin-1-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate ;

2- {4- [2-1- (acetylamino) -1-methylethyl] -6-chloro-5-trifluoromethyl) -1H-benzimidazoM-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate; and

6-chloro-2-ethyl-1- (4- {2- [methyl ({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -1 H-benzimidazole-5-carboxamide; and their salts.

The most preferred individual compounds of this invention are as follows:

6-ethyl-5- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -5 / 7-dioxolo (1,3] dioxolo [4,5- /] benzimidazole;

6-chloro-5-cyano-2-ethyl-1- (4- {2 - [({[(4-methylphenylsulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -1H-benzimidazole;

4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-b] pyridin-3-yl) phenyl] -1-methylethyl (4-methylphenyl) sulfonylcarbamate;

5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) -ami35 / 451 nojetyl} phenyl) -2- [2- (1,3-thiazo! -2 ~ yl) ethyl] -3A7-imidazo [4,5 ~ £>] pyridine;

2- ethyl-5,7-dimethit-3- {4- [2 - ({[(2-thienylsulfonyl) allyl] carbonyl} -amino) ethyl] phenyl} -3 / 7-imidazo [4,5-b] pyridine;

3- (4- {2 - [({[(2 "Chlorophenyl) sulfonyl] amino} carbonyl) amino} ethyl} phenyl) -25 ethyl-5,7-dimethyl-3/7-imidazo [4,5-b ] pyridine;

2-ethyl-5,6-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carboniJ) 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) -1tf-imidazo [4,5-c ] pyridine;

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) 15 amino] ethyl} phenyl) benzimidazole;

5- cyano-2-ethyl-1- (4- {2 - [({[(4-methylphenit) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1H-benzimidazole;

2-ethyl · 5-hydroxy-1- (4- {2 - [({[(4-methylfemΊ) sutfonyl] amino} carbomΊ) amino] ethyl} phenyl) benzimidazole;

2-ethyl-4,5-dimethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) benzimidazole;

4- (6-chloro-2-ethyl-5-trifluoromethyl 1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate; and

6- chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) ami 25 no] ethyl} phenyl) -1 H-benzimidazole-5-carboxamide;

2- [4- (2-ethyl-4,6-dimethyl-1 H-imidazzo [4,5-c] pyridin-1-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [5,7-dimethyl-2- (methylamino) -3 / - / - imidazo [4,5-jb] pyridin-3-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate;

N - {[(2- {4- [5,7-dimethyl-2- (methylamino) ~ 3H-imidazo [4,5-b] pyridin-3yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonannide;

N - {[(2- {4- [2 ~ ethyl-5- (1-hydroxy-1-methylethyl) -1 H-benzimidazol-1-yl] fe

36/451 nil} ethyl) amino] carbonyl} -4-methylbenzenesulfonarriide;

2-ethyl-4,6-dimethyl-1 ~ (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole-carboxamide;

2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazole-1-yl] -2-phenyl jet (2-chlorophenyl) sulfonylcarbamate;

2- {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] -2-pyridinyl} ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl} ethyl (5-methyl-2-pyridinyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (1 W ~ pyrazol-3yl) -5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (4-pyridinyl) ~ 5 (trifluoromethyl) -1 H-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl I-1 H-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

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-benzimidazol-1-yl] phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

N - {[({2- [4 “(2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-Z)] pyridin-3-yl) phenyl] ethyl} amino) carbonyl] -2-thiophenesulfonamide;

2- (4- (4,6-dimethyl-2-phenyl-1/7-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- [4- (2-butyl-4,6-dimethyl-1/7-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- (4- (6 (chloro-2-ethyl-5- (trifluoromethyl) -1tf-benzimidazol-1-yl) phenyl] (5-chloro-1,3-dimethyl-1 W-pyrazol-4-yl) phenyl] ethyl;

2- {4- [4,6-dimethyl ~ 2- (3-phenylpiopyl) -1 H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate;

2- {4- [6-chloro-2- (2-pyridinyl) - (5trifluoromethyl) -1 H-benzimidazol-1-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate;

(1S) -2- {4- [6-chloro-2- (ethyl) -5 (tri37 / 451 fluoromethyl) -1 / - / - benzimidazole-1-yl] phenyl (4-methylphenyl) sulfonylcarbamate} 1 -methylethyl;

2- {6- [6-chloro-2-ethyl- (5-trifluoromethyl) -1 / - / - benzimidazole-1-yl] -3-pyridinyl} -ethyl (4-methylphenyl) sulfonylcarbamate;

N - {[(2- {4- [6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1Hbenzimidazol-1-yl] phenyl} ethyl) amine] carbonyl} - 4-methylbenzenesulfonamide; and

N - {[(2- {4- [5,7-dimethyl-2- (1 / - / - pyrazol-3-yl) -3 / 7-imidazo [4,5-ó] pyridin3-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide;

2- {4- [2- (1,1-dimethylethyl) -4,6-dimethyl-1/7-imidazo [4,5-c] pyridin-1-yl] phenyl} ethyl (4-methylphenyl) sulfonylcarbamate ;

2- {4- [2-1- (acetylamino) -1-methylethyl] -6-chloro-5-trifluoromethyl) -1 / - / - benzimidazole-1-yl] phenyljeti (4-methylphenyl) sulfonylcarbamate; and

6-chloro-2-ethyl-1- (4- {2- [methyl ({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole-5-carboxamide; and their salts.

Overview

The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, Y ¹ to Y ⁴ , R ¹ to R ⁷ , A, B, W, Z, L, m, P, Q ¹ and Q ^{2 *} in the Schemes and in the text that follows are as defined above in this document.

The aryl or heteroaryl fused imidazole compounds of formula (I) of this invention can be prepared by a variety of synthetic methods known to those skilled in the art.

B

w.

(I)

In a desired step of the processes described later in this document, the protection, and the removal, of a hydroxy or amino protecting group, with substrates and reagents and under known conditions, such as those described, can be carried out. in Protective Groups in Organic Synthesis edited by TW Greene et al (John Wiley & Sons, 1991). Typical hydroxy or amino protecting groups include benzyl, C2H ₅ OC (= O), CH ₃ C (= O), t-butyldimethylsilyl (TBS), benzyloxycarbonyl represented as Z and t-But-OC (= O) represented as t-Boc or as Boc.

Reaction Scheme 1 illustrates a method for preparing the compound of formula (I) in which A is phenyl, B is ethylene, W is R ^1a -N where R ^1a is H or Cm alkyl, and R ^1b is Cm alkyl or aryl (hereinafter represented by the formula (Ia)).

Compound (Ia) can be prepared by a process that includes:

(a) a coupling reaction of a compound with the formula

1-1 with 4-aminophenethyl alcohol, where X is a starting group such as halo, mesylate (OMs) or tosylate (OTs), to obtain the nitroaniline compound of formula 1-2;

b) reducing the resulting nitroaniline compound with formula 1-2 to obtain a diamine compound with formula 1-3;

c) the formation of a benzimidazole or imidazopyridine ring from the diamine compound of formula 1-3, to obtain a compound of formula 1.4;

d) hydrolysis of the compound of formula 1-4 to obtain a compound of formula 1-5; transforming the hydroxy group compound of formula 1-5 into a suitable starting group, such as halo, OMs or OTs, to obtain a compound of formula 1-6;

e) amination of the compound of formula 1-6 to obtain an amino compound of formula 1-7; and

f) the formation of a sulfonylurea with the compound of formula 1-7 to obtain a compound of formula (Ia).

39/451

Layout 1 h ₂ n

no ₂

X

OH _Y rV ° ² ^ υ ^ νη reduction

1-1

X = starting group, such as, OTs, O Ms; of pref ^e . F or Cl

OH

1-2 γ ^ ΝΠ.

1-3 cycling

OH

hydrolysis y2 / ^y <LN y X ^x > - ^{R Y} ^ · γ4 ^ Ν γ3 <JL ^Y ^ _γ 4 ^ Ν

R ¹

OH

1-5

G

1-6

Starting G-group, such as, OTs, OMs; pref. F or Cl am ination R ¹³ NH ₂

1-7

-NH

OR Z-SO ₂ NCO (when R ² = H)

1-9

40/451

Each step can be described more particularly as follows: (a) - (b) The coupling reaction (a) can be carried out in the absence of, or in the presence of, a base, in a solvent inert to the reaction or without solvent inert to the reaction. A preferred base is selected, for example and are limited, from an alkali or alkaline earth metal hydroxide, an alkoxide, carbonate or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine, in the presence or in the absence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. The compound with formula 1-2 can then be extracted and subjected to a reduction to obtain the compound with formula 1-3. The reduction can be carried out in the presence of an appropriate reducing agent, in a reaction inert solvent or in the absence of a reaction inert solvent. A preferred reducing agent is selected for example, but is limited from LiAIH ₄ , LiBH ₄ , Fe, Sn or Zn. When the reducing agent is Fe, Sn or Zn, if desired, the reaction can be carried out under acidic conditions in the presence of water. Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, odichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4dioxane, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0

41/451 at 150 ° C but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. The reduction can also be carried out under other known hydrogenation conditions, in the presence of a metallic catalyst under a hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. A preferred, but not limited, metallic catalyst is selected from Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as PtO ₂ , or ruthenium catalysts such as (Pr ₃ P) ₃ . Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction can be carried out in the range of -100 to 150 ° C, preferably in the range of 0 to 100 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(c) The compound of formula 1 -3 can be cyclized to form a benzimidazole or imidazopyridine ring, using any of the synthetic procedures applicable to compounds with related structures known to those skilled in the art (see for example Grimmett , MR, Imidazoles and Their Benzo Derivatives; (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds .; Pergamon Press Ltd .; Oxford, UK, 1984; Vol. 5, pp. 457-498., Grimmett, MR, Imidazols.In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 3, pp. 77-220; Townsend LB; Wise DS Bicyclo 5-6 Systems: Three Heteroatoms 2: 1. In Comprehensive Heterocyclic Chemistry fl, Christopher A. Ramsden, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 7, pp. 283-349). For example, the compound of formula 1-3 is reacted with an appropriate cyclizing agent to

42/451 to obtain the compound with the formula 1-4, in a solvent inert to the reaction and in the presence, or in the absence, of a solvent inert to the reaction. If desired, this reaction can be catalyzed by an acid such as paratoiuenesulfonic acid or camphorsulfonic acid. Suitable, but limited, cyclizing agents include, a carboxylic acid, an aminocarboxylic acid, an acid anhydride (e.g. acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like), a formamidine (e.g. formamidine alkylate such as formamidine acetate), an alkylcarbonyl halide (for example a cycloalkylcarbonyl halide, a bicyclo- or bicyclo-heterocycle-carbonyl halide, a halocarbon-spirocyclo-carbonyl-carbonyl-heterocyclo-carbonyl) , an aryl- or arylalkylcarbonyl halide) (for example phenacetyl halide), a heteroarylcarboxylic acid (for example a piperidinylcarboxylic acid compound), trialkyl orthoformate (for example triethyl orthofomnia), and the like. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4dioxane, sulfoxide dimethyl (DMSO) or mixtures thereof. Suitable coupling agents are those commonly used in peptide synthesis, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), hexafluorophosphate benzotriazol-yloxy-tris (dimethylamino) phosphonium (BOP), diphenylphosphorazide (DPPA), or the like. The reaction can be carried out at a temperature in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a few days, preferably between 30 minutes and 48 hours, however longer or shorter periods may be used, if necessary.

(d) Hydrolysis of the compound of formula 1-4 can be carried out by one of the usual processes. Hydrolysis can be carried out by base treatment. A preferred base is selected, for example and

43/451 are limited to an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or halide, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium fer-butoxide, carbonate sodium, potassium carbonate or lithium iodide, in the presence or absence of a reaction inert solvent. Preferred inert reaction solvents include, but are limited to, water, methanol, ethanol, isopropanol, tetrahydrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures of these. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Steps (e) - (f) and (e) and (f) can be performed under conditions that are known to those skilled in the art. For example, the hydroxy group of the compound of formula 1-5 can be transformed into a halogen group using a halogenating agent in the presence, or in the absence, of a reaction inert solvent. Preferred halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, paratoluenesulfonyl chloride, methanesulfonyl chloride, hydrogen halides such as hydrogen chloride or hydrogen bromide, phosphorus trihalides such as trichloride phosphorus or phosphorus tribromide, phosphorus pentahalides such as phosphorus pentachloride, N-halosuccinimides such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halides such as trimethylsilyl chloride or trimethylsilyl bromide, phosphorous reagents such as triphenylphosphide, tributylphosphine or triphenylphosphine in the presence of a halogen source such as carbon tetrachloride, carbon tetrabromide, bromine, iodine, NCS or NBS. Preferred inert solvents for reaction include, but are limited to, tetrahydrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, car44 / 451 bono tetrachloride, tetrabromide carbon, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. Alternatively, a hydroxy group of the compound of the formula 1-5 can be converted to the sulfonate group using a sulfonating agent in the presence, or in the absence of a base. Preferred sulfonating agents include, but are limited to, paratoluenesulfonyl chloride, para-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like, in the presence or absence of a solvent inert to the reaction. A preferred base is selected from, for example, but are limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide , potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine, in the presence or absence of a solvent inert to the reaction. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4-dioxane, sulfoxide dimethyl (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Then, the resulting compound of formula 1-6 can be subjected to amination to obtain the compound of formula 1-7. For example, the

45/451 compound of formula 1-6 is reacted with R ^1a -NH ₂ , where R ^1a is as defined here above. The reagents can be heated together, in the absence, or presence, of an inert reaction solvent. Inert reaction solvents can be include, but are not limited to, benzene, toluene, xylene, odichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Preferably, the reaction is carried out in the presence of base. A preferred base is selected from, for example, but not limited to, an alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tert-butoxide potassium, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C to the reflux temperature, however, if necessary, lower or higher temperatures can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however, shorter or longer reaction times, if necessary, can be employed.

(g) The compound of formula 1-7 can be treated with ZSO2N (R ² ) C (= O) OR ^1b , where R ^1b is aryl or Cu alkyl, or with Z-SO ₂ NCO, to obtain the compound of formula (Ia). The reaction can be carried out in the presence or absence of a solvent inert to the reaction. Preferred but inert solvents to the reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2dichloroethane, or mixtures thereof. If desired, a reaction can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, or Nmethylmorpholine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

46/451

The compound of formula 1-2 can also be prepared by the Ullman reaction, as shown in Scheme 1a. A compound of formula 1a-1 can be treated with a compound of formula 1a-2 in the absence, or in the presence of a solvent inert to the reaction. Preferred but inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dimethylformamide (DMF), dimethoxyethane (DME), or mixtures thereof. Preferably the reaction is carried out in the presence of a metallic catalyst. A preferred metal catalyst is selected from, for example, but not limited to, nickel and copper. Preferably, the reaction is carried out in the presence of base. A preferred base is selected from, for example, but are limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium, potassium fer-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Scheme 1a

1a-2

Yr ^Y v ^N ° ^{2 Y} ' ^X Y ^ NH ^y V \ h ₂

Ullman's reaction

1a-1

X is halo, pref ^a .l, Br OR Cl

OH

1-2

As shown in Scheme 1b, an intermediate compound of formula 1b-4 (1-7 where R ^1a is H) is prepared by a process

47/451 which includes:

(a) the formation of an azide; and (b) reducing the said azide compound, with formula 1b-3b, to obtain a compound with formula 1b-4.

Layout 1 b

reduction

More in particular, the nucleophilic substitution with azide can be carried out by usual procedures, in the absence or in the presence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitro10 benzene, dichloromethane, 1,2-dichloroethane, dimethylformamide (DMF), dimethoxyethane (DME), hexamethylphosphoramide (HMPA), or mixtures of these. An acidifying agent is selected from, but limited to, sodium azide and lithium azide. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

A compound of formula 1b-3b can also be prepared

48/451 by Mitsunobu's reaction. The compound of formula 1b-2 can be treated with diphenylphosphoryl azide (DPPA) or with HN ₃ in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and a phosphine reagent such as triphenylphosphine. This reaction is preferably carried out in a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethoxyethane ( DME), or mixtures thereof. Preferably the reaction can be carried out in the presence of an appropriate reducing agent, such as lithium aluminum hydride, sodium borohydride, triethyl phosphite, triphenylphosphine, zinc, dibutyltin hydride or diborane, in a reaction inert solvent, which includes , without being limited to, THF, diethyl ether, methanol and ethanol. If desired, the reaction can be carried out under acidic conditions, in the presence of hydrochloric acid or acetic acid. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The reduction can also be carried out under known hydrogenation conditions, in the presence of a metallic catalyst such as Lindlar catalysts, Raney nickel catalysts, palladium catalysts or platinum catalysts (preferably carbon catalysts). Lindlar, palladium catalysts or platinum catalysts). This reaction can be carried out under a hydrogen atmosphere in a solvent inert to the reaction, such as methanol, ethanol, ethyl acetate or THF. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer periods may be used.

49/451 long or shorter if necessary.

As shown in Scheme 1c, an intermediate of form c-5 (1b-4) can also be prepared by a process that includes:

(a) a coupling reaction of a compound with the formula 1c- (1-1), where X is a starting group such as halo, mesylate or tosylate, with 4-aminophenylacetonitrile to give a nitroaniline compound of formula 1c -2;

(b) the chemo-selective reduction of the nitroaniline compound obtained with formula 1c-2 to obtain a diamine compound with formula 1c-3;

(c) forming a benzimidazole or imidazopyridine ring from the compound of formula 1c-3, to obtain a compound of formula 1c-4; and (d) reducing the compound of formula 1c-4 obtained to obtain an amine of formula 1c-5 (1b-4).

Scheme 1c

no ₂

X

1c-1 (1-1)

CN _Υ 2 ^ Ν ° ₂ ^υ \ Γνη chemoselective reduction

CN

1c-2 yrV ^{NHz Y} 'Y4 NH ^cycling

CN

1c-3

reduction

Each reaction step is described more particularly as follows.

(a) - (b) The coupling reactions (a) can be carried out in the presence of, or in the presence of a base, in a solvent inert to the reaction. A preferred base is selected from, for example, but are limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine, in the presence or absence of a solvent inert to the reaction. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4dioxane, dimethyl sulfoxide (DMSO), or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

If desired, the resulting compound of formula 1c-2 can be extracted and subjected to a reduction to obtain the compound of formula 1c-3. The reduction can be carried out in the presence of a reducing agent, in a reaction-inert solvent or without a solvent. A preferred reducing agent is selected for example, but is limited, from Fe, Sn or Zn. If desired, the reaction can be carried out under acidic conditions in the presence of water. Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and one day, preferably between 20 minutes and 5 hours, however longer periods may be used or

51/451 shorter if necessary.

(c) The compound of formula 1c-3 can be cyclized to form a benzimidazole or imidazopyridine ring, using any of the synthetic procedures applicable to compounds with related structures known to those skilled in the art (see for example Grimmett, MR, Imidazols and Their Benzo Derivatives: (iii) Synthesis and Applications, in Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds .; Pergamon Press Ltd .; Oxford, UK, 1984; Vol. 5, pp. 457-498., Grimmett , MR, Imidazols In Comprehensive Heterocyciic Chemistry II, Ichiro Shinkai, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 3, pp. 77-220; Townsend LB; Wise DS Bicyclo 5-6 Systems: Three Heteroatoms 2: 1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 7, pp. 283-349). For example, the compound of formula 1c-3 is reacted with an appropriate cyclizing agent to obtain the compound of formula 1c-4, in a solvent inert to the reaction and in the presence, or in the absence, of an inert solvent the reaction. If desired, this reaction can be catalyzed by an acid such as para-toluenesulfonic acid or camphorsulfonic acid. Suitable, but limited, cyclizing agents include, a carboxylic acid, an aminocarboxylic acid, an acid anhydride (e.g. acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like), a formamidine (for example a formamidine alkylate such as formamidine acetate), an alkylcarbonyl halide (for example a cycloalkylcarbonyl halide, a bicycloor or a bicyclo-heterocyclo-carbonyl halide, a halocarbon of a spirocarbocicyclocarbonyl or a carbon-spiro-heterocyclo-carbonyl ), an aryl- or arylalkylcarbonyl halide) (eg phenacetyl halide), a heteroarylcarboxylic acid (eg a piperidinylcarboxylic acid compound), trialkyl orthoformate carbon disulfate (eg triethyl orthoformate), and the like . Preferred reaction-inert solvents include, but are limited to, benzene, toluene, xylene, odichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, te52 / 451 trahydrofuran, dimethylformamide (DMF), 1,4- dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Suitable coupling agents are those commonly used in peptide synthesis, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DlPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazol-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphorazide (DPPA), or the like. The reaction can be carried out at a temperature in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a few days, preferably between 30 minutes and 48 hours, however longer or shorter periods may be used, if necessary.

The reduction of the compound of formula 1c-4 can be carried out in the presence of an appropriate reducing agent, such as diborane, borane complex with methyl sulfide, or aluminum and lithium hydride in a reaction-inert solvent, selected from, but without limited to, THF or diethyl ether. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The reduction of the compound of formula 1c-4 can be carried out under known hydrogenation conditions, such as in the presence of a metallic catalyst under a hydrogen atmosphere. This reaction can be carried out in a reaction-inert solvent such as methanol, ethanol, chloroform THF, in the presence or absence of hydrochloric acid, and a metallic catalyst such as Raney nickel catalysts, palladium catalysts, or platinum catalysts . This reaction can be carried out solvent inert to the reaction such as methanol, ethanol, chloroform, or THF in the presence or absence of hydrogen chloride. If necessary, this reduction can be carried out under suitable pressure in the range of 0.5 and 10 kg / cm ² , preferably

53/451 in the range of 1 to 6 kg / cm ² . Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The compound of formula (Ia) can also be prepared from the compound of formula 10-1 (1-7) through a carbamate compound of formula 1d-2, as shown in Scheme 1d.

Layout 1d

The compound of formula 1d-1 (1-7) can be treated with carbonating agents (R ^1d is aryl or C ₁₄ alkyl) such as haloformate

54/451 alkyl or aryl, dialkyl or diaryl dicarbonate, or hydrogen alkyl or aryl dicarbonate in the presence or absence of a base. Suitable bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium fer-butoxide , sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine, in the presence or absence of an inert solvent. reaction. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4dioxane, dimethyl sulfoxide (DMSO), or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The resulting compound of formula 1d-2 can be reacted with the sulfonamide compound in the presence of a base such as those listed above in a reaction inert solvent such as those listed above (preferably DMF). Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

As shown in Scheme 1e, an intermediate compound of formula 1e5 (1b-4) can also be prepared using the process which includes:

(a) a coupling reaction of a compound with the formula

55/451 θ- (Ί-1), where X is a starting group such as halo, mesylate, tosylate or triflate, with a 4-aminophenylethylamine protected to give a nitroaniline compound of formula 1e-2;

(b) reducing the nitroaniline compound obtained with formula 1e-2 to obtain a diamine compound with formula 1e-3;

(c) forming a benzimidazole or imidazopyridine ring from the compound of formula 1e-3, to obtain a compound of formula 1e-4; and (d) reducing the compound of formula 1e-4 obtained to obtain an amine of formula 1e-5 (1b-4).

Diagram 1e h ₂ n _Y rV ° ^{2 y} S6nh reduction _γ 2 / Υψ ^Ν ° ²

YÜ _Y À _{X H} P = protecting group, le-1 (1-1) such _{as Bn Z} Boc; of pref “

Boc

1 and 2

N i

P

Each reaction step is described more particularly as follows.

(a) - (b) The coupling reaction (a) can be carried out in the absence of, or in the presence of a base, in a solvent inert to the reaction. A preferred base is selected from, for example, but are limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, methoxide

56/451 sodium, sodium ethoxide, potassium fer-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine, in the presence or absence of a reaction-inert solvent. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4dioxane, dimethyl sulfoxide (DMSO), or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

If desired, the resulting compound of formula 1e-2 can be extracted and subjected to a reduction to obtain the compound of formula 1e-3. The reduction can be carried out in the presence of a reducing agent, in a solvent inert to the reaction. A preferred reducing agent is selected for example, but is limited, from Fe, Sn or Zn. If desired, the reaction can be carried out under acidic conditions in the presence of water. Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or mixtures thereof . Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. The reduction can be carried out under known hydrogenation conditions, in the presence of a metallic catalyst under a hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under

57/451 acids, for example in the presence of hydrochloric acid or acetic acid. A preferred, but not limited, preferred metallic catalyst is selected from Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as PtO ₂ , or ruthenium catalysts such as RuCÍ2 (Ph ₃ P) 3. Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction can be carried out under a temperature in the range of -100 to 150 ° C, preferably in the range of 0 to 100 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(c) The compound of formula 1e-3 can be cyclized to form a benzimidazole or imidazopyridine ring, using any of the synthetic procedures applicable to compounds with related structures known to those skilled in the art (see for example Grimmett, MR, Imidazols and Their Benzo Derivatives: (iii) Synthesis and Applications, in Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds .; Pergamon Press Ltd .; Oxford, UK, 1984; Vol. 5, pp. 457-498., Grimmett , MR, Imidazols.In Comprehensive Heterocyclic Chemistry //, Ichiro Shinkai, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 3, pp. 77-220; Townsend LB; Wise DS Bicyclo 5-6 Systems: Three Heteroatoms 2: 1. In Comprehensive Heterocyclic Chemistry //, Christopher A. Ramsden, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 7, pp. 283-349). For example, the compound of formula 1e-3 is reacted with an appropriate cyclizing agent to obtain the compound of formula 1e-4, in a solvent inert to the reaction and in the presence, or in the absence, of an inert solvent the reaction. If desired, this reaction can be catalyzed by an acid such as paratoluenesulfonic acid or camphorsulfonic acid. Suitable, but limited, cyclizing reagents include, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g. acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like 58/451), one formamidine (for example a formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (for example a cycloalkyl carbonyl halide, a bicyclo- or bicyclo-heterocyclo-carbonyl halide, a spiro halide carbocyclic-carbonyl or a bicyclospiro-heterocyclo-carbonyl), an aryl- or arylalkyl-carbonyl halide) (eg phenacetyl halide), a heteroaryl carboxylic acid (eg a piperidinyl carboxylic acid compound), orthoformiato carbon desulfate trialkyl (e.g. triethyl orthoformate), and the like. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4- dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Suitable coupling agents are those commonly used in peptide synthesis, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodimide (WSC), benzotriazole-1-yloxy-tris (dimethylamino) phosphonium (BOP) hexafluorophosphate (BOP), diphenylphosphorazide (DPPA), or the like. The reaction can be carried out at temperatures in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a few days, preferably between 30 minutes and 48 hours, however longer or shorter periods may be used, if necessary.

(d) Deprotection of the compound of formula 1e-4 can be carried out according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991). Typical amino protecting groups include benzyl represented by Bn, benzyloxycarbonyl represented as Cbz or Z, and t-But-O-C (= O) represented as t-Boc or as Boc. In the case of protection with Bn or with Z, the removal of the amino protecting groups can be carried out, for example and they are limited, under hydrogenolysis conditions in the presence of a metallic catalyst and in an atmosphere of

59/451 hydrogen, or in the presence of hydrogen sources such as formic acid or ammonia formate in a solvent inert to the reaction. If desired, the reaction is carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is preferably selected, but are limited, from palladium catalysts such as Pd-C. Preferred, but not limited to, reaction-inert solvents include methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction can be carried out at a temperature in the range of -100 to 150 ° C, preferably in the range of 0 to 100 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. In the case of Boc protection, the removal of the amino protecting group can take place, for example, but they are limited, under known conditions of acid hydrolysis, for example in the presence of hydrochloric acid, or trifluoroacetic acid, and of a cation trap. t-butyl inert to the reaction. The scavenger emits to the preferred reaction of t-butyl cations includes, but is not limited to, benzene, thiophenol, anisole, thioanisole, thiocresol, cresol or dimethyl sulfide. Preferred reaction-resistant solvents include, but are limited to, methanol, ethanol, ethyl acetate, dioxane, and mixtures thereof. The reaction can be carried out under temperature. They are generally in the range of 100 to 150 ° C, preferably in the range of 0 to 100 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Reaction Scheme 1f illustrates a method for preparing the compound of formula (I) where W is R ^1a -N where R ^1a is H or C _M alkyl ₎ and R ^1b is Cm alkyl or aryl (hereinafter represented by the formula (If)).

The compound can be prepared by the process comprising:

60/451 (a) a coupling reaction of a compound of formula 1f- (1 -1), with a compound of formula 1f-0 where X is a starting group such as halo, mesylate (OMs) or tosylate (OTs), to obtain a nitroaniline compound of formula 1 f-2;

(b) the reduction of the nitroaniline compound obtained with the formula

1f-2 to obtain a diamine compound of formula 1f-3;

(c) forming a benzimidazole or imidazopyridine ring from the compound of formula 1f-3, to obtain a compound of formula 1f-4;

(d) hydrolysis of the compound of formula 1f-4 to obtain the compound of formula 1f-5; transforming the hydroxy group of compound 1f-5 into an appropriate starting group, such as halo, OMs or OTs, to obtain a compound of formula 1f-6; and (e) amination of the compound of formula 1f-6 to obtain an amine of formula 1f-7; and (f) the formation of a sulfonylurea from the compound of formula 1f-7 to obtain the compound of formula (tf).

61/451

Scheme 1f ^H2N > t ° Ί _υ? Ι ^ νο ₂ 1M>

^γ3 -γΑχ

1f-1 χ = starting group, such as halo, OTs, OMs; pref®. F or Cl ^À 'B

OH

1f-3

R ¹

THE.

B

OH

1f * 5 cyclization ν; Λ ^Νθ! ^ 'Υ ^ ΝΗ ^Y I.> - ^R

Grandfather

1M

S ^ -N

i

G hydrolysis reduction

1f-6 θ_ starting group, such as halo _t OTs, OMs; pref. F or Ci am ination R ^la NH ₂

Xw VÂ R R ² _V 2 ^ 5s _-- N íi 'Σ w N N ⁴ N ^a 'b R- ™ 1f-8 OR Z-S0 ₂ NC0 (when R ² = H) A_ BR ^{2 R} ΥΛ 1f-7 1f-9 (K)

Each reaction step is described more particularly as follows.

(a) - (b) The coupling reaction (a) can be carried out in the absence of, or in the presence of a base, in a solvent inert to the reaction. A preferred base is selected from, for example, but are limited, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, methoxide sodium, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylami62 / 451 na, diisopropylethylamine, 2,6-lutidine , pyridine or dimethylaminopyridine, in the presence or absence of a solvent inert to the reaction. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4-dioxane, sulfoxide dimethyl (DMSO), or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. If desired, then the resulting compound of formula 1f-2 can be extracted and subjected to a reduction to obtain the compound of formula 1f-3. The reduction can be carried out in the presence of a reducing agent, in a solvent inert to the appropriate reaction. A preferred reducing agent is selected for example, but is limited from LiAIH ₄ , LiBH ₄ , Fe, Sn or Zn. When the reducing agent is Fe, Sn or Zn, if desired the reaction is carried out under acidic conditions, in the presence of water. Preferred inert solvents for reaction include, but are limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and one day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. The reduction can be carried out under known hydrogenation conditions, in the presence of a metallic catalyst under a hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction can be carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is preferred, but not limited, from among

63/451 Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as PtO ₂ , or ruthenium catalysts such as RuCI ₂ (Ph ₃ P) ₃ . Preferred inert solvents to the reaction include, but are limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction is generally in the range of -100 to 150 ° C, preferably in the range of 0 to 100 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(c) The compound of formula 1f-3 can be carried out to form a benzimidazole or imidazopyridine ring, using any of the synthetic procedures applicable to compounds with related structures known to those skilled in the art (see for example Grimmett, MR, Imidazols and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds .; Pergamon Press Ltd .; Oxford, UK, 1984; Vol. 5, pp. 457-498., Grimmett, MR , Imidazols In Comprehensive Heterocyclic Chemistry li, Ichiro Shinkai, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 3, pp. 77-220; Townsend LB; Wise DS Bicyclo 5-6 Systems: Three Heteroatoms 2 : 1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 7, pp. 283-349). For example, reacting the compound with formula 1f-3 is reacted with an appropriate cyclization reagent to obtain the compound with formula 1f-4, in a solvent inert to the reaction and in the presence, or in the absence, of a solvent inert to the reaction. reaction. If desired, this reaction can be catalyzed by an acid such as para-toluenesulfonic acid or camphorsulfonic acid. Suitable but limited cyclization reagents include a carboxylic acid, an aminocarboxylic acid, an acid anhydride (e.g. acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like), a formamidine (for example a formamidine alkylate such as formamidine acetate), an alkylcarbonyl halide (for example a cycloalkylcarbonyl halide, a halide of a

64/451 bicyclo- or bicyclo-heterocyclo-carbonyl, halo of spirocarbocyclic or spiro-heterocyclo-carbonyl), aryl or arylalkylcarbonyl halide) (eg phenacetyl halide), heteroarylcarboxylic acid (eg example a piperidinylcarboxylic acid compound), trialkyl orthoformate (e.g. triethyl orthoformate), the like. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those commonly used in peptide synthesis, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3 ~ (3-dimethylaminopropyl) carbodiimide (WSC), hexafluorophosphate benzotriazole-1-yloxy-tris (dimethylamino) phosphonium (BOP), diphenylphosphorazide (DPPA), or the like. The reaction The reaction can be carried out at a temperature in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a few days, preferably between 30 minutes and 48 hours, however longer or shorter periods may be used, if necessary.

(d) The hydrolysis of the compound of formula 1f-4 can be carried out by one of the usual processes. Hydrolysis can be carried out by base treatment. A preferred base is selected, for example, but are limited from an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or halide, such as sodium hydroxide, potassium hydroxide, sodium methoxide, ethoxide sodium, potassium fer-butoxide, sodium carbonate, potassium carbonate or lithium iodide, in the presence or absence of a solvent inert to the reaction. Preferred inert reaction solvents include, but are limited to, water, methanol, ethanol, isopropanol, tetrahydrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures of these. Reaction temperatures are generally within the range of

65/451

-100 to 250 ° C, preferably in the range of 0 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Steps (e) - (f) (e) and (f) can be carried out under conditions that are known to those skilled in the art. For example, the hydroxy group of the compound of formula 1f-5 can be transformed into a halogen group using a halogenating agent in the presence, or in the absence, of a reaction inert solvent. Preferred halogenating agents include, but are not limited to, thionia chloride, oxalyl chloride, paratoluenesulfonyl chloride, methanesulfonyl chloride, hydrogen halides such as hydrogen chloride or hydrogen bromide, phosphorus trihalides such as trichloride phosphorus or phosphorus tribromide, phosphorus pentahalides such as phosphorus pentachloride, N-halosuccinimides such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halides such as trimethylsilyl chloride or bromide trimethylsilyl, phosphorous reagents such as triphenylphosphine, tributylphosphine or triphenylphosphine in the presence of a halogen source such as carbon tetrachloride, carbon tetrabromide, bromine, iodine, NCS or NBS. Preferred inert solvents for reaction include, but are limited to, tetrahydrofuran (THF), benzene, toluene, xylene, odichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, carbon tetrabromide, or mixtures of these. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. Alternatively, a hydroxy group of the compound of formula 1-5 can be carried out on the sulfonate group using a sulfonating agent in the presence, or in the absence of a base. Included in the preferred sulfonating agents are, but are limited to, para-toluenesulfonyl chloride, para-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like, in the presence or in the absence of an inert solvent the reaction. A preferred base is selected from, for example, but are limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, ethoxide sodium, potassium fer-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine, in the presence or absence of a solvent inert to the reaction. Preferred inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4-dioxane, sulfoxide dimethyl (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The resulting compound of formula 1f-6 can then be subjected to an amination to obtain a compound of formula 1f-7. For example, if you make a compound of formula 1f-6 react with a compound of formula R ^1a -NH ₂ where R ^1a is as defined above. The reagents can be heated with each other in the presence or absence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction can be carried out in the presence of a base. A preferred base is selected, but are limited from an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium fer-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(g) The compound of formula 1 f-7 can be treated with ZSO2N (R ² ) C (= O) OR ^1b , where R ^1b is aryl or Cm alkyl, or with Z-SO ₂ NCO, to obtain the compound with the formula (If). The reaction can be carried out in the presence or absence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, or N-methylmorpholine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

As described in Scheme 2, the compound of formula (I) can be prepared, where A is phenyl, B is ethylene, W is NH (hereinafter represented by formula (lb)), using the process that includes:

(a) a coupling reaction between a compound of the formula 2-1 (1-1), where X is a starting group such as halo, mesylate or tosylate, with 2- (4-aminophenyl) propionic acid or a its ester (2-2) (when derivative 2-2 is used, hydrolysis follows) to obtain a nitroaniline compound of formula 2-3;

68/451 (b) a Curtius transposition of the compound of formula 2-3 followed by treatment with an alcohol or phenol to obtain a carbamate compound of formula 2-5;

(c) the formation of a sulfonylurea with a compound of formula 2-5 to obtain a compound of formula 2-6;

(d) the reproduction of the dithroaniline compound obtained with formula 2-6 to obtain a compound with formula 2-7; and (e) forming an imidazole or imadidazopyridine ring from the compound of formula 2-7 to obtain the diamine compound of formula (Ib).

Each of these reaction steps is described more particularly in the following way:

(a) The compound of formula 2-3 can be prepared from the compound of formula 2-1 (1-1), using a procedure similar to that described in Scheme 1.

(b) Curtiou's transposition of the compound with the formula 2-3 can be done by the usual procedures, in a typical procedure, the transposition is carried out by treatment with DPPA in the presence of a base and in a solvent inert to the reaction. Suitable bases include triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, tetrahydrofuran (THF), 1,4-dtoxane, or mixtures thereof. Reaction temperatures are generally in the range of at 250 ° C, preferably in the range of 25 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

The isocyanate obtained 2-4 can be treated with an alcohol or a phenol to obtain the compound of formula 2-5. Reaction temperatures are generally in the range of at 250 ° C, preferably in the range of 25 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(c) By treating the carbamate compound obtained with formula 2-5 with sulfonamide, in the presence or absence of a base, the compound with formula 2-6 can be obtained. Preferred bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tertbutoxide , sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, sodium hydride or potassium hydride, in the presence or absence of a solvent inert to the reaction. Preferred but inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(d) and (e) The reduction of compound 2-6 and the subsequent formation of a ring can be carried out in a manner analogous to those described in Scheme 1, to obtain the compound of formula (1b).

70/451

Layout 2

Υ2> * γΝΟ ₂

ΑγΛχ

2-1 (1-1)

γ ^Ν0 * ^ νο ₂ R ^{2 T} II ^γ3 γ Ah R ^ -OH JL NH Al HN. Z 0 0

NCO ^HN Y ° -r- 0 2-4 2-5 . ₂ ^ ΝΟ ₂ '3 1 _Y rV ^Hs Y \ a R ¹ CO ₂ H Y ⁴ NH OR R ^l COX

cyclization reduction

ΗΝ Ν Ζ τ κ ο ο °

2-7

2-6 ^γ '-γ ^ Ν

ΗΝ Ν Ζ

Π Α ο Ο Ο (lb)

As shown in Scheme 2a, an intermediate of formula 2a-3 (2-7) can also be prepared using a process that includes:

(a) reducing the compound obtained above, 2a-1 (2-5) to obtain a diamine compound of formula 2a-2; and (b) the formation of a sulfonylurea from the compound of formula 2a-2, obtaining the compound of formula 2a-3 (2.7).

71/451

The reduction of the compound with the formula 2a-1 (2-5) and the formation of a sulfonylurea from the obtained compound, with the formula 2a-2, can be carried out by a procedure such as that described in Schemes 1 and 1d.

As shown in Scheme 2a, a carbamate compound of formula 2a-4 can be prepared from the compound of formula 2a-2 by cyclization according to a procedure as described in scheme 1.

Scheme 2a

2a-1 (2-5)

Alternatively, an intermediate compound of formula 2b-5 (2-5) can also be prepared from the carboxylic acid compound of formula 2b-1 (2-3), by the methods shown in Scheme 2b. Path A of Scheme 2b illustrates a process for preparing a compound with formula 2b-5 (2-5) according to Hoffman's transposition (for example Wallis; Lane Org. React. 1946, 3, 267-306) . The amide compound of formula 2b-2 (for example, Org. Syn. Coll. Vol 4, 513 (1963)) can be prepared by known methods. Hoffman's transposition of the carboxamide compound obtained with formula 2b-2 can be carried out under known conditions, followed by a treatment with an alcohol or a phenol, under the same conditions as described in Scheme 2 to obtain the rank 72/451 with formula 2b-5 (2-5). Path B of Scheme 2b illustrates a process for preparing the compound with formula 2b-5 (2-5) by transposing lossen (for example, Bauer; Exner Angew. Chem. Int. Ed. Engl. 1974, 13 , 376-384). The O-acylhydroxamic acid compound of formula 2b-3 can be prepared by known methods (for example, Miller, Marvin J .; Mattingly, Phillip G .; Morrison, marjorie A .; Kerwin, James F., J. Amer. Chem. Soc., 1980, 102, 7026-7032). The carboxylic acid compound of formula 2b-1 (2-3) can be treated with a hydroxamic acid derivative, in general O-acylhydroxamic acid, in the presence of a coupling agent, such as dicyclohexylcarbodiimide (DCC ), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazole-yloxy-phosphonium (BOP) hexafluorophosphate (BOP), diphenylphosphorazide (DPPA), or the like. The reaction can be carried out at between 0 ° C and the reflux temperature of the reaction mixture, preferably between room temperature and reflux for between about 1 minute and about 120 hours, preferably between about 10 minutes and about 72 hours. Lossen's transposition of the O-acylhydroxamic acid compound obtained with formula 2b-3 can be carried out under known conditions, followed by a treatment with an alcohol or a phenol, under the same conditions as described in Scheme 2, to obtain a compound of formula 2b-5 (2-5).

73/451

Scheme 2b

Path A: Hoffman's Transposition Path B: Lossen's Transposition

2b-5 (2-5) b-4 (2-4)

The compound of formula (Ia) can be prepared from the compound of formula (Ia1), where R ² is H, by methods known to those skilled in the art as illustrated in Scheme 3. compound with the formula (Ia1) with the appropriate alkyl halides, R ² -halo, in the presence of a base such as lithium diisopropyl (LDA),

74/451 sodium hydride (NaH) or potassium t-butoxide, in a reaction-inert solvent such as THF or DMF, at about 0 ° C to 80 ° C, for between 20 minutes to 24 hours.

As shown in Scheme 4, a carbamate compound of formula 4-2 can be prepared from a compound of formula 4-1 (1-5) using conditions identical to those described in Scheme 1. More in particular, the compound of formula 4-1 can be treated with Z-SO ₂ N (R ² ) C (= O) OR ^1b , where R ^1b is Cn aryl or alkyl or with Z-SO ₂ NCO, to obtain the compound of formula (4-2). The reaction can be carried out can be carried out in the presence or in the absence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, or N-methylmorpholine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute to a day, preferably between 20 minutes to 5 hours, however longer or shorter periods may be used, if necessary.

75/451

° 2?

_z - ^s 'n ^A 0' ^r, “

R ² 1-8 or Z-SO ₂ NCO (when R ² = H} 1-9

As shown in Scheme 5, the compound of formula (I) can be prepared, in which A is phenyl, B is ethylene and W is N-OR ⁷ (hereinafter represented by the formula (id)), using the process that includes:

(a) a Mitsunobu reaction of a compound of formula 51 (1-5) to obtain a compound of formula 5-2;

(b) dividing the protecting group of the compound of formula 5-2 to give a hydroxyamine compound of formula 5-3; and (c) the formation of a sulfonylurea from the compound of formula 5-3 to obtain a compound of formula (Id).

As shown in Scheme 4a, the compound of formula 4a-1 can also be prepared with a benzene compound substituted with formula 4a-2 to obtain a 1-phenylbenzimidazole compound with formula 4a-3 (4- 2);

Compounds of formula 4a-1 can be synthesized by any of the known methods. The group G ¹⁹ of the compounds of formula 4a-2 is selected from among the acceptable starting groups, for example fluorine, chlorine, bromine, iodine, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or boronic acid.

76/451

Layout 4a

4a-2

G ^4a = starting group,

4a-1 such as halo. OTs, OMs, OTf, B (OH) ₂ ;

4a-3

The pref ^fl . F, Br, L. or B (OH) ₂

The coupling reaction can be carried out in the presence of a base and in a solvent inert to the reaction. A preferred base is selected, but are limited from an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, 2,6-butidine diisopropylethylamine, pyridine or dimethylaminopyridine. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), 1,4-dioxane , dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and several weeks, preferably between 20 minutes and 1 week, however longer or shorter periods may be used, if necessary. A compound of formula 4a-1 can advantageously be reacted with a compound of formula 4a-2 in the presence of an appropriate catalyst to form a compound of formula 4a-3 (4-2) by a synthetic process any applicable to compounds with related structure, known to those skilled in the literature (eg Lam,

77/451

P.Y.S .; Clark, C.G .; Saubern, S; Adams, J .; Winters, M.P .; Chan, D. Μ. T; Combs, A., Tetrahedron Lett., 1998, 39, 2941-2944, Kiyomori, A .; Marcoux, J .; Buchwald, S.L., Tetrahedron Lett., 1999, 40, 2657-2660, Lam, P.Y.S .; Deudon, S .; Averill, K .; Li, R .; He, M.Y .; DeShong, P .; Clark, C.G., J. Amer.

Chem. Soc., 2000, 122, 7600-7601., Collman, J.P .; Zhong, M., Org. Lett., 2000, 2, 1233-1236.). A preferred catalyst is selected for the reaction from, for example, but are limited, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (ll) chloride, copper (0), copper (l) acetate, bromide copper (l), copper chloride (l), copper iodide (l), copper oxide (l), copper triflu10 oromethanesulfonate (l), copper acetate (ll), copper bromide (ll), chloride copper (ll), copper iodide (ll), copper oxide (ll) or copper trifluoromethanesulfonate (ll).

Layout 5

or Z-S0 ₂ NCO (when R ² = H)

1-9

à RZ ^S 'N ^{> k} O' ^R R ² 1-8

1b

Each reaction step is described more specifically as follows.

78/451 (a) It can be prepared with a compound of formula 5-2 by the Mitsunobu reaction. The compound of formula 5-1 can be treated with HN (OR ⁷ ) G ¹ , where G ¹ is H or a protecting group, preferably G ¹ is an appropriate protecting group, for example methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl ( Boc), benzyloxycarbonyl (Z), phenylsulfonyl, p-toluenesulfonyl, or the like, and R ⁷ is an alkyl group (for example methyl or ethyl), or G ² (G ² is an appropriate protecting group, for example methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z), phenylsulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, or the like)). For example, the compound of formula 51 is reacted with a [hydroxy- / V, O-Bis-protected] (for example Baillie, LC; Batsanov, A .; Bearder, JR; Whiting, DA, 7. Chem Sounds perkin Trans.1, 1998, 20, 2471.) in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate (DEAD) and a phosphine reagent such as triphenylphosphine. this reaction can preferably be carried out in a reaction-inert solvent. Preferred inert solvents for reaction include, but are limited to, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethoxyethane ( DME), or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute to a day, preferably between 20 minutes to 5 hours, however longer or shorter periods may be used, if necessary.

(b) divagem the protecting group may be carried out in accordance with known to those skilled in the art procedures (e.g. Protection for the Group and Amino Group Hydroxy Protective Groups in Organic Synthesis 2nd edition, TW Greene and PGM Wuts, Ed., John Wiley & Sons, Inc. 1991, pages 10-142, 309-405).

(c) The formation of sulfonylurea can be carried out according to the conditions illustrated in Scheme 1. Specifically, the com79 / 451 post of the formula 5-3 can be treated with Z-SO ₂ N (R ² ) C (= O) OR ^1b , where R ^1b is aryl or Cm alkyl, or with Z-SO ₂ NCO, to obtain the compound with the formula (Id). The reaction can be carried out in the presence or absence of a solvent inert to the reaction. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, or N-methylmorpholine. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Reaction Scheme 6 illustrates a method for preparing a compound of formula (Ia), in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-CONH2, A is phenyl, B either ethylene and W is R ^1a -N (R ^1a is H or Cm alkyl) (hereinafter represented by Formula (Ia ² )), and that of the compound with formula (Ia), where at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-CO2H, A is phenyl, B is ethylene and W is R ^1a -N (R ^1a is H or Cm alkyl) (hereinafter represented by Formula (Ia ³ )). The compound (Ia ³ ) can be prepared by a process including:

(a) hydrolysis of the compound of formula 6-1 to obtain a compound of formula 6-2;

(b) transforming the hydroxy group of compound 6-2 into the starting group such as halo, mesylate and tosylate, to obtain a compound of formula 6-3, (c) azide formation;

(d) reduction of the resulting azide compound, followed by formation of sulfonylurea, to obtain the compound of formula (Ia ² ); and (e) hydrolysis of the compound of formula (Ia ² ) to obtain the compound of formula (Ia ³ );

80/451

Each of the reaction steps can be described more particularly as follows:

(a) Intermediate 6-1 can be prepared by the methods shown in Scheme 1. The hydrolysis of the compound of formula 6-1 can be carried out by usual procedures. Hydrolysis can be carried out by treatment with a peroxide such as hydrogen peroxide, in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or ammonia hydroxide, in an appropriate solvent such as aqueous methanol, sulfoxide of dimethyl and tetrahydrofuran. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. Hydrolysis can also be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an acid such as sulfuric acid, in an appropriate solvent such as aqueous methanol, aqueous ethanol, t-butanol or mixtures of these. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

steps (b), (c) and (d) and (b), (c) and (d) can be carried out according to the conditions illustrated in Schemes 1 and 1b.

(e) The hydrolysis of the compound (Ia ² ) can be carried out by the usual procedures. Hydrolysis can be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or with an acid such as sulfuric acid or phosphoric acid, in an appropriate solvent such as aqueous methanol, ethanol, ethylene glycol, water , tetrahydrofuran or mixtures thereof. Reaction temperatures are generally found

81/451 in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Layout 6

An alternative method for the preparation of a compound of formula (Ia ² ) is illustrated in Reaction Scheme 7. A compound of formula (Ia ⁴ ) can be prepared by the methods illustrated in Scheme 1. Hydrolysis can be carried out of the compound of formula (Ia ⁴ ) by treatment with a base such as sodium hydroxide, potassium hydroxide, hydroxide of lithium or ammonium hydroxide, in an appropriate solvent such as aqueous methanol, dimethyl sulfoxide and tetrahydrofuran. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally from 1 minute to a day, preferably between 20 minutes to 5 hours, however longer or shorter periods may be used, if necessary. Hydrolysis can be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or with an acid such as sulfuric acid or phosphoric acid, in an appropriate solvent such as aqueous methanol, aqueous ethanol, t- butanol or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

A method of preparing the compound of formula (Ia) is illustrated in Reaction Scheme 8 in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-OG ¹ , where G ¹ is as defined above, A is phenyl, B is ethylene and W is R ^1a -N (R ^1a is H or C ₁₄ alkyl) (hereinafter represented by Formula (Ia ⁵ )) and that of a compound with formula (Ia) in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-OH, A is phenyl, B is ethylene and W is R ^1a -N (R ^1a is H or Cm alkyl) (hereinafter represented by Formula ( 1a ⁶ )). The compound (Ia ⁶ ) can be prepared by a process including:

(a) dealkylation of a compound of formula 8-1 to obtain a compound of formula 8-2;

(b) protection of the hydroxy group of compound 8-2 to obtain a

83/451 compound with the formula 8-3;

(c) preparing the compound of formula (Ia ⁵ ); and (d) dividing the protecting group of the compound with formula (Ia ⁵ ) to obtain the compound with formula (Ia ⁶ ).

Layout 8

Ia6

Ia5

Each reaction step is described more in particular as follows.

(a) Intermediate 8-1 where R ⁸ is C1-C4 alkyl can be prepared, by the methods illustrated in Scheme 1. The dealkylation of the compound with formula 8-1 can be performed by a number of known standard procedures to those skilled in the art (e.g. Protection of Phenols, in Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 143-174). For example, the compound of formula 8-1 can be treated with protonic and / or Lewis acid, such as hydrogen bromide or aluminum chloride, in a suitable solvent such as water, acetic acid or dichloromethane. Reaction temperatures are generally included in the

84/451 range from -100 to 250 ° C, preferably in the range of 0 ° C at reflux temperature but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary. The reaction can be carried out in the presence of a thioalkoxide such as sodium thiomethoxide, lithium thiomethoxide, sodium thioethoxide, in the presence or in the absence of a reaction inert solvent such as DMSO; DMF or HMPA. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(b) The protection of the compound with the formula 8-2 may be performed by a number of standard procedures known to those skilled in the art (e.g. Protection of Phenols, in Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts , Ed., John Wiley and Sons, Inc. 1991, pp. 143-174).

(c) The preparation of the compound of formula (Ia ⁵ ) can be carried out using the conditions that were illustrated in Schemes 1 and 1b.

(d) divagem the protecting group can be accomplished by a number of standard known to those skilled in the art procedure (eg Protection of Phenols, in Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 143-174).

As shown in Scheme 9, the compound of formula (Ia) can be prepared in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is CSO2NH2, A is phenyl, B is ethylene and W either R ^1a -N (R ^1a is H or Cu alkyl) (hereinafter represented by Formula (Ia ⁸ )), from a compound of formula (Ia) in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is CSO2NHtBu, A is phenyl, B is ethylene and W is R ^1a -N (R ^1a is H or alkyl

85/451

Cim) (hereinafter represented by Formula (Ia ⁷ )). The compound (Ia ⁷ ) can be prepared by one of the processes illustrated in Schemes 1 and 1b. The removal of the protecting group can be performed by one of a series of standard procedures known to those skilled in the art (for example Quan, Mimi L; Ellis, Christopher D .; Liauw, Ann Y .; Alexander, Richard S .; Robert M ., et al., J. Med. Chem. 1999, 42, 2760-2773).

Layout 9

^{í1 N} T ^N X ^z deprotection

Ia7

Reaction Scheme 10 illustrates a method for preparing the compound of formula (la) in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-NHSO ₂ R ¹⁰ , A is phenyl, B is ethylene, R ^10a is Cim alkyl and W is R ^1a -N (R ^1a is H or C ^ alkyl) (hereinafter represented by Formula (la ⁹ )) ·

86/451

G

10-3 ο1θ ^ζ ^ \ Ζ ^ ^κ ς ^χ ^ ϊ Λ

Ia9

The compound (Ia ⁹ ) can be prepared by a process that includes:

(a) reducing a compound of formula 10-1 to obtain a compound of formula 10-2;

(b) sulfonylating the amino group of the compound of formula 10-2 to obtain a compound of formula 10-3; and (c) forming a compound of formula (Ia ⁹ ).

Each step of the reaction is described more specifically as follows.

(a) Intermediate 10-1 can be prepared by the methods illustrated in Scheme 1. The reduction of the nitro group using the conditions illustrated in Scheme 1.

(b) Sulfonylation of the amino group of compound 10-2 can be performed by one of several common procedures known to

87/451 skilled in the art (e.g. Protection for the Hydroxy Group and the Amino Group is ", in Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, Ed., John Wiley and Sons, Inc. 1991 , pp. 117-118, 379-384).

The formation of the sulfonylurea compound of the formula (Ia ⁹ ) can be carried out using the conditions illustrated in Schemes 1 and 1b.

Reaction Scheme 11 illustrates a method for preparing the compound of formula (la) in which at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is C-NHC (= O) N (R ³ ) ( R ⁴ ), A is phenyl, B is ethylene, R ^10a is Cm alkyl and W is R ^1a -N (R ^1a is H or C _M alkyl) (hereinafter represented by Formula (la ¹⁰ )). The compound (la ¹⁰ ) can be prepared by the process which includes:

(a) formation of a urea with a compound of formula 111 (10-2) to obtain a compound of formula 11 -2, and (b) formation of a compound of formula (la ¹⁰ ).

Each reaction step is described in more detail as follows.

(a) Intermediate 11-1 (10-2), as obtained in Scheme 10, can be treated with an isocyanate or with cyanic acid (in general with its salts) according to known processes (for example Satchell and Satchell, Chem. Soc. Rev., 1975, 4, 231-250). More particularly, this reaction can be carried out in a suitable solvent inert to the reaction such as dichloromethane, THF, benzene or toluene. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

(b) The formation of the sulfonylurea compound with the formula (la ¹⁰ ) can be carried out according to the conditions illustrated in Schemes 1 and 1b.

88/451

Layout 11

Intermediate compound 12-2 can be prepared by the methods shown in Scheme 12. Intermediate compound 12-1 can be prepared by the methods illustrated in Schemes 1 and 1b. The reaction can be carried out under known hydrogenation conditions, such as in the presence of a metallic catalyst such as palladium catalysts or platinum catalysts, in a reaction inert solvent such as methanol, ethanol, ethyl acetate or THF. If desired, the reaction can be carried out under acidic conditions, in the presence of an acid such as hydrogen acid or acetic acid. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Layout 12

Br,

,1

12-1 reduction

NH ₂

12-2

89/451

In addition, an intermediate of formula 13-2 can be prepared by the methods illustrated in Scheme 13. Intermediate 13-1 can be prepared by the methods illustrated in Scheme 1. The reduction can be accomplished by the methods described illustrated in Scheme 1.

Layout 13

13-1 γ ^ 'ίγΝΗ, reduction

13-2

An intermediate compound 14-3 can be prepared by the methods illustrated in Scheme 14. Intermediate 14-1 can be prepared by the methods illustrated in Scheme 1. The reduction of the nitro group can be carried out using the conditions illustrated in Scheme 1. The sulfonylation of the amino group of compound 14-2 can be performed by one of a series of standard procedures known to those skilled in the art (for example Protection for the Hydroxy Group and for the Amino Group, in Protective Groups in Organic Synthesis , 2nd Edition, TW Greene and PGM Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118, 379-384).

Layout 14

14-1

14-2

14-3

90/451

Intermediate compounds 15-6 and 15-7 can be prepared by the methods shown in Scheme 15. A compound of formula 15-1 can be treated with ammonia. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between one hour and one week, preferably between 3 hours and 5 days, however longer or shorter periods may be used, if necessary. In this way, intermediate 15-2 obtained with a 1,3-diketone compound with the formula 15-3 can be treated, in which groups L ¹ , L ² and L ³ are selected independently, but are limited, among halo, Cm alkyl, Cm alkyl substituted with halo, Cm alkoxy, Cm alkoxy substituted with halo, nitro, cyano, CM alkoxy Cm-alkyl, acetyl, C3.7 cycloalkyl, or two of the adjacent L ¹ , L ² and L ^{3 groups} can be joined together to form an alkylene chain having 3 or 4 members and in which one or two carbon atoms (non-adjacent) can be replaced by oxygen atoms, in the presence of a base such as pyridine, piperidine, imidazole , N, Ndimethylaminopyridine, CH3C (= O) ONa or NaH ₂ PO ₄ and in the presence or absence of an acid such as acetic acid, hydrochloric acid or boric acid. Suitable solvents inert to the reaction to water include dioxanes, DMSO; DMF, p-toluene or ethanol. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between one hour and one month, preferably between 6 hours and 14 days, however longer or shorter periods may be used, if necessary. Compounds 15-4 and 15-5 as obtained above can be treated with a halogenating agent such as POCI ₃ , SOCI ₂ or Vilsmeyer complex (for example, Laue T .; Plagens A., Eds .; NAMED ORGANIC REACTIONS, John Wiley & Sons: New York, 1998, pp. 258-262), in the presence or absence of a suitable reaction inert solvent such as dichloromethane, benzene or DMF, to obtain compounds with the formula 15-6 and / or 15-5. At

Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 ° C to the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a day, preferably between 20 minutes and 5 hours, however longer or shorter periods may be used, if necessary.

Layout 15

OEt ammonia aq.

the 15-1

Ό.

N 'nh ₂

0 '

NH4 '

O

15-2

15-3 pyridine, AcOH, H ₂ O

Reaction Scheme 16 illustrates a method for preparing the compound of formula (I) in which R ¹ is NH2, A is phenyl, B is ethylene, and W is NH (hereinafter represented by Formula (Ia ¹¹ )) and that of a compound of formula (I) in which R ¹ is NHC (= O) R ¹⁶ (R ¹⁶ is CM alkyl), A is phenyl, B is ethylene, and W is NH (hereinafter represented by Formula (Ia ¹² )), and that of a compound of formula (I) in which R ¹ is NHS (O) ₂ R ¹⁶ (R ¹⁶ is alkyl Cm), A is phenyl, B is ethylene, and W is NH (hereinafter represented by Formula (Ia ¹³ )).

92/451

Compounds (Ia ¹¹ ), (Ia ¹² ) and (Ia ¹³ ) can be prepared by the process which includes:

(a) forming a 2-amino-benzimidazole or 2-amino-imidazopyridine ring with a compound of formula 16-1 (2-7) to obtain a compound of formula (Ia ¹¹ );

(b) carbonylating a compound of formula (Ia ¹¹ ) to obtain a compound of formula (Ia ¹² ); and (c) sulfonylating the compound of formula (Ia ¹¹ ) to obtain a compound of formula (Ia ¹³ ,.

Each reaction step is described in more detail as follows.

(a) Compound 16-1 (2-7) can be cyclized to form a benzimidazole or imidazopyridine ring by reaction with the appropriate cyclizing agent, to give, in an inert solvent to the reaction, the compound with the formula (Ia ¹¹ ). Suitable cycling agents include cyanogen halides (for example cyanogen bromide), cyanamide, and guanidine carbamate. Suitable solvents include tetrahydrofuran (THF), methanol, ethanol, acetonitrile, water, dimethylformamide and the like. The reaction can be carried out at between about 0 ° C and up to reflux temperature, preferably between room temperature and reflux temperature, for between 1 minute and 120 hours, preferably between 10 minutes and 72 hours.

(b) The compound of formula (Ia ¹¹ ) can be reacted with an acylating agent such as an alkylcarbonyl halide, an acid anhydride, in the presence of a base such as triethylamine or pyridine. Suitable inert solvents for reaction include THF, DMF and benzene. The reaction can be carried out between about 0 ° C and up to reflux temperature, for between 1 minute and 120 hours, preferably between 10 minutes and 48 hours.

(c) The compound of formula (Ια ¹¹ ) can also be reacted with a sulfonylating agent such as an alkyl sulfonyl halide, a sulfonic acid anhydride, in the presence of a base such as triethyl93 / 451 mine or pyridine. Suitable inert solvents for reaction include dichloromethane, THF, DMF and benzene. The can be carried out between about 0 ° C and up to reflux temperature, for between 1 minute and 120 hours, preferably between 10 minutes and 48 hours.

Figure 16 _Y 2 ^ NH ₂ ^υ3 'Άνη _y 2.yJ N Vr ¹⁶ Y3 T WJH ^γ ' γ4 ^ Ν

HN N. _s; Z

0 ° 16-1 (2-7)

R ^{z H} N N. _S .Z Ο οθ

Ia

HN N. _S .Z Ο οθ

Ia .12 _Y 2 _t XpN ° 'SR

X ~ N γλ ^NH

R ^x

HN_N. _C .Z

II

O o ° Ia ¹³

Reaction Scheme 17 illustrates a method for preparing the compound of formula (I) in which R ¹ is R ¹⁶ NH (R ¹⁶ is C 1 alkyl), A is phenyl, B is ethylene, and W is O or NR ^1a (R ^1a is H or CM alkyl) (hereinafter represented by Formula (Ia ¹⁴ )) and that of a compound of formula (I) in which R ¹ is (R ¹⁶ ) 2N (R ¹⁶ is C 1-4 alkyl) s), A is phenyl, B is ethylene, and W is O or R ^1a N- (R ^1a is H or CM alkyl) (hereinafter represented by Formula (Ia ¹⁵ )).

Compounds (Ia ¹⁴ ) and (Ia ¹⁵ ) can be prepared by the process which includes:

(a) forming a 2-amino-benzimidazole or 2-amino-imidazopyridine ring with a compound of formula 17-1 to obtain a compound of formula (Ia ¹⁴ ); and (b) alkylating a compound of formula (Ia ¹⁴ ) to obtain a compound of formula (Ia ¹⁵ ).

Each reaction step is described in more detail as follows.

(a) Compound 17-1 may be subjected to a reaction with an isothiocyanate compound followed by de-sulfurization under known conditions to obtain the compound of formula (Ia ¹⁴ ), (for example, Y. Abe, H Kayakiri, S. Satoh etal., J. Med. Chem., 1998, 41, 4062). For example, the first reaction can be carried out in a reaction-inert solvent such as THF, acetonitrile or an alcohol (for example ethanol) at a temperature close to room temperature and about 100 ° C, for between about 30 minutes at 48 hours. Cyclization can be carried out in the presence of an alkyl halide at between about 0 ° C and the reflux temperature, for between about 30 minutes and 48 hours.

(b) The compound of formula (Ia ¹⁴ ) can be treated with the appropriate alkyl halides in the presence of a base such as lithium diisopropylamide (LDA), sodium hydride (NaH) or potassium t-butoxide, in a reaction inert solvent such as hexamethylphosphoric triamide (HMPT), THF or DMF at between about 0 ° C and about 100 ° C, for between about 5 minutes and about 48 hours.

95/451

Layout 17

, 2zyLnh ₂ '3'Y ⁴ NH MeNCS ^{s <} r ^N _y 2-yLnh ^ Y ⁴ NH Λ r π V Y i R ² _R 1aN ^, Ng-Z O Ò ° Ί R ² R ^1aN Y ^N '§ ^ O o ° 17-1 (2-7) 17-2 γ3 T? YNH Υ'γ ⁴ NR ¹⁶ Λ r ¹⁶ x _Y 2 <NR ¹⁶ Vh- n τ V ι ί? ² _Rla .N _Y N. _s; Z Ο ò ° 1 8 ² R ^1aN Y ^N 'S ^ O o ° Ia ¹⁴ Ia ¹⁵

Reaction Scheme 18 illustrates a method for preparing the compound of formula (I) in which R is RS (R is C 1 -alkyl), A is phenyl, B is ethylene, and W is O or R ^1a N ^(R1a is H or CI_ ₄ alkyl) (hereinafter represented by Formula (Ia ^17)).

Compounds (Ia ¹⁷ ) can be prepared by the process that includes:

(a) forming a 2-amino-benzimidazole or 2-amino-imidazopyridine ring with a compound of formula 18-1 to obtain a compound of formula (Ia ¹⁶ ); and (b) alkylating a compound of formula (Ia ¹⁶ ) to obtain a compound of formula (Ia ¹⁷ ).

Each reaction step is described in more detail as follows.

(a) Compound 18-1 can be subjected to a reaction with a thiocarbonyl re-agent, such as 1,1-thiocarbonylimidazole or with di (2-pyridyl) thionocar96 / 451 bonate to obtain the compound of the formula (la ¹⁶ ). (for example, Y. Abe, H. Kayakiri, S. Satoh et al., J. Med. C /? en?., 1998, 41, 4062). For example reaction can be carried out in a reaction-inert solvent such as THF, acetonitrile, dichloromethane or an alcohol (eg ethanol) at between room temperature and about 100 ° C, for between about 30 minutes and 48 hours . Cyclization can be carried out in the presence of an alkyl halide at between about 0 ° C and the reflux temperature, for between about 30 minutes and 48 hours.

(b) The compound of formula (la ¹⁶ ) can be reacted with the appropriate alkyl halides in the presence of a base such as lithium diisopropylamide (LDA), sodium hydride (NaH) or potassium t-butoxide, in a reaction inert solvent such as hexamethylphosphoric triamide (HMPT), THF or DMF at between about 0 ° C and about 100 ° C, for between about 5 minutes and about 48 hours.

Scheme 18 ^y Mnh cycling

Η

Ó3 T> = S

R 'r ¹⁸ x _R 1a .N ^ NgZ O 0 °

R ^1aN Y ^N § ^

O o ° _γ ζΥ ^ Ν R

Μ T> -S Υ'γ4 N

R ^z _R1 , V ^ O 0 °

18.1 to ^{16 to 17}

As shown in Scheme 19, the compound of formula 19-3 (1-5) can also be prepared by reacting a compound of formula 19-1 with a benzene compound substituted with formula 19-2 to obtaining a 1-phenylbenzimidazole compound of formula 19-3;

Compounds of formula 19-1 can be synthesized by any of the known methods. The group G ¹⁹ of the compounds of formula 19-2 is selected from an appropriate removable group, for example a fluorine, chlorine, bromine, iodine, trifluoromethanesulfoxy, methanesulfonyloxy, p-toluenesulfonyloxy, or boronic acid group

97/451

Layout 19

19-2

OH

19-1

G ^1S = starting group, such as halo, OTs, OMs, OTf, B (OH) ₂ ;

OH

19-3 dc ^the pref. F, Br, I, orB (OH) 2

The coupling reaction can be carried out in the presence of a base and in a solvent inert to the reaction. A preferred base is selected, but are limited from an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tert- potassium butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, butidine 2,6, pyridine or dimethylaminopyridine. Preferred inert solvents for reaction include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), 1,4-dioxane , dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 to 150 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and several weeks, preferably between 20 minutes and 1 week, however longer or shorter periods may be used, if necessary. A compound of formula 19-1 can advantageously be reacted with a compound of formula 19-2 in the presence of an appropriate catalyst to form a compound of formula 19-3, by a synthetic process whatever is applicable to compounds with related structure, known to those skilled in the literature (for example, Lam, PYS; Clark, CG; Saubern, S; Adams, J .; Winters, MP; Chan, D. Μ. T .; Combs, A., Tetrahedron

98/451

Lett., 1998, 39, 2941-2944, Kiyomori, A .; Marcoux, J .; Buchwald, S.L., Tetrahedron Lett., 1999, 40, 2657-2660, Lam, P.Y.S .; Deudon, S .; Averill, K.M; Li, R .; He, M.Y .; DeShong, P .; Clark, C.G., J. Am. Chem. Soc., 2000, 122, 7600-7601., Collman, J.P .; Zhong, M., Org. Lett., 2000, 2, 1233-1236.). A preferred catalyst is selected for the reaction from, for example, but limited, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (ll) chloride, copper (0), copper (l) acetate, bromide copper (l), copper chloride (l), copper iodide (l), copper oxide®, copper trifluoromethanesulfonate®, copper acetate (ll), copper (II) bromide, copper chloride), copper (ll) iodide, copper (II) oxide or copper trifluoromethanesulfonate®).

As shown in Scheme 20, a compound of formula 1-5 or 1e-4 can also be prepared using the process which includes:

(a) acylating the compound of formula 20-1; and (b) cyclizing the compound of formula 20-2 to a benzimidazole or imidazopyridine ring to obtain a compound of formula 20-3.

Layout 20

_γ 2 / ΥγΗΗ ₂ ^Λ Αη

20-1 (1-3 or 1e-3)

Each reaction step is described in more detail as follows.

(a) A compound of formula 20-1 (1-3 or 1e-3) is reacted with an appropriate acylating reagent to obtain a compound of formula 20-2 in a solvent inert to the appropriate reaction, in the presence or absence of a coupling reagent and / or an additive. Included are

99/451 in the appropriate but limited acylation reagents, a carboxylic acid, an aminocarboxylic acid, an acid anhydride (for example acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like), a formamidine (for example a formamidine alkylate such as formamidine acetate), an alkylcarbonyl halide (for example a cycloalkylcarbonyl halide, a bicyclo- or bicyclo-heterocyclo-carbonyl halide, a spirocarbocyclic or a spiro-heterocycle halide -carbonyl), an aryl- or arylalkyl-carbonyl halide) (for example phenylacetyl halide), a heteroarylcarboxylic acid (for example a piperidinylcarboxylic acid compound), trialkyl orthoformate (for example triethyl orthoformate), and the like. Preferred suitable inert reaction solvents include, but are limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4 -dioxane, dimethyl sulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those commonly used in peptide synthesis, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl3- (3-dimethylaminopropyl) carbodiimide (WSC), hexafluorophoszole 1-yloxy-tris (dimethylamino) phosphonium (BOP), diphenylphosphorazide (DPPA), hexafluorophosphate / V - [(1H-1,2,3-benzotriazole) -1-yloxy) (dimethylamino) -methylidene] / V-methylmethanamine (HBTU), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), bromine hexafluorophosphate [tri (1-pyrrolidinyl)] phosphonium (PyBroP), phosphine bis (2-oxo-1,3-oxazolidin-3-yl) chloride (BOP-CI ), (1 / 7-1,2,3-benzotriazole) -1-yloxy) [tri (1-pyrrolidinyl)] phosphonium hexafluorophosphate, (PyBOP), or the like. Suitable additives are included but are limited to 1 / -M, 2,3-benzotriazole-1-ol (HOBt), 3H- [1,2,3] triazolo [4,5-b] pyridin-3 -ol (HOAt), A /, / V-dimethyl-4-pyridinamine (DMAP), or the like. The reaction can be carried out at a temperature in the range of -100 to 250 ° C, preferably in the range of 0 ° C at reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and a few days, preferably between 30 minutes and 48

100/451 hours, however longer or shorter periods may be used, if necessary.

(b) The resulting amide compound with formula 20-2 can also be cyclized to form a benzimidazole or imidazopyridine ring in the presence of a base (Bashir, M; Kingston, DGI; Carman, RJ; Van Tassell, RL ; Wilkins, TD, Heterocycles, 1987, 26, 2877-2886). A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide or carbonate, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium, potassium fer-butoxide, sodium carbonate or potassium carbonate, in a solvent inert to the reaction. Preferred reaction-inert solvents include, but are not limited to, water, methanol, ethanol, tetrahydrofuran (THF), benzene, toluene, xylene, dichloromethane, ethylene glycol, or mixtures thereof. Reaction temperatures are generally in the range of -100 to 250 ° C, preferably in the range of 0 and 70 ° C, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 hour and 5 days, preferably between 3 hours and 2 days, however longer or shorter periods may be used, if necessary.

As shown in Scheme 21, an intermediate of formula 21-2 (1-4 or 1-4) can also be prepared.

Layout 21

21-1 (1-3 or 1e-3)

O

R ²¹ = OH or NP

P = protecting group, such as Bn, Z, Boc; of pref®.

Boc

(1-4 or 1e-4)

The compound of formula 21-1 can be reacted with a

101/451 aldehyde appropriated in a solvent inert to the reaction in the presence of, or in the absence of acid, to obtain an intermediate Schiff base. After that, an oxidative cyclization of the Schiff base can be done to form a benzimidazole or imidazopyridine ring, using iodine, sulfur, cupric acetate, mercury oxide, chloranil, active manganese dioxide, lead tetraacetate, peroxide nickel, barium permanganate, or the like. Preferred inert solvents for reaction include, but are limited to, methanol, ethanol, water, benzene, toluene, xylene, mesitylene, odichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethoxyethane (DME), 1,4-dioxane, dimethyl sulfoxide (DMSO), or mixtures thereof. The reaction can be under temperature in the range of 100 to 250 ° C, preferably in the range of 0 ° C to the reflux temperature, but if necessary, a higher or lower temperature can be used. Reaction periods are generally between 1 minute and several days, preferably between 30 minutes and 48 hours, however longer or shorter periods may be used, if necessary.

Aryl or heteroaryl fused imidazole compounds of Formula (II) of this invention can also be prepared by a variety of synthetic methods known to those skilled in the art.

συ

Reaction Scheme 22 illustrates a method for preparing the compound of formula (II).

102/451

Layout 22

Η, Ν _Y 2 / ^Y <Lx ^N ° 2 22-0 γ3

Y- ^Y V ^N ° ^{2 υ} 'Λνη

Á »reduction

22-1

Χ = starting group, such as halo, OTs, OMs; pref®. F or Cl

B

VV

22-2, ₂ ^ yL.nh ₂ li 'Y ⁴ ' NH i

THE.

cyclization

Ph

22-3 ζϊ'Χν »· ^Y MN ^A 'B

W.p

II

The compound of formula (II) can be prepared from the compound of formula 22-1 (1-1) using a procedure similar to that described in Scheme 1.

Aryl or heteroaryl compounds of formula (III) of this invention can also be prepared by a variety of synthetic methods known to those skilled in the art.

(ΠΙ)

Reaction Scheme 23 illustrates a method for preparing the compound of formula (III).

103/451

Layout 23

23-1 (22-3) _{(J |}

The compound of formula (III) can be prepared from the compound of formula 23-1 (22-3) using a procedure similar to that described in Scheme 20.

In addition, the benzimidazole portion of the compound of formula (I) that can be used in this document can be prepared by known methods, as illustrated in, for example: (1) Grimmett, MR, Imidazols and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds .; Pergamon Press Ltd .; Oxford, UK, 1984; Vol. 5, pp. 457-498., (2) Grimmett, M. R., Imidazols. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 3, pages 77-220.

The imidazopyridine portion of the compound of formula (I) can be prepared which can be used herein by known methods which are illustrated in, for example: Townsend L. B .; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2: 1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds .; Elsevier Science, Ltd .; Oxford, UK, 1996; Vol. 7, pages 283-349.

The starting materials 1-1, 1-8, 1-9, 1a-2, 1d-3, 1d-4, 1d-5, 1d6, 1f-0, 2-2, 5-4, 15-1, 15-3, 22-0 and the other reagents, are known compounds or can be obtained commercially, or can be prepared using procedures known to a person skilled in the art.

The present invention also includes isotopically labeled compounds, which are identical to those covered by formula (I), except for the

104/451 the fact that one or more of its atoms is replaced by another atom that has an atomic or mass number different from the atomic or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ^1S F and ³⁶ CI, respectively. The compounds of the present invention, their prodrugs and the pharmaceutically acceptable salts of those compounds, or the prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those in which radioactive isotopes such as ³ H or ¹⁴ C have been incorporated, are useful, for example, in drug and / or substrate distribution assays in tissue. Tritium isotopes, that is ³ H, and carbon-14, that is ¹⁴ C, are especially preferred, due to their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium, i.e. ² H, may confer certain therapeutic advantages due to their greater metabolic stability, for example, a longer half-life in vivo or the need for reduced doses, and may therefore be preferred. in certain circumstances. In general, isotopically labeled compounds of compounds of formula (I) of this invention can be prepared by the procedures described in the Schemes and Preparations below, replacing a non-isotopically labeled reagent with isotopically labeled reagents available for a non-isotopically labeled reagent.

The present invention includes salt forms of the compounds of formula (I), as obtained.

Certain compounds of the present invention are capable of forming pharmaceutically acceptable non-toxic cations. The pharmaceutically acceptable non-toxic cations of formula (I) can be prepared by standard techniques, providing for example a contact between said compound and a stoichiometric amount of an alkali or alkaline earth metal hydroxide or alkoxide (sodium, potassium, calcium and

105/451 magnesium), in water or in a suitable organic solvent such as ethanol, isopropanol, mixtures thereof, and the like.

The bases that are used to prepare the pharmaceutically acceptable base addition salts of the acid compounds of this invention with formula (I), are those that form non-toxic base addition salts, that is, salts containing pharmaceutically acceptable cations such as adenine, arginine, cytosine, lysine, benetamine (ie N-benzyl-2-phenylethylamine), benzathine (ie Ν, Ν-dibenzylethylenediamine), choline, diolamine (ie diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine (this is N-methylglucamine), nicotinamide, olamine (i.e. ethanolamine), ornithine, procaine, proline, pyridoxine, serine, tyrosine, valine and tromethamine (i.e. tris, or tris (hydroxymethyl) aminomethane). Base addition salts can be prepared by conventional methods.

Insofar as certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different beings with various inorganic and organic acids.

The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention with formula (I) are those that form non-toxic acid addition salts, that is, salts containing pharmaceutically acceptable anions such as chloride, bromide , iodide, nitrate, sulfate or bisulfate, acid phosphate or phosphate, acetate, lactate, acid citrate or citrate, tartrate or bi-tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethane sulfonate, benzenesulfonate, p -toluenesulfonate, adipate, aspartate, camsylate (ie 1,2-ethanedisulfonate), stolate (ie laurylsulfate), gluceptate (ie glucoheptonate), 3-hydroxy-2-naphthoate, xionophate (ie 1-hydroxy-2-naphthate) , isethionate (i.e., 2-hydroxyethane sulfonate), mucate (i.e., galactarate), 2-naphthylate (i.e., naphthalenesulfonate), stearate, cholate, glucuronate, glutamate, hypurate, lactobionate, lysinate, maleate, mandelate, napadisyl nicoti nate, polygalacturonate, salicylate, sulfo-salicylate, tannate, tryptophanate, borate, carbonate, oleate, phthalate and pamoate (i.e., Ι, Γ-methylenebis- (2-hydroxy-3-naphthoate). Acid addition salts can be prepared

106/451 by the usual procedures.

Also included within the scope of this invention are bioprecursors (also called precursors) of compounds of formula (I). A bioprecursor of a compound of formula (I) is a chemical derivative of it which is transformed back into the compound of formula (I) in biological systems. In particular, a bioprecursor of a compound of formula (I) is transformed back into the compound of formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, for example a human subject. For example, it is possible to make a bioprecursor of compounds of formula (I) in which one, or both, hydroxy groups L and W include hydroxy groups, making an ester from that hydroxy group. When only one of L and W includes a hydroxy group, only monoester is possible. When both Le W groups include hydroxy groups, di- and monoesters (which can be the same or different) can be made. Typical esters are alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when L or W include a hydroxy group, bioprecursors can be made by transforming the hydroxy group into an acyloxymethyl derivative (for example, a pivaloyloxymethyl derivative), by reaction with an acyloxymethyl halide (for example pivaloyloxymethyl chloride) .

When the compounds of formula (I) of this invention can form solvates such as hydrates, such solvates are included within the scope of this invention.

In addition, compounds of formula (I) are expected to be more effective therapeutic agents when they are co-administered with a COX-2 selective NSAID.

In addition, the present invention also encompasses a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, pain, common cold, osteoarthritis, neuropathic pain, brain tumor, diuresis, or the like, which includes a therapeutically amount effect of the imidazole compound fused to aryl or heteroaryl with formula (I), and a selective NSAID for COX-2, or its salts

107/451 pharmaceutically acceptable, with a pharmaceutically acceptable carrier.

The compounds of the invention can be advantageously used, in combination with one or more therapeutic ingredients selected from, a COX-2 selective, COX-1 selective or non-selective NSAID, opioids, anticonvulsants, antidepressants, local anesthetics , disease-modifying anti-rheumatoid diseases, or steroids.

Combination with a COX-2 selective NSAID is especially preferred for use in the prophylaxis and treatment of pain and arthritis. Examples of NSAIDs selective for COX-2 are nimesulide, celecoxib, rofecoxib and valdecoxib.

The compounds of Formula (I) have been found to have an activity with E ₂ receptor antagonists, preferably as EP ₄ receptor antagonists. Preferably, these compounds are useful as analgesics, anti-inflammatories, diuretics, and the like, in mammalian subjects, especially humans in need of such agents. Affinity, antagonistic activities and analgesic activity can be demonstrated by the following tests, respectively.

Method to assess biological activities

In vitro assays

Rat EP cell membrane binding assay:

Stable expression of rat EP1,2,3 e4 receptors in a human kidney embryonic cell line (HEK293)

The rat EP1, 2, 3, and 4 receptor cDNA clones are obtained by polymerase chain reaction (PCR) from rat kidney or heart cDNA libraries (Clontech).

Human kidney embryonic cells (HEK 293) are stably transfected with expression vectors for rat EP1, 2, 3, and 4 receptors, according to the method described in the article; The Journal of Biological Chemistry, vol.271, No. 39, pages 23642-23645.

Preparation of the membrane fraction

EP1 transfectants are grown. 2, 3 and 4 in the middle

108/451 of modified Dublin's Eagle, containing 10% fetal calf serum, 100 U / ml penicillin, 100 pg / ml streptomycin and 600 pg / ml G418 (selection medium), at 37 ° C, in a humidified atmosphere with 5% CO ₂ in air.

For membrane preparation, cells are collected with phosphate buffered saline (PBS) and centrifuged at 400 xg for 5 min. The pellet obtained is resuspended in cooled PBS (4 ° C) containing 1 mM Pefabloc (4- (2-aminoethyl) -benzenesulfonyl fluoride (AEBSF)), Phosphoramidon 10 μΜ, Pepstatin 1 μΜ, Elastatinal 10 μΜ, Antipain 100 μΜ. The cells are lysed with an ultrasonic cell disruptor by sonication for 20 seconds. The cell mixtures are then centrifuged at 45,000 xg for 30 minutes. The pellet resuspended in assay buffer (10 mM morpholinoethane sulfonic acid, (MES) -KOH, 1 mM ethylenediaminetetraacetic acid (EDTA), 10 mM MgCl ₂ , pH 6.0), and the protein concentration is determined by Bradford method (Bio-Rad assay). This membrane preparation is stored at -80 ° C in a freezer until used in the binding assay.

Link rating:

Assessment of membrane binding

Assays for determining the [ ³ H] -PGE2 binding to the membrane are performed in the reaction mixture which is 10 mM in MES / KOH (pH 6.0), 10 mM in MgCl2, 1 mM in EDTA, 1 nM in [ ³ H ] -PGE2 (Amersham TRK431, 164 Ci / mmol), containing 2 ~ 10 pg of membrane fraction protein (mouse EP 1, 2, 3, or 4 HEF293 transfectant) and test compound (total volume 0.1 mL in a 96-well polypropylene plate). The incubation is carried out for 60 min at room temperature before the separation of the free radioligand from the alloy by rapid filtration through glass fiber filters (Printed Filtermat B, 1205-404, glass fiber, double thickness, dimensions 102x258 mm, Wallac Inc ., previously soaked in 0.2% polyethyleneimine). The filters are washed with assay buffer and the residual [ ³ H] -PGE ₂ attached to the filter is determined with a liquid scintillation counter (1205 Betaplate ™). The specific bond is defined as the difference between the total bond and the non-specific bond that is determined in the presence of

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PGE ₂ 10 μΜ.

Evaluation of cAMP in rat EP * transfectant Maintained in DMEM containing 10% FCS and 600 pg / ml geneticin, HEK293 cells that express rat EP ₄ receptors (rEP ₄ cells). To collect the rEP ₄ cells, the culture medium and cells are aspirated and the cells are washed in a 75 cm ³ flask with 10 mL of fofato buffered saline (PBS). An additional 10 ml of PBS is added to the cells and incubated for 20 min. at room temperature. Rat EP4 cells are harvested by pipetting and centrifuging at 300 g for 4 min. The cells were resuspended in DMEM without neutral red, at a density of 5x10 ⁵ cells / ml. The cells (70 pL) are mixed with 70 pL of DMEM (without neutral red) containing 2 mM IBMX (PDE inhibitor), 1 nM PGE2 and test compound in PCR tubes, and incubate at 37 ° C for 10 min. The reaction is stopped by heating at 100 ° C for 10 min. with a thermal cycler. The concentration of cAMP in the reaction mixtures is determined with a cAMP SPA kit (Amersham) following the manufacturer's instructions.

Reference: Eur. J. Pharmacol. 340 (1997) 227-241.

In vivo tests

Hyperalgesia induced in carrageenan rats Fast overnight 4-week old male SD (Japan SLC) rats. Hyperalgesia is induced by intraplantar injection of λ-carrageenan (0.1 mL of a 1% suspension in saline, weight / volume, Zushikagaku). Test compounds are administered orally (1 mL of 0.1% methylcellulose / 100 g body weight), 5.5 hours after the carrageenan injection. The mechanical threshold of the pain is measured with an analgesia meter (Ugo Basile), after 4, 5, 6.5 and 7.5 hours after the injection of carrageenan, and the change in the pain threshold is calculated.

Reference: Randall L. O. & Selitto I.J., Arch. Int. Pharmacodyn. 111,409-419, 1957.

Prostaglandin-induced thermal hyperalgesia in rats

EíÍPGEí):

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They are fasted overnight from 4 week old male SD (Japan SLC) rats. Hyperalgesia is induced by intraplantar injection of 100 ng PGE2 in 5% DMSO in saline solution (100 μΙ_) in the rats' hind paw. Rats are administered either orally or intravenously one of the two vehicles (oral: 0.1% methylcellulose, endov. 10% DMSO in saline), or a test compound, 15 or 5 minutes before PGE injection. ₂ , respectively. The rats were placed in plastic cages of the plantar tester (Ugo Basile) and the source of mobile heat was focused on the rats' hind legs. The latency time (sec) of the paw movement was measured 15 min after PGE ₂ injection and the change in the movement threshold was calculated.

Reference: Hargreaves K. et al. Pain 32, 77-88, 1988.

Most of the compounds prepared in the working examples described below have demonstrated a greater affinity for EP ₄ receptors than for EP1, 2 and 3 receptors.

Some of the preferred compounds prepared in the working examples described below have been tested by the previous method, and have shown ED ₅₀ values below 60 mg / kg.

The compounds of this invention with formula (I), which are imidazoles fused to aryl or heteroaryl, can be administered either by oral, parenteral or topically, to mammals. In general, these compounds are administered to humans, preferably in doses ranging from 0.1 mg to 3000 mg, and preferably between 1 mg and 500 mg, which can be administered in a single dose or in divided doses. throughout the day, although variations may necessarily occur depending on the weight and state of the subject to whom the treatment is administered, the state of the disease being treated, and the route of administration specifically chosen. However, and for example, a dosage level in the range of between 0.01 mg and 10 mg per kg of body weight is most preferred for the treatment of pain associated with inflammation.

The compounds of the present invention can be administered per se

111/451 alone or in combination with pharmaceutically acceptable vehicles or diluents by any of the routes indicated above, and such administration may occur in single or multiple doses. More specifically, the new therapeutic agents of the present invention can be administered in a wide variety of dosage forms, that is, they can be combined with a variety of pharmaceutically acceptable and inert carriers in the form of tablets, capsules, lozenges, troches , hard candies, powders, aerosols, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, pharmaceutical compositions for oral administration can be sweetened and / or flavored as desired. In general, the therapeutically effective compounds of this invention are present in such dosage forms in levels ranging from 5% to 95% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine can be used together with various disintegrants such as starch (corn starch, potato or tapioca preferred) , alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for the production of tablets. Solid compositions of a similar kind may also be used as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, coloring material or pigments, and, if desired, also emulsifying and / or suspending agents, together with thinners such as

112/451 water, ethanol, propylene glycol, glycerin and various similar combinations.

For parenteral administration, solutions of a compound of the present invention can be used either in sesame or peanut oil or in aqueous propylene glycol solution. The aqueous solutions must be adequately buffered (preferably pH> 8), if necessary, and the liquid diluent must be made isotonic first. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intramuscular and subcutaneous intra-articular injection purposes. The preparation of all these solutions is readily accomplished under sterile conditions following standard pharmaceutical techniques well known to those skilled in the art. In addition, it is also possible to administer the compounds of the present invention topically, when treating inflammatory conditions of the skin, and this purpose can preferably be achieved using creams, jellies, gels, pastes, ointments, and the like, according to practice usual pharmaceutical company.

EXAMPLES

The invention is illustrated by the following non-limiting examples, in which and unless otherwise indicated: all operations were carried out at the laboratory or ambient temperature, that is, in the range of 1825 ° C; evaporation of the solvent was carried out on a rotary evaporator under reduced pressure and with a bath whose temperature did not exceed 60 ° C; the reactions were followed by thin layer chromatography (TLC) and the reaction periods are recorded for indicative purposes only: the melting points shown (mp) are uncorrected (from the polymorphism different melting points may result); indication of the structure and purity of all isolated compounds was obtained by at least one of the following techniques: TLC (Merck Silica gel 60 F ₂ 54 in pre-coated TLC plates), mass spectrometry, nuclear magnetic resonance ( NMR), infrared (IR) absorption spectrum or microanalysis. The yields are shown as an indication. Flash column chromatography was performed

113/451 with Merck 60 silica gel columns (230-400 mesh ASTM). Low resolution mass spectrometry (IE) data were obtained on an Automass 120 mass spectrometer (JEOL). Low resolution mass spectrometry (IED) data were obtained on a Quattro II mass spectrometer (Micromass) or on a ZMD (Micromass). NMR data are reported and were obtained at 270 MHz (on a JEOL JNM-LA 270 spectrometer) or at 300 MHz (on a JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9 % D) as solvents, unless otherwise indicated; for tumethylsilane (TMS) in parts per million (ppm) for tetramethylsilane as an internal standard, the conventional abbreviations used were: s = simple, d = doublet, t = triple, q = quartet, quint = quintet, m = multiple, lg = wide, etc. The IR spectra were measured on a Shimadzu infrared spectrometer (IR-470). Chemical symbols have their usual meanings; p.b. (boiling point), mp (melting point), L (liter (s)), mL (milliliter (s)), g (gram (s)), mg milligram (s)), mol (moles), mmol (miilimoles), eq. (equivalents), quant. (quantitative yield.

EXAMPLE 1

2-ETlL-5,7-DIMETHYL 3- (4-f2-f ((f (4-METlLFENIL) SULFONIL] AMINO) CARBONIL) AMINOlETYL) PHENYL) -3H-IMIDAZOr4,5-blPYRIDINE

STEP 1. 4,6-Dimethyl-3-nitro-2 (1/7) -pyridine

A mixture of ethyl nitroacetate (80.0 g, 601 mmoles) in ammonium hydroxide (25% NH ₃ in water, 400 ml) was stirred at room temperature for 3 days, and then the solution was concentrated by drying with air. The residue was dissolved in water (450 ml). 2,4pentanedione (73.1 g, 730 mmoles), pyridine (16.2 ml, 200 mmoles) and acetic acid (11.4 ml, 200 ml) were added to the solution, and the mixture was stirred for a further 7 days. The resulting precipitates were removed by filtration and dried under reduced pressure, to obtain 35.0 g (35%) of the title compound, as yellow solids: ¹ H NMR (DMSO-d ₆ ) δ 12.44 (1H, s lg.), 6.06 (1H, s), 2.19 (3H, s), 2.13 (3H, s).

STEP 2. 2-Chlorine-4,6-dimethyl-3-nitropyridine

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A mixture of 4,6-dimethyl-3-nitro-2 (1 / - /) - pyridinone (step 1, 10.0 g, 29.7 mmoles) in phosphorus oxychloride (35 ml, 187.3 mmoles) at 95 ° C for 3 hours, then cooling to 45 ° C. Excess phosphorus oxychloride was removed by distillation under reduced pressure at 45 ° C. The residue was cooled to room temperature, and diluted with dichloromethane (75 ml). The resulting solution was cooled to 0 ° C, and 2N hydrochloric acid (50 ml) was added dropwise to the solution. The organic phase was separated, and washed with 2N hydrochloric acid (4 x 25 ml), 2N NaOH (2 x 50 ml) and brine (50 ml). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to obtain 10.0 g (90%) of the title compound as white solids: ¹ H NMR (CDCl ₃ ) δ 7 , 07 (1H, s), 2.56 (3H, s), 2.35 (3H, s).

STEP 3. 2- (44 (4,6-Dimethyl-3-nitro-2-pyridinyl) amino1phenyl) ethanol

A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (step 2, 1.3 g, 7.0 mmoles) and 4-aminophenylethyl alcohol (1.4 g, 10.2 mmoles) was placed in a sealed tube and heated at 150 ° C 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 obtain 1.6 g (80%) of the title compound under in the form of orange solids: ¹ H NMR (CDCIs) δ 9.55 (1H, s lg.), 7.57 (2H, d, J = 8.4 Hz), 7.20 (2H, d , J = 8.4 Hz), 6.52 (1H, s), 3.84 (2H, t, J = 6.4 Hz), 2.85 (2H, t, J = 6.4 Hz), 2.54 (3H, s), 2.42 (3H, s).

STEP 4. 2- {4-r (3-Amino-4,6-dimethyl-2-pyridinyl) amino1phenyl) -ethanol

10% Pd-C (160 mg) was added to a stirred solution of 2 {4 - [(4,6-dimethyl-3-nitro-2-pyridinyl) amino] phenyl} ethanol (step 3, 1.6 g, 5.6 mmoles) in ethyl acetate (15 mL). The mixture was stirred at room temperature for 6 hours under an atmosphere of hydrogen. The palladium catalyst was removed by filtration and washed with ethanol (100 ml). The filtrate was concentrated under reduced pressure to obtain 1.3 g (92%) of the title compound as light yellow solids: ¹ H NMR (CDCI ₃ ) δ 7.10 (4H, s), 6.61 (1H, s), 3.81 (2H, t, J = 6.4 Hz), 2.80 (2H, t, J = 6.4 Hz), 2.36 (3H,

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s), 2.19 (3H, s).

STEP 5. 2-r4- (2-Ethyl-57-dimethyl-3H-imidazor4,5-ò1pyridin-3-yl) phenylethylpropionate

Propionyl chloride (990 mg, 10.7 mmol) at 0 ° C was added dropwise to a stirred suspension of 2- {4 - [(3-amino-4,6-d imethyl-2-pyridinyl) ) amino] phenyl} ethanol (step 4, 1.3 g, 5.1 mmoles) in toluene (30 ml), and the reaction mixture was heated at reflux temperature for 2 hours. After cooling, the mixture was poured into water (50 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with 2N aqueous NaOH solution (50 ml) and brine (50 ml), then dried (MgSO4). Upon removal of the solvent, 1.8 g (quant.) Of the title compound was obtained as brown solids: ¹ H NMR (CDCI ₃ ) δ 7.41 (2H, d, J = 8 , 4 Hz), 7.33 (2H, d, J = 8.4 Hz), 6.90 (1H, s), 4.37 (2H, t, J = 6.9 Hz), 3.04 ( 2H, t, J = 6.9 Hz), 2.82 (2H, q, J = 7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.35 ( 2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.14 (3H, t, J = 7.6 Hz).

STEP 6. 2-í4- (2-Ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-olpyridin-3-yl) phenylethanol

4N aqueous LiOH solution (4.6 mL, 18.4 mmol) was added to a 2- [4- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-ó) propionate solution ] pyridin-3-yl) phenyl] ethyl (step 5, 1.75 g, 5.1 mmoles) in methanol / THF (volume / volume, 1: 1, 28 ml), and the resulting mixture was stirred at room temperature environment. After 3 hours, the mixture was concentrated. The residue was dissolved in water (30 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purified by flash column chromatography on silica gel with hexane / ethyl acetate elution (gradient elution from 2: 1 to 0: 1) to obtain 1.3 g (86%) of the compound in title, in the form of light brown solids: ¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz) , 6.91 (1H, s), 3.81 - 3.75 (2H, m), 3.47 (1H, s lg.), 2.92 (2H, t, J = 6.9 Hz), 2.81 (2H, q, J = 7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t, J = 7.6 Hz).

STEP 7. 3-r4- (2-Chloroethyl) phenin-2-ethyl-5,7-dimethyl-3/7-imidazoY4,5-Ò1pyridine

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Thionyl chloride (2.0 mL, 23.6 mmol) was added to a solution of 2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-b] pyridin-3-yl) phenyl] ethanol (step 6, 2.2 g, 7.4 mmoles) in toluene (40 ml), and the resulting mixture was stirred at 80 ° C for 3 hours. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel, with an elution of hexane / ethyl acetate (gradient elution from 2: 1 to 1: 1), to obtain 2.1 g (90%) of the title compound as white solids: ¹ H NMR (CDCI ₃ ) δ 7.41 (2H, d, J = 8.4 Hz), 7.35 ( 2H, d, J = 8.4 Hz), 6.90 (1H, s), 3.78 (2H, t, J = 7.4 Hz), 3.15 (2H, t, J = 7.4 Hz), 2.83 (2H, q, J = 7.6 Hz), 2.71 (3H, s), 2.54 (3H, s), 1.28 (3H, t, J = 7.6 Hz).

STEP 8. 2-F4- (2-ethyl-5,7-dimethyl-3/7-imidazoí4.5-51pyridin-3-yl) phenylethyl azide

Sodium azide was added to a stirred solution of 3 [4- (2-chloroethyl) phenyl] -2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridine ( step 7, 2.8 g, 9.0 mmoles) and Kl (1.5 g, 9.0 mmoles) in DMF (50 ml), and the resulting mixture was stirred overnight at 100 ° C . The reaction mixture was poured into water (100 ml), and extracted with ethyl acetate (100 ml). The organic phase was washed with water (50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 1), to obtain 2.35 g (85%) of the title compound, as white solids: ¹ H NMR (CDCfe) 8 7.41 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 6.90 (1H, s), 3.59 (2H, t, J = 7.1 Hz), 2.99 (2H, t, J = 7.1 Hz), 2.83 (2H, q, J = 7, 6 Hz), 2.65 (3H, s), 2.52 (3H, s), 1.27 (3H, t, J = 7.6 Hz).

STEP 9. 2-f4- (2-Ethyl-5.7-dimethyl-3H-imidazoí4,5-iblPÍridin-3-yl) phenylethylamine

10% Pd-C (200 mg) was added to a solution of 2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-b] pyridine- 3-yl) phenyl] ethyl (step 8, 2.35 g, 7.3 mmoles) in methanol (50 ml). The resulting mixture was stirred for 4 hours under an atmosphere of hydrogen. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography, eluting with dichlorome117 / 451 tane / methanol / triethylamine (100: 5: 1), to obtain 2.01 g (94%) of the title compound as of white solids: ¹ H NMR (CDCb) δ 7.39 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 6.90 (1H, s), 3.05 (2H, t, J = 7.3 Hz), 2.88-2.78 (4H, m), 2.65 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J = 7.6 Hz).

STEP 10. 2-Ethyl-5,7-dimethyl-3- (4f2-r (ir (4-methylphenyl) sulfoniH-aminoJcarbonyl) amino1ethylphenyl) -3 / 7-imidazo [4,5 ~ d1pyridine

P-Toluenesulfonyl isocyanate (805 mg, 4.0 mmol) was added to a solution of 2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-ó] pyridin-3yl) phenyl] ethylamine (step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 ml). The resulting mixture was stirred at room temperature for 3 hours. After removing the solvent, the residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (20: 1), to obtain 1.10 g (56%) of the title compound, in the form of white solids: ¹ H NMR (CDCI ₃ ) δ 7.85 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7, 23 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 6.12 (1H, s lg.), 3.55-3.46 (2H, m), 2.85 (2H, t, J = 6.3 Hz), 2.74-2.64 (5H, m), 2.42 (3H, s) , 2.41 (3H, s), 1.21 (3H, t, J = 7.6 Hz).

EXAMPLE 2

SODIUM SALT OF 2-ETHYL-5.7-DIMETLL-3- (4- {2 - [(fr (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETHYL) PHENYL) -3H-IMIDAZO r4,5-b1PYRIDINE

A 2N aqueous solution of NaOH (5.1 mL, 10.2 mmol) was added to a solution of 2-ethyl-5,7-dimethyl-3- (4 {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3H-imidazo [4,5-ô] pyridine (Example 1, 5.0 g, 10.2 mmoles) in methanol (20 ml). The resulting mixture was stirred at room temperature for 5 minutes and concentrated. Residual solids were collected by filtration and dried under reduced pressure at 50 ° C to

118/451 obtain the title compound as white solids: ¹ H NMR (DMSO-de) δ 7.60 (2H, d, J = 8.2 Hz), 7.31-7.39 (4H , m), 7.14 (2H, d, J = 8.2 Hz), 6.96 (1H, s), 3.15 (2H, s lg.), 2-66-2.75 (4H, m), 2.53 (3H, s), 2.40 (3H, s), 2.28 (3H, s), 1.20 (3H, t, J = 7.6 Hz).

EXAMPLE 3 (4-METHYLPHYL) 2-y4- (2-ETHYL-5,7DLMETHIL-3H-IMIDAZOr4,5-b1PYRIDINE-3-IL) SULPHONYL CARBAMATE

P-Toluenesulfonyl isocyanate (237 mg, 1.2 mmol) was added to a solution of 2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-b] pyridin-3yl) phenyl] ethanol (step 6 of Example 1, 300 mg, 1.0 mmol) in dichloromethane (10 ml). The resulting mixture was stirred at room temperature overnight. After removing the solvent, residual solids were recrystallized from ethyl acetate to obtain 454 mg (92%) of the title compound as white solids: ¹ H NMR (CDCl ₃ ) δ 7, 93 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.22 (4H, s), 6.92 (1H, s), 4, 87 (1H, s lg.), 4.35 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.6 Hz), 2.78 (2H, q, J = 7.7 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.43 (3H, s), 1.24 (3H, t, J = 7.7 Hz).

EXAMPLE 4

2-ETYL-5,7-DIMETHIL-3- (4-f2-r «METYL (4-METHYLphenyl) -SULPHONYL1AMINO | CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZOÍ4,5-Ó1-PYRIDINE

A solution of lithium diisopropylamide (LDA) (2.0 N in heptane / hexane / ethylbenzene, 0.8 mL, 1.6 mmol) was added dropwise with stirring to a solution of 2-ethyl -5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amine} carbonyl) -amino] ethyl} phenyl) -3 / - / - Imidazo [4,5-b ] pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL), with ice cooling, over a 10 minute period. Upon completion of the addition, stirring was continued for another 20 minutes at the same temperature. Honey (0.5 ml) at 0 ° C was added dropwise to the resulting mixture, and stirred at room temperature for 15 hours. The mixture was poured into a phosphate buffer solution (100 ml) and extracted with dichloromethane (100 ml). The organic phase was washed with brine (50 ml), dried (Na ₂ SO4), and

119/451 concentrated. Purify the residue by flash chromatography on silica gel eluting with dichloromethane / methanol (10: 1) to give 10 mg (5%) are title compound as a colorless oil: 1H NMR H (CDCI ₃ ) δ 7.64 (2H, d, J = 8.3 Hz), 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 = 6.7 Hz), 2.82 (2H, q, J = 7.6 Hz), 2, 66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J = 7.6 Hz).

EXAMPLE 5

2-ETHYL-5,7-DIMETHYL 3- (4- {2-rMETHIL ({r (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL} PHENYL) -3WMIDAZOf4,5-Z? 1PYRIDINE

STEP 1. A / - {2-í4- (2-Ethyl-5,7-dimethyl-3 / - / - imidazoí4,5-d1pyridin-3yl) phenyl1ethyl) -A / -methylamine

A mixture of 3- [4- (2-chloroethyl) phenyl] -2-ethyl-5,7dimethyl-3H-imidazo [4,5-b] pyridine (step 7 of Example 1, 627 mg, 9, 0 mmoles), a solution of methylamine (40% in methanol, 6 ml) and water (6 ml) in a sealed tube, and heated overnight at 130 ° C. The reaction mixture was fractionated by pouring over dichloromethane (50 ml) 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 (50 ml) and dried (Na2SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (5: 1), to obtain 523 mg (85%) of the title compound, under the form of white solids: ¹ H NMR (CDCl 3) δ 7.41 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.90 ( 1H, s), 4.73 (1H, s lg.), 2.93 (4H, s), 2.82 (2H, q, J = 7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H, t, J = 7.5 Hz).

STEP 2. 2-Ethyl-5,7-dimethyl-3- (4-f2-methyl ((((4-methylphenyl) -sulfonillamino} carbonyl) amino1-ethyl} phenyl) -3 / - / - imidazoí4 ₁ 5-fr | pyridine

P-toluenesulfonyl isocyanate 400 mg, 2.0 mmol) was added to a solution of N- {2- [4- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-o] pyridin -3-yl) phenyl] ethyl} - / V-methylamine (step 1, 523 mg, 1.7 mmol) in dichloromethane 120/451 no (10 mL) and triethylamine (2 mL). The resulting reaction mixture was stirred at room temperature for 6 hours. After removing the solvent, the residue was purified by flash column chromatography on silica gel with dichloromethane / methanol (10: 1) to obtain 358 mg (42%) of the title compound as white solids: NMR ¹ H (CDCI ₃ ) δ 7.93 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.4 Hz), 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 = 7.2 Hz).

EXAMPLE 6

2-ETYL-5,7-DIMETHYL 3- (4- {2-i (ir (4-METHYLPHYL) -SULPHONY] AMINO) CARBONlL) AMINOlPROPIL) PHENYL) -3B-IMIDAZOr4,5-bl-PYRIDINE

STEP 1. 1- (4-Aminophenyl) -2-propanol

A mixture of 1- (4-nitrophenyl) -2-propanol (Schadt, FL; et al., J.Am.Chem.Soc., 1978, 100, 228., 2.2 g, 12.3 mmoles) was heated ), powdered iron (3.3 g, 59.1 mmoles), ammonium chloride (370 mg, 6.9 mmoles), ethanol (48 ml) and water (24 ml) at reflux temperature 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 (200 ml) and washed with water (2 x 100 ml). The organic phase was dried (MgSO ₄ ) and concentrated. Purified by flash column chromatography on silica gel with hexane / ethyl acetate (1: 1) to obtain 1.45 g (78%) of the title compound as a yellow oil: NMR of ¹ H (CDCI ₃ ) δ 7.00 (2H, d, J = 8.6 Hz), 6.64 (2H, d, J = 8.8 Hz), 3.99-3.89 (1H, m ), 3.60 (2H, s lg.), 2.722.52 (2H, m), 1.22 (3H, d, J = 6.2 Hz).

STEP 2. 1 ^ - ^ X-Dimethyl-S-nitro ^ -pyridineDaminolfeniD ^ -propanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 1- (4-aminophenyl) -2-propanol (step 1) and 2-chloro-4,6-dimethyl-3- nitropyridine (step 2 of Example 1).

¹ H NMR (CDCI ₃ ) δ 9.59 (1H, s lg.), 7.58 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz ), 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, t, J = 6.2 Hz).

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STEP 3. 1- {4 - [(3-AminoA6-dimethyl-2-pyridinyl) amino1phenyl} -2-propanol

A mixture of 1- {4 - [(4,6-dimethyl-3-nitro-2pyridinyl) amino] phenyl} -2-propanol (step 2, 500 mg, 1.66 mmol), iron powder ( 440 mg, 7.88 mmoles), ammonium chloride (80 mg, 1.5 mmol) in ethanol / water (volume / volume, 31: 8, 39 ml) at reflux temperature for 2 hours. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with water (2 x 100 ml). The organic phase was dried (MgSO ₄ ), and concentrated. Removal of the solvent gave 450 mg (quant.) Of the title compound, as brown solids: TLC Rf = 0.10 (hexane / ethyl acetate = 1: 1).

STEP 4. 2-R4- (2-ethyl-5,7-dimethyl-3H-imidazo [4,55lpiridin-3-yl) phenyl1-1-methylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- {4 - [(3-amino-4,6-dimethyl-2pyridinyl) amino-phenyl} -2-propanol (step 3 ) and propionyl chloride.

TLC Rf = 0.30 (hexane / ethyl acetate = 1: 1).

STEP 5. 1- [4- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b1pyridin-3-yl) phenill-2-propanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5,7dimethyl-3H-imidazo [4,5-b] pyridinium propionate) 3-yl) phenyl] -1-methylethyl (step 4).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 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 6. 3- [4- (2-Chloropropyl) phenyl1-2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-blpiridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 1- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-O] pyridin ~ 3-yl) phenyl] -2-propanol (step 5).

TLC Rf = 0.50 (hexane / ethyl acetate = 1: 1).

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STEP 7. 2-yl- (2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-b1pyridin-3-yl) phenyl1-1-methylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloropropyl) phenyl] -2ethyl-5,7-dimethyl-3H-imidazo [4,5 -b] pyridine (step 6).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 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 = 6.6 Hz), 1.27 (3H, t, J = 7.5 Hz).

STEP 8. 1-f4- (2-Ethyl-5.7-dimethyl-3H-imidazo [4.5-5lpiridin-3-yl) phenill-2-propanamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine-azide) 3-yl) phenyl] -1-methylethyl (step 7).

¹ H 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 = 8.3 Hz), 1.19 (3H, d, J = 6.8 Hz).

STEP 9. 2-Ethyl-5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonillamino) carbonyl) amino1propyl) phenyl) -3 / - / - imidazo [4.5-jb1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- 3yl) phenyl] -2-propanamine (step 8).

Mp: 128 ° C; MS (IED) m / z 506.19 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.74 (2H, d, J = 8.3 Hz), 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-f4- (2-ETHYL-5,7DIMETHYL-3H-IMIDAZO-4.5-BLPYRIDIN-3-IL) 4-METHYLENIDSULFONYL CARBAMATE) PHENYL-1-Methylethyl

The title compound was prepared according to the procedure described in Example 3 from 1- [4- (2-ethyl-5,7-dimethyl-37 / -imidazo [4,5b] pyridin-3-yl) phenyl] -2-propanol (step 5 of Example 6).

Mp: 108 ° C; MS (IED) m / z 507.18 (M + Hf; ¹ H NMR (CDCI ₃ ) δ 7.91 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.23 (4H, s), 6.91 (1H, s),

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5.10-5.04 (1Η, 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) SULFONYLAMINO) CARBQNIL) AMINO1ETYL} PHENYL) -2-PROPIL-3/7-IMIDAZO [4 ₁ 5- £> 1PYRIDINE

STEP 1. 2-f4- (5 ₁ 7-dimethyl-2-propyl-3/7-imidazo [4,5pyridin-3-yl) pheniHetifa butyrate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-4,6-dimethyl-2pyridintl) amino] phenyl} ethanol (step 4 of Example 1) and butyryl chloride.

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 6.92 (1H, s), 4.39 (2H, t, J = 6.4 Hz), 3.09 (2H, t, J = 6.4 Hz), 2.77 (2H, t, J = 7.7 Hz), 2, 66 (3H, s), 2.52 (3H, s), 2.32 (2H, t, J = 7.7 Hz), 1.81-1.58 (4H, m), 1.00-0 , 86 (6H, m).

STEP 2. 2-r4- (5,7-Dimethyl-2-propit-3Wmidazof4.5-ò1pyridin-3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5,7-dimethyl2-propyl-3H-imidazo [4,5-b] pyridine-butyrate) 3-yl) phenyl] ethyl (step 1).

¹ H NMR (CDCl ₃ ) δ 7.43 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 6.90 (1H, s), 4.00-3.89 (2H, m), 2.97 (2H, t, J = 6.4 Hz), 2.78 (2H, t, J = 7.8 Hz), 2.65 (3H , s), 2.51 (3H, s), 1.80-1.64 (2H, m), 0.92 (3H, t, J = 7.4 Hz).

STEP 3. 3-f4- (2-Chloroethylphenin-5,7-dimethyl-2-propyl-3 / - / - imidazole ^ .S-pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (5,7-dimethyl-2-propyl-3 / - / imidazo [4,5-b] pyridine-3-yl) phenyl] ethanol (step 2).

MS (IE) m / z 327 (M ⁺ ).

STEP 4. 2- [4- (5,7-dimethyl-2-propyl-3/7-imidazo] [4,5- £> 1pyridin-3-ihpheninetyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -5.7124 / 451 dimethyl-2-propyl-3 / 7- imidazo [4,5-ò] pyridine (step 3).

MS (IE) m / z 334 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 3.60 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.8 Hz), 2, 65 (3H, s), 2.52 (3H, s), 1.75-1.62 (2H, m), 0.90 (3H, t, J = 7.4 Hz).

STEP 5. 2-f4- (5.7-Dimethyl-2-propii-3/7-imidazo [4,5-Ó1pyridin-3-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (5,7-dimethyl-2propyl-3/7-imidazo [4,5-2] azide] pyridin-3-yl) phenyl] ethyl (step 4).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 6.88 (1H, s), 3.89 (2H, s lg.), 3.18 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 6.8 Hz), 2.75 (2H, t , J = 7.5 Hz), 2.64 (3H, s), 2.48 (3H, s), 1.78-1.63 (2H, m), 0.90 (3H, t, J = 7.3 Hz).

STEP 6. 5,7-Dimethyl-3- (4- {2-i ({í (4-methylphenyl) sulfonyl-amino> carbonyl) amine-ethyl) phenyl) -2-propyl-3/7-imidazoF4,5-b1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5,7-dimethyl-2-propyl3H-imidazo [4,5-b] pyridin-3- il) phenyl] ethylamine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.86 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.23 (2H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.3 Hz), 6.90 (1H, s), 6.10 (1H, s lg.), 3.58-3.46 (2H, m), 2.87 (2H, t, J = 6.4 Hz), 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 = 7.0 Hz).

EXAMPLE 9

2-ISOPROPIL-5,7-DIMETHYL 3- (4- {2-í ({r (4-METHYLphenyl) -SULPHONYL1AMINO) CARBONIL) AMINO1ETYL} PHENYL-3/7-1MIDAZOF4,5-b1PIRlDINA

STEP 1, 5-Bromo-4,6-dimethyl-3-nitro-2-pyridinol

Sodium nitrite (1.1 g, 16 mmol) was added in small portions to a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine (Heitsch, H .; et al., Bioorg. Med. Chem., 1997, 5, 673., 2.0 g, 8.1 mmoles) in trifluoroacetic acid / water (volume / volume, 2: 1, 30 mL) at temperature

125/451 at room temperature, and the reaction mixture was stirred overnight. The resulting precipitates were removed by filtration, washed with water, and dried under reduced pressure to obtain 2.2 g (quant.) Of the title compound: ¹ H NMR (CDCl ₃ ) S 2.53 (3 H , s), 2.38 (3H, s).

STEP 2. 3-Bromo-6-chloro-2,4-dimethyl-5-nitropyridine

The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-bromo-4,6-dimethyl-3-nitro-2pyridinol (step 1).

¹ H NMR (CDCI ₃ ) δ 2.72 (3H, s), 2.41 (3H, s).

STEP 3. 2- {4 - [(5-Bromo-4,6-dimethyl-3-nitro-2-pyridinyl) amino1phenyethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-bromo-6-chloro-2,4-dimethyl5-nitropyridine (step 2) and aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) ô 8.66 (1H, s lg.), 7.51 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz ), 3.90-3.77 (2H, m), 2.88 (2H, t, J = 6.5 Hz), 2.65 (3H, s), 2.59 (3H, s).

STEP 4. 2-f4-i (3-Amino-5-bromo-4,6-dimethyl-pyridinyl) amino1-phenylethanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2 {4 - [(5-bromo-4,6-dimethyl-3nitro-2-pyridinyl) amino] phenyl} ethanol ( step 3).

¹ H NMR (CDCI ₃ ) δ 7.12 (4H, s), 6.21 (1H, s), 3.38 (1H, s lg.), 3.82 (2H, t, J = 6, 5 Hz), 2.80 (2H, t, J = 6.5 Hz), 2.54 (3H, s), 2.38 (3H, s).

STEP 5. 2-3,4- (6-bromo-2-isopropyl-5.7dimethyl-3H-imidazoyl4,5-blpiridin-3-yl) 2-methylpropanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5-bromo-4,6dimethyl-2-pyridinyl) amino] phenyl} ethanol (step 4) and isobutyryl chloride.

MS (IE) m / z457 (M ⁺ ).

STEP 6. 2- [4- (6-Bromo-2-isopropyl-5,7-dimethyl-3/7-imidazoyl4,5frlpyridin-3-yl) phenyl1ethanol

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The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6bromo-2-isopropyl-5,7-dimethyl-3/7-imidazo [2-methylpropanoate] 4,5-ò] pyridin-3-yl) phenyl] ethyl (step 5).

¹ H NMR (CDCl ₃ ) δ 7.45 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 3.96 (2H, t, J = 7.3 Hz), 3.15-3.03 (1H, m), 2.97 (2H, t, J = 7.3 Hz), 2.76 (3H, s), 2.67 (3H , s), 1.34 (6H, d, J = 6.8 Hz).

STEP 7,6-Bromo-3-f4- (2-chloroethyl) phenin-2-isopropyl-5,7-dimethyl3 / 7-imidazoí4.5-b1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-bromo-2-isopropyl5,7-dimethyl-3 / - / - imidazo [4,5 -b] pyridin-3-yl) phenyl] ethanol (step 6).

¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.3 Hz), 7.32 (2H, t, J = 8.3 Hz), 3.81 (2H, t, J = 7.3 Hz), 3.19 (2H, t, J = 7.3 Hz), 3.15-3.02 (1H, m), 2.76 (3H, s), 2.66 (3H , s), 1.33 (6H, d, J = 6.9 Hz).

STEP 8. 2-yl- (6-bromo-2-isopropyl-5 _< 7-dimethyl-3 / - / imidazof4,5-frlpyridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-bromo-3- [4- (2-chloroethyl) phenyl] -2-isopropyl-5,7-dimethyl-3 / 7-imidazo [4,5-b] pyridine (step 7).

MS (IE) m / z 412 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 3.60 (2H, t, J = 6.5 Hz), 3.16-3.02 (1H, m), 3.02 (2H, t, J = 6.5 Hz), 2.77 (3H, s), 2.68 (3H , s), 1.33 (6H, d, J = 6.9 Hz).

STEP 9. f4- (2-lsopropyl-5,7-dimethyl-3/7-imidazoi4,5-blpiridin-3ihphenyethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-bromo-2isopropyl-5,7-dimethyl-3/7-imidazo [4, 5-b] pyridin-3-II) phenyl] ethyl (step 8).

¹ H NMR (CDCI ₃ ) δ 7.49 (2H, d, J = 8.3 Hz), 7.28 (2H, t, J = 8.3 Hz), 6.93 (1H, s), 6.60 (2H, s lg.), 3.32-3.00 (5H, m), 2.65 (3H, s), 2.48 (3H, s), 1.31 (6H, d, J = 6.8 Hz).

STEP 10. 2-lsopropyl-5,7-dimethyl-3- (4- {2-r (ph (4-methylphenyl) -sulfonylamino} carbonihaminoletyl) phenyl) -3 / - / - imidazof4,5-j £ ) l pyridine

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The title compound was prepared according to the procedure described in step 10 of Example 1 from [4- (2-lsopropyl-5,7-dimethyl3H-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 9).

¹ H NMR (CDCI ₃ ) δ 7.87 (2H, d, J = 8.3 Hz), 7.31 (2H, t, J = 8.3 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 6.08 (1H, s lg.), 3.56-3.43 (2H, m), 3.02-2.89 (1H, m), 2.85 (2H, t, J = 6.3 Hz), 2.67 (3H, s), 2.41 (6H, s), 1.26 (6H, d, J = 6.8 Hz).

EXAMPLE 10

SODIUM SALT OF 2-ISOPROPIL-5,7-DIMETHYL 3- (4- (2-r ({í (4METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3 / 7-IMIDAZE [4,5- £> 1PYRIDINE

The title compound was prepared according to the procedure described in Example 2 from 2-isopropyl-5,7-dimethyl-3- (4- {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-b] pyridine (Example 9).

MS (IED) m / z 506 (M + H) ⁺ .

EXAMPLE 11

2-BUTYL-5,7-DIMETHYL-3- (4-22-r «r (4-METHYLphenyl) -SULPHONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -3WMIDAZOr4,5-òlPyridine

STEP 1. 2-yl- (6-bromo-2-butyl-5,7-dimethyl-3 / - / imidazo [4,5-blpiridin-3-yl) phenyl1ethyl pentanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5-bromo-4,6dimethyl-2-pyridinyl) amino] phenyl} ethanol (step 4 of Example 9) and pentanoyl chloride.

MS (IE) m / z 485 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 4.37 (2H, t, J = 6.9 Hz), 3.05 (2H, d, J = 6.9 Hz), 2.79 (2H, t, J = 7.7 Hz), 2.75 (3H, s), 2, 67 (3H, s), 2.33 (2H, t, J = 7.5 Hz), 1,751.54 (4H, m), 1.40-1.20 (4H, m), 0.91 (3H , t,> 7.3 Hz), 0.84 (3H, t, J = 7.3 Hz).

STEP 2. 2-f4- (6-Bromo-2-butyl-5,7-dimethyl-3/7-imidazo [4,5-ib1pyridin-3-yl) phenyl1ethanol

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The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6bromo-2-butyl-5,7-dimethyl-3H-imidazo [4,5- b] pyridin-3-yl) phenyl] ethyl (step 1).

MS (IE) m / z 401 (M ⁺ ).

STEP 3. 6-Bromo-2-butyl-3-i4- (2-chloroethyl) phenyl1-5,7-dimethyl-3Himidazor4.5-b1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-bromo-2-butyl-5,7dimethyl-3/7-imidazo [4,5- ò] pyridin-3-yl) phenyl] ethanol (step 2).

MS (IE) m / z 419 (M ⁺ ).

STEP 4, 2- [4- (6-bromo-2-butyl-5,7-dimethyl-3 / - / - imidazof4,5-b1pyridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-bromo-2-butyl-3- [4- (2 chloroethyl) phenyl] -5,7-dimethyl-3H-imidazo [4,5-b] pyridine (step 3).

MS (IE) m / z 426 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.4 Hz), 7.33 (2H, t, J = 8.4 Hz), 3.61 (2H, t, J = 7.2 Hz), 3.01 (2H, d, J = 7.2 Hz), 2.79 (2H, t, J = 7.9 Hz), 2.75 (3H, s), 2, 67 (3H, s), 1.75-1.60 (2H, m), 1.361.20 (2H, m), 0.84 (3H, t, J = 7.3 Hz).

STEP 5, 2-r4- (2-Butyl-5,7-dimethyl-3H-imidazor4,5-b1pyridin-3-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-bromo-2butyl-5,7-dimethyl-3tf-imidazo [4,5- ò] pyridin-3-yl) phenyl] ethyl (step 4).

¹ H NMR (CDCIs) 8 7.59 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 6.90 (1H, s), 3 , 52-3.22 (4H, m), 3.01 (2H, s lg.), 2.90 (2H, t, J = 7.7 Hz), 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 = 7.5 Hz).

STEP 6. 2-Butyl-5.7-dimethyl-3- (4- (2-i ((f (4-methylphenyl) sulfonillamino) carbonyl) amino1ethyl | phenyl) -3 / - / - imidazor4,5-òlpyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-butyl129 / 451 pentanoate

5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.86 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.91 (1H, s), 6.09 (1H, s lg.), 3.56-3.44 (2H, m), 2.84 (2H, t, J = 6.4 Hz), 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 = 7.3 Hz).

EXAMPLE 12

2-BUTYL-5 SODIUM SALT ₁ 7-DIMETHYL-3- (4-f2T ({f (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZO

Γ4.5-51 PYRIDINE

The title compound was prepared according to the procedure described in Example 2 from 2-Butyl-5,7-dimethyl-3- (4- {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / - / - imidazo [4,5-5] pyridine (Example 11).

EXAMPLE 13

2-ISOBUTYL-5,7-DIMETHYL-3- (4- {2-f (fr (4-METHYLphenyl) SULPHONYLAMINO) CARBONlL) AMlNO1ETIL) PHENYL) -3H-IMlDAZOí4,5-blPYRIDINE

STEP 1. 2-R4- (2-isobutyl-5,7-dimethyl-3Himidazoí4 ₁ 5-51pyridin-3-i) phenylethyl 3-methylbutanoate

The title compound was prepared according to the procedure described in step 5 in Example 1 from 2- {4- [3-amino-4,6-dimethyl-2pyridinyl) amino] -phenyl] ethyl (step 4 of Example 1) and isovaleryl chloride.

MS (IE) m / z 407 (M ⁺ ).

STEP 2. 2-4- (2-lsobutil-5,7-dimethyl-3H-imidazoí4 b1piridin _I 5-3-yl) fenir | ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2isobutyl-5,7-dimethyl-3/7-imidazo [4,5- 3-methylbutanoate] b] pyridin-3-yl) phenyl] ethyl (step 1).

MS (IE) m / z 323 (M ⁺ ).

STEP 3. 3- [4- (2-Chloroethyl) phenyl1-2-isobutyl-5,7-dimethyl-3/7-imidazo [4,5-frlpyridine

The title compound was prepared according to the procedure 130/451 as described in step 7 of Example 1 from 2- [4- (2-isobutyl-5,7-dimethyl3H-imidazo [4,5-b] pyridin ~ 3-yl) phenyl] ethanol (step 2).

MS (IE) m / z 341 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.41 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 6.90 (1H, s), 3.80 (2H, t, J = 6.5 Hz), 3.18 (2H, t, J = 6.5 Hz), 2.68 (2H, d, J = 7.5 Hz), 2, 66 (3H, s), 2.51 (3H, s), 2.14-1.96 (1H, m), 0.86 (6H, d, J = 6.6 Hz).

STEP 4. 2-Í4- (2-isobutyl-5,7-dimethyl-3/7-imidazoyl4,5-51 pyridin-3-yl) pheninetyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -2isobutyl-5,7-dimethyl-3H-imidazo [4,5 -b] pyridine (step 3).

MS (IE) m / z 348 (M ⁺ ); ¹ H NMR (CDCfe) δ 7.42 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 3 , 60 (2H, t, J = 6.5 Hz), 3.00 (2H, t, J = 6.5 Hz), 2.69 (2H, d, J = 7.5 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.08-1.98 (1H, m), 0.87 (6H, d, J = 6.7 Hz).

STEP 5. 2-í4- (2-lsobutyl-5,7-dimethyl-3/7-imidazo [4,5-ò1pyridin-3ipphenyrethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-isobutyl-5,7dimethyl-3H-imidazo [4,5-b] pyridine-azide) 3-yl) phenyl] ethyl (step 4).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 6.91 (1H, s), 3.09 (2H, t, J = 6.4 Hz), 2.93 (2H, t, J = 6.4 Hz), 2.80 (2H, s lg.), 2.68 (2H, d , J = 7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 2.18-2.00 (1H, m), 0.88 (6H, d, J = 6.8 Hz).

STEP 6. 2-lsobutyl-5,7-dimethyl-3- (4- (2-y (n (4-methylphenyl) sulfonyl-amino) carbonyl) amine-ethyl) phenyl) -3H-imidazof4.5-Z? Lpyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-isobutyl-5,7-dimethyl3 / 7-imidazo [4,5-b] pyridin- 3-yl) phenyl] ethylamine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.85 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 6.91 (1H, s), 6.14 (1H, s lg.), 3.55-3.42 (2H, m), 2.82 (2H, t, J = 6.3 Hz), 2.65 (3H, s), 2.53 (2H,

131/451 d, J = 7.3 Hz), 2.41 (3H, s), 2.39 (3H, s), 2.10 - 1.92 (1H, m), 0.81 (6H, d, J = 6.6 Hz).

EXAMPLE 14

SODIUM SALT OF 24SOBUTYL-5 ₁ 7-DIMETHYL-3- (4-f2-f '(4-METHYLPHENYL) SULPHONYLAMINO) CARBONYL) AMINQ1ETYL} PHENYL) -3H-IM1DAZOÍ4,5-fc> 1PYRIDINE

The title compound was prepared according to the procedure described in Example 2 from 2-1-butyl-5,7-dimethyl-3- (4- {2 - [({[(4methylphenyl) sulfonyl] -amino} carbonyl ) amino] ethyl} phenyl) -3H-imidazo [4,5-b] pyridine (Example 13).

MS (IE) m / z 520 (M + H ⁺ ).

EXAMPLE 15

5 ₁ 7-DIMETHIL-3- (4-f2-r (U (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) FENlL) -2-NEOPENTlL-3H-IMIDAZOr4,5-ò] PIRl ·

PINA

STEP 1. 2-3,4- (2-neopentyl-5,7-dimethyl3H-imidazo [4,5-frlpiridin-3-yl) phenyl1ethyl] 3,3-dimethylbutanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-4,6-dimethyl-2pyridinyl) amino] phenyl} ethanol (step 4 of Example 1) and tertbutylacetyl chloride.

MS (IE) m / z 435 (M ⁺ ).

STEP 2. 2-r4- (2-Neopentyl-5 ₁ 7-dimethyl-3/7-imidazo [4,5-ò1pyridin3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4 (2-neopentyl-5,7-dimethyl-3H-imidazo [4,5] 3,3-dimethylbutanoate] -b] pyridin-3-yl) phenyl] ethyl (step 1).

MS (IE) m / z 337 (M ⁺ ).

STEP 3. 3-r4- (2-Chloroethyl) phenyl1-2-neopentyl-5 ₁ 7-dimethyl-3 / - / - imidazoí4,5-ò1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-neopentyl-5,7-dimethyl132 / 451

3H-imidazo [4,5-b] pyridin-3-yl) phenyl] ethanol (step 2).

¹ H NMR (CDCI ₃ ) δ 7.41 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 6.89 (1H, s), 3.81 (2H, t, J = 6.5 Hz), 3.18 (2H, t, J = 6.5 Hz), 2.79 (2H, s), 2.66 (3H, s), 2.51 (3H, s), 0.89 (9H, s).

STEP 4. 2-R4- (2-neopentyl-5,7-dimethyl-3H-imidazo [4,5ò1pyridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (3-chloroethyl) phenyl] -2neopentyl-5,7-dimethyl-3 / - / - imidazo [ 4,5-b] pyridine (step 3).

MS (IE) m / z 362 (M *); ¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.91 (1H, s), 3.62 (2H, t, J = 6.5 Hz), 3.02 (2H, t, J = 6.5 Hz), 2.78 (2H, S), 2.68 (3H, s), 2.53 (3H, s), 0.88 (9H, s).

STEP 5. 2- [4- (2-Neopentyl-5,7-dimethyl-3/7-imidazo [4 ₁ 5-b1pyridin3-yl) phenyl1ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-neopentyl5,7-dimethyl-3/7-imidazo [4,5-ò] azide pyridin-3-yl) phenyl] ethyl (step 4).

MS (IE) m / z 336 (M ⁺ ).

STEP 6. 2-Neopentyl-5,7-dimethyl-3- (4- {2-r (U (4-methylphenyl) -sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -3H-imidazo [4,5-piroline

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-neopentyl-5,7dimethyl-3tf-imidazo [4,5-b] pyridin-3- il) phenyl] ethylamine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.86 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.91 (1H, s), 6.18 (1H, s lg.), 3.56-3.46 (2H, m), 2.85 (2H, t, J = 6.4 Hz), 2.65 (3H, s), 2.60 (2H, s), 2.41 (3H, s), 2 , 40 (3H, s), 0.87 (9H, s).

EXAMPLE 16

5,7-DIMETHIL-3- (4- {2-r ((r (4-METHYLFENlL) SULFONYL1AMINO) CARBONlL) AMINO1ETYL) PHENYL) -2-NEOPENTYL-3/7-IMIDAZOr4,5-frlPIRIDINE SODIUM SALT

The title compound was prepared according to the procedure

133/451 as described in Example 2 from 5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] -amino} carbonyl) amino] ethyl} phenyl) -2- neopentyl-3 / - / - imidazo [4,5-b] pyridine (Example 15).

MS (IED) m / z 534 (M + H ⁺ ).

EXAMPLE 17

5,7-DIMETHYL 3- (4- {2 - [({[(4-METHYLPHENYL) SULFONIL1AMINQ} CARBONYL) AMINO1ETYL) PHENYL) -2- [2- (1,3-TIAZQL-2-IL) ETILl- 3/7-IMIDAZOF4,5-ò1PYRIDINE

STEP 1. / V-14- (2-Chloroethyl) phenyl1- / V- (4,6-dimethyl-3-nitro-2-pyridinyl) amine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4 - [(4,6-dimethyl-3-nitro-2pyridyl) amino] phenyl] ethanol (step 3 of Example 1).

¹ H NMR (CDCI ₃ ) δ 9.46 (1H, s lg.), 8.29 (1H, d, J = 8.8 Hz), 7.42 (1H, d, J = 1.7 Hz ), 7.35 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 6.97 (1H, dd, J = 8.8 Hz, 1, 7 Hz), 3.77 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz).

STEP 2. A / ² - ['4- (2-Chloroethyl) phenill-4 ₁ 6-dimethyl ~ 2,3-pyridinediamine

The title compound was prepared according to the procedure described in step 3 of Example 6 from / V- [4- (2-chloroethyl) phenyl] - / V- (4,6 dimethyl-3-nitro-2- pyridinyl) amine (step 1).

MS (IE) m / z 383 (M ⁺ ).

STEP 3. 3- [4- (2-Chloroethyl) phenill-5,7-dimethyl-2-r2- (1,3-thiazol-2yl) ethyl-3 / - / - imidazoí4.5-bl pyridine

1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (192 mg, 1.0 mmol) was added, in a single portion, to a mixture of A / ² - [4- (2-chloroethyl ) phenyl] -4 _> 6-dimethy-2,3-pyridinedietaryrin (step 2, 276 mg, 1.0 mmol) and 3- (1,3-thiazol-2-yl) propanoic acid (157 mg, 1.0 mmol) in dichloromethane (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene (20 ml) and heated at 150 ° C for 5 hours. The reaction mixture was poured into water (50 ml), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (45 ml) (100 ml). The combined organic phases were washed with brine (50 ml) and dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), to obtain 210 mg (53%) of the title compound : MS (IE) m / z 396 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.63 (1H, d, J = 3.4 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.15 (1H, d, J = 3.4 Hz), 6.93 (1H, s), 3.78 (2H, t, J = 7.4 Hz), 3.69 -3.50 (2H, m), 3.39-3.20 (2H, m), 3.15 (2H, t, J = 7.4 Hz), 2.66 (3H, s), 2, 53 (3H, s).

STEP 4. 2- (4- (5,7-dimethyl-2-f2- (1,3-thiazol-2-yl) ethin-3Hididazo | 4,5-òlpyridin-3-yl} phenyl) ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-Chloroethyl) phenyl] -5,7dimethyl-2- [2- (1,3-thiazole -2-yl) ethyl] -3H-imidazo [4,5-o] pyridine (step 3).

MS (IE) m / z 403 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.63 (1H, d. J = 3.5 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.15 (1H, d, J = 3.5 Hz), 6.93 (1H, s), 3.63-3.54 (4H, m), 3.34-3 , 26 (2H, m), 2.98 (2H, t, J = 7.4 Hz), 2.68 (3H, s), 2.53 (3H, s).

STEP 5. 2- (4f-5,7-Dimethyl-2-j2- (1,3-thiazol ~ 2-yl) ethyl-3 / - / - imidazo r4.5-ò1pyridin-3-yl} phenyl) - Ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- (4- {5,7-dimethyl-2 [2- (1,3-thiazol-2-yl) azide ) ethyl] -3H-imidazo [4,5-ò] pyridin-3-yl} phenyl) ethyl (step 4).

MS (IE) m / z 377 (M ⁺ ).

STEP 6. 5,7-Dimethyl-3- (4- {2-r (if (4-methylphenyl) sulfonillamino) carbonyl) aminoletyl} phenyl) 2f2- (1,3-thiazol-2-yl) ethyl -3H- imidazor4,5-b1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- (4 {-5,7-Dimethyl-2- [2- (1,3thiazol-2-yl) ethyl] -3H-imidazo [4,5-b] pyridin-3-yl} phenyl) ethylamine (step 5).

MS (IED) m / z 575 (M + H ⁺ ); ¹ H NMR (CDCl 3) δ 7.83 (2H, d, J = 8.3 Hz), 7.61 (1H, d, J = 3.5 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.19-7.15 (3H, m), 7.07 (2H, d, J = 8.2 Hz), 6.91 (1H, s), 6.21 (1H, s lg.), 3.52-3.40 (4H, m), 3.203.13 (2H, m), 2.81 (2H, t, J = 6.1 Hz), 2.65 (3H, s ), 2.44 (3H, s), 2.41 (3H, s).

135/451

EXAMPLE 18

3- {4- [2 - ({[(4-BIPhenylSULFONIL) AMINQ1CARBONIL) -AMINO) ETYL1-PHENYL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-ò1PIRLDINA

STEP 1. 2- [4- (2-ethyl-5,7-dimethyl-3 / - / - imidazo _[4-I 5 ólpiridin-3-yl) Phenyl fenilletilcarbamato

Phenyl chloroformate (0.69 mL, 5.5 mmol) was added dropwise to a solution, with stirring, of 2- [4- (2-ethyl-5,7-dimethyl-3 / 7- imidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmoles) and triethylamine (0.80 ml, 5.8 mmoles) in dichloromethane ( 26 ml), cooled in an ice bath, and the mixture was stirred at room temperature. After 30 minutes, the reaction mixture was fractionated by pouring over saturated aqueous sodium bicarbonate solution (30 ml) and dichloromethane (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane / hexane to obtain 1.90 g (87%) of the title compound as light brown crystals: ¹ H NMR (CDCl ₃ ) δ 7.43-7, 11 (9H, m), 6.91 (1H, s), 5.50 (1H, s lg.), 3.57 (2H, pseudo q, J = 6.9 Hz), 2.98 (2H, t, J = 6.9 Hz), 2.83 (2H, q, J = 7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J = 7.6 Hz).

STEP 2. 3- {4-1,2- (U (4-Biphenylsulfonyl) amino1carbonyl) amino) -ethin phenyl | -2-ethyl-5.7-dimethyl-3 / - / - imidazo [4,5-ópyridine

NaH (60% oil dispersion, 20 mg, 0.5 mmol) was added to a solution, under stirring, of 4-biphenylsulfonamide (Greenlee, WJ; Walsh, TF; et al., Eur. Pat. AppL, EP 617001 (1994); 56 mg, 0.24 mmol) in DMF (3 mL) at room temperature. After 5 minutes, added 2- [4- (2-ethyl-5,7dimethyl-3H-imidazo [4,5-ó] pyridin-3-yl) phenyl] ethyl phenylcarbamate (step 1, 100 mg, 0.24 mmol), and the mixture was stirred for an additional 1 hour. The mixture was poured into water (50 ml) and extracted with diethyl ether (2 x 50 ml). The combined extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO ₄ ). Removal of the solvent yielded white oily solids. Purification by preparative TLC (ethyl acetate) obtained

136/451 mg (50%) of the title compound, as a colorless oil: MS (IED) m / z 554 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.06 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.60-7.53 (2H , m), 7.48-7.36 (3H, m), 7.21 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.3 Hz), 6 , 92 (1H, s), 6.11 (1H, t lg., J = 5.5 Hz), 3.54 (2H, dt, J = 5.9, 6.0 Hz), 2.89 ( 2H, d, J = 6.0 Hz), 2.64 (2H, q, J = 7.5 Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 ( 3H, t, J = 7.5 Hz).

EXAMPLE 19

2-ETIL-57-DIMETHIL-3- {4-r2- (f [(1-NAFTILSULFONIL) -AMINO1

CARBONIL) AMINO) ETYL1-PHENYL) -3H-IMIDAZOr4,5-ò1PYRIDINE

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / - / imidazo [4,5-ó] pyridin-3-yl) phenyl] ethyl phenylcarbamate (step 1 of Example 18) and 1-naphthylsulfonamide (Arnswald, M .; Neumann, WP; Chem. Ber., 1991, 124, 1997; Khorgami, Μ. H .; Synfhesis, 1972, 574).

MS (IED) m / z 528 (M + H ⁺ ); ¹ H NMR (CDCl ₃ ) δ 8.52-8.48 (1H, m), 8.36 (1H, dd, J = 1.1, 7.3 Hz), 8.11 (1H, d, 8.3 Hz), 8.00-7.94 (1H, m), 7.63-7.50 (3H, m), 7.20 (2H, d, J = 8.4 Hz), 7, 13 (2H, d, J = 8.4 Hz), 6.94 (1H, s), 6.32 (1H, t lg., J = 5.7 Hz), 3.50 (2H, dt, J = 5.9, 6.0 Hz), 2.82 (2H, t, J = 6.2 Hz), 2.68 (2H, q, J = 7.5 Hz), 2.65 (3H, s ), 2.41 (3H, s), 1.21 (3H, t, J = 7.5 Hz). EXAMPLE 20

2-ETHYL-5,7-D1METHIL-3- (4- [2- (f [(2-NAFTYLSULFONIL) -AMINOLCARBONYL) AMINO) ETHYLphenyl} -3H-IMIDAZOr4,5-ó1Pyridine

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-h] pyridin- Phenyl 3-yl) phenyl] ethylcarbamate (step 1 of Example 18) and 2-naphthylsulfonamide.

MS (IED) m / z 528 (M + H ⁺ ); ¹ H NMR (CDCI ₃ ) 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 = 5.6 Hz), 3.52-3.45 (2H, q, J = 6.1 Hz ), 2.84-2.80 (2H, t, J = 6.3 Hz), 2.71-2.62 (2H, q, J = 6.6 Hz), 2.66 (3H, s) , 2.43 (3H, s), 1.22-1.16 (3H, t, J = 6.6 Hz).

137/451

EXAMPLE 21

2- ETHYL-5,7-DIMETHIL-3- (4- {2-r «r (2-THENYL) SULPHONYL-AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZOr4,5-51PYRIDINE

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- 3-yl) phenyl] phenyl ethyl carbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, HC; Reinhard, EJ; Reitz, DB; Tetrahedron Lett., 1994, 35, 7201; Graham, SL; Scholz, TH ; Synthesis, 1986, 1031).

¹ H NMR (CDCI ₃ ) δ 8.01 (1H, s), 7.78 (1H, dd, J = 1.3, 4.9 Hz), 7.63 (1H, dd, 1.3, 4.9 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.09 (1H, dd, J = 3, 8, 5.0 Hz), 6.92 (1H, s), 6.05 (1H, t, J = 5.3 Hz), 3.53 (2H, q, J-6.2 Hz), 2 , 96 (3H, s), 2.88 (3H, s), 2.87 (2H, t, J = 6.2 Hz), 2.67 (2H, q, J = 7.5 Hz), 2 , 65 (3H, s), 2.43 (3H, s), 1.20 (3H, t, J = 7.5 Hz).

EXAMPLE 22

3- (4- {2-r (U (5-CHLORO-2-THENYL) SULFONYL1AMINO) -CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-blPYRIDINE

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- Phenyl 3-yl) phenyl] ethylcarbamate (step 1 of Example 18) and 5-chloro-2-thiophenesulfonamide.

MS (IED) m / z 518 (M + H ⁺ ); ¹ H NMR (CDCI ₃ ) 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, lg.), 3.533.51 (2H, m), 2.87 (2H, m), 2.73-2.65 (2H, q, J = 7 , 6 Hz), 2.65 (3H, s), 2.44 (3H, s), 1.21 (3H, t, J = 7.6 Hz).

EXAMPLE 23

3- (4- {2 - [((r (4,5-DICLORO-2-THENYL) SULFONYL1AMlNO) -CARBONYL) AMlNO1ETIL) FENlL) -2-ETHYL-5 ₁ 7-DIMETHIL-3H-lMIDAZOr4,5-blPIRID1NA

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / - / imidazo [4,5-b] pyridin-3-yl) phenyl] phenyl ethylcarbamate (step 1 of Example

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18) and 5,6-dichloro-2-thiophenesulfonamide.

MS (IED) m / z 552 (M + H ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.49 (1H, s), 7.27-7.14 (4H, m), 6.84 (1H, s), 3.47 (2H, lg.), 2.75 (2H, lg.), 2.69 (2H, q, J = 7.6 Hz), 2.64 (3H, s), 2.38 (3H, s), 1.22 (3H, t, J = 7.6 Hz).

EXAMPLE 24

3- (4-í2 - ({[(1-BENZOTIEN-2-ILSULFONIL) AMINO '| -CARBONIL)

AMINO) ETHYLphenyl} -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOÍ4,5-òlPyridine

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3Himidazo [4,5-b] pyridine-3- il) phenyl] phenyl ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J .; Leu, Y .; et al; J. Med Chem., 1997, 40, 227Q; Graham, SL; Shepard, KL; et al; J. Med. Chem., 1989, 32, 2548).

Mp: 128.0-130.0 ° C; MS (IED) m / z 534 (M + H) ⁺ ; ¹ H NMR (DMSO-d ₆ ) δ 8.05-8.00 (3H, m), 7.50-7.42 (2H, m), 7.36 (2H, d, J = 7.4 Hz), 7.32 (2H, d, J = 7.4 Hz), 6.96 (1H, s), 6.61-6.56 (1H, m), 3.34-3.28 (2H , m), 2.80 (2H, t, J = 6.6 Hz), 2.68 (2H, q, J = 7.5 Hz), 2.54 (3H, s), 2.40 (3H , s), 1.19 (3H, t, J = 7.5 Hz).

EXAMPLE 25

3- (4- (2-f «r (2-CHLOROPHENYL) SULFONYLAMINO) -CARBONYL)

AMINO1ETHIL) PHENYL) -2-ETHYL-5 ₁ 7-DIMETHLL-3H-IMIDAZOY4,5-blPYRIDINE

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- (4- (2-ethyl-5,7-dimethyl-3Himidazo [4,5-b] pyridin-3- (1) phenyl] ethylamine (step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.

MS (IED) m / z 512 (M + H ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.21-8.17 (1H, d, 7.7 Hz), 7.57-7.43 (3H, m), 7.32-7.22 (4H, m), 6.93 (1H, s), 6.34 (1H, t, J = 5.6 Hz), 3.56-3.49 (2H, q, J = 6.3 Hz), 2, 89-2.85 (2H, t, J = 6.4 Hz), 2.80-2.71 (2H, q, J = 7.6 Hz), 2.67 (3H, s), 2.49 (3H, s), 1.28-1.22 (3H, t, J = 7.6 Hz).

EXAMPLE 26

2-ETYL-5-METHYL-3- (4- {2-r «r (4-METHYLPHYL) SULFONYLAMINO) CARBONYL) AMINOLETYL) PHENYL) -3H-IMIDAZO (4,5-d1PYRIDINE

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STEP 1. 2- {4-f (6-Methyl-3-nitro-2-pyridinyl) amino1phenyl) ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-6-methyl-3-nitropyridine (Takayama, K .; Iwata, Μ .; Kono, N .; et a!. \ Jpn. Kokai Tokkyo Koho, JP11292877 (1999); Ding, CZ; Hunt, JT; Kim, S .; et al; PCT Int. Appí, WO 9730992 (1997) and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI3) δ 8.24 (1H, d, J = 9.1 Hz), 7.28-7.33 (4H, m), 6.65 (1H, d, J = 9.2 Hz), 3.89 (2H, d, J = 6.4 Hz), 2.89 (2H, d, J = 6.4 Hz), 2.81 (3H, s).

STEP 2. 2- (4-r (3-Amino-6-methyl-2-pyridinyl) amino1phenyl) ethanol

10% Pd-C (300 mg) was added to a solution of 2- {4 - [(6methyl-3-nitro-2-pyridinyl) amino] phenyl} ethanol (step 1, 4.6 g, 16, 9 mmoles) in methanol (100 ml). The resulting mixture was stirred for 2 hours under an atmosphere of hydrogen. 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 1: 2 to 1: 5) to obtain 3.8 g (92%) of the title compound as of yellow solids: ¹ H NMR (CDCI ₃ ) δ 7.10-7.16 (4H, m), 6.91 (1H, d, J = 8.4 Hz), 6.70 (1H, d, J = 8.4 Hz), 6.19 (1H, s), 3.83 (2H, t, J = 6.4 Hz), 2.81 (2H, t, J = 6.4 Hz), 2 , 35 (3H, s).

STEP 3. 2T4- (2-ethyl-5-methyl-3H-imidazor4,5-fr | pyridin-3-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-6-methyl-2pyridinyl) amino] phenyl} ethanol (step 2) and chloride propionyl.

MS (IE) m / z 337 (M ⁺ ).

STEP 4. 2-r4- (2-Ethyl-5-methyl-3H-imidazor4,5-olpyridin-3-yl) phenyl1 ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4 ~ (2-ethyl-5methyl-3 / - / - imidazo [4,5-ó] pyridine propionate -3-yl) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 7.90 (1H, d, J = 8.3 Hz), 7.43 (2H, d, J = 8.2

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Hz), 7.34 (2H, d, J = 8.2 Hz), 7.07 (1H, d, J = 8.3 Hz), 3.93 (2H, t, J = 6.6 Hz) , 2.97 (2H, t, J = 6.6 Hz), 2.80 (2H, q, J = 7.5 Hz), 2.56 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

STEP 5. 2-4- (2-ethyl-5-methyl-3/7-imidazo [4 ₁ 5-blpiridin-3iQphenylethyl azide)

Diethyl azodicarboxylate (DEAD) (0.3 mL, 1.5 mmol), triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl azide (DPPA) (0.4 mL, 1.5 mmol) were added to a mixture of 2- [4- (2-ethyl-5-methyl-3/7-imidazo [4,5b] pyridin-3-yl) phenyl] ethanol (step 4, 217 mg, 0.77 mmol) in THF ( 20 mL). The mixture was stirred at room temperature for 4.5 hours. After removing 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 obtain 70 mg (30% ) of the title compound as a brown oil: ¹ H NMR (CDCI ₃ ) δ 7.90 (1H, d, J = 8.1 Hz), 7.34-7.44 (4H, m ), 7.08 (1H, d, J = 8.1 Hz), 3.60 (2H, t, J = 7.1 Hz), 3.00 (2H, t, J = 7.1 Hz), 2.80 (2H, q, J = 7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

STEP 6. 2-r4- (2-Ethyl-5-methyl-3H-imidazor4,5-blpiridin-3-yl) phenin ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5-methyl3 / 7-imidazo [4,5-b] pyridine-azide) 3-yl) phenyl] ethyl (step 5).

¹ H NMR (CDCb) δ 7.91 (1H, d, J = 8.1 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.06 (1H, d, J = 8.1 Hz), 3.13 (2H, t, J = 6.8 Hz), 2.95 (2H, t, J = 6, 8 Hz), 2.81 (2H, q, J = 7.6 Hz), 2.55 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 7. 2-Ethyl-5-methyl-3- (4-1,2-r ((r (4-methylphenyl) sulfonyl1amyrio) carbonyl) amino1ethyl) phenyl) -3 / 7-imidazoí4,5-51pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5-methyl-3Himidazo [4,5-ô] pyridin-3-yl) phenyl] ethylamine (step 6).

MS (IED) m / z 476 (M + Hf; ¹ H NMR (CDCb) δ 7.95 (1H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.2

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Hz), 7.17 (2H, d, J = 8.2 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.17 (1H, s lg.), 3.52 ( 2H, t, J = 6.6 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.69 (2H, q, J = 7.5 Hz), 2.49 (3H, s), 2.41 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

EXAMPLE 27

SODIUM SALT OF 2-ETHYL-5-METHYL 3- (4- {2-f (ff (4-METJLFENIL) SULFONYL1AMINO) CARBONYL) AMINO1ETHYL} PHENYL) -3H-IMIDAZOÍ4,5bjPIRIDINE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5-methyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / - / - imidazo [4,5-ò] pyridine (Example 26).

¹ H NMR (DMSO-d ₆ ) δ 7.91 (1H. D, J = 7.9 Hz). 7.61 (2H. D, J = 6.8 Hz), 7.36 (4H, s), 7.11-7.15 (3H, m), 2.67-2.75 (4H, m) , 2.50 (2H, s lg.), 2.45 (3H, s), 2.28 (3H, s), 1.21-1.24 (3H, m).

EXAMPLE 28

2-ETIL-5-M ETOXY-3- (4- (2 - [((í (4-METI LFENI L) SU LFONIΠAMINO) CARBONIL) AMINOlETYL) PHENYL) -3 / 7-IMIDAZOf4.5-blPYRIDINE

STEP 1. 2- {4 - [(6-Methoxy-3-nitro-2-pyridinyl) aminolfenyl) ethanol

The title compound was prepared according to the procedure described in Step 3 in Example 1 from 2-chloro-6-methoxy-3-nitropyridine and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 10.59 (1H, s lg.), 8.38 (1H, d, J = 9.2 Hz), 7.59 (2H, d, J = 8.3 Hz ), 7.23 (2H, d, J = 8.3 Hz), 6.20 (1H, d, J = 9.2 Hz), 3.94 (3H, s), 3.87 (2H, t , J = 6.6 Hz), 2.87 (2H, t, J = 6.6 Hz).

STEP 2. 2- {4-r (3-Amino-6-methoxy-2-pyridinyl) amino1phenyl) ethanol

A mixture of 2- {4 - [(6-methoxy-3-nitro-2-pyridinyl) amino] phenyl} ethanol (step 1, 3.52 g, 12.17 mmol), iron powder (3 , 4 g, 60.84 mmoles) and ammonium chloride (325 mg, 6.08 mmoles) in ethanol / water (volume / volume, 2.Ί, 90 mL), at reflux temperature for 1 hour. After cooling, the catalyst was removed and the filtrate was concentrated. The residue was extracted with ethyl acetate (100 ml) and washed with water. The organic phase was dried (MgSO ₄ ), and concentrated to obtain 3.41 g (quant) of

142/451 title compound as a black oil: ¹ H NMR (CDCI ₃ ) δ 7.48 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.04 (1H, d, J = 8.2 Hz), 6.75 (1H, s lg.), 6.13 (1H, d, J = 8.2 Hz), 3 , 87 (3H, s), 3.83 (2H, t, J = 6.6 Hz), 2.81 (2H, t, J = 6.6 Hz).

STEP 3. 2- [4- (2-ethyl-5-methoxy-3H-5-ol imidazoí4 _Í pyridin-3-yl) feniNetila

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-6-methoxy-2pyridinyl) amino] phenyl} ethanol (step 2) and chloride propionyl.

TLC Rf = 0.50 (hexane / ethyl acetate = 2: 1).

STEP 4. 2- [4- (2-Ethyl-5-methoxy-3/7-imidazo [4,5-blpiridin-3-yl) phenyljetanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5-methoxy-3/7-imidazo [4,5-ò] pyridine-propionate) 3-yl) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 7.91 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.6 Hz), 3.98-3.88 (2H, m), 3.82 (3H, s), 2.99 (2H , t, J = 6.4 Hz), 2.81 (2H, q, J = 7.4 Hz), 1.34 (3H, t, J = 7.4 Hz).

STEP 5. 2-R4- (2-ethyl-5-methoxy-3/7-imidazoí4,5-ô1pyridin3-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-ethyl-5-methoxy-3 / 7imidazo [4,5-ô] pyridin-3- il) phenyl] ethanol (step 4).

TLC Rf = 0.78 (hexane / ethyl acetate = 1/1).

STEP 6. 2-i4- (2-Ethyl-5-methoxy-3H-imidazo [4,5-blpiridin-3-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5-methoxy-3H-imidazo [4,5-b] pyridin-3- azide il) phenyl] ethyl (step 5).

¹ H NMR (CDCb) δ 7.92 (1H, d, J = 8.6 Hz), 7.40-7.31 (4H, m), 6.67 (1H, d, J = 8.6 Hz), 3.82 (3H, s), 3.13-3.10 (2H, m), 3.00-2.97 (2H, m), 2.80 (2H, q, J = 7, 6 Hz), 1.33 (3H, t, J = 7.6 Hz).

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STEP 7. 2-Ethyl-5-methoxy-3- (4-F2-F (U (4-methylphenyl) sulfonyl1-amino} carbonyl) amino1ethyl) phenyl) -3 / 7-imidazoF4,5-Z) 1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5-methoxy-3 / 7imidazo [4,5-b] pyridin-3- il) phenyl] ethylamine (step 6).

¹ H NMR (CDCI ₃ ) δ 7.95 (1H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.34-7.27 (6H , m), 6.69 (1H, d, J = 8.7 Hz), 6.55 (1H, m), 3.79 (3H, s), 3.60-3.53 (2H, m) , 2.90 (2H, t, J = 6.8 Hz), 2.77 (2H, q, J = 7.4 Hz), 1.30 (3H, t, J = 7.4 Hz).

EXAMPLE 29

SODIUM SALT OF 2-ETHYL-5-METHYXY-3- (4- {2-f ((F (4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) FENlL) -3 / 7-lMIDAZOF4 ₁ 5-b1

PYRIDINE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5-methoxy-3- (4- {2 - [({[(4-methylphenyl) sulfoni [] amino} carbonyl ) amino] ethyl} phenyl) -3F / -imidazo [4,5-b] pyridine (Example 28).

'H (DMSO-d ₆ ) δ 7.94 (1H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.41-7.34 (4H, m), 7.12 (2H, d, J = 8.1 Hz), 6.68 (1H, d, J = 8.4 Hz), 3.71 (3H, s), 3.14 (2H, m), 2.75-2.68 (4H, m), 2.27 (3H, s), 1.20 (3H, t, J = 7.5 Hz); IV (KBr) v _max 1597, 1518, 1489, 1425, 1389, 1261, 1130, 1086 cm ^-1 .

EXAMPLE 30

6-CHLORINE-2-ETHYL-3- (4- (2-i ((f (4-METHYLPHYL) SULFONYLAMINO} CARBONYL) AMINOLETYL) FENIU-3H-IMIDAZO [4.5-b1PYRIDINE

STEP 1. 2- {4-F (5-Methyl-3-nitro-2-pyridinyl) amino1phenyl} ethanol

The title compound was prepared according to the procedure described in Step 3 in Example 1 from 2-chloro-5-methyl-3-nitropyridine and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.96 (1H, S lg.), 8.32-8.31 (2H, m), 7.55 (2H, d, J = 8.3 Hz), 7 , 24 (2H, d, J = 8.3 Hz), 3.85 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 2.32 (3H, s).

STEP 2. 2-f4-F (3-Amino-5-methyl-2-pyridiniDamino1fenii) ethanol

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The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(5-methyl-3-nitro-2pyridinyl) amino] phenyl} ethanol (step 1).

¹ H NMR (CDCl 3) 6 7.59 (1H, m), 7.08-7.00 (4H, m), 6.80 (1H, m), 3.74 5 (2H, t, J = 6.6 Hz), 2.74 (2H, t, J = 6.6 Hz), 2.19 (3H, s).

STEP 3. 2-44- (2-ethyl-6-methyl-3 / - / - imidazoí4,5-dlpyridin-3-yl) phenionyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5-methyl-210 pyridinyl) amino] phenyl} ethanol (step 2) and propionyl chloride.

TLC Rf = 0.74 (dichloromethane / methanol = 10: 1).

STEP 4. 2- [4- (2-Ethyl-6-methyl-3/7-imidazor4,5-b1pyridin-3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-emethyl-3H-imidazo [4,5-b] pyridin-3 propionate -yl) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 8.12 (1H, s), 7.84 (1H, s), 7.44 (2H, d, J = 8.1 Hz), 7.33 (2H, d , J = 8.1 Hz), 3.91 - 3.85 (2H, m), 2.96 (2H, t, J = 6.7 Hz), 2.82 (2H, q, J = 7, 5 Hz), 2.46 (3H, s), 1.36 (3H, t, J = 7.5 Hz).

STEP 5. 2- [4- (2-ethyl-6-methyl-3H-imidazo [4,5-frlpyridin-3yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-ethyl-6-methyl-3 / 7imidazo [4,5-ò] pyridin-3- il) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 8.13 (1H, s), 7.84 (1H, s), 7.44 (2H, d, J = 8.4 Hz), 7.36 (2H, d , J = 8.4 Hz), 3.59 (2H, t, J = 7.3 Hz), 3.00 (2H, t, J = 7.3 Hz), 2.83 (2H, q, J = 7.6 Hz), 2.46 (3H, s), 1.36 (3H, t, J = 7.6 Hz).

STEP 4. 2-í4- (2-Ethyl-6-methyl-3H-imidazo [4,5-frlpiridin-3-yl) -phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-6-methyl3 / 7-imidazo [4,5-b] pyridine-azide) 3-yl) phenyl] ethyl (step 5).

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¹ H NMR (CDCI ₃ ) δ 8.12 (1H, s), 7.84 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.33 (2H, d , J = 8.4 Hz), 3.07 (2H, t, J = 6.8 Hz), 2.91-2.78 (4H, m), 2.46 (3H, s), 1.36 (3H, t, J = 7.5 Hz).

STEP 5. 2-Ethyl-6-methyl-3- (4-f2-phenyl (4-methylphenyl) suffoniHamino) carbonyl) aminoletyl) phenyl) -3 / 7-imidazo [4,5-51pyridine

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).

¹ H NMR (CDCI ₃ ) δ 8.04 (1H, d, J = 1.8 Hz), 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 = 6.8 Hz), 2.76 (2H, q, J = 7 , 6 Hz), 2.45 (3H, s), 2.41 (3H, s), 1.30 (3H, t, J = 7.6 Hz).

EXAMPLE 31

SODIUM SALT OF 6-CHLORINE-2-ETHYL-3- (4- (2-r (ír (4-METiLFENIL) SULFONIL1AMlNO) CARBONlL) AMlNO1ETinFENIL) -3H-lMIDAZO [4,5-òlPIRIDINA

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-6-methyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-b] pyridine (Example 30).

¹ H NMR (DMSO-d ₆ ) δ 8.04 (1H, m), 7.84 (1H, m), 7.60 (2H, d, J = 8.1 Hz), 7.36 (4H , s), 7.12 (2H, d, J = 8.1 Hz), 3.13 (2H, m), 2.78-2.71 (4H, m), 2.39 (3H, s) , 2.27 (3H, s), 1.22 (3H, t, J = 7.5 Hz); IV (KBr) v _max 1601, 1518, 1423, 1375, 1283, 1250, 1128, 1084 cm ^-1 .

EXAMPLE 32

6-CHLORINE-2-ETlL-3- (4- {2-i ({f (4-METHYLPHYL) SULPHONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZOr4.5-blPyridine

STEP 1. 2- (4-i (5-Chloro-3-nitro-2-pyridinyl) amino1phenyl} ethanol- The title compound was prepared according to the procedure described in step 3 of Example 1 from 2, 5-dichloro-3-nitropyridine (Marfat, A .; Robinson, RP; US Pat. Appl., US 5811432 (1998); Haessig, R .; Siegrist, U .; Eur. Pat. Appl., EP 483061 (1992 )) and 4-aminophenylethyl alcohol.

¹ H NMR (CDCf ₃ ) δ 10.00 (1H, s lg.), 8.51-8.50 (1H, m), 8.41 (1H, d, J = 2.4 Hz), 7 , 53 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 3.88-3.87

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STEP 2. 2- {4 - [(3-Amino-5-chloro-2-pyridinyl) aminolfenyl) ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(5-chloro-3-nitro-2pyridinyl) amino] phenyl} ethanol (step 1).

⁴ H NMR (CDCI ₃ ) δ 7.73 (1H, d, J = 2.2 Hz), 7.19-7.01 (4H, m), 6.97 (1H, d, J = 2, 2 Hz), 6.12 (1H, s lg.), 3.81 (2H, t, J = 6.4 Hz), 2.80 (2H, t, J = 6.4 Hz).

STEP 3. 2-í4- (6-chloro-2-ethyl-3/7-imidazoí4,5fr | pyridin-3-yl) phenionyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5-chloro-2pyridinyl) amino] phenyl} ethanol (step 2).

TLC Rf = 0.43 (hexane / ethyl acetate = 2: 1).

STEP 4. 2- [4- (6-Chloro-2-ethyl-3 / - / - imidazoí4.5-d1pyridin-3-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-chloro2-ethyl-3/7-imidazo [4,5-ò] pyridine) propionate 3-yl) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 8.23 (1H, d, J = 2.1 Hz), 8.01 (1H, d, J = 2.1 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.09 (1H, s), 3.92 (2H, t, J = 6.4 Hz), 2, 95 (2H, t, J = 6.4 Hz), 2.83 (2H, q, J = 7.4 Hz), 1.36 (3H, t, J = 7.4 Hz).

STEP 5. 2-r4- (6-chloro-2-ethyl-3/7-imidazo [4 ₁ 5-ib1pyridin3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (6-chloro-2-ethyl-3 / - / imidazo [4,5-b] pyridin- 3-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCl ₃ ) δ 8.25 (1H, d, J = 2.2 Hz), 8.02 (1H, d, J = 2.2 Hz), 7.46 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 3.60 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 7 , 2 Hz), 2.84 (2H, q, J = 7.5 Hz), 1.37 (3H, t, J = 7.5 Hz).

STEP 6. 2T4- (6-Chloro-2-ethyl-3 / - / - imidazo [4,5-d1pyridin-3-yl) -phenin ethylamine

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The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-chloro-2-ethyl3 / 7-imidazo [4,5-b] pyridinazide) 3-yl) phenyl] ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 8.22 (1H, d, J = 2.1 Hz), 8.01 (1H, d, J = 2.1 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 3.13-3.08 (2H, m), 2,952.78 (4H, m), 1.36 (3H , t, J = 7.6 Hz).

STEP 7. 6-Chloro-2-ethyl-3- (4-1,2-f ((r (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl} phenyl) -3 / 7-imidazo [4,5-ò1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (6-chloro-2-ethyl-3Himidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 6).

¹ H NMR (CDCI ₃ ) δ 8.20 (1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.38-7.27 (6H, m), 6.51-6.48 (1H, m), 3.57-3.50 (2H, m), 2.90 ( 2H, t, J = 6.8 Hz), 2.81 (2H, t, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz). EXAMPLE 33

SODIUM SALT OF 6-CHLORINE-2-ETHYL-3- (4- {2-f ({i (4-METHYLphenyl) SULFONYL1AMINO} CARBONYL) AMINO1ETHIL) PHENYL) -3 / 7-IMIDAZE [4,5-blPYRIDINE

The title compound was prepared according to the procedure described in Example 2 from 6-chloro-2-ethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-ô] pyridine (Example 32).

¹ H NMR (DMSO-d ₆ ) δ 8.24-8.21 (2H, m), 7.60 (2H, d, J = 8.1 Hz), 7.42-7.34 (4H, m), 7.12 (2H, d, J = 8.1 Hz), 3.13 (2H, m), 2.81-2.69 (4H, m), 2.27 (3H, s), 1.24 (3H, t, J = 7.4 Hz); IV (KBr) v _max 1597, 1516, 1421, 1375, 1246, 1128, 1084 cm ^-1 .

EXAMPLE 34

2-ETYL-5.6-DIMETHYL-3- (4- {2-r (ir (4-METHYLphenyl) SULFONYLAMINO} CARBONYL) AMINOLETYL) PHENYL) -3H-IMIDAZOr4,5-b1PYRIDINE

STEP 1. 2- (44 (5,6-Dimethyl-3-nitro-2-pyridinyl) aminolfenyl} ethanol

A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard, A .; Rocca, P .; Pomel, V .; eia / .; J. Organomet. Chem., 1996, 517, 25; Rocca, P .; Marsais, F .; Godard, A .; et al; Tetrahedron Lett., 1993, 34, 2937,

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3.3 g, 17.5 mmoles), 4-aminophenylethyl alcohol (3.6 g, 26.3 mmoles) and 2.6lutidine (3.7 ml) in toluene (80 ml) at reflux temperature for 19 hours. The mixture was diluted with ethyl acetate (100 ml) and washed with 1N aqueous NaOH solution (50 ml) and brine (50 ml). The organic phase was dried (Na ₂ SO ₄ ) and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1) to obtain 1.8 g (37%) of the title compound as orange solids. : ¹ H NMR (CDCI ₃ ) δ 8.24 (1H, s lg.), 7.68 (2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz), 3.88 (2H, dt, J = 6.1, 7.6 Hz), 2.88 (2H, t, J = 7.6 Hz), 2.49 (3H, s), 2, 26 (3H, s), 1.43 (1H, t, J = 6.1 Hz).

STEP 2. 2- {4-i (3-Amino-5,6-dimethyl-2-pyridinyl) amino1phenyl) -ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(5,6-dimethyl-3-nitro-2pyridinyl) amino] phenyl} ethanol (step 1) .

¹ H NMR (CDCI ₃ ) δ 6.97 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz), 6.71 (1H, s), 6.22 (1H, s lg.), 3.67 (2H, t, J = 6.8 Hz), 2.68 (2H, t, J = 6.8 Hz), 2.29 (3H, s ), 2.12 (3H, s).

STEP 3. 2- [4- (2-ethyl-5,6-dimethyl-3 / - / - imidazo [4,5frlpyridin-3-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5,6-dimethyl-2pyridinyl) amino] phenyl} ethanol (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, s lg.), 7.42 (2H, d, J = 8.6 Hz), 7.34 (2H, t, J = 8.6 Hz ), 4.37 (2H, t, J = 6.6 Hz), 3.05 (2H, d, J = 6.6 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 2.37-2.28 (2H, m), 1.34 (3H, t, J = 7.6 Hz), 1.18 (3H, t, J = 7.5 Hz).

STEP 4. 2- [4- (2-Ethyl-5 ₁ 6-dimethyl-3/7-imidazoyl4,5-h1pyridin-3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5,6dimethyl-3H-imidazo [4,5-b] pyridinium propionate) 3-yl) phenyl] ethyl (step 3).

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MS (IED) m / z 296 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ: 7.75 (1H, s Ig.), 7.43 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 3.92 (2H, t Ig., J = 6.6 Hz), 2.97 (2H, t, J = 6.6 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 5. 3- [4- (2-Chloroethyl) phenylT2-ethyl-5,6-dimethyl ~ 3 / - / - imidazor4,5-d1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5,6-dimethyl-3 / - / imidazo [4,5-b] pyridin-3-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, s Ig.), 7.43 (2H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.6 Hz ), 3.80 (2H, t, J = 7.3 Hz), 3.18 (2H, t, J = 7.3 Hz), 2.81 (2H, q, J = 7.6 Hz), 2.50 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 6. 2-yl- (2-ethyl-5,6-dimethyl-3H-imidazof4.5-blpiridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -2-ethyl5,6-dimethyl-3/7-imidazo [4 , 5-b] pyridine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, s Ig.), 7.42 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J = 8.4 Hz ), 3.60 (2H, t, J = 7.3 Hz), 3.00 (2H, t, J = 7.3 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 7. 2-r4- (2-Ethyl-5,6-dimethyl-3H-imidazo [4.5-frlpiridin-3-yl) -phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5,6dimethyl-3H-imidazo [4,5-b] pyridine-azide) 3-yl) phenyl] ethyl (step 6).

¹ H NMR (CDCI ₃ ) δ 7.76 (1H, s Ig.), 7.41 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz ), 3.12 (2H, t, J = 6.9 Hz), 2.95 (2H, t, J = 6.9 Hz), 2.79 (2H, q, J = 6.9 Hz), 2.47 (3H, s), 2.37 (3H, s), 1.33 (3H, t, J = 6.9 Hz).

STEP 8. 2-Ethyl-5,6-dimethyl-3- (4-r2-r ((((4-methylphenyl) sulfonillamino) carbonyl) amino1ethyl} phenyl) -3 / - / - imidazo [4 ₁ 5-b1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5,6-dimethyl-3/7150/451 imidazo [4,5-b ] pyridin-3-yl) phenyl] ethylamine (step 7).

MS (IED) m / z 492 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ: 7.87 (2H, d, J = 8.2 Hz), 7.79 (1H, s), 7.31 (2H, d, J = 8.2 Hz) , 7.23 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 6.24 (1H, m), 3.51 (2H, m) , 2.85 (2H, t, J = 6.1 Hz), 2.66 (2H, q, J = 7.4 Hz), 2.39 (3H, s), 2.38 (3H, s) , 2.36 (3H, s), 1.25 (3H, t, J = 7.4 Hz).

EXAMPLE 35

SODIUM SALT OF 2-ETHYL-5 ₁ 6-DIMETHYL 3- (4- {2-f ({í (4METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL |

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5,6-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazo [4,5-b] pyridine (Example 34).

Mp: 156.0-158.5 ° C; ¹ H NMR (DMSO-dg) δ 7.58 (1H, s), 7.48 (2H, d, J = 8.1 Hz), 7.19-7.13 (4H, m), 6, 98 (2H, d, J = 8.1 Hz), 6.01 (1H, s lg.), 3.15-2.98 (2H, m), 2.59-2.55 (2H, m) , 2.50 (2H, q, J = 7.6 Hz), 2.19 (3H, s), 2.13 (3H, s), 2.09 (3H, s), 1.01 (3H, t, J = 7.6 Hz).

EXAMPLE 36 (2-R4- (2-ETHYL-5,6DIMETlL-3/4-METHylphenylusphonylcarbonate) / - / - IMlDAZOÍ4,5-b1PIRIDlN-3-lL) PHENYL1ETHIL

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5,6-dimethyl-3/7-imidazo [4,5b] pyridin-3-yl ) phenyl] ethanol (step 4 of Example 34).

MS (IED) m / z 493 (M + H) ⁺ ; ¹ H NMR (DMSO-d ₆ ) δ 7.94 (2H, d, J = 8.4 Hz), 7.78 (1H, s), 7.33 (2H, d, J = 8.1 Hz ), 7.25-7.16 (4H, m), 4.35 (2H, t, J = 6.6 Hz), 2.93 (2H, t, J = 6.6 Hz), 2.73 (2H, q, J = 7.4 Hz), 2.46 (3H, s), 2.43 (3H, s), 2.39 (3H, s), 1.28 (3H, t, J = 7.4 Hz).

EXAMPLE 37

5,6-DICLORO-2-ETHYL-3- (4- {2-i (U (4-METHYLPHYL) SULPHONYLAMINO) CARBONYL) AMINOLETYL) PHENYL) -3H-IMIDAZOr4,5-blPYRIDINE

STEP 1. 2- (4 - ((5,6-Dichloro-3-nitro-2-pyridinyl) amino1phenyl} ethanol

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The title compound was prepared according to the procedure described in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine (Horn, U .; Mutterer, F .; Weis, CD; Helv. Chim. Acta., 1976, 59, 190) and 4-aminophenylethyl alcohol.

MS (IE) m / z 327 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 10.11 (1H, s lg.), 8.58 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.28 (2H , d, J = 8.4 Hz), 3.93-3.86 (2H, m), 2.89 (2H, t, J = 6.6 Hz).

STEP 2. 2- (4-i (3-Amino-5,6-dichloro-2-pyridinyl) amino1phenyl} -ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(5,6-dichloro-3-nitro-2pyridinyl) amino] phenyl} ethanol (step 1) .

MS (IE) m / z 297 (M ⁺ ).

STEP 3. 2-propionate í4- (2-ethyl-5 _I 6-dichloro-3H-imidazo [4,551piridin-3-yl) feninetila

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5,6-dichloro-2pyridinyl) amino] phenyl} ethanol (step 2) and propionyl chloride.

TLC Rf = 0.63 (ethyl acetate / hexane = 1: 1).

STEP 4. 2-i4- (2-Ethyl-5,6-dichloro-3 / - / - imidazor4,5-d1pyridin-3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5,6dichloro-3H-imidazo [4,5-ò] pyridinium propionate) 3-yl) phenyl] ethyl (step 3).

MS (IE) m / z 335 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s), 7.46 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 3.97 (2H, t, J = 6.2 Hz), 2.99 (2H, t, J = 6.2 Hz), 2.82 (2H, q, J = 7.5 Hz), 1, 36 (3H, t, J = 7.5 Hz).

STEP 5. 3-í4- (2-Chloroethyl) phenin-2-ethyl-5,6-dichloro-3H-imidazo [4,5-òlpyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5,6-dichloro-3 / - / imidazo [4,5-jb] pyridin-3-yl) phenyl] ethanol (step 4).

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¹ H NMR (CDCI ₃ ) δ 8.13 (1H, s), 7.45 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 3.80 (2H, t, J = 7.2 Hz), 3.19 (2H, t, J = 7.2 Hz), 2.82 (2H, q, J = 7.5 Hz), 1, 36 (3H, t, J = 7.5 Hz).

STEP 6. 2- [4- (2-ethyl-5,6-dichloro-3 / - / - imidazo [4.5-l) 1pyridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -2-ethyl5,6-dichloro-3/7-imidazo [4 , 5-b] pyridine (step 5).

MS (IE) m / z 360 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s), 7.44 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 3.61 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 7.2 Hz), 2.81 (2H, q, J = 7.5 Hz), 1, 35 (3H, t, J = 7.5 Hz).

STEP 7. 2- [4- (2-Ethyl-5.6-dichloro-3 / - / - imidazoí4,5-b1pyridin-3-yl) phenyljetylamine

Lindlar catalyst (5 mg) was added to a 2- [4- (2-ethyl-5,6-dichloro-3/7-imidazo [4,5-o] pyridin-3-yl) azide solution phenyl] ethyl (step 6, 69 mg, 0.2 mmol) in methanol (10 ml). The resulting mixture was stirred for 6 hours under a hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. Purification by preparative TLC (dichloromethane / methanol = 10: 1) made it possible to obtain 60 mg (94%) of the title compound as colorless solids: MS (IE) m / z 334 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s), 7.43 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 3.11 (2H, t, J = 6.6 Hz), 2.92 (2H, t, J = 6.6 Hz), 2.81 (2H, q, J = 7.5 Hz), 1, 35 (3H, t, J = 7.5 Hz).

STEP 8. 5,6-Dichloro-2-ethyl-3- (4-r2-r (fr (4-methylphenyl) sulfonyl1-amino) carbonyl) amino1ethyl) phenyl) -3 / - / - imÍdazoF4,5-fr | pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5,6-dichloro-3 / 7imidazo [4,5-b] pyridin- 3-yl) phenyl] ethylamine (step 7).

Mp: 188.0-189.0 ° C; MS (IED) m / z 532 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 8.12 (1H, s), 7.77 (2H, d, J = 8.4 Hz), 7.36-7.25 (6H, m), 6.49 (1H, t lg., J = 5.9 Hz), 3.54 (2H, dt, J = 5.9, 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz) , 2.78 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 1.33 (3H, t, J = 7.5 Hz).

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EXAMPLE 38

5-CHLORINE-2-ETHYL-6-METHYL-3- (4- (2 - [(fl (4-METHYLphenyl) -SULPHONYL1AMINO) CARBONYL) AMINOlETIUFENYL) -3H-IMIDAZOf4 ₁ 5-Z) lPyridine

STEP 1.2T4-í (6-Chloro-5-methyl-3-nitro-2-pyridinyl) amino1phenyl} -ethanol

The title compound was prepared according to the procedure described in step 1 of Example 34 from 2,6-dichloro-5-methyl-3-nitropyridine (Horn, U .; Mutterer, F .; Weis, CD; Helv. Chim. Acta., 1976, 59, 190) and 4-aminophenylethyl alcohol.

¹ H NMR (CDCb) δ 10.05 (1H, s lg), 8.34 (1H, s), 7.57 (2H, d, J = 7.7 Hz), 7.24 (2H, d , J = 7.7 Hz), 3.86 (2H, t, J = 5.9 Hz), 2.87 (2H, t, J = 5.9 Hz), 2.33 (3H, s).

STEP 2. 2- {4-f (3-Amino-6-chloro-5-methyl-2-pyridinyl) amino1phenylT ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(6-chloro-5-methyl-3-nitro-2-pyridinyl) amino] phenyl} ethanol (step 1).

¹ H NMR (CDCb) δ 7.14-7.08 (4H, m), 6.86 (1H, s), 6.21 (1H, s lg.), 3.79 (2H, t, J = 6.4 Hz), 2.78 (2H, t, J = 6.4 Hz), 2.33 (3H, s).

STEP 3. 2- [4- (5-Chloro-2-ethyl-6-methyl-3/7-imidazoí4 ₁ 5-ò1pyridin-3-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-6-chloro-5methyl-2-pyridinyl) amino] phenyl} ethanol (step 2) and propionyl chloride.

MS (IE) m / z 371 (M ⁺ ).

STEP 4. 2-F4- (5-Chloro-2-ethyl-6-methyl-3/7-imidazo [4,5-51pyridin-3yl) ~ phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-chloro2-ethyl-6-methyl-3/7-imidazo [4,5- propionate] jb] pyridin-3-yl) phenyl] ethyl (step 3).

MS (IE) m / z 315 (M *); ¹ H NMR (CDCb) δ 7.87 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 3 , 92 (2H, t, J = 6.6 Hz), 2.96 (2H, t,

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J = 6.6 Hz), 2.79 (2H, q, J = 7.7 Hz), 2.47 (3H, s), 1.34 (3H, t, J = 7.7 Hz).

STEP 5. 344- (2-Chloroethyl) phenyl1-5-chloro-2-ethyl-5-methyl-3/7-imidazo [4,5-ô1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (5-chloro-2-ethyl-6-methyl3H-imidazo [4,5-ò] pyridin- 3-yl) phenyl] ethanol (step 4).

MS (IE) m / z 333 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.88 (1H, s), 7.42 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 3.79 (2H, t, J = 7.3 Hz), 3.17 (2H, t, J = 7.3 Hz), 2.80 (2H, q, J = 7.0 Hz), 2, 48 (3H, s), 1.35 (3H, t, J = 7.0 Hz).

STEP 6. 2- [4- (5-chloro-2-ethyl-6-methyl-3H-imidazoy4,5-b1 pyridin-3-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -5-chloro2-ethyl-5-methyl-3H-imidazo [4 , 5-b] pyridine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.87 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 3.59 (2H, t, J = 7.1 Hz), 2.98 (2H, t, J = 7.1 Hz), 2.81 (2H, q, J = 7.6 Hz), 2, 48 (3H, s), 1.35 (3H, t, J = 7.6 Hz).

STEP 7. 2-i4- (5-Chloro-2-ethyl-6-methyl-3 / - / - imidazoí4 ₁ 5-ò1pyridin-3yl) -phenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (5-chloro-2-ethyl6-methyl-3/7-imidazo [4,5- b] pyridin-3-yl) phenyl] ethyl (step 6).

¹ H NMR (CDCI ₃ ) δ 7.88 (1H, s), 7.40 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 3.07 (2H, t, J = 6.8 Hz), 2.87 (2H, t, J = 6.8 Hz), 2.80 (2H, q, J = 7.3 Hz), 2, 48 (3H, s), 1.34 (3H, t, J = 7.3 Hz).

STEP 8. 5-Chloro-2-ethyl-6-methyl-3- (4-r2-r (ph (4-methylphenyl) sulfoninamino) carbonyl) amino1ethyl) phenyl) -3 / - / - imidazoí4,5-b1piridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5-chloro-2-ethyl-6-methyl3 / 7-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 7).

Mp: 205-206 ° C; MS (IED) m / z 512 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.90 (1H, s), 7.79 (2H, d, J = 8.3 Hz), 7.33-7.23 (6H, m), 6.46 (1H, s lg.), 3.55155 / 451

3.49 (2Η, m), 2.88 (2H, t, J = 6.8 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.48 (3H, s), 2.41 (3H, s), 1.31 (3H, t, J = 7.6 Hz).

EXAMPLE 39

5-CHLORINE-2-ETHYL-7-METlL-3- (4- {2 - [({r (4-METHYLphenyl) -SULPHONYL1AMINO) CARBONYL) AMINO1ETHIL) PHENYL) -3H-IMIDAZOr4,5-Z) lPyridine

STEP 1. 2- {4-r (6-Chloro-4-methyl3-nitro-2-pyridinyl) aminophenyl) ethanol

The title compound was prepared according to the procedure described in step 1 of Example 34 from 2,6-dichloro-4-methyl-3-nitropyridine (Inubushi, A .; Kawano, E .; Shimada, Ke .; et al .; PCT Int. Appl., (WO 9802442) and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCl ₃ ) δ: 9.56 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz) , 6.64 (1H, s), 3.84 (2H, t, J = 6.4 Hz), 2.84 (2H, t, J = 6.4 Hz), 2.55 (3H, s) .

STEP 2. 2- {4-f (3-Amino-6-chloro-4-methyl-2-pyridinyl) amino1phenyl} ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(6-chloro-4-methyl-3-nitro-2-pyridinyl) amino] phenyl} ethanol (step 1).

MS (IE) m / z277 (M ⁺ ).

STEP 3. 2-r4- (5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-frlpiridin-3-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-6-chloro-4methyl-2-pyridinyl) amino] phenyl} ethanol (step 2).

TLC Rf = 0.46 (ethyl acetate / hexane = 1: 1).

STEP 4. 2-F4- (5-Chloro-2-ethyl-7-methyl-3 / V-imidazo [4.5-frlpiridin-3yl) -pheninethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-chloro2-ethyl-7-methyl-3H-imidate [4,5-b] propionate pyridin-3-yl) phenyl] ethyl (step 3).

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MS (IE) m / z 315 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.07 (1H, s), 4.00-3.85 (2 H, m), 2.97 (2H, t, J = 6.6 Hz), 2.83 (2H, q, J = 7.5 Hz), 2.68 ( 3H, s), 1.30 (3H, t, J = 7.5 Hz).

STEP 5. 3- [4- (2-Chloroethyl) phenyl15 ~ chloro-2-ethyl-7-methyl-3H-imidazole4.5-ò1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (5-chloro-2-ethyl-7-methyl3 / 7-imidazo [4,5-ó] pyridin-3-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.07 (1H, s), 3.79 (2H, t, J = 7.3 Hz), 3.17 (2H, t, J = 7.3 Hz), 2.83 (2H, q, J = 7.5 Hz), 2, 68 (3H, s), 1.30 (3H, t, J = 7.5 Hz).

STEP 6. 2-Γ4- (5-οΙθΓθ-2-θΐίΙ-7-ητΊ6ϋΙ-3Η-ίίτ ^ 3ζοΓ4,5-ό1 pyridin-3-yl) phenethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -5-chloro2-ethyl-7-methyl-3H-imidazo [4 , 5-b] pyridine (step 5).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.07 (1H, s), 3.56 (2H, t, J = 7.2 Hz), 2.99 (2H, t, J = 7.2 Hz), 2.83 (2H, q, J = 7.5 Hz), 2, 68 (3H, s), 1.29 (3H, t, J = 7.5 Hz).

STEP 7. 2- [4- (5-Chloro-2-ethyl-7-methyl-3B-imidazoyl4,5-frlpyridin-3yl) -phenylethylamine

Triphenylphosphine (47 mg, 0.2 mmol) was added to a solution, with stirring, of 2- [4- (5-chloro-2-ethyl-7-methyl-3 / - / - imidazo [4, 5-b] pyridin-3-yl) phenyl] ethyl (step 6, 57 mg, 0.2 mmol) in THF (5 ml), at room temperature. After the addition was complete, stirring was continued for another 3 hours at the same temperature. Water (0.1 ml) was added to the resulting mixture at room temperature, and the reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated to obtain colorless solids. Purification by preparative TLC (dichloromethane / methanol / triethylamine = 10: 1: 1) gave 13 mg (25%) of the title compound as colorless solids: EM (IE) m / z 313 (M ⁺ ) .

STEP 8. 5-Chloro-2-ethyl-7-methyl-3- (4-r2-F ({[(4-methylphenyl) sulfonill157 / 451 amino) carbonyl) amino1ethyl} phenyl) -3 / - / - imidazo [ 4,5-b1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5-chloro-2-ethyl-7-methyl] / 7-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylamine (step 7).

MS (IED) m / z 512 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.80 (2H, d, J = 8.4 Hz), 7.34-7.23 (6H, m), 7.09 (1H, s), 6.37 (1H, s lg.), 3.56-3.52 (2H, m), 2.88 (2H, t, J = 6.8 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.69 (3H, s), 2.42 (3H, s), 1.26 (3H, t, J = 7.5 Hz).

EXAMPLE 40

2-ETIL-7-METIL-3- (4- {2-r ({r (4-METILFENlL) SULFONYL-AMINO)

CARBONIL) AMINOlETIL} FENlL) -6 - [(METILSULFONlL) AMINO1-3 / - / - IMIDAZO [4,5-fr | PYRIDINE

STEP 1. 2- {4 - [(4-Methyl-3,5-dinitro-2-pyridinyl) amino1phenyl) ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-4-methyl-3,5-dinitropyridine (Czuba; Rocz. Chem., 1967, 41, 479) and alcohol 4 -aminophenylethyl.

¹ H NMR (CDCI ₃ ) δ 8.90 (1H, s), 8.50 (1H, s lg.), 7.40 (2H, d, J = 8.4 Hz), 7.23 (2H , d, J = 8.4 Hz), 3.82 (2H, t, J = 6.6 Hz), 2.84 (2H, t, J = 6.6 Hz), 2.62 (3H, s ).

STEP 2. 2- (4 - [(3-Amino-4-methyl-5-nitro-2-pyridinyl) amino1phenyl | ethanol

A solution of formic acid (2.3 mL, 61.0 mmol) in acetonitrile (6.2 mL) was added dropwise at 0 ° C over 30 minutes to a solution, under stirring, of 2- {4 - [(4-methyl-3,5-dinyl-2-pyridinyl) amino] phenyl} ethanol (step 1, 4.2 g, 13.1 mmoles), triethylamine (9.6 ml, 68.9 mmoles ), 10% Pd-C (624 mg, 0.59 mmol) in acetonitrile (14 mL). 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 NaOH solution (50 ml), brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography on silica gel, eluting with hexa158 / 451 in / ethyl acetate (gradient elution from 1: 1 to 1: 2) allowed to obtain 2.2 g (60%) of the title compound, as red crystals: ¹ H NMR (CDCIs) δ 8.42 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 6.7 (1H, s lg.), 3.85 (2H, t, J = 6.4 Hz), 2.86 (2H, t, J = 6.6 Hz), 2 , 47 (3H, s).

STEP 3. 2-R4- (2-ethyl-7-methyl-6-nitro-3/7-imidazof4,5-d1pyridin-3-yl) propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-4-methyl-5nitro-2-pyridinyl) amino] phenyl} ethanol (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 9.03 (1H, s), 7.48 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.4 Hz), 4.38 (2H, t, J = 6.9 Hz), 3.07 (2H, t, J = 6.9 Hz), 3.03 (3H, s), 2.87 (2H, q, J = 7.6 Hz), 2.35 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.4 Hz), 1.13 (3H, t, J = 7 , 4 Hz).

STEP 4. 2-F4- (6-Amino-2-ethyl-7-methyl-3F / -imidazoyl4,5-frlpiridin-3-yl) propionate pheninetyl

A 2- [4- (2-ethyl-7-methyl-6-nitro-3/7-imidazo [4,5-b] pyridin-3-yl) phenyl] ethyl propionate suspension was stirred (step 3, 2 , 5 g, 6.6 mmoles) and 10% Pd-C (250 mg, 0.23 mmol) in methanol (100 mL) under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to obtain 2.4 g (99%) of the title compound as a brown oil: ¹ H NMR (CDCh) δ 7.82 (1H, s), 7.41 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 4.35 (2H, t, J = 7.0 Hz), 3.51 (2H, s lg.), 3.03 (2 H, t, J = 7.0 Hz), 2.82 (2H, q, J = 7.5 Hz) , 2.53 (3H, s), 2.35 (2H, q, J = 7.5 Hz), 1.29 (3H, t, J = 7.5 Hz), 1.44 (3H, t, J = 7.5 Hz).

STEP 5. 2- (4- {2-ethyl-7-methyl-6-F (methylsulfonyl) amino 1-3 / V-imidazo [4,5-b1pyridin-3-yl) phenyl) ethyl propionate

Methanesulfonyl chloride (372 mg, 3.3 mmoles) at 0 ° C was added to a solution, with stirring, of 2- [4- (6-amino-2-ethyl-7methyl-3tf-imidazo [4 , 5-o] pyridin-3-yl) phenyl] ethyl (step 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 mL), and stirred the mixture at room temperature for 16 hours. The blast suddenly cooled

159/451 reaction with the addition of water (10 ml), and the mixture was extracted with dichloromethane (50 ml). The organic phase was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate (gradient elution from 1: 1 to 1: 2) made it possible to obtain 890 mg (70%) of the title compound as an amber oil. : ¹ H NMR (CDCI ₃ ) δ 8.26 (1H, s), 7.43 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.2 Hz) , 7.00 (1H, s lg.), 4.35 (2H, t, J = 7.0 Hz), 3.03-3.01 (5H, m), 2.85 (2H, q, J = 7.5 Hz), 2.75 (3H, s), 2.35 (2H, q, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz), 1, 14 (3H, t, J = 7.5 Hz).

STEP 6. A / - {2-Ethyl-3-i4- (2-hydroxyethyl) phenyl1-7-methyl-3H-imidazo 4,5-blpiridin-6-yl} methanesulfonamide

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- {2-ethyl-7methyl-6 - [(methylsulfonyl) amino] -3 / 7-imidazo propionate [4,5-o] pyridin-yl} phenyl) ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 8.22 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.4 Hz), 6.52 (1H, s lg.), 3.93 (2H, t, J = 6.6 Hz), 3.03 (3H, s), 2.97 (2H, t, J = 6.6 Hz ), 2.85 (2H, q, J = 7.6 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 7.4 Hz).

STEP 7. / V-f3-14- (2-Chloroethyl) phenyl1-2-ethyl-7-methyl-3/7-imidazoyl4,5blpiridin-6-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from / V- {2-ethyl-3- [4- (2hydroxyethyl) phenyl] -7-methyl-3/7-imidazo [4,5-b] pyridin-6-yl} methanesulfonamide (step 6).

TLC Rf = 0.40 (ethyl acetate).

STEP 8. / V- {3-r4- (2-Azidoethyl) phenin-2-ethyl-7-methyl-3H-imidazor4,5b1pyridin-6-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from A / - {3- [4- (2-chloroethyl) phenyl] -2ethyl-7-methyl-3H-imidazo [4 , 5-o] pyridin-6-yl} methanesulfonamide (step 7).

¹ H NMR (CDCI ₃ ) δ 8.26 (1H, s), 7.44 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 6.65 (1H, s lg.), 3.59 (2H, t, J = 7.0, Hz), 3.03 (3H, s), 2.99 (2H, t, J = 7.1 Hz), 2.86 (2H, q, J = 7.4 Hz), 2.75 (3H, s), 1.31 (3H, t, J = 7.5 Hz).

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STEP 9. / \ Z-f3-F4- (2-Aminoethyl) phenin-2-ethyl-7-methyl-3 / - / - imidazoí4 ₁ 5-òlpiridin-6-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 9 of Example 1 from / \ / - {3- [4- (2-azidoethyl) phenyl] -2ethyl-7-methyl-3H-imidazo [ 4,5-b] pyridin-6-yl} methanesulfonamide (step 8).

TLC Rf = 0.05 (ethyl acetate).

STEP 10. 2-Ethyl-7-methyl-3- (4- (2-f (Íf (4-methylphenyl) sulfonyl1-amino) carbonyl) amino1ethyl} phenyl) -6-F (methylsulfonyl) amino1-3 / 7- imidazoF4 ₁ 5-òlpyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from / V- {3- [4- (2-aminoethyl) phenyl] -2ethyl-7-methyl-3H-imidazo [4 , 5-o] pyridin-6-yl} methanesulfonamide (step 9).

Mp: 166 ° C; MS (IED) m / z 571.25 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.16 (1H, s), 7.81 (2H, d, J = 8.1 Hz), 7.31-7.18 (6H, m), 6.39 (1H, s lg.), 3,483.46 (2H, m), 3.00 (3H, s), 2.82-2.71 (7H, m), 2.39 (3H, s), 1, 26 (3H, t, J = 7.2 Hz).

EXAMPLE 41

6-CYAN-2-ETHYL-5,7-DIMETHYL-3- (4- {2-F ({F (4-METHYLphenyl) -SULPHONYLAMINO) CARBONYL) AMlNOlETYL) PHENYL) -3H-IMIDAZOF4,5-b1PYRIDINE

STEP 1. 6-Hydroxy-2,4-dimethylnicotinonitrile

A solution of sodium nitrite (25.2 g, 365 mmoles) in water (100 mL) at 0 ° C was added dropwise to a solution, under stirring, of 6-amino-2,4- dimethylnicotinonitrile (Sato, K .; et al .; Bull. Chem. Soc. Jpn., 1969, 42, 2319; 22.4 g, 152 mmoles) in 5% aqueous sulfuric acid solution (600 mL). The resulting precipitate was removed by filtration to obtain 10.2 g (45%) of the title compound: ¹ H NMR (DMSO-de) δ 12.27 (1H, s lg.), 6.17 (1H , s), 2.38 (3H, s), 2.20 (3H, s).

STEP 2. e-Hydroxy ^ Adimethyl-S-nitronicotinonitrile

6-hydroxy-2,4-dimethylnicotinonitrile (step 1, 9.0 g, 60.8 mmoles) was added in one portion to a solution, with stirring, of nitric acid (smoker, 36 mL) and sulfuric acid (18 ml), and the mixture was stirred at room temperature. After 1 hour, the mixture was poured into water (100 mL) and

161/451 was neutralized with 2N aqueous NaOH solution. The resulting precipitates were removed by filtration to obtain 3.2 g (2.7%) of the title compound: ¹ H NMR (DMSO-de) δ 2.28 (3H. S), 2.11 (3H , s).

STEP 3. 6-Chlorine-2,4-dimethyl-5-nitronicotinonitrile

A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinonitrile (step 2, 3.2 g, 16.6 mmoles) and phosphorus oxychloride (20 ml) was stirred at 100 ° C for 16 hours. After cooling, the mixture was poured into water (100 ml). The resulting mixture was extracted with dichloromethane (3 x 100 ml). Wash the organic phase with brine (50 mL), dried (MgSO ₄₎ and concentrated to afford 2.3 g (66%) of the title compound as brown solids: 1H-NMR H (DMSO-d ₆ ) δ 2.82 (3H, s), 2.52 (3H, s).

STEP 4. 6-f4- (2-Hydroxyethyl) anilino1-2,4-dimethyl-5-nitronicotinonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from 6-chloro-2,4-dimethyl-5nitronicotinonitrile (step 3) and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.37 (1H, s lg.), 7.51 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz ), 3.89-3.87 (2H, m), 2.89 (2H, t, J = 6.4 Hz), 2.72 (3H, s), 2.65 (3H, s), 1 , 46 (1H, t, J = 5.8 Hz).

STEP 5. 5-Amino-6-f4- (2-hydroxyethyl) anilinol-2,4-dimethylnicotinonitrile

The title compound was prepared according to the procedure described in step 4 of Example 1 from 6- [4- (2-hydroxyethyl) anilino] 2,4-dimethyl-5-nitronicotinonitrile (step 4).

¹ H NMR (CDCI ₃ ) δ 7.49 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.4 Hz), 6.89 (1H, s lg. ), 3.89-3.82 (2H, m), 3.11 (2H, s lg.), 2.85 (2H, t, J = 6.6 Hz), 2.58 (3H, s) , 2.38 (3H, s), 1.44 (1H, t, J = 5.6 Hz).

STEP 6. 2- [4- (6-cyano-2-ethyl-5,7-dimethyl-3/7-imidazo [4.5-dlpiridin-3-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 5-amino-6- [4- (2-hydroxyethyl) anilino] -2,4-dimethylnicotinonitrile (step 5) and chloride propionyl.

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TLC Rf = 0.4 (hexane / ethyl acetate = 1: 1).

STEP 7. 2-Ethyl-3-14- (2-hydroxyethyl) phenyl1-5,7-dimethyl-3H-imidazor4,5-hyrpyridine-6-carbonitrile

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-cyano2-ethyl-5,7-dimethyl-3/7-imidazo [4, 5-ò] pyridin-3-yl) phenyl] ethyl (step 6).

¹ H NMR (CDCb) δ 7.46 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 4.01-3.94 (2H, m), 3.49-3.47 (1H, m), 3.00 (2H, t, J = 6.3 Hz), 2.86 (3H, s), 2.83 (2H, q, J = 7.4 Hz), 2.74 (3H, s), 1.32 (3H, t, J = 7.6 Hz).

STEP 8. 3-i4- (2-Chlorethyl) phenin-2-ethyl-5,7-dimethyl-3/7-imidazor4,5-frlpyridine-6-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2-ethyl-3- [4- (2-hydroxyethyl) phenyl] 5.7-dimethyl-3/7-imidazo [4, 5-b] pyridine-6-carbonitrile (step 7).

TLC Rf = 0.8 (hexane / ethyl acetate = 1: 1).

STEP 9. 3- [4- (2Azidoethyl) phenyl1-2-ethyl · 5,7-dimethyl-3 / - / - imidazoí4,5- £) 1pyridine-6-carbonitrile

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -2-ethyl6-dimethyl-SH-imidazo ^ .6-blpyridine- e-carbonitrile (step 8).

¹ H NMR (CDCI ₃ ) δ 7.46 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.2 Hz), 3.62 (2H, t, J = 7.1 Hz), 3.02 (2H, t, J = 7.1 Hz), 2.86 (3H, s), 2.82 (2H, q, J = 7.6 Hz), 2, 73 (3H, s), 1.31 (3H, t, J = 7.6 Hz).

STEP 10. 3-i4- (2-Aminoethyl) phenyl1-2-ethyl-5 ₁ 7-dimethyl-3 / - / - imidazoKS-blpiridine-and-carbonitrile

The title compound was prepared according to the procedure described in step 9 of Example 1 from 3- [4- (2-azidoethyl) phenyl] -2-ethyl5.7-dimethyl-3H-imidazo [4,5 -b] pyridine-6-carbonitrile (step 9).

TLC Rf = 0.05 (hexane / ethyl acetate = 1: 1).

STEP 11. 6-Cyano-2-ethyl-5,7-dimethyl-3- (4- {2-i ({r (4-methylphenyl) sulfonillaminolcarboni l) aminoylethyl} phenyl) -3 / - / - imidazo [ 4.5-Z? L pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 3- [4- (2-aminoethyl) phenyl] -2ethyl-5,7-dimethyl-3 / 7- imidazo [4,5-b] pyridine-6-carbonitrile (step 10).

Mp: 133 ° C; MS (IED) m / z 517.12 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.78 (2H, d, J = 8.1 Hz), 7.37-7.25 (6H, m), 6.46 (1H, s lg.), 3 , 56-3.54 (2H, m), 2.92 (2H, t, J = 7.0 Hz), 2.85 (3H, s), 2.76 (2H, q, J = 6.0 Hz), 2.68 (3H, s), 2.41 (3H, s), 1.29 (3H, t, J = 6.2 Hz).

EXAMPLE 42

2-ETIL-4,6-DIMETfL-1- (4- (2 - [({F (4-METHYLphenyl) SULFONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -1H-1MIDAZOr4,5-c1PYRIDINE

STEP 1. 2- (44 (2,6-Dimethyl-3-nitro-4-pyridinyl) aminolfenyl) ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-2,6-dimethyl-3-nitropyridine (Tanaka, A .; et al. ', J. Med. Chem. , 1999, 41, 4408) and aminophenyl ethyl alcohol 4.

¹ H NMR (CDCI ₃ ) δ 8.74 (1H, s lg.), 7.31 (2H, d, J = 8.2 Hz), 7.18 (2H, d, J = 8.2 Hz ), 6.68 (1H, s), 3.95-3.89 (2H, m), 2.91 (2H, t, J = 6.6 Hz), 2.72 (3H, s), 2 , 36 (3H, s).

STEP 2. 2- {4 - [(3-Amino-2 ₁ 6-dimethyl-4-pyridinyl) amino1phenyl) -ethanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- {4 - [(2,6-dimethyl-3-nitro-4pyridinyl) amino] phenyl} ethanol (step 1) .

¹ H NMR (CDCI ₃ ) δ 7.19 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.6 Hz), 6.76 (1H, s), 5.82 (1H, s lg.), 3.87 (2H, t, J = 6.4 Hz), 3.18 (2H, s lg.), 2.85 (2H, t, J = 6, 4 Hz), 2.44 (3H, s), 2.35 (3H, s).

STEP 3. 2-R4- (2-ethyl-4.6-dimethyl-1H-imidazo | 4.5clpiridin-1-yl) phenyl1ethyl propionate

A mixture of 2- {4 - [(3-amino-2,6-dimethyl-4-pyridinyl) amino] phenyl} ethanol (step 2, 2.4 g, 9.3 mmol), propionic anhydride ( 13 ml, 101 mmoles) and propionic acid (13 ml, 174 mmoles) at 120 ° C for 16 hours. After cooling, the mixture was diluted with 2N aqueous NaOH solution (150 ml), and extracted with dichloromethane (3 x 150 ml). Washed

164/451 the organic extracts combined with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography on silica gel, eluting with dichloromethane / methanol (gradient elution from 20: 1 to 10: 1) made it possible to obtain 2.3 g (69%) of the title compound as a brown oil: ¹ H NMR (CDCfe) δ 7.44 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.2 Hz), 6.72 (1H, s ), 4.38 (2H, t, J = 6.9 Hz), 3.07 (2H, t, J = 7.1 Hz), 2.88 (3H, s), 2.82 (2H, q , J = 7.6 Hz), 2.56 (3H, s), 2.36 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.15 (3H, t, J = 7.7 Hz).

STEP 4. 2-í4- (2-Ethyl-4,6-dimethyl-1 / - / - Imidazoí4,5-clpiridin-1-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl 1-4,6dimethyl-1 H-imidazo [4,5-c] propionate pyridin-1-yl) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.46 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 6.73 (1H, s) , 4.00 (2H, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.88 (3H, s), 2.81 (2H, q, J = 7.5 Hz), 2.54 (3H, s), 1.29 (3H, t, J = 7.5 Hz).

STEP 5. 1 - [4- (2-Chloroethyl) phenii1-2-ethyl-4 ₁ 6-dimethyl-1 H-imidazoí4,5-c1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-4,6-dimethyl-1Himidazo [4,5-c] pyridin-1- il) phenyl] ethanol (step 4).

TLC Rf = 0.1 (ethyl acetate).

STEP 6. 1- [4- (2-Azidoethyl) phenyl1-2-ethyl-4,6-dimethyl-1 / - / - imidazof4,5-c1pyridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl4,6-dimethyl-1H-imidazo [4,5 -c] pyridine (step 5).

¹ H NMR (CDCl 3) δ 7.46 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 7.7 Hz), 6.72 (1H, s), 3 , 62 (2H, t, J = 6.9 Hz), 3.02 (2H, t, J = 6.9 Hz), 2.88 (3H, s), 2.81 (2H, q, J = 7.4 Hz), 2.56 (3H, s), 1.29 (3H, t, J = 7.6 Hz).

STEP 7. 2-í4- (2-Ethyl-4.6-dimethyl-1 / - / - imidazoí4.5-clpiridin-1-yl) -phenylethylamine

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The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -2-ethyl4,6-d imethyl-1 / - / - imidazo [4,5-c] pyridine (step 6).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.4 Hz), 6.73 (1H, s), 3.08 (2H, t, J = 6.9 Hz), 2.90-2.78 (4H, m), 2.88 (3H, s), 2.56 (3H, s), 1.30 (3H, t, J = 7.3 Hz).

STEP 8. 2-Ethyl-4,6-dimethyl-1 - (4-F2-i ({[(4-methylphenyl) sulfoniU-amino) carbonyl) amino1ethyl) phenyl) -1 / 7-imidazo [4,5- c1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-4,6-dimethyl-1 / 7imidazo [4,5-c] pyridin- 1-yl) phenyl] ethylamine (step 7).

Mp: 143 ° C; MS (IED) m / z 492.12 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.77 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 6.77 (1H, s), 3.58-3.51 (2H, m), 2.92 (2H , t, J = 7.0 Hz), 2.89 (3H, s), 2.79 (2H, q, J = 7.5 Hz), 2.53 (3H, s), 2.38 (3H , s), 1.28 (3H, t, J = 7.5 Hz).

EXAMPLE 43

2-ETHYL-1- (4- (2 - [({((4-METHYLphenyl) SULFONYLAMINE) -CARBONYL) AMINO1ETHYL} PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2- [4- (2-Nitroanilino) fenirietanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloronitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.47 (1H, s), 8.21 (1H, dd, J = 1.5, 8.8 Hz), 7.40-7.16 (6H, m) , 6.81-6.70 (1H, m), 3.91 (2H, t, J = 6.5 Hz), 2.90 (2H, t, J = 6.5 Hz).

STEP 2. 2-i4- (2-Aminoanilino) pheninethanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- [4- (2-nitroanilino) phenyljetanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.15-6.96 (4H, m), 6.82-6.66 (4H, m), 5.14 (1H, s), 3.80 (2H, t, J = 6.6 Hz), 3.75 (2H, s lg.), 2.79 (2H, t, J = 6.6 Hz).

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STEP 3. 2-R4- (2-ethyl-1H-benzimidazol-1-yl) phenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-aminoanilino) phenyl] ethanol (step 2) and propionyl chloride.

MS (IE) m / z 322 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.79 (1H, d, J = 7.7 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.34-7.06 (5H , m), 4.38 (2H, t, J = 7.0 Hz), 3.07 (2H, t, J = 7.0 Hz), 2.80 (2H, q, J = 7.5 Hz ), 2.36 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.5 Hz), 1.15 (3H, t, J = 7.6 Hz).

STEP 4. 2-r4- (2-Ethyl-1H-benzimidazol-1-yl) phenethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-1 Hbenzimidazol-1-yl) phenyl] ethyl propionate (step 3).

'H NMR (CDCIs) δ 7.81-7.75 (1H, m), 7.45 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.25-7.08 (3H, m), 3.98 (2H, t, J = 6.5 Hz), 3.00 (2H, t, J = 6.5 Hz), 2, 80 (2H, q, J = 7.5 Hz), 1.26 (3H, t, J = 7.5 Hz).

STEP 5. 2-F4- (2-ethyl-1B-benzimidazole-1-ihphenylethyl azide)

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-ethyl-1H-benzimidazol-1-yl) phenyl] ethanol (step 4).

MS (IE) m / z 291 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.81-7.76 (1H, m), 7.43 (2H, d, J = 8.3 Hz), 7.40-7.06 (5H, m) , 3.62 (2H, t, J = 6.5 Hz), 3.04 (2H, t, J = 6.5 Hz), 2.80 (2H, q, J = 7.5 Hz), 1 , 27 (3H, t, J = 7.5 Hz).

STEP 6. 2- [4- (2-Ethyl-1 / - / - benzimidazol ~ 1-yl) phenyl1ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-1 Hbenzimidazol-1-yl) phenyl] ethyl azide (step 5).

¹ H NMR (CDCI ₃ ) δ 7.80-7.74 (1H, m), 7.45-7.06 (7H, m), 3.06 (2H, t, J = 6.5 Hz) , 2.89 (2H, t, J = 6.5 Hz), 2.76 (2H, q, J = 7.5 Hz), 1.26 (3H, t, J = 7.5 Hz).

STEP 7. 2-Ethyl-1 - (4-r2-r (ff (4-methylphenyl) sulfonillamino) carbonyl) amino1ethyl) phenyl) -1 / - / - benzimidazole

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The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] ethylamine (step 6) .

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, d, J = 8.8 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.39-7.14 (8H , m), 7.07 (1H, d, J = 8.8 Hz), 6.68 (1H, s Ig.), 3.62-3.54 (2H, m), 2.94 (2H, t, J = 6.3 Hz), 2.79 (2H, q, J = 7.0 Hz), 2.41 (3H, s), 1.33 (3H, t, J = 7.0 Hz) .

EXAMPLE 44 2- [4- (2-ETHYL-1HBENZIMIDAZOL-1-1L) PHENYL-ETHYL 4-METHYLENIDSULFONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-1H-benzimidazol-1yl) phenyl] ethanol (step 4 of Example 43).

¹ H NMR (CDCI ₃ ) δ 7.93 (2H, d, J = 8.3 Hz), 7.85-7.75 (2H, m), 7.40-7.15 (7H, m) , 7.08 (1H, d, J = 8.8 Hz), 4.77 (1H, s Ig.), 4.36 (2H, t, J = 6.4 Hz), 3.00 (2H, t, J = 6.4 Hz), 2.78 (2H, t, J = 7.0 Hz), 2.44 (3H, s), 1.32 (3H, t, J = 7.0 Hz) .

EXAMPLE 45

4-METHYL-2-ETlL-3- (4- (2-r «r (4-METHYLphenyl) SULFONYL-AMINO)

CARBONIDAMINOIETIUFENID-W-BENZIMIDAZOL

STEP 1. 2- [4- (3-Methyl-2-nitroanilino) phenyl1ethanol

A mixture of 2-nitro-3-methylaniline (Newman, MS; Kannan, R .; J. Org. Chem., 1976, 41, 3356; 1.9 g, 12.4 mmoles) was placed in a sealed tube. , 4-bromophenyl ethyl alcohol (2.5 g, 12.4 mmoles), K ₂ CO ₃ (1.7 g, 12.4 mmoles) and Cul (230 mg, 1.24 mmoles), and heated to 200 ° C for 2 hours. After cooling, the mixture was poured into water (100 ml) and extracted with ethyl acetate (300 ml). The organic phase was washed with 2N aqueous NaOH solution (100 ml) and brine (100 ml), then dried (Na ₂ SO ₄ ), and concentrated. Purification by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), gave 700 mg (21%) of the title compound as an orange oil: NMR ¹ H (CDCI ₃ ) δ 7.77 (1H, s Ig.), 7.09- 7.45 (6H, m), 6.69

168/451 (1H, d, J = 6.3 Hz), 3.83 (2H, t, J = 6.6 Hz), 2.82 (2H, t, J = 6.6 Hz), 2, 59 (3H, s).

STEP 2. 2-r4- (2-Amino-3-methylanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [4- (3-methyl-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.02 (2H, d, J = 8.2 Hz), 6.95 (1H, d, J = 7.7 Hz), 6.91 (1H, d, J = 7.0 Hz), 6.65 (1H, dd, J = 7.0 Hz, 7.7 Hz), 6.62 (2H, d, J = 8.2 Hz), 5.15 (1H, s lg.), 3.75 (2H, t, J = 6.6 Hz), 2.73 (2H, t, J = 6.6 Hz), 2.19 (3H, s).

STEP 3. 2- [4- (2-ethyl-4-methyl-1A / -benzimidazole-1iDphenylethyl propionate)

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-3methylanilino) phenyl] ethanol (step 2) and propionyl chloride.

TLC Rf = 0.6 (hexane: ethyl acetate = 1: 1).

STEP 4. 2-i4- (2-Ethyl-4-methyl-1/7-benzimidazol-1-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-4methyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3 ).

¹ H NMR (CDCI ₃ ) δ 7.41-7.43 (2H, m), 7.29 (2H, d, J = 6.4 Hz), 7.07 (2H, d, J = 6, 4 Hz), 6.91-6.94 (1H, m), 3.97 (2H, t, J = 6.6 Hz), 2.99 (2H, t, J = 6.6 Hz), 2 , 84 (2H, q, J = 7.5 Hz), 2.71 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

STEP 5. 1-i4- (2-Chloroethyl) phenyl12-ethyl-4-methyl-1/7-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-4-methyl-1 Hbenzimídazol-1-yl) phenyl] ethanol (step 4) .

¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.07-7.09 (2H , m), 6.90-6.95 (1H, m), 3.81 (2H, t, J = 7.2 Hz), 3.19 (2H, t, J = 7.2 Hz), 2 , 84 (2H, q, J = 7.5 Hz), 2.72 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

STEP 6. 2-R4- (2-ethyl-4-methyl-1/7-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethiMmethyl-1/7-benzimidazole (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.05-7.09 (2H , m), 6.90-6.94 (1H, m), 3.61 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.0 Hz), 2 , 84 (2H, q, J = 7.5 Hz), 2.72 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

STEP 7. 2-i4- (2-Ethyl-4-methyl-1 H-benzimidazol-1-yl) phenyethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-4-methyl1 / - / - benzimidazol-1-yl) phenyl] ethyl azide (step 6).

¹ H NMR (CDCIs) δ 7.40 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.04-7.11 (2H, m), 6.86-6.95 (1H, m), 3.07 (2H, t, J = 6.6 Hz), 2.87 (2H, t, J = 6.6 Hz), 2, 84 (2H, q, J = 7.5 Hz), 2.71 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

STEP 8. 2-Ethyl-4-methyl-1- (4- (2 - ['(4-methylphenyl) sulfonimino) carbonyl) aminoletyl} phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-4-methyl-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 7) .

MS (IED) m / z 477 (M + H) ⁺ ; 'H (DMSO-d ₆ ) δ 7.65 (2H, d, J = 7.7 Hz), 7.33-7.41 (4H, m), 7.15 (2H, d, J = 7.7 Hz), 7.01-7.07 (2H, m), 6.86 (1H, d, J = 6.8 Hz), 3.19 (2H, s lg.), 2.68- 2.74 (4H, m), 2.56 (3H, s), 2.28 (3H, s), 1.21 (3H, t, J = 7.1 Hz); IV (KBr) v _max 3390, 1602, 1519, 1429, 1230, 1130, 1085 cm ^-1 .

EXAMPLE 46

SODIUM SALT OF 4-METHYL-2-ETHYL-3- (4- (2-r ((r (4-METHYLphenyl) SULFONYL1AMINO) CARBONY) AMINOIETHIL) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-4-methyl-1 - (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 45).

¹ H NMR (DMSO-d ₆ ) δ 7.65 (2H, d, J = 7.7 Hz), 7.33-7.41 (4H, m), 7.15 (2H, d, J = 7.7 Hz), 7.01-7.07 (2H, m), 6.86 (1H, d, J = 6.8 Hz), 3.19 (2H, s lg.), 2.68- 2.74 (4H, m), 2.56 (3H, s), 2.28 (3H, s), 1.21 (3H, t, J = 7.1 Hz); IV (KBr) v _max 3390, 1602, 1519, 1429, 1230, 1130, 1085 cm ^-1 .

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EXAMPLE 47

2-ETIL-5-METHYL 1- (4- {2-r (q (4-METHYLPHYL) SULFONYL1-AMINO) CARBONI DAM INQ1ETYL) PHENYL) -1 / - / - BENZIMIDAZOLE

STEP 1. 2-r (4-Methyl-2-nitroanilino) phenillethane

The title compound was prepared according to the procedure described in step 1 of Example 45 from 4-methyl-2-nitroaniline and 4-iodophenyl ethyl alcohol.

¹ H NMR (CDCb) δ 9.35 (1H, s lg.), 8.00 (1H, s), 7.33-7.09 (6H, m), 3.91-3.89 (2H , m), 2.89 (2H, t, J = 6.4 Hz), 2.30 (3H, s).

STEP 2. 2-f (2-Amino-4-methylanilino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(4-methyl-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCb) δ 7.05 (2H, d, J = 8.3 Hz), 6.98 (1H, d, J = 7.7 Hz), 6.67-6.64 (3H, m), 6.58-6.55 (1H, m), 5.06 (1H, s lg.), 3.80-3.78 (4H, m), 2.77 (2H, t, J = 6.4 Hz), 2.28 (3H, s).

STEP 3. 2-R4- (2-ethyl-5-methyl-1 / - / - benzimidazole-1iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-4-methylanilino) phenyl] ethanol (step 2) and propionyl chloride.

TLC Rf = 0.33 (hexane: ethyl acetate = 2: 1).

STEP 4. 2- [4- (2-Ethyl-5-methyl-1 H-benzimidazol-1-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5methyl-1 / - / - benzimidazol-1-yl) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.55 (1H, s), 7.43 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 6.99-6.95 (2H, m), 3.99 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.77 (2H , q, J = 7.7 Hz), 2.47 (3H, s), 1.32 (3H, t, J = 7.7 Hz).

STEP 5. 2-R4- (2-ethyl-5-methyl-1F / -benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure171 / 451 as described in step 5 of Example 26 from 2- [4- (2-ethyl-5-methyl-1 / 7benzimidazol-1-yl) phenyl] ethanol (step 4).

TLC Rf = 0.74 (hexane / ethyl acetate = 1: 1).

STEP 6. 2-i4- (2-Ethyl-5-methyl-1H-benzimidazol-1-yl) phenethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5-methyl1H-benzimidazol-1-yl) phenyl] ethyl azide (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.55 (1H, s), 7.43 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.01-6.95 (2H, m), 4.85 (2H, s lg.), 3.30-3.25 (2H, m), 3.16-3.11 (2H, m), 2.76 (2H, q, J = 7.6 Hz), 2.45 (3H, s), 1.31 (3H, t, J = 7.6 Hz).

STEP 7. 2-Ethyl-5-methyl-1 - (4- {2-i ({í (4-methylphenyl) sulfoninamino) carbonyl) amino1ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5-methyl-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 6) .

¹ H NMR (DMSO-d ₆ ) δ 7.76 (2H, d, J = 8.4 Hz), 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 = 7.4 Hz).

EXAMPLE 48

SODIUM SALT OF 2-ETHYL-5-METHYL 1- (4-f2-r (f (4-METHYLphenyl) SULFONYL1AMINO) CARBONY) AMINO1ETHIL) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5-methyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 H-benzimidazole (Example 47).

¹ H NMR (DMSO-d ₆ ) δ 7.60 (2H, d, J = 7.7 Hz), 7.42-7.33 (5H, m), 7.13 (2H, d, J = 7.7 Hz), 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 = 7.5 Hz); IV (KBr) v _max 1599, 1514, 1285, 1232, 1130, 1086 cm ^-1 .

EXAMPLE 49

2-BUTYL-5-METHYL 1- (4- {2-i (U (4-METHYLFENlL) SULFONYLAMINO) CARBONY) AMINO1BUTYL) PHENYL) -1H-BENZIMIDAZOLE

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STEP 1. 2-F4- (2-butyl-5-methyl-1/7-benzimidazol1-yl) phenyl1ethyl pentanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-4-methylanilino) phenyl] -ethanol (step 2 of Example 47) and pentanoyl chloride.

¹ H NMR (CDCb) δ 7.56-7.55 (1H, m), 7.43-7.40 (2H, m), 7,297.26 (2H, m), 7.02-6.94 (2H, m), 4.38 (2H, t, J = 6.9 Hz), 3.06 (2H, t, J = 6.9 Hz), 2.75 (2H, t, J = 7, 4 Hz), 2.47 (3H, s), 2.33 (2H, t, J = 7.4 Hz), 1.80-1.55 (4H, m), 1.41-1.23 ( 4H, m), 0.94-0.83 (6H, m).

STEP 2. 2-r4- (2-Butyl-6-methyl-1 / - / - benzimidazole-1-hyphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-butyl-6methyl-1A / -benzimidazol-1-yl) phenyl] ethyl pentanoate (step 1).

¹ H NMR (CDCb) δ 7.55 (1H, s), 7.44 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 7 , 02-6.95 (2H, m), 3.99 (2H, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.47 (3H, s), 1.79-1.68 (2H, m), 1.36-1.23 (2H, m), 0.85 (3H , t, J = 7.3 Hz).

STEP 3. 2-yl- (2-butyl-6-methyl-1H-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4 ~ (2-butyl6-methyl-1/7-benzimidazol-1-yl) phenyl] ethanol pentanoate ( step 2).

¹ H NMR (CDCb) δ 7.56 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7 , 03-6.95 (2H, m), 3.61 (2H, t, J = 6.9 Hz), 3.01 (2H, t, J = 6.9 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.47 (3H, s), 1.80-1.68 (2H, m), 1.37-1.26 (2H, m), 0.85 (3H , t, J = 7.3 Hz).

STEP 4. 2-f4- (2-Butyl-6-methyl-1 H-benzimidazol-1-yl) pheniri-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-butyl-6-methyl1H-benzimidazol-1-II) phenyl] ethyl azide (step 3 ).

¹ H NMR (CDCb) δ 7.55 (1H, s), 7.40 (2H, d, J = 8.3 Hz), 7.26

173/451 (2Η, d, J = 8.3 Hz), 7.01-6.94 (2H, m), 3.15 (2H, t, J = 7.3 Hz), 2.98 (2H , t, J = 7.3 Hz), 2.74 (2H, t, J = 7.7 Hz), 2.46 (3H, s), 1.77-1.67 (2H, m), 1 , 35-1.28 (2H, m), 0.84 (3H, t, J = 7.7 Hz).

STEP 5. 2-Butyl-5-methyl-1 - (4- {2-i ({[(4-methylphenyl) sulfonyl-amino} carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-butyl-6-methyl-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 4) .

¹ H NMR (CDCI ₃ ) δ 7.76 (2H, d, J = 8.2 Hz), 7.54 (1H, m), 7.317.21 (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 = 7.1 Hz), 2.73 ( 2H, t, J = 7.3 Hz), 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 = 7.3 Hz).

EXAMPLE 50

SODIUM SALT OF 2-BUTYL-5-METHYL 1- (4-f2-r ((í (4-METHYLphenyl) SULFONYL1-AMINO) CARBONYL) AMINO1BUTYL) PHENYL) -1 / 7-BENZIMLDAZOL

The title compound was prepared according to the procedure described in Example 2 from 2-butyl-5-methyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 W-benzimidazole (Example 49).

Mp: 130-140 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.59 (2H, d, J = 7.8 Hz), 7.40-7.31 (5H, m), 7.11 (2H, d, J = 7.8 Hz), 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 = 7.5 Hz); IV (KBr) v _max 1599, 1514, 1400, 1130, 1086 cm ^-1 .

EXAMPLE 51

6-METHYL-2-ETYL-3- (4- {2 - [(U (4-METHYLphenyl) SULFONYL-AMINO)

CARBONIL) AMINO1ETYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2- [4- (5-Methyl-2-nitroanilino) pheniHethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-fluoro-4-methylnitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCIj) δ 9.51 (1H, s lg.), 8.10 (1H, d, J = 8.8 Hz),

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7.20-7.31 (4Η, m), 6.98 (1H, s), 6.58 (1H, d, J = 8.4 Hz), 3.91 (2H, t, J = 6, 4 Hz), 2.89 (t, J = 6.4 Hz), 2.27 (3H, s).

STEP 2. 2-i4- (2-Amino-5-methylaniline) pheninethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [4- (5-methyl-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.07 (2H, d, J = 8.3 Hz), 6.93 (1H, s), 6.81 (1H, d, J = 8.1 Hz), 6.70-6.72 (3H, m), 3.81 (2H, t, J = 6.4 Hz), 3.61 (2H, s lg.), 2.78 (2H, t, J = 6.4 Hz), 2.22 (3H, s).

STEP 3. 2-R4- (2-ethyl-6-methyl-1H-benzimidazole-1iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-5-methylanilino) phenyl] ethanol (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.08 (1H, d, J = 8.3 Hz), 6.87 (1H, s), 4.38 (2H, t, J = 6.9 Hz), 3, 06 (2H, t, J = 6.9 Hz), 2.76 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 2.36 (2H, q, J = 7 , 7 Hz), 1.35 (3H, t, J = 7.5 Hz), 1.15 (3H, t, J = 7.7 Hz).

STEP 4. 2-f4- (2-Ethyl-6-methyl-1/7-benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-6methyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3 ).

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, d, J = 8.1 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.19-7.30 (2H , m), 7.08 (1H, d, J = 8.1 Hz), 6.88 (1H, s), 3.99 (2H, t, J = 6.6 Hz), 3.00 (2H , t, J = 6.6 Hz), 2.77 (2H, q, J = 7.6 Hz), 2.40 (3H, s), 1.33 (3H, t, J = 7.6 Hz ).

STEP 5. 1 -4- (2-Chloroethyl) phenill-2-ethyl-6-methyl-1 H-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-6-methyl-1Hbenzimidazol-1-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 7.65 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.07 (1H, d, J = 8.2 Hz), 6.88 (1H, s), 3.82 (2H, t,

175/451

J = 7.0 Hz), 3.19 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.6 Hz), 2.41 (3H, s), 1 , 33 (3H, t, J = 7.6 Hz).

STEP 6. 2-R4- (2-ethyl-6-methyl-1H-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1 ~ [4- (2-chloroethyl) phenyl] -2-ethyl-6methyl-1/7-benzimidazole (step 5) .

¹ H NMR (CDCfe) δ 7.64 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.08 (1H, d, J = 8.2 Hz), 6.87 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.6 Hz), 2.37 (3H, s), 1.33 (3H, t, J = 7, 6 Hz).

STEP 7. 2- [4- (2-Ethyl-6-methyl-1 / - / - benzimidazole-1-hyphenethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-6-methyl1H-benzimidazol-1-yl) phenyl] ethyl azide (step 6 ).

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.07 (1H, d, J = 8.3 Hz), 6.88 (1H, s), 3.07 (2H, s lg), 2.87 (2H, t, J = 6.8 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.40 (3H, s), 1.33 (3H, t, J = 7.6 Hz).

STEP 8. 6-Methyl-2-ethyl-3- (4- {2-i ({[(4-methylphenyl) sulfonillamino) carbonyl) aminoletyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-6-methyl-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 7) .

¹ H NMR (CDCl 3) δ 7.73 (2H, d, J = 8.3 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.27-7.38 (6H, m), 7.09 (1H, d, J = 8.0 Hz), 6.88 (1H, s), 3.59-3.63 (2H, m), 2.95 (2H, t, J = 6.6 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 2.39 (3H, s), 1.33 (3H, t, J = 7.5 Hz).

176/451

EXAMPLE 52

SODIUM SALT OF 6-METHYL-2-ETHYL-3- (4- (2-y '(4-METHYLPHYL) SULPHONYLAMINO) CARBONYL) AMINO-BUTYL) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in 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 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.64 (2H, d, J = 8.0 Hz),

7.51 (1H, d, J = 8.2 Hz), 7.33-7.42 (4H, m), 7.15 (2H, d, J = 8.0 Hz), 7.02 (1H, dd , J = 1.4 Hz, 8.2 Hz), 6.87 (1H, s), 3.18 (2H, s lg.), 2.65-2.78 (4H, m), 2.34 (3H, s), 2.78 (3H, s), 1.21 (3H, t, J = 7.6 Hz).

EXAMPLE 53

7-METHYL-2-ETYL-3- (4- {2-y ((y (4-METHYLphenyl) SULFONYl-AMINO)

CARBONIL) AMINO1ET1L) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2- [4- (2-Methyl-6-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 1 of Example 45 from 6-methyl-2-nitroaniline and 4-bromophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 8.28 (1H, s lg.), 7.96 (1H, d, J = 8.4 Hz), 7.39-7.44 (1H, m), 7 , 02-7.12 (3H, m), 6.72 (2H, d, J = 8.4 Hz), 3.82 (2H, t, J = 6.5 Hz), 2.81 (2H, t, J = 6.5 Hz), 2.08 (3H, s).

STEP 2. 2-i4- (2-Amino-6-methylanilino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [4- (2-methyl-6-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 6.97-7.03 (3H, m), 6.66 (2H, d, J = 7.6 Hz),

6.52 (2H, d, J = 7.6 Hz), 4.97 (1H, s lg.), 3.86 (2H, s lg.), 3.79 (2H, t, J = 6.4 Hz ), 2.76 (2H, t, J = 6.4 Hz), 2.16 (3H, s).

STEP 3. 2-R4- (2-ethyl-7-methyl-1H-benzimidazole-1iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-6-methyl177 / 451 lanilino) phenyl] ethanol (step 2) and propionyl chloride .

TLC Rf = 0.6 (hexane: ethyl acetate = 1: 1).

STEP 4. 2- [4- (2-Ethyl-7-methyl [-1 / - / - benzimidazol-1-yl) pheninethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-7methyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3 ).

¹ H NMR (CDCI ₃ ) δ 7.63 (1H, d, J = 8.0 Hz), 7.38-7.41 (2H, m), 7.26-7.31 (2H, m) , 7.14 (1H, dd, J = 7.4 Hz, 8.0 Hz), 6.91 (1H, d, J = 7.4 Hz), 3.98 (2H, t, J = 6, 6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.63 (2H, q, J = 7.5 Hz), 1.89 (3H, s), 1.31 (3H , t, J = 7.5 Hz).

STEP 5. 1-i4- (2-Chloroethyl) phenyl1-2-ethyl-7-methyl-1 H-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-7-methyl-1 / 7benzimidazol-1-yl) phenyl] ethanol (step 4 ).

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, d, J = 8.1 Hz), 7.26-7.39 (4H, m), 7.14 (1H, dd, J = 7, 4 Hz, 8.1 Hz), 6.91 (1H, d, J = 7.4 Hz), 3.81 (2H, t, J = 7.2 Hz), 3.19 (2H, d, J = 7.2 Hz), 2.63 (2H, q, J = 7.6 Hz), 1.88 (3H, s), 1.32 (3H, t, J = 7.6 Hz).

STEP 6. 2- [4- (2-ethyl-7-methyl-1/7-benzimidazol-1-yl) phenyl azide azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl-7methyl-1/7-benzimidazole (step 5) .

¹ H NMR (CDCb) δ 7.64 (1H, d, J = 7.4 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.14 (1H, dd, J = 7.4 Hz, 8.1 Hz), 6.91 (1H, d, J = 8.1 Hz), 3.61 (2H, t , J = 6.8 Hz), 3.02 (2H, t, J = 6.8 Hz), 2.63 (2H, q, J = 7.6 Hz), 1.89 (3H, S), 1.31 (3H, t, J = 7.5 Hz).

STEP 7. 2- [4- (2-Ethyl-7-methyl-1/7-benzimidazol-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-7-methyl1 / 7-benzimidazol-1-yl) phenyl] ethyl azide ( step 6).

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, d, J = 7.9 Hz), 7.36 (2H, d, J =

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8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.14 (1H, dd, J = 7.5 Hz, 7.9 Hz), 6.91 (1H, d , J = 7.5 Hz), 3.06 (2H, t, J = 6.8 Hz), 2.87 (2H, t, J = 6.8 Hz), 2.63 (2H, q, J = 7.5 Hz), 1.89 (3H, s), 1.32 (3H, t, J = 7.5 Hz).

STEP 8. 2-Ethyl-7-methyl-1- (4-f2 - [(U (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-7-methyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 7 ).

MS (IED) m / z 477 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.75 (2H, d, J = 8.3 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.28-7.33 (5H , m), 7.14 (2H, d, J = 7.6 Hz), 6.91 (1H, d, J = 7.9 Hz), 6.72 (1H, s lg.), 3.58 (2H, d, J = 6.8 Hz), 2.93 (2H, t, J = 6.8 Hz), 2.62 (2H, q, J = 7.6 Hz), 2.41 (3H , s), 1.86 (3H, s), 1.29 (3H, t, J = 7.6 Hz).

EXAMPLE 54

SODIUM SALT OF 7-METHYL-2-ETHYL-3- (4- (2-i «[(4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AM1NO1ETYL) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-7-methyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 53).

¹ H NMR (DMSO-d _s ) δ 7.63 (2H, d, J = 7.4 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.36 (4H, s ), 7.15 (2H, d, J = 7.7 Hz), 7.06 (1H, dd, J = 7.2 Hz, 8.1 Hz), 6.87 (1H, d, J = 7 , 2 Hz), 5.99 (1H, s lg.), 3.16 (2H, s lg.), 2.76 (2H, s lg.),

2.52 (2H, q, J = 7.6 Hz), 2.28 (3H, s), 1.82 (3H, s), 1.19 (3H, t, J = 7.6 Hz); IV (KBr) v _max 3400, 1610, 1525, 1290, 1132, 1095, 820, 751 cm ^-1 .

EXAMPLE 55

4-CHLORINE-2-ETHYL-3- (4- {2-i ({F (4-METHYLPHYL) SULPHONYL-AMINO) CARBONYL) AMINO1ETHIL) PHENYL) -1H-BENZIMIDYZOL

STEP 1. 2-r4- (3-Chloro-2-nitroanilino) phenylethanol

A mixture of 2,6-dichloronitrobenzene (Norman, MH; Chen, N .; et al.} PCT Int. Appl., WO 9940091 (1999); Spada, AP; Fink, CA; Myers was placed in a sealed tube. , MR; PCT Int. Appl., WO 9205177 (1992); 6.3 g, 32.8 mmol), 4-aminophenylethyl alcohol (4.9 g, 36 mmol) and

179/451 sodium acetate (3.2 g, 39.3 mmoles), and heated at 160 ° C for 3 hours. After cooling, the mixture was poured into water (100 ml) and extracted with ethyl acetate (300 ml). The organic phase was washed with 2N aqueous NaOH solution (100 ml) and brine (100 ml), then dried (Na ₂ SO ₄ ), and concentrated. Purification by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), gave 4.57 g (72%) of the title compound as a red oil: NMR ¹ H (CDCI ₃ ) δ 7.09-7.28 (6H, m), 6.91 (1H, dd, J = 2.0, 7.1 Hz), 3.87 (2H, t, J = 6.6 Hz), 2.86 (2H, t, J = 6.6 Hz).

STEP 2. 2- [4- (2-Amino-3-chloroanilino) phenyl ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4- (3-chloro-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.06-7.10 (3H, m), 7.00 (1H, dd, J = 1.0 Hz,

7.9 Hz), 6.62-6.73 (3H, m), 5.16 (1H, s lg.), 4.14 (2H, s lg.), 3.81 (2H, t, J = 6.1 Hz), 2.77 (2H, t, J = 6.1 Hz).

STEP 3. 2-R4- (4-chloro-2-ethyl-1 / - / - benzimidazol-1 yl) phenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-3-chloroanilino) phenyl] ethanol (step 2) and propionyl chloride.

TLC Rf = 0.5 (hexane: ethyl acetate = 1: 1).

STEP 4. 2- [4- (4-Chloro-2-ethyl-1 / - / - benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (4-chloro2-ethyl-1/7-benzimidazol-1-yl) phenyl] ethyl propionate ( step 3).

¹ H NMR (CDCb) δ 7.45 (2H, d, J = 8.6 Hz), 7.26-7.31 (3H, m), 7.09 (1H, d, J = 7.9 Hz), 6.96 (1H, dd, J = 0.9 Hz, 7.9 Hz), 3.99 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.84 (2H, q, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz).

STEP 5. 4-Chloro-1-14- (2-chloroethyl) phenyl1-2-ethyl-1/7-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (4-chloro-2-ethyl (-1H180 / 451 benzimidazol-1-yl) phenyl] ethanol ( step 4).

¹ H NMR (CDCI ₃ ) δ 7.45 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.27 (1H, s), 7.10 (1H, d, J = 8.1 Hz), 6.98 (1H, d, J = 8.1 Hz), 3.81 (2H, t, J = 7.1 Hz), 3, 19 (2H, t, J = 7.1 Hz), 2.84 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz).

STEP 6. 2- [4- (4-chloro-2-ethyl-1B-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 4-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-1/7-benzimidazole (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.45 (2H, d, J = 8.2 Hz), 7.29-7.33 (3H, m),

7.10 (1H, dd, J = 8.1 Hz, 7.7 Hz), 6.96 (1H, d, J = 7.7 Hz), 3.62 (2H, t, J = 7.1 Hz), 3.02 (2H, t, J = 7.1 Hz), 2.84 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J = 7.6 Hz) .

STEP 7. 2- [4- (4-Chloro-2-ethyl-1 B-benzimidazole-1-ibphenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (4-chloro-2-ethyl1H-benzimidazol-1-yl) phenyl] ethyl azide (step 6 ).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.1 Hz), 7.29-7.33 (3H, m), 7.09 (1H, dd, J = 7, 7 Hz, 7.9 Hz), 7.99 (1H, d, J = 7.9 Hz), 3.07 (2H, t, J = 6.8 Hz), 2.87 (2H, t, J = 6.8 Hz), 2.85 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J = 7.6 Hz).

STEP 8. 4-Chloro-2-ethyl-1- (4- {2-r ({[(4-methylphenyl) sulfonillamino} carbonyl) aminoletyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (4-chloro-2-ethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 7 ).

MS (IED) m / z 498 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.73 (2H, d, J = 8.5 Hz), 7.28-7.38 (7H, m), 7.09 (1H, d, J = 7, 9 Hz), 6.97 (1H, d, J = 7.9 Hz), 6.69 (1H, s Ig.), 3.58 (2H, t, J = 6.9 Hz), 2.94 (2H, t, J = 6.9 Hz), 2.83 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.31 (3H, t, J = 7, 5 Hz).

EXAMPLE 56

SODIUM SALT OF 4-CHLORINE-2-ETHYL-3- (4- {2 - [({r (4-METHYLPHYL) SULFON1L1AMINO} CARBONY) AMINO1ETHIL) PHENYL) -1H-BENZIMIDA181 / 451

ZQL

The title compound was prepared according to the procedure described in Example 2 from 4-chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / - / - benzimidazole (Example 54).

¹ H NMR (DMSO-d ₆ ) δ 7.62 (2H, d, J = 8.0 Hz), 7.41 (4H, s), 7.29 (1H, d, J = 6.6 Hz ), 7.12-7.18 (3H, m), 7.02-7.04 (1H, m), 3.18 (2H, s lg.), 2.70-2.79 (4H, m ), 2.27 (3H, s), 1.23 (3H, t, J = 7.4 Hz); IV (KBr) v _max 3385, 1602, 1519, 1433, 1174, 1130, 1085, 813 cm · ¹ .

EXAMPLE 57

5-CHLORINE-2-ETYL-1- (4- {2-i ({[(4-METHYLPHYL) SULFONYL1-AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1H-BENZ1MIDAZOLE

STEP 1. 2- [4- (4-Chloro-2-nitroanilino) phenylethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-dichloronitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.42 (1H, s), 8.20 (1H, d, J = 2.0 Hz), 7,357.10 (6H, m), 3.96-3.85 (2H, m), 2.91 (2H, t, J = 7.0 Hz).

STEP 2. 2-r4- (2-Amino-4-chloroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 6 from 2- [4- (4-chloro-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.30-7.05 (4H, m), 6.83-6.62 (3H, m), 5.15 (1H, s lg.), 3.86- 3.75 (2H, m), 3.75 (2H, s lg.), 2.77 (2H, t, J = 7.0 Hz).

STEP 3. 2-i4- (5-chloro-2-ethyl-1Z7-benzimidazole-1iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-4-chloroanilino) phenyl] ethanol (step 2) and propionyl chloride.

'H NMR (CDCI ₃ ) δ 7.75 (1H, d, J = 2.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.15 (1H, dd, J = 2.0 Hz, 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 4.38 (2H, t, J = 7.0 Hz), 3.07 (2H, t, J = 7.0 Hz), 2.78 (2H, q, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 1.24 (3H, t, J = 7.5 Hz), 1.15 (3H, t, J = 7.5 Hz).

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STEP 4. 2-f4- (5-Chloro-2-ethyl-1 H-benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-chloro2-ethyl-1 H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, d, J = 2.0 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.15 (1H, dd, J = 2.0 Hz, 8.6 Hz), 7.00 (1H, d, J = 8.6 Hz), 3.99 (2H, t, J = 6.5 Hz), 3.00 (2H, t, J = 6.5 Hz), 2.78 (2H, q, J = 7.5 Hz), 1.26 (3H, t, J = 7.5 Hz).

STEP 5. 2- [4- (5-chloro-2-ethyl-1/7-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (5-chloro-2-ethyl-1 / - / benzimidazol-1-yl) phenyl] ethanol ( step 4).

MS (IE) m / z 325 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.75 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.15 (1H, dd, J = 2.0, 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 3.62 (2H, t , J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz), 2.78 (2H, q, J = 7.5 Hz), 1.26 (3H, t, J = 7.5 Hz).

STEP 6. 2-r4- (5-Chloro-2-ethyl-1 / - / - benzimidazole-1-phenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (5-chloro-2-ethyl1H-benzimidazol-1-yl) phenyl] ethyl azide (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, d, J = 2.0 Hz), 7.41 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.14 (1H, dd, J = 2.0 Hz, 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 3.08 (2H, t, J = 7.0 Hz), 2.86 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 7. 5-Chloro-2-ethyl-1 - (4- (2 - [((F (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5-chloro-2-ethyl-1 / - / benzimidazol-1-yl) phenyl] ethylamine ( step 6).

¹ H NMR (CDCl 3) δ 7.76 (1H, d, J = 1.8 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.3 Hz),

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7.17 (1Η, dd, J = 8.6, 1.8 Hz), 7.00 (1H, d, J = 8.6 Hz), 6.73 (1H, s lg.), 3,593.53 (2H, m), 2.94 (2H, t, J = 7.0 Hz), 2.81 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7, 5 Hz).

EXAMPLE 58 2- (4--5-CHLORO-2-ETHYL-1/7-BENZIMIDAZQL-1-IL) (4-METHYLFENIL) PHENYL-ETHYL

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (5-chloro-2-ethyl-1H-benzimidazol-1yl) phenyl] ethanol (step 4 of Example 57).

¹ H NMR (CDCI ₃ ) δ 7.92 (2H, d, J = 8.4 Hz), 7.74 (1H, d, J = 2.0 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 8 , 5, 2.0 Hz), 6.99 (1H, d, J = 8.5 Hz), 4.74 (1H, s lg.), 4.37 (2H, t, J = 6.8 Hz ), 3.01 (2H, t, J = 6.8 Hz), 2.75 (2H, q, J = 7.6 Hz), 1.33 (3H, t, J = 7.6 Hz).

EXAMPLE 59

6-CHLORINE-2-ETYL-1- (4- {2-r (U (4-METHYLPHYL) SULFONYL-AMINO) CARBONY) AMINO1ETHYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2 - [(5-Chloro-2-nitroanilino) phenylethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloronitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.52 (1H, s lg.), 8.16 (1H, d, J = 9.2 Hz), 7.33 (2H, d, J = 8.2 Hz ), 7.25 (2H, d, J = 8.2 Hz), 7.13 (1H, d, J = 2.2 Hz), 6.71 (1H, dd, J = 9.2, 2, 2 Hz), 3.92 (2H, q, J = 6.4 Hz), 2.92 (t, 2H, J = 6.4 Hz).

STEP 2. 2-i (2-Amino-5-chloroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(5-chloro-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCl ₃ ) δ 7.12-7.09 (3H, m), 6.92 (1H, dd, J = 8.4, 2.4 Hz), 6.78-6.70 ( 3H, m), 5.16 (1H, s lg.), 3.83 (2H, t, J = 6.6 Hz), 2.81 (2H, t, J = 6.6 Hz).

STEP 3. 2-r4- (6-chloro-2-ethyl-1/7-benzimidazole-1184/451 propionate iDphenylethyl

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-5-chloroanilino) phenyl] ethanol (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.4

Hz), 7.28 (2H, d, J = 8.4 Hz), 7.22 (1H, dd, J = 8.4, 2.0 Hz), 7.07 (1H, d, J = 2 , 0

Hz), 4.38 (2H, t, J = 7.0 Hz), 3.07 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.5 Hz) ,

2.36 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz), 1.15 (3H, t, J = 7.5 Hz).

STEP 4. 2- [4- (6-Chloro-2-ethyl-1/7-benzimidazol-1-yl) phenyl] ethanol 10 The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-chloro2-ethyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, d, J = 8.6 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.30-7.26 (3H , m), 7.22 (1H, dd, J = 8.6, 2.2 Hz), 7.08 (1H, d, J = 2.0 Hz),

3.99 (2H, q, J = 6.4 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.78 (2H, q, J = 7.6 Hz), 1, 72 (1H, t, J = 5.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 5. 2-Γ4- (6-οΙθΓθ-2-θίίΙ-1Η-5θηζϊηΊΐ ^ 3ΖθΙ-1-ίΙ) azide ί6nilletila

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (6-chloro-2-ethyl-1tfbenzimidazol-1-yl) phenyl] ethanol (step 4) .

MS (IE) m / z 325 (M ⁺ ).

STEP 6. 2- [4- (6-Chloro-2-ethyl-1-rt-benzimidazole-1-yl) phenyl1-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-chloro-2-ethyl1H-benzimidazol-1-yl) phenyl] ethyl azide (step 5).

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.4

Hz), 7.31-7.19 (3H, m), 7.12 (1H, d, J = 2.0 Hz), 4.66 (2H, s lg.), 3.23-3.17 (2H, m), 3.08-3.04 (2H, m), 2.75 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz) .

STEP 7. 6-Chloro-2-ethyl-1- (4- {2-r (fl (4-methylphenyl) sulfonillamino) carbonyl) aminoletyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure185 / 451 as described in step 10 of Example 1 from 2- [4- (6-chloro-2-ethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 6).

¹ H NMR (CDCI ₃ ) δ 7.74 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.30-7.20 (6H, m), 7.05 (1H, d, J = 2.0 Hz), 6.73 (1H, m), 3.62-3 , 55 (2H, m), 2.93 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.5 Hz), 1.32 (3H, t, J = 7.5 Hz).

EXAMPLE 60

SODIUM SALT OF 6-CHLORINE-2-ETHYL-1- (4- {2 - [(fr (4-METHYLphenyl) SULFONYL1AMINO | CARBONYL) AM1NO1ET1L) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 6-chloro-2-ethyl-1 - (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 59).

¹ H NMR (DMSO-d ₆ ) δ 7.64 (1H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.38 (4H, m ), 7.22 (1H, dd, J = 8.6, 2.0 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.05 (1H, d, J = 2, 0 Hz), 3.15 (2H, m), 2.74-2.66 (4H, m), 2.25 (3H, s), 1.21 (3H, t, J = 7.4 Hz) ; IV (KBr) v _max 1601, 1516, 1398, 1178, 1130, 1084 cm ^-1 . EXAMPLE 61 4- (6-CHLORINE-2-ETHYL-1H-BENZIMIDAZOL-1-IDFENETYL (4-METHYLphenyl) SULPHONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (6-chloro-2-ethyl-1/7-benzimidazol-1yl) phenyl] ethanol (step 4 of Example 59 ).

Mp: 183-187 ° C; ¹ H NMR (CDCI ₃ ) δ 7.75 (2H, d, J = 8.1 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.43 (4H, s), 7.40 (2H, d, J = 8.1 Hz), 7.24 (1H, dd, J = 8.6, 2.0 Hz), 7.03 (1H, d, J = 2.0 Hz ), 4.27 (2H, t, J = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz), 2.70 (2H, q, J = 7.5 Hz), 2.34 (3H, s), 1.22 (3H, t, J = 7.5 Hz); IV (KBr) v _max 1744, 1516, 1352, 1225, 1165 cm “ ¹ .

EXAMPLE 62

2-BUTYL-6-CHLORINE-1- (4- {2 - [({r (4-METHYLPHYL) SULFONYL1-AMINO) CARBON1L) AMINO1BUTYL) PHENYL) -1H-BENZ1MIDAZOLE

STEP 1. 2-r4- (2-Butyl-6-chloro-1 / - / - benzimidazole pentanoate186 / 451

1-yl) phenyl1ethyl

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-5-chloroanilino) phenyl] -ethanol (step 2 of Example 59) and pentanoyl chloride.

¹ H NMR (CDCI ₃ ) δ 7.66 (1H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.22 (1H, dd, J = 8.4, 2.0 Hz), 7.06 (1H, d, J = 2.0 Hz), 4.38 (2H, t , J = 6.8 Hz), 3.07 (2H, t, J = 6.8 Hz), 2.74 (2H, t, J = 7.7 Hz), 2.33 (2H, t, J = 7.5 Hz), 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 2. 2- [4- (2-Butyl-6-chloro-1 / - / - benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-butyl-6chloro-1/7-benzimidazol-1-yl) phenyl] ethyl pentanoate ( step 1).

¹ H NMR (CDCI ₃ ) δ 7.66 (1H, d, J = 8.6 Hz), 7.46 (2H, d, J = 8.1 Hz), 7.29-7.26 (2H , m), 7.22 (1H, dd, J = 8.6, 2.0 Hz), 7.07 (1H, d, J = 2.0 Hz), 4.00 (2H, q, J = 6.4 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.75 (2H, t, J = 7.5 Hz), 2,242.19 (1H, m), 1.81 -1.71 (2H, m), 1.37-1.26 (2H, m), 0.87 (3H, t, J = 7.3 Hz).

STEP 3. 2-yl- (2-butyl-6-chloro-1H-benzimidazole-1-ii) phenylethyl azide

The title compound was prepared according to the procedure described in step 4 of the Example from 2- [4- (2-butyl-6-chloro-1/7-benzimidazol-1-yl) phenyl] ethanol pentanoate (step 2).

¹ H NMR (CDCI ₃ ) δ 7.66 (1H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.22 (1H, dd, J = 8.6, 2.0 Hz), 7.07 (1H, d, J = 2.0 Hz), 3.62 (2H, t , J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz), 2.74 (2H, t, J = 7.5 Hz), 1.80-1.70 (2H , m), 1.40-1.26 (2H, m), 0.86 (2H, t, J = 7.3 Hz).

STEP 4. 2-r4- (2-Butyl-6-chloro-1 / - / - benzimidazole-1-iDphenyl-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-butyl-6-chloro1 / 7-benzimidazol-1-yl) phenyl] ethyl azide ( step 3).

¹ H NMR (CDCI ₃ ) δ 7.66 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.2

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Hz), 7.27 (2H, d, J = 8.2 Hz), 7.21 (1H, dd, J = 8.6, 2.0 Hz), 7.08 (1H, d, J = 2 , 0 Hz), 3.11 (2H, t, J = 7.1 Hz), 2.91 (2H, t, J = 7.1 Hz), 2.74 (2H, t, J = 7.4 Hz), 1.81 to 1.70 (2H, m), 1.41 to 1.27 (2H, m), 0.86 (3H, t, J = 7.4 Hz).

STEP 5, 2-Butyl-6-chloro-1 - (4- (2- [Gf (4 ~ methylphenyl) sulfonin-amino} carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-butyl-6-chloro-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 4 ).

¹ H NMR (CDCI ₃ ) δ 7.75 (2H, d, J = 8.4 Hz), 7.66 (1H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.30-7.20 (6H, m), 7.05 (1H, d, J = 2.0 Hz), 6,776.72 (1H, m), 3.61 , 55 (2H, m), 2.96-2.92 (2H, m), 2.74 (2H, t, J = 7.5 Hz), 2.39 (3H, s), 1.78- 1.67 (2H, m), 1.35-1.26 (2H, m), 0.84 (3H, t, J = 7.3 Hz). EXAMPLE 63

SODIUM SALT OF 2-BUTYL-6-CHLORINE-1- (4- <2-r (f ((4-METHYLphenyl) SULFONYL1-AMINO) CARBONYL) AMINO1BUTYL) PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-butyl-6-chloro-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 62).

Mp: 137-145 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.63 (1H, m), 7.59 (2H, d, J = 7.8 Hz), 7.38 (4H, s), 7 , 23-7.20 (1H, m), 7.12 (2H, d, J = 7.8 Hz), 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 = 7.5 Hz); IV (KBr) v _max 1603, 1520, 1458, 1396, 1130, 1086 cm ¹ .

EXAMPLE 64

7-CHLORINE-2-ETHYL-3- (4- {2-r (f (4-METHYLPHYL) SULPHONYL-AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2- [4- (2-Chloro-6-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,3-dichloronitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s lg.), 8.00 (1H, dd, J = 1.5 Hz, 8.5

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Hz), 7.61 (1H, dd, J = 1.5 Hz, 7.9 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.03 (1H, dd, J = 7.9 Hz, 8.5 Hz), 6.80 (2H, d, J = 8.4 Hz), 3.82 (2H, t, J = 6.6 Hz), 2.81 (2H, d , J = 6.6 Hz).

STEP 2. 2- [4- (2-Amino-6-chloroanilino) pheniHethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4- (2-chloro-6-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.04 (2H, d, J = 7.8 Hz), 6.97 (1H, dd, J = 7.9 Hz, 8.0 Hz), 6.82 ( 1H, dd, J = 1.5 Hz, 7.9 Hz), 6.66 (1H, dd, J = 1.5 Hz, 8.0 Hz), 6.59 (2H, d, J = 7, 8 Hz), 5.36 (1H, s lg.), 3.94 (2H, s lg.), 3.78 (2H, t, J = 6.6 Hz), 2.75 (2H, d, J = 6.6 Hz).

STEP 3. 2-r4- (7-chloro-2-ethyl-1H-benzimidazole-1iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-6-chloroanilino) phenyl] ethanol (step 2) and propionyl chloride.

TLC Rf = 0.6 (hexane: ethyl acetate = 1: 1).

STEP 4. 2- [4- (7-Chloro-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-amino6-chloroanilino) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.68 (1H, dd, J = 1.9 Hz, 7.0 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.28 ( 2H, d, J = 8.2 Hz), 7.11-7.20 (2H, m), 3.97 (2H, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.65 (2H, q, J = 7.6 Hz), 1.32 (3H, t, J = 7.6 Hz).

STEP 5. 7-Chloro-1 - [4- (2-chloroethyl) phenill-2-ethyl-1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (7-chloro-2-ethyl-1Hbenzimidazol-1-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 7.69 (1H, dd, J = 2.2 Hz, 7.1 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.31 ( 2H, d, J = 8.2 Hz), 7.11-7.17 (2H, m), 3.81 (2H, t, J = 7.3 Hz), 3.19 (2H, t, J = 7.3 Hz), 2.65 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz).

STEP 6. 2-yl- (7-chloro-2-ethyl-1 / - / - benzimidazol-1-yl) azide fe189 / 451 nilletila

The title compound was prepared according to the procedure described in step 8 of Example 1 from 7-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-1/7-benzimidazole (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.69 (1H, dd, J = 1.8, 7.4 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.34 (2H , d, J = 8.2 Hz), 7.11-7.28 (2H, m), 3.60 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz), 2.64 (2H, q, J = 7.6 Hz), 1.32 (3H, t, J = 7.6 Hz).

STEP 7. 2-F4- (7-Chloro-2-ethyl-1 / - / - benzimidazole-1-hyphenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (7-chloro-2-ethyl1 / - / - benzimidazol-1-yl) phenyl] ethyl azide (step 6).

¹ H NMR (CDCI ₃ ) δ 7.69 (1H, d, J = 7.9 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.11-7.19 (2H, m), 3.06 (2H, t, J = 6.8 Hz), 2.88 (2H, t, J = 6.8 Hz ), 2.65 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz).

STEP 8. 7-Chloro-2-ethyl-1 - (4- {2-r (U (4-methylphenyl) sulfonyl1amino} carbonihamino1ethyl} phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (7-chloro-2-ethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 7 ).

MS (IE) m / z 498 (M + H) ⁺ ; ¹ H NMR (CDCI3) δ 7.74 (2H, d, J = 8.4 Hz), 7.69 (1H, dd, J = 1.9 Hz, 7.4 Hz), 7.29-7 , 32 (6H, m), 7.11-7.20 (2H, m), 6.72 (1H, s lg.), 3.59 (2H, t, J = 6.9 Hz), 2, 93 (2H, t, J = 6.9 Hz), 2.64 (2H, q, J = 7.6 Hz), 2.42 (3H, s), 1.31 (3H, t, J = 7 , 6 Hz).

EXAMPLE 65

SODIUM SALT OF 7-CHLORINE-2-ETlL-3- (4- (2-K (K4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL1-PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 7-chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 64).

¹ H NMR (DMSO-d ₆ ) δ 7.62-7.64 (3H, m), 7.31-7.39 (4H, m), 7.14-7.20 (4H, m), 6.00 (1H, s lg.), 3.17 (2H, s lg.), 2.75 (2H, s lg.), 2.55 (2H,

190/451 q, J = 7.8 Hz), 2.29 (3H, s), 1.21 (3H, t, J = 7.8 Hz); IV (KBr) v _max 3380, 2891, 1605, 1520, 1425, 1285, 1126, 1075, 798 cm ^-1 .

EXAMPLE 66

5-FLUOR-2-ETHYL-3- (4- {2-r ({r (4-METHYLphenyl) SULFONYL-AMl ·

NO> CARBQNIL) AMINO1ETHIL) PHENYL) -1 / 7-BENZIMIDAZOLE

STEP 1. 2-f4- (4-Fluorine-2-nitroanilino) pheninethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-difluoronitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.32 (1H, s), 7.88-7.93 (1H, m), 7.11 - 7.30 (5H, m), 3.90 (2H, t, J = 6.2 Hz), 2.90 (2H, t, J = 6.2 Hz).

STEP 2. 2-i4- (2-Amino-4-fluoroanilino) pheninethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [4- (4-fluoro-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 6.98-7.06 (3H, m), 6.60 (2H, d, J = 8.2 Hz), 6.49 (1H, dd, J = 2, 8 Hz, 12.8 Hz), 6.41 (1H, dd, J = 2.8 Hz, 8.4 Hz), 4.99 (1H, s lg.), 3.94 (2H, s lg. ), 3.79 (2H, s lg.), 2.76 (2H, t, J = 6.4 Hz).

STEP 3. 2-yl- (2-ethyl-5-fluoro-1/7-benzimidazole-1yl) pheninetyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-4-fluoroanilino) phenyl] ethanol (step 2) and propionyl chloride.

MS (IE) m / z 340 (M ⁺ ).

STEP 4. 2-i4- (2-Ethyl-5-fluoro-1H-benzimidazol-1-yl) pheninethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-amino4-fluoroanilino) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.40-7.47 (3H, m), 7.28 (2H, d, J = 8.0 Hz),

6.88-7.02 (2H, m), 3.98 (2H, t, J = 6.3 Hz), 3.01 (2H, t, J = 6.3 Hz), 2.78 (2H , q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 5. 1- [4- (2-Chloroethyl) phenyl1-2-ethyl-5-fluor-1 H-benzimidazole

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The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5-fluoro-1 Hbenzimidazol-1-yl) phenyl] ethanol (step 4) ,

¹ H NMR (CDCI ₃ ) δ 7.42-7.46 (3H, m), 7.31 (2H, d, J = 8.1 Hz),

6.89-7.02 (2H, m), 3.81 (2H, t, J = 7.1 Hz), 3.19 (2H, t, J = 7.1 Hz), 2.78 (2H , q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 6. 2-yl- (2-ethyl-5-fluoro-1 / - / - benzimidazol-1-yl) phenyl ethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl-5-fluor-1/7-benzimidazole (step 5) .

¹ H NMR (CDCI ₃ ) δ 7.43- 7.45 (3H, m), 7.31 (2H, d, J = 8.2 Hz),

6.89-7.02 (2H, m), 3.62 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.0 Hz), 2.77 (2H , q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 7. 2- | 4- (2-Ethyl-5-fluorine-1/7-benzimidazole-1-iOphenylTetylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5-fluoro1 / 7-benzimidazol-1-yl) phenyl] ethyl azide ( step 6).

¹ H NMR (CDCI ₃ ) δ 7.40-7.46 (3H, m), 7.27-7.29 (2H, m), 6.876.99 (2H, m), 3.06 (2H, t, J = 7.1 Hz), 2.87 (2H, t, J = 7.1 Hz), 2.78 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz).

STEP 8. 5-Fluorine-2-ethyl-3- (4- (2-i ({F (4-methylphenyl) sulfonyl1amino) carbonit) amino-ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5-fluoro-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 7) .

MS (IED) m / z 481 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.73 (2H, d, J = 8.2 Hz), 7.35-7.45 (3H, m), 7.24-7.29 (4H, m) , 6.87-7.00 (2H, m), 6.73 (1H, S lg.), 3.57 (2H, t, J = 7.0 Hz), 2.93 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.6 Hz), 2.39 (3H, s), 1.31 (3H, t, J = 7.6 Hz).

EXAMPLE 67

SODIUM SALT OF 5-FLUOR-2-ETHYL-3- (4- (2-r ((í (4-METHYLFENIU

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SULFONYLAMINO} CARBQNIL) AMINOIETHIL} FENJL) -1 / 7-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 5-fluor-2-ethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 66).

Mp: 135-146 ° C; MS (IED) m / z 481 (M + H) ⁺ ; ¹ H NMR (DMSOd ₆ ) δ 7.62 (2H, d, J = 8.1 Hz), 7.39-7.48 (5H, m), 6.97-7.15 (4H, m) , 5.92 (1H, s lg.), 2.67-2.76 (4H, m), 2.51 (2H, s lg.), 2.27 (3H, s), 1.23 (3H , t, J = 7.6 Hz). EXAMPLE 68

2-BUTYL-6-FLUOR-1- {2 - [({[(4-METHYLphenyl) SULFONYL1-AMINO} CARBONYL) AMINO1ETHIL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2-i4- (5-Fluorine-2-nitroanilino) phenyrethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-difluoronitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCb) δ 9.61 (1H, s lg.), 8.26 (1H, dd, J = 6.1, 9.5 Hz), 7.32 (2H, d, J = 8 , 2 Hz), 7.22 (2H, d, J = 8.3 Hz), 6.78 (1H, dd, J = 2.6, 11.3 Hz), 6.47 (1H, dd, J = 2.2, 7.2, 9.7 Hz), 3.91 (2H, dt, J = 6.2, 6.2 Hz), 2.91 (2H, t, J = 6.4 Hz) , 1.52 (1H, t, J = 5.7 Hz).

STEP 2. 2- [4- (2-Amino-5-fluoroanilino) pheninethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4- (5-fluoro-2-nitroanine) phenyl] ethanol (step 1).

¹ H NMR (CDCb) δ 7.12 (2H, d, J = 8.4 Hz), 6.87 (1H, dd, J = 2.7, 10.1 Hz), 6.83 (2H, d, J = 8.4 Hz), 6.72 (1H, dd, J = 5.7, 8.6 Hz), 6.63 (1H, dd, J = 2.7, 8.4, 8, 4 Hz), 5.30 (1H, s), 3.83 (2H, t, J = 6.4 Hz), 2.80 (2H, t, J = 6.4 Hz).

STEP 3. 2- [4- (2-Butyl-6-fluor-1 / - / - benzimidazole-1ihfenilletil pentanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-5-fluoroanilino) phenyl] ethanol (step 2) and pentanoyl chloride.

¹ H NMR (CDCb) δ 7.67 (1H, dd, J = 4.8, 8.8 Hz), 7.44 (2H, d,

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J = 8.3 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.04-6.95 (1H, m), 6.76 (1H, dd, J = 2.6 , 8.8 Hz), 4.38 (2H, t, J = 6.8 Hz), 3.07 (2H, t, J = 6.8 Hz), 2.74 (2H, t, J = 7 , 5 Hz, 2.33 (2H, t, J = 7.7 Hz), 1.81-1.55 (4H, m), 1.42-1.25 (4H, m), 6.91 ( 3H, t, J = 7.3 Hz), 0.87 (3H, t, J = 7.3 Hz).

STEP 4. 2-r4- (2-Butyl-6-fluorine-1 / - / - benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 of 2- [4- (2-butyl-6-fluoro1 / - / - benzimidazol-1-yl) phenyl] ethyl pentanoate (step 3).

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, dd, J = 4.8, 8.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.28 (2H , d, J = 8.3 Hz), 6.99 (1H, dd, J = 2.4, 9.0, 9.5 Hz), 4,103.85 (2H, m), 3.01 (2H, t, J = 6.4 Hz), 2.74 (2H, t, J = 7.7 Hz), 1.84-1.69 (2H, m), 1.41-1.27 (2H, m ), 0.87 (3H, t, J = 7.3 Hz).

STEP 5. 2- [4- (2-Butyl-6-fluor-1 / - / - benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-butyl-6-fluoro-1 Hbenzimidazol-1-yl) phenyl] ethanol (step 4) .

MS (IE) m / z 337 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.68 (1H, dd, J = 4.8,

8.8 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.04-6.94 (1H, m) , 6.77 (1H, dd, J = 2.4, 8.6 Hz), 3.62 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 6.8 Hz), 2.74 (2H, t, J = 7.7 Hz), 1.86-1.69 (2H, m), 1.41-1.2 (2H, m), 0.86 (3H , t, J = 7.3 Hz).

STEP 6, 2- [4- (2-Butyl-6-fluorine-1 / - / - benzimidazole-1-ihphenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (2-butyl-6-fluoro-1/7-benzimidazol-1-yl) phenyl] ethyl azide ( step 5).

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, dd, J = 4.8, 8.8 Hz), 7.42 (2H, d, J = 8.1 Hz), 7.27 (2H , d, J = 8.2 Hz), 7.05-6.95 (1H, m), 6.78 (1H, dd, J = 2.6, 8.6 Hz), 3.08 (2H, t, J = 7.1 Hz), 2.88 (2H, t, J = 6.8 Hz), 2.75 (2H, t, J = 7.5 Hz), 1.82-1.69 ( 2H, m), 1.41-1.24 (2H, m), 0.87 (3H, t, J = 7.3 Hz).

STEP 7. 2-Butyl-6-fluorine-3- (4- (2-i (n (4-methylphenyl) sulfonin-amino)

194/451 carbonyl) amino1ethyl) phenyl) -1 / 7-benzimídazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-butyl-6-fluoro-1 Hbenzimidazol-1-yl) phenyl] ethylamine (step 6) .

¹ H NMR (CDCI ₃ ) δ 7.73 (2H, d, J = 8.4 Hz), 7.68 (1H, dd, J = 4.6, 8.8 Hz), 7.38 (2H , d, J = 8.4 Hz), 7.32-7.24 (4H, m), 7.00 (1H, dd, J = 2.4, 8.8, 11.2 Hz), 6, 75 (1H, dd, J = 2.4, 8.6 Hz), 3.64-3.54 (2H, m), 2.94 (2H, t, J = 7.0 Hz), 2.74 (2H, d, J = 7.5 Hz), 1.80-1.65 (2H, m), 1.40-1.20 (2H, m), 0.84 (3H, t, J = 7 , 3 Hz).

EXAMPLE 69

2-BUTYL-6-FLUORIDE 1- SODIUM SALT (2-r ({((4-METHYLphenyl) SULFON1L1AMINO) CARBONYL) AMINO1ETHYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-butyl-6-fluor-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) benzimidazole (Example 69).

¹ H NMR (DMSO-de) δ 7.70-7.57 (3H, m), 7.39 (4H, br), 7.14 (2H, d, J = 8.0 Hz), 7, 11-7.02 (1H, m), 8.85 (1H, dd, J = 2.4, 9.2 Hz), 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 = 7.1 Hz); IV (KBr) v _max 3387, 2872, 1601, 1516, 1479, 1400, 1130, 1086 cm '.

EXAMPLE 70

2-ETYL-6-FLUOR-1- (4- (2-y ({f (4-METHYLPHYL) SULFONYL-AMINO) CARBONYL) AMINOLETYL) PHENYL) -1 / 7-BENZIMIDAZOLE

STEP 1. 2- [4- (6-fluorine-2-ethyl-1/7-benzimidazole-1ihphenylethyl propionate)

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-5-fluoroanilino) phenyl] ethanol (step 2 of example 68) and propionyl chloride.

MS (IE) m / z 340 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.67 (1H, dd, J = 4.8,

8.8 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 6.99 (1H, dd, J = 2, 5, 8.8, 9.5 Hz), 6.77 (1H, dd, J = 2.5, 8.8 Hz), 4.38 (2H, t, J = 6.6 Hz), 3, 07 (2H, t, J = 6.6 Hz), 2.79 (2H, q, J = 7.4 Hz), 2.35 (2H, q, J = 7.4 Hz), 1.35 ( 3H, t, J = 7.4

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Hz), 1.14 (3H, t, J = 7.4 Hz).

STEP 2. 2-r4- (6-Fluorine-2-ethyl-1 / - / - benzimidazole-1-ihpheninethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-fluoro-2-ethyl-1/7-benzimidazol-1-yl) phenyl] ethyl propionate ( step 1).

¹ H NMR (CDCI ₃ ) δ 7.67 (1H, dd, J = 4.8, 8.8 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.29 (2H , d, J = 8.4 Hz), 6.99 (1H, dd, J = 2.5, 8.8, 9.5 Hz), 6.78 (1H, dd, J = 2.5, 8 , 8 Hz), 3.99 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.77 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz).

STEP 3. 6-Fluorine-1 ~ 4- (2-chloroethyl) phenyl1-2-ethyl - // - / - benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-fluoro-2-ethyl-1 Hbenzimidazol-1-yl) phenyl] ethanol (step 2) .

MS (IE) m / z 302 (M ⁺ ).

STEP 4. 2-4- (6-Fluor-2-ethyl-1H-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 of 6-fluoro-1- [4- (2-chloroethyl) phenyl] -2-ethyl1 / 7-benzimidazole (step 3).

MS (IE) m / z 309 (M ⁺ ); ¹ H NMR (CDCb) δ 7.68 (1H, dd, J = 4.8,

8.8 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.99 (1H, dd, J = 2, 5, 8.8, 9.6 Hz), 6.77 (1H, dd, J = 2.5, 8.8 Hz), 3.62 (2H, t, J = 6.9 Hz), 3, 02 (2H, t, J = 6.9 Hz), 2.77 (2H, q, J = 7.4 Hz), 1.34 (3H, t, J = 7.4 Hz).

STEP 5. 2- [4- (6-Fluorine-2-ethyl-1 H-benzimidazol-1-yl) phenyl] -ethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- [4- (6-fluoro-2-ethyl1 / 7-benzimidazol-1-yl) phenyl] ethyl azide ( step 4).

¹ H NMR (CDCb) δ 7.68 (1H, dd, J = 4.8, 8.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 6.98 (1H, dd, J = 2.4, 8.8, 8.8 Hz), 6.82 (1H, dd, J = 2.4, 8, 8 Hz), 3.37 (2H, brs), 3.18 (2H, t, J = 7.1 Hz), 3.01 (2H, t, J = 7.1 Hz), 2.76 (2H , q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz).

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STEP 6. 2-Ethyl-6-fluoro-1- (4- {2 - [(((4-methylphenyl) sulfonyl-amino) carbonyl) amino-ethyl) phenyl) -1 H -benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (6-fluoro-2-ethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 5 ).

¹ H NMR (CDCI ₃ ) δ 7.73 (2H, d, J = 8.4 Hz), 7.68 (1H, dd, J = 8.7, 4.9 Hz), 7.37 (2H , d, J = 8.4 Hz), 7.32-7.23 (4H, m), 7.00 (1H, dd, J = 9.5, 8.7, 2.5 Hz), 6, 79-6.69 (2H, m), 3.63-3.53 (2H, m), 2.94 (2H, t, J = 7.5 Hz), 2.76 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.32 (3H, t, J = 7.5 Hz).

EXAMPLE 71

5-METOXY-2-ETHYL-3- (4- <2 - [(ff (4-METHYLPHYL) SULPHONYL-AMINO) CARBONYL) AMINO1ETYL) -FENYL) -1H-BENZIMIDAZOLE

STEP 1. 2- [4- (4-Methoxy-2-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-5-methoxy nitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCb) δ 9.33 (1H, s lg.), 7.63 (1H, d, J = 3.0 Hz), 7.17-7.27 (5H, m), 7, 04-7.08 (1H, m), 3.88 (2H, s lg.), 3.82 (3H, s), 2.88 (2H, t, J = 6.6 Hz).

STEP 2. 2- [4- (2-Amino-4-methoxyanilino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [4- (4-methoxy-2-nitroanilino) phenyl] ethanol (step 1).

'H NMR (CDCI ₃ ) δ 7.03 (2H, d, J = 8.6 Hz), 6.98 (1H, d, J = 8.4 Hz), 6.59 (2H, d, J = 8.6 Hz), 6.28-6.36 (2H, m), 3.77-3.85 (5H, m), 2.76 (2H, t, J = 6.6 Hz).

STEP 3. 2-44- (2-ethyl-5-methoxy-1/7-benzirnidazole1-ihfenifletyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-4-methoxyanilino) phenyl] ethanol (step 2).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.0 Hz), 7.12-7.29 (3H, m),

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6.97 (1Η, d, J = 8.8 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.8 Hz), 4.37 (2H, t, J = 6.7 Hz) , 3.86 (3H, s), 3.05 (2H, t, J = 6.7 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 1.36 (3H, t, J = 7.5 Hz), 1.14 (3H, t, J = 7.5 Hz).

STEP 4. 2-r4- (2-Ethyl-5-methoxy-1 / V-benzimidazole-1-hyphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 3 ).

¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.2 Hz), 7.27-7.30 (3H, m),

6.98 (1H, d, J = 8.8 Hz), 6.82 (1H, dd, J = 2.3 Hz, 8.8 Hz), 3.98 (2H, t, J = 6.5 Hz) , 3.86 (3H, s), 2.99 (2H, t, J = 6.5 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.33 (3H, t, J = 7.6 Hz).

STEP 5. 1 -í4- (2-Chloroethyl) phenill-2-ethyl-5-methoxy-1 / - / - benzimídazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5-methoxy-1 / 7benzimidazol-1-yl) phenyl] ethanol (step 4 ).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.2 Hz), 7.26-7.33 (3H, m),

6.99 (1H, d, J = 8.8 Hz), 6.82 (1H, dd, J = 2.5 Hz, 8.8 Hz), 3.86 (3H, s), 3.81 (2H, t, J = 7.2 Hz), 3.18 (2H, t, J = 7.2 Hz), 2.78 (2H, q, J = 7.6 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 6. 1-F4- (2-azidoethyl) phenin-2-ethyl-1H-benzimidazol-5-yl methyl ether

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl-5methoxy-1 H-benzimidazole (step 5).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.4 Hz), 7.27-7.32 (3H, m), 6.98 (1H, d, J — 8, 8 Hz), 6.82 (1H, dd, J = 2.3 Hz, 8.8 Hz), 3.87 (3H, s), 3.61 (2H, t, J = 6.9 Hz), 3 , 01 (2H, t, J = 6.9 Hz), 2.76 (2H, q, J = 7.7 Hz), 1.34 (3H, t, J = 7.7 Hz).

STEP 7. 2-r4- (2-Ethyl-5-methoxy-1 / V-benzimidazole-1-ihphenyl-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2198/451 azidoethyl) phenyl] -2-ethyl-1 H-benzimidazole-5- methyl ether ila (step 6).

¹ H NMR (CDCI ₃ ) δ 7.39 (2H, d, J = 8.2 Hz), 7.26-7.30 (3H, m),

6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, dd, J = 2.3 Hz, 8.7 Hz), 3.86 (3H, s), 3.07 ( 2H, t, J = 6.9 Hz), 2.84 (2H, t, J = 6.9 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 8. 5-Methoxy-2-ethyl-3- (4- {2-i ((f / 4-methylphenyl) sulfonyl-amino) carbonyl) amino-ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5-methoxy-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 7 ).

¹ H NMR (CDCI ₃ ) δ 7.74 (2H, d, J = 8.2 Hz), 7.23-7.34 (7H, m), 6.97 (1H, d, J = 8, 7 Hz), 6.82 (1H, dd, J = 1.8 Hz, 8.7 Hz), 6.67 (1H, s lg.), 3.86 (3H, s), 3.57 (2H , t, J = 6.4 Hz), 2.92 (2H, t, J = 6.4 Hz), 2.75 (2H, q, J = 7.6 Hz), 2.40 (3H, s ), 1.31 (3H, t, J = 7.6 Hz).

EXAMPLE 72

SODIUM SALT OF 5-METHODYL-2-ETHYL-3- (4- (2 - [(((((4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AM1NO1ETYL} PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 5-methoxy-2-ethyl-3- (4- {2 [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino ] ethyl} phenyl) -1 / 7-benzimidazole (Example 72).

Mp: 163-175 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.60 (2H, d, J = 7.5 Hz), 7.34-7.41 (4H, m), 7.12-7.18 (3H, m), 6.97 (1H, d, J = 8.7 Hz), 6.78 (1H, d, J = 8.7), 3.78 (3H, s), 2.66-2.76 (4H, m), 2.50 (2H, s lg.), 2.78 (3H, s), 1.22 (3H, t, J = 7.6 Hz); IV (KBr) v _max 3363, 2833, 1596, 1404, 1128, 1085, 1026, 950 cm ^-1 .

EXAMPLE 73 2- [4- (2-ETHYL-5-METHYXY-1H-BENZIM1DAZOL-1-IDFEN1L1ETYL) SULPHONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5-methoxy-1H-benzimidazol-1yl) phenyl] ethanol (step 4 of Example 71).

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Mp: 95-98 ° C; MS (IED) m / z 494 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.93 (2H, d, J = 8.2 Hz), 7.23-7.30 (3H, m), 7.16 (2H, d, J = 8, 2 Hz), 7.06 (2H, d, J = 8.3 Hz), 6.92 (1H, d, J = 8.8 Hz), 6.81 (1H, dd, J = 2.2 Hz , 8.6 Hz), 4.33 (2H, t, J = 6.3 Hz), 3.84 (3H, s), 2.93 (2H, t, J = 6.3 Hz), 2, 68 (2H, q, J = 7.5 Hz), 2.37 (3H, s), 1.22 (3H, t, J = 7.5 Hz); IV (KBr) v _max 1743, 1596, 1517, 1487, 1444, 1278, 1159, 1074, 813 cm ^-1 .

EXAMPLE 74

2-ETYL-6-METHYXY-1- (4- {2-r «f (4-METHYLPHYL) SULFONYLAMINO) CARBONYL) AMINO1ETHYL) PHENYL) -1 / 7-BENZlMIDAZOLE

STEP 1. 2-r (5-Methoxy-2-nitroanilino) pheninethanol

The compound in was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-4-methoxynitrobenzene and 4-aminophenylethyl alcohol.

'H (CDCI ₃ ) δ 9.74 (1H, s lg.), 8.18 (1H, d, J = 9.5 Hz), 7.30 (2H, d, J = 8.4 Hz ), 7.24 (2H, d, J = 8.4 Hz), 6.55 (1H, d, J = 28 Hz), 6.34 (1H, dd, J = 9.5, 2.8 Hz ), 3.90 (2H, m), 3.75 (3H, s), 2.90 (3H, t, J = 6.6 Hz).

STEP 2. 2-i (2-Amino-5-methoxyanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(5-methoxy-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCb) δ 7.09 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.4 Hz), 6.76-6.73 (2H, m), 6.54 (1H, dd, J = 8.6, 2.8 Hz), 3.81 (2H, t, J = 6.6 Hz), 3.71 (3H, s), 2, 79 (2H, t, J = 6.6 Hz).

STEP 3. 2-f4- (2-etit-6-methoxy-1 / - / - benzimidazol · 1-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-5-methoxyanilino) phenyl] ethanol (step 2) and propionyl chloride.

MS (IE) m / z 352 (M ⁺ ).

STEP 4. 2-f4- (2-Ethyl-6-methoxy-1 / - / - benzimidazole-1-hyphenyl-ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-6200/451 methoxy-1 / - / - benzimidazol-1-yl) propionate phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 7.63 (1H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 8.8, 2.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 4.00 (2H, t , J = 6.6 Hz), 3.75 (3H, s), 3.01 (2H, t, J = 6.6 Hz), 2.74 (2H, q, J = 7.5 Hz), 1.32 (3H, t, J = 7.5 Hz).

STEP 5. 2-F4- (2-Ethyl-6-methoxy-1 / - / - benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 4 of Example 26 from 2- [4- (2-ethyl-6-methoxy-1 / 7benzimidazol-1-yl) phenyl] ethanol (step 4 ).

TLC Rf = 0.50 (hexane / ethyl acetate = 1: 1).

STEP 6. 2-j4- (2-Ethyl-6-methoxy-1 / - / - benzimidazol-1-yl) phenyl1ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-6-methoxy-1 / y-benzimidazol-1-yl) phenyl] ethyl azide ( step 5).

¹ H NMR (CDCI ₃ ) δ 7.65 (1H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 8.8, 2.4 Hz), 6.56 (1H, d, J = 2.4 Hz), 3.76 (3H, s ), 3.09 (2H, t, J = 7.0 Hz), 2.89 (2H, t, J = 7.0 Hz), 2.75 (2H, q, J = 7.5 Hz), 1.32 (3H, t, J = 7.5 Hz).

STEP 7. 2-Ethyl-6-methoxy-1- (4- {2-i ((r (4-methylphenyl) sulfonyl1amino} carbonyl) amino1ethyl} phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-6-methoxy-1 / - / benzimidazol-1-yl) phenyl] ethylamine ( step 6).

¹ H NMR (CDCI ₃ ) δ 7.75 (2H, d, J = 8.2 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.35-7.23 (6H , m), 6.89 (1H, dd, J = 8.7, 2.5 Hz), 6.66 (1H, m), 6.55 (1H, d, J = 2.5 Hz), 3 , 72 (3H, s), 3.59-3.57 (2H, m), 2.93 (2H, t, J = 7.0 Hz), 2.73 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz).

EXAMPLE 75

SODIUM SALT OF 2-ETHYL-6-METHYXY-1- (4- {2-r ({j (4-METHYLPHYL) SULFON1L1AMINO) CARBONY) AMINQ1ETYL) PHENYL) -1H-BENZIM1DA201 / 451

ZQL

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-6-methoxy-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1H-benzimidazole (Example 74).

¹ H NMR (DMSO-d ₆ ) δ 7.59 (2H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.41-7.35 (4H, m), 7.12 (2H, d, J = 8.3 Hz), 6.80 (1H, dd, J = 8.8, 2.4 Hz), 6.53 (1H, d, J = 2.4 Hz), 3.67 (3H, s), 3.15 (2H, m), 2.73-2.62 (4H, m), 1.19 (3H, t, J = 7 , 7 Hz); IV (KBr) v _max 1595, 1516, 1485, 1454, 1400, 1157, 1128, 1086 cm ^-1 .

EXAMPLE 76

5-TRIFLUOROMETHYL-2-ETHYL-3- (4-f2-Kfí (4-METHYLPHYL) SULFONYL1AMINO) CARBONY) AMINO1ETIUFENIL) -1H-BENZIMIDAZOLE

STEP 1. 2-1,2-Nitro-4- (trifluoromethyl) anilino1phenyl} ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-5-trifluoromethylnitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.68 (1H, s lg.), 8.50 (1H, s), 7.51 (1H, dd, J = 2.2 Hz, 9.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.19-7.26 (3H, m), 3.92 (2H, t, J = 6.3 Hz), 2.92 (2H , t, J = 6.3 Hz).

STEP 2. 2- [2-Amino-4- (trifluoromethyl) anilinolfenyl) ethanol

The title compound was prepared according to the procedure described in step 2 of Example 26 from 2- [2-nitro-4- (trifluoromethyl) anilino] phenyl} ethanol (step 1).

'H (CDCI ₃ ) δ 7.10-7.16 (3H, m), 6.97 (2H, d, J = 8.2 Hz), 6.82 (2H, d, J = 8, 2 Hz), 3.82 (2H, t, J = 6.6 Hz), 2.79 (2H, t, J = 6.6 Hz).

STEP 3. 2-f4-r2-ethyl-5- (triofluoromethyl) -1 / 7-benzimidazole-1-iHphenyl) ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 ~ [2 amino-4- (trifluoromethyl) -anilone] -phenyl} ethanol propionyl chloride (step 2).

¹ H NMR (CDCI ₃ ) δ 8.05 (1H, s), 7.42-7.47 (2H, m), 7.27-7.31 (2H, m), 7.13 (2H, d, J = 8.4 Hz), 4.39 (2H, t, J = 7.0 Hz), 3.08 (2H, t, J = 7.0 Hz),

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2.80 (2Η, q, J = 7.6 Hz), 2.36 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz), 1, 14 (3H, t, J = 7.6 Hz).

STEP 4. 2- (4- [2-Ethyl-5- (trifluoroethyl) -1 / - / - benzimidazole-1-amylphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [2-ethyl-5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl propionate } ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 8.05 (1H, s), 7.49 (1H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.4 Hz), 4.01 (2H, t, J = 6.4 Hz), 3, 03 (2H, t, J = 6.4 Hz), 2.80 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 5. 2- (4-r2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazol1-yl1phenyl) ethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- {4- [2-ethyl-5- (trifluoromethyl ΟΙ / - / - benzimidazol-1-yl] phenyl} ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 8.05 (1H, s), 7.22-7.48 (5H, m), 7.15 (1H, d, J = 8.4 Hz), 3.62 (2H, t, J = 6.8 Hz), 3.02 (2H, t, J = 6.8 Hz), 2.80 (2H, q, J = 7.5 Hz), 1.36 (3H , t, J = 7.5 Hz).

STEP 6. 2- {4-1,2-Ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole-1 -illphenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- {4- [2-Ethyl-5 (trifluoromethyl) -1 / - / - benzimidazol-1-yl] azide phenyl} ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 8.05 (1H, s), 7.44 (3H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.16 (1H, d, J = 8.6 Hz), 3.09 (2H, t, J = 6.8 Hz), 2.89 (2H, t, J = 6.8 Hz), 2, 81 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 7. 5-Trifluoromethyl-2-ethyl-3- (4- {2 [(U (4-methylphenyl) sulfonin amino} carboniDamino1etit) phenit-1E / -benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [2-ethyl-5- (trifluoromethyl) 1H-benzimidazol-1-yl] phenyl} ethylamine (step 6).

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MS (IED) m / z 533 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.03 (1H, s),

7.80 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.2 Hz), 7.38-7.43 (3H, m), 7.26-7 , 29 (2H, m), 7.13 (1H, d, J = 8.4 Hz), 6.70 (1H, s lg.), 3.57 (2H, t, 6.7 Hz), 2 , 94 (2H, t, J = 6.7 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.43 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

EXAMPLE 77

SODIUM SALT OF 5-TRIFLUOROMETHYL-2-ETHYL-3- (4- {2-i ({f (4METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) -FENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 5-Trifluoromethyl-2-Ethyl-3- (4 {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl } phenyl) -1 / - / - benzimidazole (Example 76) ¹ H NMR (DMSO-de) δ 8.02 (1H, s), 7.61-7.66 (4H, m), 7,487.51 ( 1H, m), 7.24-7.28 (3H, m), 7.14 (2H, d, 7.9 Hz), 3.09 (2H, s lg.), 2.602.83 (4H, m ), 2.22 (3H, s), 1.13 (3H, t, J = 7.5 Hz).

EXAMPLE 78

5-ACETYL-2-ETYL-3- (4- (2-i (U (4-METHYLPHYL) SULFONYL1AMINO) CARBONY) AMINO1ETYL) FEN1L) -1H-BENZIM1DAZOL

STEP 1. 1- {4-r4- (2-Hydroxyethyl) anilinol-3-nitrophenylethanone

A mixture of 2-chloro-5acetylnitrobenzene (Oelschlaeger, H .; Schreiber, O. LiebigsAnn Chem; 1961, 641, 81; 2g, 10 mmol), 4-aminophenyl ethyl alcohol (3) was heated at 150 ° C for 3 hours. 1.64 g, 12 mmol) and NaHCO ₃ (1 g, 12 mmol) in DMF (60 ML). After cooling, the mixture was poured into water (100 ml) and extracted with ethyl acetate (300 ml). The organic phase was washed with 2N aqueous NaOH solution (100 ml) and brine (100 ml), then dried (Na ₂ SO ₄ ), and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), providing 1.36 g (45%) of the title compound as an orange oil; ¹ H NMR (CDCI ₃ ) δ 9.83 (1H, s lg.), 8.20 (1H, d, J = 2.1 Hz), 7.94 (1H, dd, J = 2.1 Hz , 9.3 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.16 (1H, d, J = 9 , 3 Hz), 3.91 (2H, t, J = 6.6 Hz), 2.92 (2H, t, J = 6.6 Hz), 2.57 (3H, s).

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STEP 2. 1- {3-Amino-4-i4- (2-hydroxyethyl) anilino1phenyl) ethanone

The title compound was prepared according to the procedure described in step 4 of Example 1 from 1- {4- [4- (2-hydroxyethyl) aniline] 3-nitrophenyl} ethanone (step 1).

¹ H NMR (CDCI ₃ ) δ 7.41 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.11- 7.17 (3H, m), 6.94 (2H, d, J = 8.2 Hz), 5.72 (1H, s lg.), 3.85 (2H, t, J = 6.6 Hz ), 3.65 (2H, s lg.), 2.83 (2H, t, J = 6.6 Hz), 2.52 (3H, s).

STEP 3. 2-f4- (5-acetyl-2-ethyl-1/7-benzimidazole-1ipphenylethyl propionate)

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- {3-amino-4- [4- (2hydroxyethyl) anilino] phenyl} ethanone (step 2) and propionyl chloride .

TLC Rf = 0.4 (hexane / ethyl acetate = 1: 1).

STEP 4. 1 - {2-Ethyl-1 -F4- (2-hydroxyethylPhenyl1-1 Z - / - benzimidazol-5-yl) ethyl

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-acetyl2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 8.39, (1H, d, J = 1.2 Hz), 7.89 (1H, dd, J = 1.2 Hz, 8.6 Hz), 7.48 (2H, d,> 7.4 Hz, 7.30 (2H, d, J = 7.4 Hz), 7.13 (1H, d, J = 8.6 Hz), 4.00 (2H, t , J = 6.4 Hz), 3.02 (2H, t,> 6.4 Hz), 2.80 (2H, q,> 7.6 Hz), 2.68 (3H, s), 1, 38 (2H, t,> 7.6 Hz).

STEP 5, 1- (1-í4- (2-ChloroethiPphenin-2-ethyl-1 / - / - benzimidazol-5-yl) ethanone

The title compound was prepared according to the procedure described in step 7 of Example 1 from 1- {2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1H-benzimidazol-5-yl} ethanone (step 4).

¹ H NMR (CDCl3) δ 8.40. (1H, d, J = 1.2 Hz), 7.90 (1H, dd, J = 1.2 Hz, 8.4 Hz), 7.47 (2H, d, J = 8.4), 7 , 32 (2H, d, J = 8.4 Hz), 7.13 (1H, d, J = 8.4 Hz), 3.83 (2H, t, J = 7.3 Hz), 3.21 (2H, t, J = 7.3 Hz), 2.82 (2H, q, J = 7.6 Hz), 2.68 (3H, s), 1.38 (2H, t, J = 7, 6 Hz).

STEP 6. 1 - {1 -4- (2-Azidoethyl) phenyl1-2-ethyl-1 H-benzimidazol-S-yl)

205/451 ethanone

The title compound was prepared according to the procedure described in step 8 of Example 1 using 1- {1- [4- (2-chloroethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl} ethanone (step 5).

¹ H NMR (CDCb) δ 8.40, (1H, d, J = 1.5 Hz), 7.90 (1H, dd, J = 1.5 Hz, 8.6 Hz), 7.46 ( 2H, d, J = 8.3), 7.12 (2H, d, J = 8.3 Hz), 7.02 (1H, d, J = 8.6 Hz), 3.63 (2H, t , J = 6.9 Hz), 3.03 (2H, t, J = 6.9 Hz), 2.80 (2H, q, J = 7.4 Hz), 2.67 (3H, s), 1.37 (3H, t, J = 7.4 Hz).

STEP 7. 1-f1- [4- (2-Aminoethyl) phenyl1-2-ethyl-1A7-benzimidazol-5-yl) ethanone

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- {1- [4- (2-azidoethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl} ethanone (step 6).

¹ H NMR (CDCb) δ 8.40, (1H, d, J = 1.7 Hz), 7.90 (1H, dd, J = 1.7 Hz, 8.6 Hz), 7.43 ( 2H, d, J = 8.2), 7.30 (2H, d, J = 8.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 3.08 (2H, t , J = 6.7 Hz), 2.88 (2H, t, J = 6.7 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.68 (3H, s), 1.38 (3H, t, J = 7.6 Hz).

STEP 8. 5-Acetyl-2-ethyl-1 - (4- (2 - [(U (4-methylphenyl) sulfonyl1-amino) carbonyl) amino1ethyl} phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- {1- [4- (2-aminoethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl} ethanone (step 7).

MS (IED) m / z (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.40, (1H, d, J = 1.1 Hz), 7.88 (1H, dd, J = 1.1 Hz, 8.6 Hz), 7.73 (2H, d, J = 8.4), 7.40 (2H, d, J = 8.4 Hz), 7.27-7.31 (4H, m), 7.10 (1H, d, J = 8.6 Hz), 6.74 (1H, s lg.), 3.59 (2H, t, J = 6.9 Hz), 2.95 (2H, t, J = 6.9 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.67 (3H, s), 2.40 (3H, s), 1.36 (3H, t, J = 7.6 Hz).

EXAMPLE 79

SODIUM SALT OF 5-ACETYL-2-ETHYL-3- (4- (2-r «r (4-METHYLphenyl) SULFONYL1AMINO) CARBONY) AMINQ1ETIUFENIL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure 206/451 as described in Example 2 from 5-acetyl-2-ethyl-1- (4-2 - [({[(4-methylphenyl) sulfonyl) amine} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 78).

Mp: 155-160 ° C; ¹ H NMR (DMSO-d ₆ ) δ 8.32, (1H, d, J = 1.6 Hz),

7.81 (1H, dd, J = 1.6 Hz, 8.6 Hz), 7.62 (2H, d, J = 8.1), 7.42 (4H, s), 7.12-7 , 17 (3H, m), 3.18 (2H, s lg.), 2.71-2.79 (4H, m), 2.63 (3H, s), 2.27 (3H, s), 1.25 (3H, t, J = 7.4 Hz); IV (KBr) v _max 3373, 1676, 1604, 1519, 1294, 1130, 1085, 885, 813 cm ^-1 .

EXAMPLE 80

2-ETYL-5-METHYLSULFONlL-1- (4- (2-r (ír (4-METHYLphenyl) -SULFONYLAMINO} CARBONlL) AMINO1ETYL) PHENYL) /

STEP 1, 2- {4-f4- (Methylsulfonyl) -2-nitroanilino1phenyl} ethanoyl

A mixture of 2-chloro-5-methylsulfonylnitrobenzene (Kavalek, J .; et al; Collect. Czech. Chem. Commun, 1971, 36, 209; 2 g, 8.5 mmol) was stirred at 100 ° C for 16 hours. ), 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) and Na ₂ CO ₃ (1.4 g, 12.7 mmol) in ethanok 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), providing 960 mg (34%) of the title compound as of yellow solids: ¹ H NMR (CDCb) δ 9.84 (1H, s lg.), 8.82 (1H, d, J = 2.1 Hz), 7.79 (1H, dd, J = 2 , 1 Hz, 9.1 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.22-7.38 (3H, m), 3.94 (2H, s lg.), 3.07 (3H, s), 2.93 (2H, t, J = 6.6 Hz).

STEP 2. 2- {4- [2-Amino-4- (methylsulfonyl) anilinolfenyl) ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4- [4- (methylsulfonyl) -2nitroanilino] phenyl} ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.31 (1H, s), 7.28 (1H, s), 7.16-7.21 (3H, m), 6.96 (2H, d, J = 8.5 Hz), 5.56 (1H, s lg.), 3.86 (2H, t, J = 6.4 Hz), 3.76 (2H, s lg.), 3.03 (3H, s), 2.84 (2H, t, J = 6.4 Hz).

STEP 3. 2- {4-1,2-ethyl-5- (methylsulfonyl) -1H-benzimidazole-1-illfenyl) ethyl propionate

The title compound was prepared according to the procedure 207/451 as described in step 5 of Example 1 from 2- {4- [2-amino-4- (methylsulfonyl) anilino] phenyl} ethanol (step 2) and propionyl chloride.

TLC Rf = 0.8 (dichloromethane / methanol = 10: 1).

STEP 4. 2- {4-1,2-Ethyl-5- (methylsulfonyl) -1 / - / - benzimidazole-1-amylphenyl} ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [2-ethyl-5 (methylsulfonyl) -1 / - / - benzimidazole-1-yl] propionate phenyl} ethyl (step 3).

¹ H NMR (CDCI3) δ 8.38 (1H, d, J = 1.4 Hz), 7.77 (1H, dd, J = 1.4 Hz, 8.6 Hz), 7.50 (2H , d, J = 8.4 Hz), 7.24-7.32 (2H, m), 7.22 (1H, d, J = 8.6 Hz), 4.01 (t, J = 6, 6 Hz), 3.08 (3H, s), 3.02 (2H, t, J = 6.6 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.37 (3H , t, J = 7.6 Hz).

STEP 5. 1 -r4- (2-Chloroethyl) phenyl1-2-ethyl-5- (methylsulfonyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [2-ethyl-5- (methylsulfonyl) 1/7-benzimidazol-1-yl] phenyl} ethanol (step 4).

¹ H NMR (CDCI3) δ 8.38 (1H, d, J = 1.6 Hz), 7.78 (1H, d, J = 1.6 Hz, 8.6 Hz), 7.49 (2H , d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.23 (1H, d, J = 8.6 Hz), 3.84 (2H, t , J = 6.9 Hz), 3.22 (2H, t, J = 6.9 Hz), 3.08 (3H, s), 2.82 (2H, q, J = 7.5 Hz), 1.38 (3H, t, J = 7.5 Hz).

STEP 6. 1- [4- (2-azidoethyl) phenyl-2-ethyl-1 / - / benzimidazol-5-yl methyl sulfone

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2 chloroethyl) phenyl] -2-ethyl-5- (methylsulfonyl) -1 / 7-benzimidazole propionate (step 5).

¹ H NMR (CDCI ₃ ) δ 8.38 (1H, d, J = 1.5 Hz), 7.78 (1H, dd, J = 1.5 Hz, 8.6 Hz), 7.49 ( 2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.21 (1H, d, J = 8.6 Hz), 3.64 (2H, t, J = 6.9 Hz), 3.08 (3H, s), 3.03 (2H, t, J = 6.9 Hz), 2.83 (2H, q, J = 7.6 Hz) , 1.37 (3H, t, J = 7.6 Hz).

STEP 7. 2- (4-f2-Ethyl-5- (methylsutphonyl) -1 H-benzimfdazol-1 -illfentl) ethylamine

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The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2azidoethyl) phenyl] -2-ethyl-1 / - / - benzimidazol-5-yl methyl sulfone (step 6).

¹ H NMR (CDCI3) δ 8.38 (1H, d, J = 1.7 Hz), 7.77 (1H, dd, J = 1.7 Hz, 8.6 Hz), 7.46 (2H , d, J = 8.4 Hz), 7.21-7.30 (3H, m), 3.03-3.08 (5H, m), 2.89 (2H, t, J = 6.7 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 8. 2-Ethyl-5- (methylsulfonyl) -1- (4- (2-i ((f (4-methylphenyl) -sulfonyl1amino) carbonyl) aminoletyl} phenyl) -1F / -benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [2-ethyl-5- (methylsulfonyl) 1 / - / - benzimidazol-1-yl] phenyl} ethylamine (step 7).

¹ H NMR (CDCI ₃ ) δ 8.37 (1H, d, J = 1.6 Hz), 7.75 (1H, dd, J = 1.6 Hz, 8.6 Hz), 7.74 ( 2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.27-7.32 (4H, m), 7.18 (1H, d, J = 8.6 Hz), 6.70 (1H, s lg.), 3.59 (2H, t, J = 6.8 Hz), 3.08 (3H, s), 2.96 (2H, t , J = 6.8 Hz), 2.82 (2H, q, J = 7.6 Hz), 2.41 (3H, s), 1.35 (4H, t, J = 7.6 Hz).

EXAMPLE 81

SODIUM SALT OF 2-ETHYL-5-METHYLSULPHONYL-3- (4- {2-F ((r (4Methylphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) -FEN1L) -W-BENZIMIDAZOL

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5- (methylsulfonyl) -1- (4- {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / - / - benzimidazole (Example 80).

Mp: 171-178 ° C; ¹ H NMR (DMSO-d ₆ ) δ 8.08 (1H, s lg.), 7.517.62 (3H, m), 7.32 (4H, s), 7.16 (1H, d, J = 8.6 Hz), 7.03 (2H, d, J = 7.3), 3.093.25 (7H, m), 2.63-2.66 (2H, m), 2.16 (3H, s ), 1.13 (3H, t, J = 7.3 Hz); IV (KBr) v _max 3386, 1604, 1519, 1396, 1299, 1128, 1085, 962.887 cm ^-1 .

EXAMPLE 82

5-CYAN-2-ETYL-1- (4- (2 - [({(4-METHYLphenyl) SULFONYL-AMlNO)

CARBONIL) AM1NO1ETIL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2-r (4-Cyano-2-nitroanilino) phenylethanol

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The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-3-nitrobenzonitrile and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.80 (1H, s Ig.), 8.54 (1H, d, J = 2.0 Hz), 7.50 (1H, dd, J = 9.1, 2.0 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.16 (1H, d, J = 9, 1 Hz), 3.94-3.91 (2H, m), 2.93 (2H, t, J = 6.6 Hz), 1.81 (1H, m).

STEP 2. 2 - [(2-Amino-4 ~ cyanoanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(4-cyano-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.18-7.10 (3H, m), 7.01-6.95 (4H, m), 6.09 (1H, m), 3.97 (2H, s Ig.), 3.83-3.82 (2H, m), 2.83 (2H, t, J = 6.8 Hz), 2.31 (1H, m).

STEP 3. 2- [4- (5-cyano-2-ethyl-1B-benzimidazole-1iDphenylethyl propionate)

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amine-4-cyanoanilino) phenyl] ethanol (step 2).

MS (IE) m / z 347 (M ⁺ ).

STEP 4. 2-r4- (5-Cyano-2-ethyl-1B-benzimidazol-1-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-cyano2-ethyl-1B-benzimidazol-1-yl) phenyl] ethyl propionate (step 3 ).

¹ H NMR (CDCI ₃ ) δ 8.09 (1H, s), 7.50-7.43 (3H, m), 7.32-7.28 (2H, m), 7.15 (1H, d, J = 8.2 Hz), 4.00 (2H, q, J = 6.4 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.81 (2H, t, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 5. 2-yl- (5-cyano-2-ethyl-1B-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (5-cyano-2-ethyl-1Bbenzimidazol-1-yl) phenyl] ethanol (step 4).

TLC Rf = 0.83 (dichloromethane / methanol = 10: 1).

STEP 6. 2-f4- (5-Cyano-2-ethyl-1B-benzimidazol-1-yl) phenin-ethyl210 / 451 mine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (5-cyano-2-ethyl1 / 7-benzimidazol-1-yl) phenyl] ethyl azide ( step 5).

¹ H NMR (CDCI ₃ ) δ 8.09 (1H, s), 7.47-7.42 (3H, m), 7.29-7.26 (2H, m), 7.15 (1H, d, J = 8.4 Hz), 3.09 (2H, t, J = 6.8 Hz), 2.91 (2H, t, J = 6.8 Hz),

2.81 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 7. 5-Cyano-2-ethyl-1 - (4- {2-r ((r (4-methylphenyl) sulfonyl1-amino) carbonyl) amino1ethyl} phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5-cyano2-ethyl-1H-benzimidazol-1-yl) phenyl] ethylamine propionate (step 6 ).

¹ H NMR (CDCI ₃ ) δ 8.05 (1H, d, J = 0.9 Hz), 7.75 (2H, d, J = 8.4 Hz), 7.43-7.40 (3H , m), 7.30-7.26 (4H, m), 7.12 (1H, d, J = 8.4 Hz), 6.74 (1H, m), 3.60-3.58 ( 2H, m), 2.96 (2H, t, J = 7.0 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 1.34 ( 3H, t, J = 7.5 Hz).

EXAMPLE 83

SODIUM SALT OF 5-CYAN-2-ETHYL-1- (4- {2-r (U (4-METHYLphenyl) SULFONlL1AMlNO) CARBONYL) AMINO1ETHIL} PHENYL) -1 / 7-BENZIMlDAZOL

The title compound was prepared according to the procedure described in Example 2 from 5-cyano-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 ΛΖ-benzimidazole (Example 82).

¹ H NMR (DMSO-d ₆ ) δ 8.19 (1H, d, J = 1.5 Hz), 7.59 (2H, d, J = 7.9 Hz), 7.54 (1H, dd , J = 8.4, 1.5 Hz), 7.41 (4H, s), 7.23 (1H, d, J = 8.4 Hz), 7.11 (2H, d, J = 7, 9 Hz), 3.14 (2H, m), 2.78-2.70 (4H, m), 2.26 (3H, s), 1.24 (3H, t, J = 7.4 Hz) .

EXAMPLE 84

2-ETYL-1- (4- {2-r (n (4-METHYLphenyl) SULFONYLAMINO) -CARBONYL) AMINO1ETYL) PHENYL) -1 / 7-BENZIMIDAZOL-5-CARBOXAMIDE

STEP 1. 2-Ethyl-1-r4- (2-hydroxyethyl) phenyl-1/7-benzimidazoi-5-carboxamide

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A 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and a 0.2 M aqueous solution of NaOH (0.06 mL) were added to a mixture of 2- [4- (5- cyano-2-ethyl ~ 1tf-benzimidazol-1-yl) phenyl] ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL ). The mixture was stirred at 50 ° C for 4 hours, and then cooled. The mixture was poured into water (50 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with 2N aqueous NaOH solution (50 ml) and brine (50 ml), and then dried (Na2SO ₄ ), and concentrated to provide the title compound as yellow solids. clear: ¹ H NMR (CDCI3) δ 8.23 (1H, d, J = 1.1 Hz), 7.96 (1H, s lg.), 7.76 (1H, dd, J = 1.1 Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25 (1H s lg.), 7.09 (1H, d, J = 8.4 Hz), 3.70 2H, t, J = 6.6 Hz), 2.85 (2H, t, J = 6.9 Hz), 2.76 (2H, q, J = 7.4 Hz), 1.24 (3H, t , J = 7.4 Hz).

STEP 2. 1-i4- (2-Chloroethyl) phenyl1-2-ethyl-1/7-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl] 1/7-benzimidazole-5-carboxamide (step 1 ).

¹ H NMR (CDCI ₃ ) δ 8.17 (1H, d, J = 1.7 Hz), 7.79 (1H, dd, J = 1.7 Hz, 8.5 Hz), 7.46 ( 2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.15 (1H, d, J = 8.5 Hz), 3.83 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 7.0 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 3. 1-r4- (2-Azidoethyl) pheniH-2-ethyl-1/7-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl1 / 7-benzimidazole-5-carboxamide (step 2) .

¹ H NMR (CDCI ₃ ) δ 8.17 (1H, d, J = 1.5 Hz), 7.78 (1H, dd, J = 1.5 Hz, 8.4 Hz), 7.46 ( 2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.13 (1H, d, J = 8.4 Hz), 3.62 (2H, t, J = 6.8 Hz), 3.03 (2H, t, J = 6.8 Hz), 2.81 (2H, q, J = 7.5 Hz), 1.36 (3H, t, J = 7.5 Hz).

STEP 4. 1- [4- (2-Aminoethyl) phenyl1-2-ethyl-1/7-benzimidazole-5-car212 / 451 boxamide

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -2-ethyl1 / 7-benzimidazole-5-carboxamide (step 3) .

¹ H NMR (CDCI ₃ ) δ 8.21 (1H, d, J = 1.5 Hz), 7.79 (1H, dd, J = 1.5 Hz, 8.4 Hz), 7.43 ( 2H, d, J = 8.2 Hz), 7.28-7.31 (2H, m), 7.13 (1H, d, J = 8.4 Hz), 3.05 (2H, t, J = 6.7 Hz), 2.88 (2H, t, J = 6.7 Hz), 2.81 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7 , 6 Hz).

STEP 5. 2-Ethyl-1- (4- (2-r (U (4-methylphenyl) sulfonyl-amino) carbonyl) amino) ethyl) phenyl) -1 / 7-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -2ethyl-1/7-benzimidazole-5-carboxamide (step 4) .

MS (IED) m / z 506 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD) δ 8.13 (1H, s), 7.65-7.73 (3H, m), 7.32 (2H, d, J = 8.2 Hz), 7, 16-7.21 (4H, m), 7.00 (1H, d, J = 8.6 Hz), 3.31 (2H, t, J = 6.9 Hz), 2.75 (2H, t , J = 6.9 Hz), 2.69 (2H, q, J = 7.6 Hz), 2.21 (3H, s), 1.48 (3H, t, J = 7.6 Hz).

EXAMPLE 85

6-CYAN-2-ETYL-1- (4-f2-r (U (4-METHYLPHYL) SULFONYLAMiNO} CARBONYL) AMINO1ETHYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 3- [4- (2-hydroxyethyl) anilino1-4-nitrobenzonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile (Tsuji, K; Chem. Pharm. Bull. 1992, 40, 2399) and alcohol 4- aminophenylethyl.

MS (IE) m / z 383 (M ⁺ ).

STEP 2. 3-f4- (2-Chloroethyl) anilino1-4-nitrobenzonitrile

The title compound was prepared according to the procedure described in step 7 of Example 1 from 3- [4- (2-hydroxyethyl) anilino] -4nitrobenzonitrile (step 1).

¹ H NMR (CDCI ₃ ) δ 9.46 (1H, s lg.), 8.29 (1H, d, J = 8.8 Hz), 7.42 (1H, d, J = 1.7 Hz ), 7.35 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 6.97 (1H, dd, J = 8.8, 1, 7 Hz), 3.77 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz).

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STEP 3. 4-Amino-3- [4- (2-chloroethyl) anilino1benzonitrile

The title compound was prepared according to the procedure described in step 4 of Example 1 from 3- [4- (2-chloroethyl) anilino] -4-nitrobenzonitrile (step 2).

MS (IE) m / z 383 (M ⁺ ).

STEP 4. 1 -4- (2-Chloroethyl) phenin-2-ethyl-1 / - / - benzimidazole-6-carbonitrile

The title compound was prepared according to the procedure described in step 5 of Example 1 from 4-amino-3-4- (2-chloroethyl) anilino] benzonitrile (step 3) and propionyl chloride.

MS (IE) m / z 309 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.82 (1H, d, J = 8.6 Hz), 7.53 (1H, dd, J = 8.6, 2.0 Hz), 7.48 (2H , d, J = 8.3 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.31 (2H, d, J = 8.3 Hz), 3.84 (2H, t , J = 7.0 Hz), 3.21 (2H, t, J = 7.0 Hz),

2.82 (2H, q, J = 7.4 Hz), 1.39 (3H, t, J = 7.4 Hz).

STEP 5. 2- [4- (6-cyano-2-ethyl-1/7-benzimidazole-1-iDphenylethyl azide)

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl1 / - / - benzimidazole-6-carbonitrile (step 4 ).

MS (IE) m / z 316 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.83 (1H, d, J = 8.4 Hz), 7.54 (1H, dd, J = 8.4, 2.0 Hz), 7.50 (2H , d, J = 8.3 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.30 (2H, d, J = 8.3 Hz), 3.64 (2H, t , J = 6.5 Hz), 3.04 (2H, t, J = 6.5 Hz),

2.83 (2H, q, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz).

STEP 6. 2-i4- (6-Cyano-2-ethyl-1H-benzimidazol-1-yl) phenyl-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-cyano-2-ethyl1 / - / - benzimidazol-1-yl) phenyl] ethyl azide (step 5).

¹ H NMR (DMSO-de) δ 8.11 (2H, s lg.), 7.87 (1H, d, J = 8.4 Hz), 7.64 (1H, dd, J = 8.4 , 2.0 Hz), 7.60-7.53 (5H, m), 3.20-3.02 (4H, m), 2.79 (2H, q, J = 7.4 Hz), 1 , 28 (3H, t, J = 7.4 Hz).

STEP 7. 6-Cyano-2-ethyl-1 - (4- {2 - [({í (4-methylphenylSulfonyl1-amino)

214/451 carbonyl) amino1ethyl} phenyl) -1H-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (6-cyano-2-ethyl-1Hbenzimidazol-1-yl) phenyl] ethylannine (step 6).

¹ H NMR (CDCb) δ 7.83 (1H, d, J = 8.4 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.53 (1H, dd, J = 8.4, 1.5 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 1.5 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz, 6.75 (1H, s lg.), 3.65-3.54 (2H, m), 2.97 (2H, t, J = 7.0 Hz), 2.82 (2H, q, J = 7.5 Hz), 2.42 (3H, s), 1.37 (3H, t, J = 7, 5 Hz).

EXAMPLE 86

2-ETYL-1- (4- (2-r ({f (4-METHYLFENlL) SULFONYLAMINE) -CARBONYL) AMINO1ETYL) PHENYL) -1H-BENZIMIDAZOL-6-CARBOXAMIDE

Powdered KOH (66 mg, 1.0 mmol) was added to a solution of 6-cyano-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 H-benzimidazole (Example 85, 162 mg, 0.33 mmol) in 2-methyl-2propanol (10 ml). The resulting mixture was heated at reflux temperature for 3 hours. After removing the solvent, the reaction mixture was poured over dichloromethane (50 ml) 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 (50 ml), dried (Na2SO ₄ ) and concentrated. Residual solids were recrystallized from ethyl acetate to obtain 105 mg (63%) of the title compound as white solids: ¹ H NMR (CDCb) δ: 7.79 (2H, d, J =

8.4 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.71-7.63 (2H, m), 7.35-7.25 (4H, m), 7, 16 (2H, d, J = 8.4 Hz), 6.75 (2H, s lg.), 6.55 (1H, s lg.), 3.54 (2H, t, J = 6.4 Hz ), 2.88 (2H, t, J = 6.4 Hz), 2.79 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.34 (3H, t , J = 7.5 Hz).

EXAMPLE 87

5 - [(ferc-BUTYLAMINO) SULFONYL1-2-ETYL-1- (4-f2-r ({r (4-METHYLPHYL) $ ULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1HBENZIMIDAZOLE

STEP 1. N- (ferc-Butyl) -4-chloro-3-nitrobenzenesulfonamide

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A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in dichloromethane (100 mL) was added dropwise at room temperature over a period of 30 minutes to a solution, with stirring. , of tert-butylamine (5.1 g, 70 mmol) in dichloromethane (200 ml), and then the reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (100 ml), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml). Washed the combined organic extracts with water (50 mL) and brine (20 mL), dried (Na 2 SO ₄₎ and concentrated to give 21.3 g (quant.) Of the title compound, under the yellow solids form: ¹ H NMR (CDCI ₃ ) δ 8.38 (1H, d, J = 2.0 Hz), 8.02 (1H, dd, J = 2.0, 8.6 Hz), 7.70 (1H, d, J = 8.6 Hz), 4.95 (1H, s lg.), 1.28 (9H, s).

STEP 2. / V-ether-ButylM ^^ - hydroxyethylDanilinol ^ -nitrobenzenesulfonamide

The title compound was prepared according to the procedure described in step 3 of Example 1 from / V- (tert-butyl) -4-chloro-3-nitrobenzenesulfonamide (step 1) and 4-aminophenyl ethyl alcohol.

MS (IE) m / z 393 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 9.76 (1H, s lg.), 8.75 (1H, d, J = 2.0 Hz), 7.74 (1H, dd, J = 2.0, 8.5 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.17 (1H, d, J = 8, 5 Hz), 4.42 (1H, s lg.), 3.97-3.88 (2H, m), 2.94 (2H, t, J = 7.0 Hz), 1.27 (9H, s).

STEP 3. / V- (tert-Butyl) -4- [4- (2-chloroethyl) anilino1-3-nitrobenzenesulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from / V- (tert-butyl) -4- [4- (2hydroxyethyl) anilino] -3-nitrobenzenesulfonamide (step 2).

MS (IE) m / z 411 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 9.77 (1H, s lg.), 8.77 (1H, d, J = 2.0 Hz), 7.77 (1H, dd, J = 2.0, 8.4 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.18 (1H, d, J = 8, 4 Hz), 4.46 (1H, s lg.), 3.76 (2H, t, J = 6.8 Hz), 3.13 (2H, t, J = 6.8 Hz), 1.28 (9H, s).

STEP 4. 3-Amino- / V- (tert-butyl) -4- [4- (2-chloroethyl) anilino1 benzenesulfonamide

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The title compound was prepared according to the procedure described in step 4 of Example 1 from / V- (tert-butyl) -4 ~ [4- (2-chloroethyl) anilino] -3-nitrobenzenesulfonamide (step 2 ).

¹ H NMR (CDCI ₃ ) δ 7.31 (1H, d, J = 2.0 Hz), 7.26 (1H, dd, J = 2.0, 83 Hz), 7.15 (1H, d , J = 8.3 Hz), 7.14 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz), 5.49 (1H, s lg. ), 4.64 (1H, s lg.), 3.77 (2H, s lg.), 3.69 (2H, t, J = 7.4 Hz), 3.02 (2H, t, J = 7.4 Hz), 1.24 (9H, s).

STEP 5. Z \ / - (tert-Butyl) -1-r4- (2-chloroethyl) phenyl1-2-ethyl-1/7-benzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 5 of Example 1 from 3-amino-A / - (ferc-butyl) -4- [4 (2-chloroethyl) anilino] benzenesulfonamide (step 4 ) and propionyl chloride.

MS (IE) m / z 419 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.34 (1H, d, J = 2.0, 7.74 (1H, dd, J = 2.0, 8.3 Hz), 7.47 (2H, d , J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.3 Hz), 4.62 (1H, s lg. ), 3.83 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 7.0 Hz), 2.82 (2H, q, J = 7.4 Hz), 1.39 (3H, t, J = 7.4 Hz), 1.24 (9H, s).

STEP 6. 1- [4- (2-Azidoethyl) phenyl1- / V- (ferc-butyl) -2-ethyl-1H-benzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from / V- (tert-butyl) -1- [4- (2 chloroethyl) phenyl] -2-ethyl-1 / - / -benzimidazole-5-sulfonamide (step 5).

MS (IE) m / z 426 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 8.33 (1H, d, J = 2.0 Hz), 7.73 (1H, dd, J = 2.0, 8.4 Hz), 7.48 (2H , d, J = 8.4 Hz), 7.33 (2H, d, J =

8.4 Hz), 7.14 (1H, d, J = 8.4 Hz), 4.47 (1H, s lg.), 3.62 (2H, t, J = 7.0 Hz), 3 , 03 (2H, t, J = 7.0 Hz), 2.82 (2H, q, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz), 1.24 (9H, s).

STEP 7. 1-i4- (2-Aminoethyl) phenyl1 - / \ / - (tert-butyl) -2-ethyl-1 / - / - benzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] - / V (tert-butyl) -2-ethyl-1/7 -benzimidazole-5-sulfonamide (step 6).

¹ H NMR (CDCI ₃ ) δ 8.34 (1H, d, J = 1.9 Hz), 7.74 (1H, dd,

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J = 1.9, 8.3 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.15 (1H, d, J = 8.3 Hz), 4.88 (1H, s lg.), 3.09 (2H, t, J = 7.0 Hz), 2.95 (2H, t, J = 7.0 Hz), 2.83 (2H, q, J = 7.4 Hz), 1.37 (3H, t, J = 7.4 Hz), 1.23 (9H, s).

STEP 8. 5-i (/ erc-Butylamino) sulfonyl1-2-ethyl-1- (4 - [({[(4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -A / (tert-butyl) -2-ethyl-1tf-benzimidazole -5-sulfonamide (step 7).

MS (IE) m / z 598 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.32 (1H, d,> 1.3 Hz), 7.77-7.69 (3H, m), 7.41 (2H, d,> 8.3 Hz ), 7.33-7.25 (4H, m), 7.11 (1H, d,> 8.6 Hz), 6.65 (1H, s lg.), 4.59 (1H, s lg. ), 3.63-3.53 (2H, m), 2.95 (2H, t,> 7.0 Hz), 2.80 (2H, q,> 7.6 Hz), 2.41 (3H , s), 1.36 (3H, t,> 7.6 Hz), 1.23 (9H, s).

EXAMPLE 88

5- (AMINOSULFQNIL) -2-ETYL-1- (4-f2 - [({[(4-METHYLphenyl) SULFONYL1AMINO) CARBONIL) AMINO1ETYL | PHENYL) -1H-BENZIMIDAZOLE

A solution of 5 - [(tertbutylamino) sulfonyl] -2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl] was heated at 80 ° C for 2 hours ) -amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 87, 330 mg, 0.55 mmol) in trifluoroacetic acid (10 mL). The mixture was concentrated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10: 1) to provide 215 mg (73%) of the title compound: EM (IED) m / z 542 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.32 (1H, d,> 1.3 Hz), 7.77-7.69 (3H, m), 7.41 (2H, d,> 8.3 Hz ), 7.33-7.25 (4H, m), 7.11 (1H, d,> 8.6 Hz), 6.65 (1H, s lg.), 4.59 (1H, s lg. ), 3.63-3.53 (2H, m), 2.95 (2H, t,> 7.0 Hz), 2.80 (2H, q,> 7.6 Hz), 2.41 (3H , s), 1.36 (3H, t,> 7.6 Hz), 1.23 (9H, s).

EXAMPLE 89

2-ETIL-1- {2-i (([((4-METHYLphenyl) SULFONYL1AMINO) -CARBONYL) AMINO1ETYL) -5-f (METHYLSULFONYL) AMINO1-1H-BENZIMIDAZOLE

STEP 1.2- [4- (2 ₁ 4-Dinitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure188 / 451 as described in step 3 of Example 1 from 2-chloro-1,5-dinitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.95 (1H, s), 9.18 (1H, d, J = 2.4 Hz), 8.16 (1H, dd, J = 2.7, 9, 7 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.16 (1H, d, J = 9.5 Hz ), 3.93 (2H, dt, J = 5.7, 6.2 Hz), 2.94 (2H, t, J = 6.8 Hz), 1.50 (1H, t, J = 5, 7 Hz).

STEP 2. 2- [4- (2-Amino-4-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 40 from 2- [4- (2,4-dinitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.73-7.67 (2H, m), 7.22 (2H, d, J = 8.3 Hz),

7.11 (1H, d, J = 9.3 Hz), 7.04 (2H, d, J = 8.3 Hz), 5.80 (1H, s), 3.88 (2H, dt, J = 5 , 7, 6.0 Hz), 3.69 (2H, s lg.), 2.87 (2H, t, J = 6.4 Hz), 1.48 (1H, s lg.).

STEP 3. 2- [4- (2-ethyl-5-nitro-1 / - / - benzimidazole-1ipphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-4-nitroanilino) phenyl] ethanol (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 8.68 (1H, d, J = 2.2 Hz), 8.13 (1H, dd, J = 2.2, 9.0 Hz), 7.48 (2H , d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.13 (1H, d, J = 8.97 Hz), 4.39 (2H, t , J = 6.8 Hz), 3.09 (2H, t, J = 7.0 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 1.38 (3H, t, J = 7.5 Hz), 1.15 (3H, q, J = 7.5 Hz).

STEP 4. 2-F4- (5-amino-2-ethyl-1 / - / - benzimidazole-1ipphenylethyl propionate

Ammonium chloride (80 mg, 1.5 mmol) and powdered iron (840 g, 15 mmol) were added at room temperature with stirring to a 2- [4- (2-ethyl- 5-nitro-1/7-benzimidazol-1-yl) phenyl] ethyl (step 3,

1.12 g, 3.0 mmol) in ethanol / water (volume / volume, 2: 1, 15 mL). The mixture was heated to reflux for 4 hours and filtered through a pad of Celite. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 ml), then dried (MgSO ₄ ). Removal of the solvent provided 0.84 g (83%) of the title compound, as a

219/451 yellow oil: ¹ H NMR (CDCI ₃ ) δ 7.41 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.10 (1H, d, J = 1.8 Hz), 6.89 (1H, d, J = 8.4 Hz), 6.63 (1H, dd, J = 2.2,

8.4 Hz), 4.37 (2H, t, J = 7.0 Hz), 3.05 (2H, t, J = 7.1 Hz), 2.79 (2H, q, J = 7, 5 Hz), 2.35 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.50 Hz), 1.14 (3H, t, J = 7.7 Hz ).

STEP 5. 2- (4- {2-ethyl-5 - [(methylsulfonyl) amino11 / - / - benzimidazole-1-hyphenylethyl propionate

Methanesulfonyl chloride (0.40 ml, 5.25 mmoles) and pyridine (0.40 ml, 5.25 mmol) were added, at room temperature, with stirring, to a 2- [4- ( 5-amino-2-ethyl-1H-benzimidazol-1-yl) phenyl] ethyl (step 4, 1.18 g, 3.50 mmol). After stirring for 6 hours, the mixture was poured into 10% aqueous citric acid solution (100 ml), and extracted with ethyl acetate (100 ml). The aqueous phase was made basic with saturated aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine (100 ml) and dried (MgSCM, and concentrated to obtain 1.28 g (88%) of the title compound as a brown amorphous substance: NMR ¹ H (CDCI ₃ ) δ 8.47 (1H, s), 7.66 (1H, d, J = 1.7 Hz), 7.50 (2H, d, J = 8.4 Hz), 7 , 42 (1H, dd, J = 2.0, 8.8 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.09 (1H, d, J = 8.8 Hz) , 4.39 (2H, t, J = 7.0 Hz), 3.09 (2H, t, J = 6.8 Hz), 3.00 (2H, q, J = 7.7 Hz), 2 , 36 (2H, q, J = 7.7 Hz), 1.42 (3H, t, J = 7.7 Hz), 1.15 (3H, t, J = 7.5 Hz).

STEP 6. 2-Ethyl-1- [4- (2-hydroxyethyl) pheniri-1 / - / - benzimidazol-5-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- {2-ethyl-5 [methylsulfonyl) amino] -1 / - / - benzimidazole-1- propionate il} phenyl) ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 7.63 (1H, d, J “1.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.18 (1H, dd, J = 2.1, 8.6 Hz), 7.07 (1H, d, J = 8.6 Hz), 6.68 (1H, s lg.), 3.99 (2H, t, J = 6.4 Hz), 3.01 (2H, t, J = 6.8 Hz), 2.98 (3H, s), 2.79 (2H , q, J = 7.4 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 7. A / - {1- [4- (2-chloroethyl) phenyl1-2-ethyl-1/7-benzimidazol-5-yl) methanesulfonamide

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The title compound was prepared according to the procedure described in step 7 of Example 1 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl] 1/7-benzimidazol-5-yl} methanesulfonamide ( step 6).

¹ H NMR (CDCI ₃ ) δ 7.74-6.85 (7H, m), 3.83 (2H, t, J = 7.1 Hz), 3.21 (2H, t, J = 7, 1 Hz), 2.98 (3H, s), 2.85 (2H, q, J = 7.5 Hz), 1.38 (3H, t, J =

7.5 Hz).

STEP 8. Λ / -Ι1 -í4- (2-Azidoethyl) phenyl1-2-ethyl-1 B-benzimidazol-5-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from / V- {1- [4- (2-chloroethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl } methanesulfonamide (step 7).

¹ H NMR (CDCI ₃ ) δ 7.64 (1H, s lg.), 7.45 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.1 Hz ), 7.19 (1H, dd, J = 1.8, 8.8 Hz), 7.07 (1H, d, J = 8.4 Hz), 6.81 (1H, s), 3.62 (2H, t, J = 6.8 Hz), 3.02 (2H, t, J = 7.0 Hz), 2.98 (3H, s), 2.79 (2H, q, = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz).

STEP 9. / V- {1-r4- (2-Aminoethyl) phenyl1-6-chloro-2-ethyl-1B-benzimidazol-5-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 9 of Example 1 from / V- {1- [4- (2-azidoethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl } methanesulfonamide (step 8).

MS (IE) m / z 358 (M ⁺ ).

STEP 10. A / T1-f4- (2-Aminoethyl) phenyl1-2-ethyl-1H-benzimidazol-5-yl} methanesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from / V- {1- [4- (2-aminoethyl) phenyl] 6-chloro-2-ethyl-1 / 7- benzimidazol-5-yl} methanesulfonamide (step 9).

MS (IED) m / z 556 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 9.49 (1H, s), 7.76 (2H, d, J = 7.1 Hz), 7.51 (1H, s lg.), 7.42-7 , 34 (6H, m), 7.07 (1H, d, J = 8.6 Hz), 7.01 (1H, d, J = 8.6 Hz), 6.53 (1H, s lg.) , 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 = 7.5 Hz); IV (KBr) v _max 1697, 1684, 1508, 1458, 1148cm ^-1 .

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EXAMPLE 90

2-ETIL-5-HYDROXY-1- (4- {2-í (ff (METlLFENIL) SULFONIL1AMlNO) CARBQNIL) AMINQ1ETIL) FENlL-1/7-BENZIMlDAZQL

STEP 1. 1-r4- (2-Bromoethyl) phenyl1-2-ethyl-1/7-benzimidazo-5-ol

A mixture of 1- [4- (2-chloroethyl) phenyl] -2-ethyl-5-methoxy1A7-benzimidazole (step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid ( 60 mL) at 100 ° C for 6 hours. After cooling, the mixture was neutralized with 2N aqueous NaOH solution and extracted with ethyl acetate (100 ml). The organic phase was washed with brine (50 ml), dried (Na ₂ SO ₄ ), and concentrated to obtain 890 mg (quant.) Of the title compound as light yellow solids: NMR ¹ H (CDCh) δ 7.64 (4H, s), 7.16 (2H, m), 6.97-7.01 (1H, m), 3.86 (2H, t, J = 7, 1 Hz), 3.30 (2H, t, J = 7.1 Hz), 2.92 (2H, q, J = 7.8 Hz), 1.29 (3H, t, J = 7.8 Hz ).

STEP 2. Ferc-Butyl (dimethyl) silyl ether and 1-r4- (2-bromoethyl) phenill2-ethyl-1/7-benzimidazol5-yl

A mixture of 1- [4- (2-bromoethyl) phenyl] -2-ethyl-1/7-benzimidazol-5-ol (step 1, 200 mg, 0.58 mol), ferc-butyldimethylsilyl chloride was stirred (100 mg, 0.7 mmol) and imidazole (47 mg, 1.45 mmol) in DMF (5 mL) at room temperature for 3 hours. The reaction mixture was poured into water (50 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), and dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), to provide 119 mg (45%) of the title compound, as white solids: ¹ H NMR (CDCh) δ 7.20 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.01 (1H, d, J = 2.3 Hz), 6.72 (1H, d, J = 8.6 Hz), 6.52 (1H, dd, J = 2.3 Hz,

8.6 Hz), 3.45 (2H, t, J = 7.4 Hz), 3.07 (2H, t, J = 7.4 Hz), 2.56 (2H, q, J = 7, 5 Hz), 1.14 (3H, t, J = 7.5 Hz), 0.79 (9H, s), 0.05 (6H, s).

STEP 3. Ferc-Butyl (dimethyl) silyl ether 1- [4- (2-azidoethyl) phenyl-2ethyl-1/7-benzimidazol-5-yl

The title compound was prepared according to the procedure described in step 8 of Example 1 from tert-butyl (dimethyl) silyl ether

222/451 and 1- [4- (2-bromoethyl) phenyl] -2-ethyl / 7-benzfmidazol-5-yl (step 2).

¹ H NMR (CDCI ₃ ) δ 7.20 (2H, d, J = 8.3 Hz), 7.02-7.12 (3H, m), 6.70 (1H, d, J = 8, 6 Hz), 6.50-6.54 (1H, m), 3.39 (2H, t, J = 6.9 Hz), 2.79 (2H, t, J = 6.9 Hz), 2 , 55 (2H, q, J = 7.6 Hz), 1.13 (3H, t, J = 7.6), 0.79 (9H, s), 0.00 (6H, s).

STEP 4. 2-F4- (5- {ether-Butyl (dimethyl) silinoxy) -2-ethyl-1H-benzimidazol-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -2 »ethyl-1 / tert-butyl (dimethyl) ethyl ether - / - benzimidazol-5-yl (step 3).

¹ H NMR (CDCI ₃ ) δ 7.18 (2H, d, J = 8.2 Hz), 7.02-7.08 (3H, m), 6.72 (1H, d, J = 8, 6 Hz), 6.52 (1H, dd, J = 2.2 Hz, 8.6 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.66 (2H, t, J = 6.6 Hz), 2.55 (2H, q, J = 7.5 Hz), 1.13 (3H, t, J = 7.5), 0.79 (9H, s), 0.00 (6H, s).

STEP 5. 5-Uterc-Butyl (dimethyl) silyloxy) -2-ethyl-1- (4- (2-y ((y (4-methylphenyl) sulfonillamino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5 - {[tert-butyl (dimethyl) silyl] oxy} -2-ethyl-1 H- benzimidazol-1-yl) phenyljetylamine (step 4).

¹ H NMR (CDCI ₃ ) δ 7.53 (2H, d, J = 8.3 Hz), 7.02-7.13 (7H, m), 6.70 (1H, d, J = 8, 6 Hz), 6.52 (1H, dd, J = 2.2 Hz, 8.6 Hz), 6.46 (1H, s lg.), 3.37 (2H, t, J = 6.4 Hz ), 2.71 (2H, t, J = 6.4 Hz), 2.53 (2H, q, J = 7.6 Hz), 2.18 (3H, s), 1.11 (3H, t , J = 7.6 Hz), 0.79 (9H, s) 0.00 (6H, s).

STEP 6. 2-Ethyl-5-hydroxy-1- (4- (2-í ((í (4-methylphenyl) sulfonill-amino | carbonyl) amino1ethyl} phenyl) -1 / - / - benzimidazole

Tetrabutylammonium fluoride (1.0 M solution in THF, 0.16 mL, 0.16 mmol) was added at 0 ° C to a solution of 5 - {[tert-butyl (dimethyl) silyl] oxy} - 2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) 1/7-benzimidazole (step 5, 78 mg, 0.13 mmol ) in THF (5 ml). The mixture was stirred at 0 ° C for 2.5 hours, then concentrated. The residue was dissolved in water (30 ml) and extracted with dichloromethane (50 ml). The organic layer was dried (Na ₂ SO4) and concentrated. The residue was purified by

223/451 flash column chromatography on silica gel, eluting with dichloromethane / methanol (gradient elution from 20: 1 to 10: 1), to provide 57 mg (92%) of the title compound as a substance white amorphous: MS (IED) m / z 479 (M + H) ⁺ ; ¹ H NMR (DMSO-d _s ) δ 7.76 (2H, d, J =

7.6 Hz), 7.35-7.39 (6H, m), 6.96 (1H, s), 6.85 (1H, d, J = 8.6 Hz), 6.65 (1H, d,

J = 8.6 Hz.), 6.51 (1H, s lg.), 3.17 (2H, s lg.), 2.76 (2H, t, J = 6.6 Hz), 2.67 (2H , q, 3 = 7.6 Hz), 2.34 (3H, s) 1.20 (3H, t, 3 = 7.6 Hz).

EXAMPLE 91

2-ETYL-4.5-DIMETHYL 1- (4- {2-y ({y (4-METHYLphenyl) -SULPHONYL A10 MlNO) CARBONYL) AMINO1ETYL) PHENYL) -1 / 7-BENZIMIDAZOLE

STEP 1.2 - [(3,4-dimethyl-2-nitroaniline) phenyl1ethanol The title compound was prepared according to the procedure described in step 1 of Example 45 from 3,4-dimethyl-2-nitroaniline and ethanol 4 -bromophenylethyl.

¹ H NMR (CDCI ₃ ) δ 7.16 (2H, d, J = 8.4 Hz), 7.09 (1H, s), 7.03 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 3.89-3.81 (2H, m), 2.83 (2H, t, J = 6.4 Hz), 2.27 (3H, s), 2.25 (3H, s).

STEP 2. 2-f (2-Amino-3,4-dimethylanilino) phenyl1ethanol The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(3,4-dimethyl -2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.02 (2H, d, J = 8.6 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.62-6.58 (3H , m), 5.09 (1H, s lg.), 3.77 (2H, t, J = 6.6 Hz), 2.74 (2H, t, J = 6.6 Hz), 2.27 (3H, s), 2.11 (3H, s).

STEP 3. 2- [4- (2-Ethyl-4,5-dimethyl-1 / - / - benzimidazol-1-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-3,4-dimethylanilino) phenyl] ethanol (step 2) and propionyl chloride.

MS (IE) m / z 350 (M ⁺ )

STEP 4. 2-f4- (2-Ethyl-4,5-dimethyl-1 / - / - benzimidazol-1-yl) pheninethanol

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The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl-4,5-dimethyl-1/7-benzimidazol-1-yl) phenyl] propionate ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.3 Hz), 6.82 (1H, d, J = 8.3 Hz), 3.98 (2H, t, J = 6.6 Hz), 2.99 (2H, t, J = 6 , 6, Hz), 2.82 (2H, q, J = 7.5 Hz), 2.63 (3H, s), 2.39 (3H, s), 1.26 (3H, t, J = 7.5 Hz).

STEP 5. 2- [4- (2-Ethyl-4,5-dimethyl-1H-benzimidazole-1iQphenylethyl azide)

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-ethyl-4,5-dimethyl-1Hbenzimidazol-1-yl) phenyl] ethanol (step 4 ).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.00 (1H, d, J = 8.2 Hz), 6.82 (1H, d, J = 8.2 Hz), 3.61 (2H, t, J = 7.1 Hz), 3, 01 (2H, t, J = 7 , 1 Hz), 2.83 (2H, q, J = 7.6 Hz), 2.63 (3H, s), 2.39 (3H, s), 1.26 (3H, t, J = 7 , 6 Hz).

STEP 6. 2-r4- (2-Ethyl-4,5-dimethyl-1/7-benzimidazol-1-yl) pheninetylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-4,5-dimethyl-1/7-benzimidazol-1-yl) phenyl] azide ethyl (step 5).

⁴ H NMR (CDCI ₃ ) δ 7.39 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.2 Hz), 6.82 (1H, d, J = 8.2 Hz), 3.09 (2H, t, J = 6.6 Hz), 2.92-2.79 (4H, m ), 2.63 (3H, s), 2.39 (3H, s), 1.27 (3H, t, J = 7.6 Hz).

STEP 7. 2-Ethyl-4.5-dimethyl-1- (4-f2-i (ph (4-methylphenyl) sulfonillamino} carbonihamino1ethyl} phenyl) -1A7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl ~ 4,5-dimethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine ( step 6).

¹ H NMR (CDCI ₃ ) δ 7.76 (2H, d, J = 8.2 Hz), 7.30-7.19 (6H, m), 7.00 (1H, d, J = 8, 2 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.65 (1H, m), 3.56-3.54 (2H, m), 2.89 (2H, t, J = 6.9 Hz), 2.80 (2H, q, J = 7.6 Hz), 2.59 (3H, s), 2.38 (6H, s),

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1.22 (3Η, t, J = 7.6 Hz).

EXAMPLE 92

SODIUM SALT OF 2-ETHYL-4,5-DIMETHI-1- (4-f2-r (U (4-METHYLFENlL) SULFONY | AMINQ} CARBONYL) AMINO1ETYL) PHENYL) -1 / 7-BENZIMIDAZOL

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-4,5-dimethyl-1- (4- {2 [({[(4-methylphenyl) sulfonyl] amino} carbonyl ) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 91).

¹ H NMR (DMSO-de) δ 7.59 (2H, d, J = 8.4 Hz), 7.39-7.30 (4H, m), 7.12 (2H, d, J = 8 , 4 Hz), 6.94 (1H, d, J = 8.3 Hz), 6.77 (1H, d, J = 8.3 Hz),

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 = 7.5 Hz); IV (KBr) v _max 1599, 1516, 1425, 1227, 1128, 1086 cm ^-1 . EXAMPLE 93

4,6-DIMETHYL-2-ETHYL-3- (4- (2-r (U (4-METHYLPHYL) SULFONYLAMINO) CARBONYL) AMINO1ETYL) FENfL) -1 / 7-BENZIMIDAZOLE

STEP 1. 2-í4- (3,5-Dimethyl-2-nitroanilino) pheninetanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-dimethyl-2-fluoronitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 8.08 (1H, s lg.), 7.22 (2H, d, J = 8.4 Hz),

7.13 (2H, d, J = 8.4 Hz), 6.91 (1H, s), 6.51 (1H, s), 3.89 (2H, t, J = 6.4 hz), 2, 87 (2H, t, J = 6.4 Hz), 2.47 (3H, s), 2.22 (3H, s).

STEP 2. 2- [4- (2-Amino-3,5-dimethylanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- [4- (3,5-dimethyl-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCb) δ 6.97-7.04 (2H, m), 6.78 (1H, s), 6.74 (1H, s), 6.59-6.67 (1H, s ), 5.15 (1H, s lg.), 3.76 (2H, t, J = 6.6 Hz), 2.74 (2H, t, J = 6.6 Hz), 2.18 (3H , s), 2.17 (3H, s)

STEP 3. 2- [4- (2-Ethyl-4,6-dimethyl-1/7-benzimidazol-1-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure 226/451 as described in step 5 of Example 1 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 4. 2-i4- (2-Ethyl-4,6-dirnetyl-1A / -benzirrirdazol-1-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-amino3.5-dimethylanilino) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCfe) δ 7.42 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz), 6.90 (1H, s), 6 , 71 (1H, s), 3.98 (2H, t, J = 6.4 Hz), 2.99 (2H, t, J = 6.4 Hz), 2.81 (2H, q, J = 7.3 Hz), 2.65 (3H, s), 2.36 (3H, s), 1.24 (3H, t, J = 7.3 Hz).

STEP 5, 1 -4- (2-Chloroethyl) phenyl1-2-ethyl-4,6-dimethyl-1 B-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-4,6-dimethyl-1Hbenzimidazol-1-yl) phenyl] ethanol (step 4 ).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 6.90 (1H, s), 6, 71 (1H, s), 3.81 (2H, t, J = 7.2 Hz), 3.19 (2H, t, J = 7.2 Hz), 2.81 (2H, q, J = 7 , 7 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.25 (3H, t, J = 7.7 Hz).

STEP 6. 2-Í4- (2-Ethyl-4,6-dimethyl-1 / - / - benzimidazole-1ihfenilletiía azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl4.6-dimethyl-1/7-benzimidazole (step 5).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 6.90 (1H, s), 6.69 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.01 (2H, d, J = 7.0 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.66 (3H, s), 2.36 (3H, s), 1.25 (3H, t, J = 7.5 Hz).

STEP 7. 2- [4- (2-Ethyl-4,6-dimethyl-1 / - / - benzimidazol-1-yl) phenyl1-ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-4,6227 / 451 dimethyl-1/7-benzimidazol-1-yl azide ) phenyl] ethyl (step 6).

¹ H NMR (CDCI ₃ ) δ 7.4o (2H. D. J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 6.89 (1H, s), 6.71 (1H, s), 3.07 (2H, t, J = 6.9 Hz), 2.77-8.99 (4H, m), 2.67 (3H, s), 2.36 (3H, s), 1.25 (3H, t, J = 7.6 Hz).

STEP 8. 2-Ethyl-4,6-dimethyl-1- (4- (2 - [((í (4-methylphenyl) sulfonill-amino) carbonyl) amino1ethyl} phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-4,6-dimethyl-1 / 7benzimidazol-1-yl) phenyl] ethylamine ( step 7).

Mp08-112 ° C; MS (IED) m / z 491 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.75 (2H, d,> 8.2 Hz), 7.18-7.29 (6H, m), 6.89 (1H, s), 6.67 ( 1H, s), 6.62 (1H, s lg.), 3. 51 (2H, s lg.), 2.86 (2H, s lg.), 2.76 (2H, q, J = 7, 4 Hz), 2.63 (3H, s), 2.37 (3H, s), 2.33 (3H, s), 1.20 (3H, t, J = 7.4 Hz).

EXAMPLE 94

5,6-DIMETHIL-1- (4-f2-f «r (4-METHYLphenyl) SULFONYL1-AMINO}

CARBONIL) AMINO1ETlL) FENIL) -1 / 7-BENZIMIDAZQL

STEP 1. 2 - [(4.5-Dimethyl-2-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 1 of Example 45 from 4,5-dimethyl-2-nitroaniline and 4-bromophenyl ethyl alcohol.

¹ H NMR (CDCb) δ 9.39 (1H, s lg.), 7.96 1H, s), 7.27 (2H, d, J = 8.4 Hz), 7.21 (2H, d , J = 8.4 Hz), 7.01 (1H, s), 3.91 (2H, q, J = 6.4 Hz), 2.90 (2H, t, J = 6.4 Hz), 2, 20 (3H, s), 2.19 (3H, s).

STEP 2, 2 - [(2-Amino-4,5-dimethylanilino) pheninethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(4,5-dimethyl-2-nitroanilino) phenyl] ethanol (step 1).

'H (CDCb) δ 7.04 NMR (2H, d, J = 8.4 Hz), 6.86 (1H, s), 6.64 (2H, d, J = 8.4 Hz), 6 , 61 (1H, s), 3.79 (2H, t, J = 6.6 Hz), 2.76 (2H, t, J = 6.6 Hz), 2.19 (3H, s), 2 , 12 (3H, s).

STEP 3. 2- [4- (2-Ethyl-5 _I 6-dimethyl-1/7-benzimidazol-1-yl) fenil1etila

228/451

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-4,5-dimethylanilino) phenyl] ethanol (step 2) and propionyl chloride.

MS (IE) m / z 350 (M ⁺ ).

STEP 4. 2- [4- (2-Ethyl-5 ₍ 6-dimethyl-1A / -benzimidazoyl-1-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-ethyl, 5,6dimethyl-1 / - / - benzimidazol-1-yl) phenyl propionate ] ethyl (step 3).

¹ H NMR (CDCb) δ 7.52 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 6 , 87 (1H, s), 4.00 (2, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.6 Hz),

2.76 (2H, q, J = 7.5 Hz), 2.36 (3H, s), 2.29 (3H, s), 1.31 (3H, t, J = 7.5 Hz).

STEP 5. 2- [4- (2-Ethyl l-5,6-di methyl-1 / - / - benzimidazole-1iOphenylethyl azide)

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (2-ethyl-5,6-dimethyl-1 / 7benzimidazol-1-yl) phenyl] ethanol ( step 4).

TLC Rf = 0.70 (hexane / ethyl acetate = 1: 1).

STEP 6. 2-r4- (2-Ethyl-5,6-dimethyl-1 H-benzimidazole-1-phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl) phenyl] ethyl azide ( step 5).

¹ H NMR (CDCI ₃ ) δ 7.53 (1H, s), 7.40 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 6.87 (1H, s), 3.17 (2H, t, J = 7.3 Hz), 3.00 (2H, t, J = 7.3 Hz),

2.76 (2H, q, J = 7.5 Hz), 2.36 (3H, s), 2.29 (3H, s), 1.31 (3H, t, J = 7.5 Hz).

STEP 7. 2-Ethyl-5,6-dimethyl-1- (4- {2-i (fr (4-methylphenyl) sulfonill-amino) carbonyl) amino1ethyl) phenyl) -1H-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5,6-dimethyl-1 / - / benzimidazol-1-yl) phenyl] ethylamine (step 6).

¹ H NMR (CDCb) δ 7.79 (2H, d, J = 8.1 Hz), 7.48 (1H, s), 7.29229 / 451

7.15 (6Η, m), 6.86 (1H, s), 6.60 (1H, s Ig.), 3.57-3.55 (2H, m), 2.91-2.89 ( 2H, m), 2.70 (2H, q, J = 7.5 Hz), 2.39 (3H, s), 2.35 (3H, s), 2.27 (3H, s), 1, 25 (3H, t, J = 7.5 Hz).

EXAMPLE 95

SODIUM SALT OF 5,6-DIMETHIL-1- (4- (2-f «r (4-METHYLPHYL) SULFONYL1AMINO) CARBQNIL) AMINO1ETYL} PHENYL) -1B-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5,6-dimethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1B-benzimidazole (Example 94).

¹ H NMR (DMSO-d ₆ ) δ 7.60 (2H, d, J = 8.1 Hz), 7.39-7.32 (5H, m), 7.13 (2H, d, J = 8.1 Hz), 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 = 7.4 Hz); IV (KBr) v _max 1599, 1516, 1468, 1404, 1283, 1236, 1130, 1086 cm ^-1 .

EXAMPLE 96

5,6-DICLORO-2-ETHYL-1- (4- (2 - [((f (4-METHYLphenyl) -SULFONIL1

AMINO) CARBONIL) AMINO1ETHIL} FENIL) -1B-BENZIMIDAZOLE

STEP 1. 2-i4- (4,5-Dichloro-2-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and 4-aminopheniethyl alcohol.

MS (IE) m / z 327 (M ⁺ ).

STEP 2. 2-r4- (2-Amino-4.5-dichloroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4- (4,5-dichloro-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCl ₃ ) δ 7.16 (1H, s), 7.11 (2H, d, J = 8.0 Hz), 6.87 (1H, s), 6.74 (2H, d , J = 8.0 Hz), 5.10 (1H, s Ig.), 3.90-3.60 (2H, m), 2.79 (2H, t, J = 7.0 Hz).

STEP 3. 244- (5,6-dichloro-2-ethyl-1B-benzimidazole1 -iDphenylethyl propionate)

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4- (2-amino-4,5230 / 451 dichloroanilino) phenyl] ethanol (step 2) and propionyl chloride .

MS (IE) m / z 390 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.84 (1H, s), 7.45 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.16 (1H, s), 4.37 (2H, t, J = 6.8 Hz), 3.09 (2H, t, J = 6.8 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz), 1.16 (3H, t, J = 7 , 5 Hz).

STEP 4. 2-f4- (5,6-Dichloro-2-ethyl-1/7-benzimidazol-1-yl) pheninethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- (5,6dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate ( step 3).

¹ H NMR (CDCI ₃ ) δ 7.84 (1H, s), 7.47 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.18 (1H, s), 4.10-3.49 (2H, m), 3.01 (2H, t, J = 6.4 Hz),

2.77 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 5, 2- (4- (5,6-Dichloro-2-ethyl-1tt-benzimidazole-1iDphenylethyl) azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- (4- (5,6-dichloro-2-ethyl-1 Hbenzimidazol-1-yl) phenyl] ethanol (step 4).

MS (IE) m / z 359 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.85 (1H, s), 7.46 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.17 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz), 2.76 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 6. 2- (4- (5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 2- (4- (5,6-dichloro-2ethyl-1 / - / - benzimidazol-1-yl) phenyl azide ] ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 7.84 (1H, s), 7.43 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.22 (1H, s), 3.14 (2H, t, J = 7.2 Hz), 2.97 (2H, t, J = 7.2 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.10 (2H, s lg.), 1.34 (3H, t, J = 7.6 Hz).

STEP 7. 5,6-Dichloro-2-ethyl-1 - (4T2-f ({[(4-methylphenyl) sulfonylbamino) carbonyl) amino1ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- (4- (5,6-dichloro-2-ethyl-1Hbenzimidazot-1-yl) phenyl] ethylamine (step 6).

¹ H NMR (CDCI ₃ ) δ 8.01 (1H, s), 7.70 (2H, d, J = 8.3 Hz), 7.46 (2H, d, J = 8.3 Hz), 7.36-7.29 (3H, m), 7.24 (2H, d, J = 8.3), 6.81 (1H, s lg.), 3.57-3.46 (2H, m ), 3.06-2.88 (4H, m), 2.38 (3H, s), 1.43 (3H, t, J = 6.9 Hz). EXAMPLE 97 (2-14- (5,6-DICLORO-2-ETHYL-1H-BENZIMIDAZOL-1-IDFEN1L1ETYL) 4-METHYLENIDSULFONYL CARE

The title compound was prepared according to the procedure described in Example 3 from 2- (4- (5,6-dichloro-2-ethyl-1/7-benzimidazol1-yl) phenyl] ethanol (step 4 of Example 96).

¹ H NMR (CDCI ₃ ) δ 7.92 (2H, d, J = 8.4 Hz), 7.85 (1H, s), 7.37 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.16 (1H, s), 4.72 (1H, s lg) , 4.38 (2H, t, J = 6.8 Hz), 3.03 (2H, t, J = 6.8 Hz), 2.75 (2H, q, J = 7.5 Hz), 2 , 44 (3H, s), 1.34 (3H, t, J = 7.5 Hz).

EXAMPLE 98

5,6-DICLORO-2-ETHYL-1- (4- {2- [HYDROXY ({(((4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 1- [4- (2 - ((ferc-Butoxycarbonyl) (ferc-butoxycarbonyl) -oxyamino) ethyl) phenyl1-5,6-dichloro-2-ethyl-1/7-benzimidazole

Diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol) was added with stirring to a mixture of 2- (4- (5,6-dichloro-2-ethyl-1H-benzimidazol-1yl) phenyl] ethanol (Example 96, 100 mg, 0.3 mmol), Λ /, Ο-Bis-tert-butoxycarbonylhydroxy (Baillie, LC; Batsanov, A .; Bearder, JR; Whiting, DAJ Chem. Soc. Perkin Trans. 7, 1998, 20, 3471; 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours The solvent was removed and the residue was purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1), providing 174 mg (quant.) Of the title compound as a yellow amorphous substance: ¹ H NMR (CDCl 3) δ 7.84 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8, 4 Hz), 7.16 (1H, s), 3.92 (2H, t, J = 6.7 Hz), 3.05 (2H, t, J = 6.7

232/451

Hz), 2.76 (2H, q, J = 7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J = 7.6 Hz).

STEP 2. A / -f2-F4- (5,6-Dichloro-2-ethyl-1/7-benzimidazole-1-yl) phenilletillhydroxyimine

A mixture of 1- [4- (2 - {(ferc-butoxycarbonyl)] (ferc-butoxycarbonyl) oxy] amino} ethyl) phenyl] -5,6 ~ dichloro-2 was stirred at room temperature for one day. -ethyl-1/7-benzimidazole (step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 ml) in ethyl acetate (20 ml). The reaction mixture was poured into water (100 ml), neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated to give 162 mg (quant.) Of the title compound as a yellow oil: ¹ H NMR (CDCb) δ 10.35 (2H, s lg.), 7.89 (1H, s), 7.46-7.50 (2H, m), 7.29 (2H, d, J = 6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J = 6.9 Hz), 3.12 (2H, t, J = 6.9 Hz), 2.80 (2H, q, J = 6.9 Hz), 1.34 (3H, m).

STEP 3. 5,6-Dichloro-2-ethyl-1 - (4- (2-rhhydroxy ((f (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -1 H-benzimidazole

The reaction was conducted according to the procedure described in step 10 of Example 1 from / \ / - {2- [4- (5,6-dichloro-2-ethyl-1/7-benzimidazol-1-yl ) phenyl] ethyl} hydroxy (step 2).

MS (IED) m / z 547 (M + H) ⁺ ; ¹ H NMR (CDCb) δ 7.92 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 7.2 Hz), 7.34-7.45 (2H, m), 7.13-7.18 (4H, m), 3.85 (1H, s lg.), 3.05 (2H, s lg.), 2.66-2.80 (4H, m) , 2.38 (3H, s), 1.32 (3H, t, J = 7.4 Hz); IV (KBr) v _max 1654, 1517, 1452, 1164, 1095, 869 cm ^-1 .

EXAMPLE 99

5 ₁ 6-DICLORO-2-ETHYL-1- (4-fc / s-3-F (fF (4-METHYLphenyl) SULFONlL]

AMINO | CARBONIL) AMINO] CYCLEBUTYL) PHENYL) -1 / 7-BENZIMIDAZOLE

STEP 1. Free / 7s-3-phenylcyclobutyl benzoate

Diethyl azidocarboxylate (DEAD) (10.9 g, 62.3 mmol) was added, at room temperature, with stirring, to a solution of c / s-3 phenylcyclobutanol (Eckerhard, VD; et a /.; Chem. Ber 1993, 126, 2759; 4.6 g,

30.2 mmoles) triphenylphosphine (3.3 g, 59.1 mmoles) and benzoic acid (7.6 mg,

62.3 mmoles). The resulting mixture was stirred at room temperature for 233/451 t and 40 minutes, then the mixture was concentrated. The residue was dissolved in diethyl ether (100 ml) and washed with saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and brine (50 ml). The organic layer was dried (Na2SO ₄ ), and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (10: 1) providing 6.52 g (86%) of the title compound as a light yellow oil: NMR ¹ H (CDCI ₃ ) 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. frans-3-Phenylcyclobutanol

A 4N aqueous solution of LiOH (20 ml, 80 mmoles) was added to a solution of frans-2-phenylcyclobutyl benzoate (step 1, 6.5 g, 26.0 mmoles) in methanol (100 ml), and stirred. the resulting mixture at room temperature for 10 minutes. The mixture was concentrated. The residue was dissolved in water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (5: 1), providing 3.65 g (93%) of the title compound, as a colorless oil: NMR ¹ H (CDCI ₃ ) 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. frans-3- (4-Nitrophenyl) cyclobutanol

A mixture of trans-3-phenylcyclobutyl benzoate (step 2, 3.7 g, 24.6 mmoles) and sulfuric acid in acetic anhydride (25 ml) at -23 ° C was added dropwise to a mixture of nitric acid (smoker, 2.3 mL) and acetic anhydride (25 mL). The resulting mixture was stirred in an ice bath for 1.5 hours. The mixture was poured into ice water (200 ml) and extracted with dichloromethane (2 x 100 ml). The organic layer was washed with water and brine (100 ml), then dried (Na ₂ SO ₄ ), and concentrated. The oily residue was dissolved in methanol (100 ml), and 4N aqueous LiOH solution (50 ml) was added. The resulting mixture was stirred at room temperature for 10 minutes, then concentrated. The residue was dissolved in water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried (Na ₂ SO ₄ ),

234/451 and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (2: 1), providing 2.7 g (56%) of the title compound as a light yellow oil: EM ( IE) m / z 193 (M *); ¹ H NMR (CDCI ₃ ) δ 8.18 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 4.62-4.52 (1H , m), 3.81-3.71 (1H, m), 2.54-2.45 (4H, m).

STEP 4. frans-3- (4-Aminophenyl) cyclobutanol

10% Pd-C (50 mg) was added to a solution of trans-3- (4-nitrophenif) cyclobutanol (step 3, 1.0 g, 4.9 mmoles) in methanol (20 ml). 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 (100 ml) and ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure providing 0.9 g (quant) of the title compound, as light yellow solids: EM (IE) m / z 163 (M ⁺ ); ¹ H NMR (CDCIj) δ 703 (2H, d, J = 8.3 Hz), 6.6 (2H, d, J = 8.3 Hz), 4.56-4.47 (1H, m) , 3.58-3.48 (3H, m), 2.48-2.31 (2H, m), 1.73 (1H, d, J = 5.1 Hz).

STEP 5. frans-3-F4- (4,5-Dichloro-2-nitroanilino) phenylcyclobutanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and trans-3- (4-aminophenyl) cyclobutanol (step 4).

¹ H NMR (CDCI ₃ ) δ 9.40 (1H, s lg.), 8.21 (1H, s), 7.33 (2H, d, J = 8.1 Hz), 7.22 (2H , d, J = 8.1 Hz), 7.19 (1H, s), 4.63-4.55 (1H, m), 3.73-3.63 (1H, m), 2.57- 2.43 (4H, m). MS (IE) m / z: 352 (M ⁺ ).

STEP 6. frans-3-r4- (2-Amino-4.5-dichloroanilino) phenyl1-cyclobutanol

The title compound was prepared according to the procedure described in step 3 of Example 6 from frans-3- [4- (4,5-dichloro-2-nitroanilino) phenyl] cyclobutanol (step 5).

¹ H NMR (CDCI ₃ ) δ 7.16 (1H, s), 7.12 (2H, d, J = 8.6 Hz), 6.86 (1H, s), 6.75 (2H, d , J = 8.6 Hz), 5.08 (1H, s lg.), 4.58-4.49 (1H, m), 3.77 (2H, s lg.), 3.62-3, 52 (1H, m), 2.50-2.34 (4H, m).

STEP 7. Frar7S-3- [4- (5,6-dichloro-2-ethyl-1 / - / - benzimidazol-1-yl) pheninciclobutyl propionate

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The title compound was prepared according to the procedure described in step 5 of Example 1 from irans-3- [4- (2-amino-4,5dichloroanilino) phenyl] cyclobutanol (step 6) and propionyl chloride.

TLC Rf = 0.56 (ethyl acetate / hexane = 1: 1).

STEP 8. / rans-3T4- (5,6-Dichloro-2-ethyl-1 Z7-benzimidazol-1-yl) -phenyl-cyclobutanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from irans-3- [4- (2 amino-4,5- dichloroanilino) phenyl] cyclobutyl propionate (step 7).

MS (IE) m / z: 360 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.85 (1H, s lg.), 7.45 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz ), 7.18 (1H, s lg.), 4.65-4.55 (1H, m), 3.83-3.73 (1H, m), 2.77 (2H, q, J = 7 , 5 Hz), 2.63-2.48 (4H, m), 1.34 (3H, t, J = 7.5 Hz).

STEP 9. C / s-3- [4- (5,6-Dichloro-2-ethyl-1 / - / - benzimidazol1-yl) phenylcyclobutyl azide

Diethyl azodicarboxylate (415 mg, 2.4 mmol) was added, at room temperature, with stirring, to a solution of frans-3- [4- (5,6-dichloro-2ethyl-1H-benzimidazol-1-yl) phenyl] cyclobutanol (step 8, 572 mg, 1.6 mmol), triphenylphosphine (623 mg, 2.4 mmol) and diphenylphosphoryl azide (DPPA) (655 mg, 2.4 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 3 hours, and then the mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). The organic layer was dried (Na ₂ SO ₄ ), and concentrated. Purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (2: 1), providing 506 mg (83%) of the title compound, as colorless solids: EM (IE) m / z 385 (M ⁺ ); ¹ H NMR (CDCI ₃ ) δ 7.84 (1H, s lg.), 7.42 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz ), 7.17 (1H, s lg.), 3.98-3.88 (1H, m), 3.37-3.25 (1H, m), 2.89-2.75 (2H, m ), 2.77 (2H, q, J = 7.6 Hz), 2,342.23 (2H, m), 1.34 (3H, t, J = 7.6 Hz).

STEP 10. c / s-3-F4- (5,6-Dichloro-2-ethyl-1 Z7-benzimidazol-1-yl) phenylcyclobutylamine

The title compound was prepared according to the procedure 236/451 as described in step 7 of Example 37 from c / s-3 [4- (5,6dichloro-2-ethyl-1H-benzimidazole-1- azide) il) phenyl] cyclobutyl (step 9).

MS (IE) m / z 359 (M ⁺ ); ¹ H NMR (CDCb) δ 7.84 (1H, s lg.), 7.41 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz) , 7.17 (1H, s lg.), 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 = 7.5 Hz).

STEP 11. 5,6-Dichloro-2-ethyl-1-r4- (c / 's-3-í ({r (4-methylphenid-sulfoninamino) carbonyl) amino1cyclobutyl} phenyl) -1 H-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from c / s-3 [4- (5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl) phenyl] cyclobutylamine (step 10).

MS (IE) m / z 557 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.85 (1H, s lg.), 7.79 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.1 Hz ), 7.36 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.17 (1H, s lg.), 4.35-4 , 26 (1H, m), 3.35-3.25 (1H, m), 2.93-2.83 (2H, m), 2.78 (2H, q, J = 7.6 Hz), 2.46 (3H, s), 2.19-2.07 (2H, m), 1.34 (3H, t, J = 7.6 Hz).

EXAMPLE 100

5.6-DlCHLORO-1- (4- {1,1-DIMETHYL-2-f ({[(4-METHYLphenyl) -SULFONI LIAM INOlCARBONIL) AMINO1ETYL) PHENYL) -2-ETHYL-1 H-BENZIMIDAZOLE

STEP 1. 2-14- (4,5-Dichloro-2-nitroanilino) phenin-2-methylpropanonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitroaniline and 2 (4-aminophenyl) -2-methylpropanonitrile (Axton, CA; et al. J. Chem. Soc. Perkin Trans. 1,1992, 77, 2203).

¹ H NMR (CDCb) δ 9.38 (1H, s lg.), 8.31 (1H, s), 7.54 (2H, d, J = 8.58 Hz), 7.30-7, 22 (3H, m), 1.75 (6H, s).

STEP 2. 2-f4- (2-Amino-4.5-dichloroanilino) pheniH-2-methylpropanonitrile

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4- (4,5-dichloro-2-nitroanilino) phenyl] -2-methylpropanonitrile (step 1)

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¹ H NMR (CDCI ₃ ) δ 7.41 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.09 (1H, s), 6.90 (1H, s ), 6.80 (2H, d, J = 8.4 Hz), 5.22 (2H, s), 1.62 (6H, s).

STEP 3. 2- (4- (5,6-Dichloro-2-ethyl-1/7-benzimidazol-1-yl) phenyl1-2methylpropanonitrile

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 [4- (2-amino-4,5-dichloroanilino) phenyl] -2-methylpropanonitrile (step 2) and chloride propionyl.

¹ H NMR (CDCl ₃ ) δ 7.91 (1H, s), 7.78 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.24 (1H, s), 2.38 (2H, q, J = 7.5 Hz), 1.89 (6H, s), 1.42 (3H, t, J = 7.3 Hz).

STEP 4. 5,6-Dichloro-1- (4- (1,1-dimethyl-2 - [({(((4-methylphenyl) -sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -2-ethyl-1 / 7- benzimidazole

A mixture of 2- (4- (5,6-dichloro-2-ethyl-1/7-benzimidazol-1-yl) phenyl] -2-methylpropanonitrile (step 3, 102 mg, 0.28 mmol) was stirred , PtO ₂ (one portion), chloroform (0.5 mL) in ethanol (15 mL) under a hydrogen atmosphere (4.5 Kg / cm ² ) at room temperature After 8 hours, the mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was suspended in dichloromethane (10 mL). p-Toluenesulfonyl isocyanate (0.3 mL, 1.96 mmol) and triethylamine (0.3 mL, 2.1 mmoles), to the suspension at room temperature, After 0.5 hour, the mixture was concentrated, the residue was dissolved in dichloromethane (100 ml) and washed with 10% aqueous citric acid solution (50 ml) ml), water (50 ml), and brine (50 ml) The organic layer was dried (MgSO4) and concentrated The residue was purified by preparative TLC (ethyl acetate / hexane = 2: 1) to obtain 62 mg (37%) of the title compound, as white solids: ¹ H NMR (CDCl 3) δ 7.83 (1H, s), 7.67 (2H, d, J = 9.3 Hz), 7.55 (2H, d, J = 9.3 Hz), 7.38-7.22 (4H, m), 7.18 (1H, s), 3.45 (1H, lg), 2.76 (2H, q, J = 8.4 Hz), 2.34 (3H, s), 1.37 (6H, s), 1.31 (3H, t, J = 8.2 Hz).

EXAMPLE 101

STEP 1. ethyl r4- (4,5-Dichloro-2-nitroanilino) pheninacetate

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene

238/451 ethyl and 4-aminophenylacetate.

¹ H NMR (CDCb) δ 9.41 (1H, s), 8.32 (1H, s), 7.37 (2H, d, J = 8.4 Hz), 7.28 (1H, s) , 7.22 (2H, d, J = 8.3 Hz), 4.19 (2H, q, J = 7.1 Hz), 3.66 (2H, s), 1.29 (3H, t, J = 7.1 Hz).

STEP 2. f4- (2-Amino-4,5-dichloroanilino) phenyl1 ethyl acetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from ethyl [4- (4,5-dichloro-2-nitroanilino) phenyl] acetate (step 1).

¹ H NMR (CDCb) δ 7.16 (1H, s), 7.15 (2H, d, J = 7.5 Hz), 6.86 (1H, s), 6.72 (2H, d, J = 7.1 Hz), 5.12 (1H, s lg.), 4.15 (2H, q, J = 7.0 Hz), 3.79 (2H, lg.), 3.54 (2H , s), 1.26 (3H, t, J = 7.1 Hz).

STEP 3. Ethyl4- (5,6-dichloro-2-ethyl-1 / - / - benzimidazole-1-ihphenylacetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from ethyl [4- (2-amine-4,5-dichloroanilino) phenyl] acetate (step 2) and propionyl chloride.

¹ H NMR (CDCI ₃ ) δ 7.84 (1H, s), 7.52 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.19 (1H, s), 4.22 (2H, q, J = 7.1 Hz), 3.75 (2H, s), 3.77 (2H, q, J = 7.5 Hz), 1.34 (3H, t,> 7.5 Hz), 1.32 (3H, t,> 7.1 Hz).

STEP 4. [4- (5,6-dichloro-2-ethyl-1/7-benzimidazole-1-II) pheninacetic acid

A 2N aqueous solution of NaOH (3.4 mL) was added at room temperature, with stirring, to a solution of [4- (5,6-dichloro-2-ethyl-1 Hbenzimidazol-1-yl) phenyl] acetate of ethyl (step 3, 1.30 g, 3.4 mmoles) in methanol. After 1 hour, the mixture was concentrated and the residue was diluted with water (200 ml) and the mixture was washed with diethyl ether (100 ml). The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate / THF (volume / volume, 1: 1, 300 ml). The organic extract was washed with water (200 ml), brine (200 ml), and dried (MgSO ₄ ). Removal of the solvent gave 1.02 g (86%) of the title compound as a white powder: ¹ H NMR (CDCl ₃ ) δ 7.94 (1H, s), 7.56- 7.45 (4H, m), 7.26 (1H, s), 3.72 (2H, s), 2.72 (2H, q, J = 7.3 Hz), 1.22 (3H, t , J = 7.5 Hz).

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STEP 5. 244- (5.6-Dichloroethyl-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl1acetamide

A mixture of [4- (5,6-dichloro-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] acetic acid (step 4, 0.81 g, 2.3 mmol) was stirred and thionyl chloride (10 mL) for 0.5 hour, and concentrated. Ammonia hydroxide (28% NH ₃ in water, 50 ml) was added and the mixture was extracted with ethyl acetate / THF (volume / volume, 1: 1, 200 ml). The extract was washed with brine (2 x 100 mL), dried (Mg $ O ₄ ), and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (20: 1), to obtain 349 mg (44%) of the title compound as yellow solids: NMR of ¹ H (CDCI ₃ ) δ 7.93 (1H, s), 7.58 (1H, lg.), 7.51 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.27 (1H, s), 7.00 (1H, lg.), 3.51 (2H, s), 2.71 (2H, q, J = 7.5 Hz ), 1.21 (3H, t, J = 7.5 Hz).

STEP 6. 244- (5,6-Dichloro-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl1- / V '(4-methylphenyl) sulfonylamino) carbonyl) acetamide

A mixture of 2- [4- (5,6dichloro-2-ethyl-1/7-benzimidazol-1-yl) phenyl] acetamide (step 5, 105 mg, 0.30 mmol) was heated at reflux temperature ), p-toluenesulfonyl isocyanate (0.07 ml, 0.45 mmol), toluene (10 ml) and THF (5 ml). After 6 hours, an additional 0.1 ml of ptoluenesulfonyl isocyanate was added, and the mixture was heated for 3 hours. The mixture was cooled and left to stand at room temperature for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to obtain 150 mg (92%) of the title compound as colorless amorphous solids: ¹ H NMR (CDCI ₃ ) δ 9.78 (1H, s), 7.95 (2H, d, J = 8.3 Hz), 7.84 (1H, s), 7.54 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

EXAMPLE 102

5,6-DICLORO-1- (4- {2-í (([(4-METHYLPHENYL) SULPHONYL-AMINO) CARBO NI DAM INO1ETYL) PHENYL) -1 / - / - BENZIMIDAZOL

STEP 1. 2- [4- (5,6-dichloro-1 / - / - benzimidazol-1-yl) phenylethyl formate

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A mixture of 2 - [(4,5-dichloro-2-aniline) phenyl] ethanol (450 mg, 1.42 mmol) and formic acid (7 mL) was stirred at reflux for 4 hours. After cooling, the mixture was made basic with 2N aqueous NaOH solution and extracted with ethyl acetate (50 ml). The extracts were dried (MgSO ₄ ) to obtain 480 mg (quant.) Of the title compound as a brown oil: ¹ H NMR (CDCl ₃ ) δ 8.10 (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 , 8 Hz), 3.10 (2H, t, J = 6.8 Hz).

STEP 2. 2-i4- (5,6-Dichloro-1/7-benzimidazol-1-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5,6-dichloro1 / 7-benzimidazol-1-yl) phenyl] ethyl formate (step 1 ).

¹ H NMR (CDCI ₃ ) δ 8.08 (1H, s), 7.96 (1H, s), 7.61 (1H, s), 7.49-7.40 (4H, m), 3 , 97 (2H, q, J = 6.4 Hz), 2.99 (2H, t, J = 6.4 Hz).

STEP 3. 2-R4- (5,6-dichloro-1H-benzimidazol-1-yl) phenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (5,6-dichloro-1 / 7benzimidazol-1-yl) phenyl] ethanol (step 2).

MS (IE) m / z 332 (M ⁺ ).

STEP 4. 2-i4- (5,6-Dichloro-1/7-benzimidazol-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (5,6-dichloro-1 / 7benzimidazol-1-yl) phenyl] ethyl azide (step 3 ).

¹ H NMR (CDCI ₃ ) 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 = 6.6 Hz).

STEP 5. 5,6-Dichloro-1 - (4-f2-i (ff (4-methylphenyl) sulfonylamino) -carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5,6-dichloro-1 / 7benzimidazol-1-yl) phenyl] ethylamine (step 3).

¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s), 7.96 (1H, s), 7.72 (2H, d,

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J = 8.4 Hz), 7.58 (1H, s), 7.38 (4H, s), 7.28 (2H, d, J = 8.4 Hz), 6.72 (1H, m) , 3.56 (2H, q, J = 6.9 Hz), 2.92 (2H, t, J = 6.9 Hz), 2.38 (3H, s).

EXAMPLE 103

SODIUM SALT OF 5,6-DICLORQ-1- (4- {2-F (ÍF (4-METHYLphenyl) SULFONlL1AMINO} CARBONYL) AMINOLETYL) PHENYL) -1 / 7-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 5,6-dichloro-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] -amino} carbonyl) amino ] ethyl} phenyl) -1 / 7-benzimidazole (Example 102).

¹ H NMR (DMSO-d ₆ ) δ 8.55 (1H, s), 7.97 (1H, s), 7.71 (1H, s), 7.50-7.44 (4H, m) , 7.29 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.4 Hz), 3.02 (2H, m), 2.61 (2H, m) , 2.16 (3H, s); IV (KBr) v _max 1601, 1516, 1487, 1450, 1128, 1084 cm ^-1 .

EXAMPLE 104

6-CHLORINE-5-TRIFLUOROMETHYL 1- (4- {2-F ((r (4-METHYLphenyl) SULFONYL1AMINO) CARBONY) AMINO1ETHYL} FEN1L) -1 / 7-BENZIMIDAZOLE

STEP 1. 2-F (5-Chloro-4-trifluoromethyl-2-nitroanilino) pheninethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro-5-trifluoromethylnitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.69 (1H, s lg.), 8.58 (1H, s), 7.37 (2H, d, J = 8.4 Hz), 7.23 (2H , d, J = 8.4 Hz), 7.19 (1H, s), 3.93 (2H, t, J = 6.4 Hz), 2.94 (2H, t, J = 6.4 Hz ).

STEP 2. 2 ~ F (2-Amino-5-chloro-4-trifluoromethylanilino) pheninethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(5-chloro-4-trifluoromethyl-2-nitroanilino) phenyl] ethanoyl (step 1).

¹ H NMR (CDCh) δ 7.17-7.15 (3H, m), 7.05 (1H, s), 6.92-6.88 (2H, m), 5.48 (1H, s lg.), 3.85 (2H, t, J = 6.6 Hz), 2.83 (2H, t, J = 6.6 Hz).

STEP 3. 2-F4- (6-chloro-2-ethyl-5-trifluoromethyl-1 / 7benzimidazol-1-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-5-chloro-4242/451 trifluoromethylanilino) phenyl] ethanol (step 2) and propionyl chloride .

MS (IE) m / z 424 (M ⁺ ).

STEP 4. 2- [4- (6-Chloro-2-ethyl-5-trifluoromethyl-1/7-benzimidazole-1 ihphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-chloro2-ethyl-5-trifluoromethyl-1 / - / - benzimidazole-1-yl propionate ) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 8.11 (1H, s), 7.50 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.21 (1H, s), 4.03-3.98 (2H, m), 3.02 (2H, t, J = 6.4 Hz), 2.79 (2H, q, J = 7, 5 Hz), 1.36 (3H, t, J = 7.5 Hz).

STEP 5. 2-R4- (6-chloro-2-ethyl-5-trifluoromethyl-1 / Vbenzimidazole-1-hyphenphenylethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (6-chloro-2-ethyl-5trifluoromethyl-1/7-benzimidazol-1-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCIs) δ 8.11 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7 , 20 (1H, s), 3.63 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 6.9 Hz), 2.79 (2H, q, J = 7.4 Hz), 1.36 (3H, t, J = 7.4 Hz).

STEP 6. 2-f4- (6-Chloro-2-ethyl-5-trifluoromethyl-1 / - / - benzimidazol-1yl) phenyl1ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-chloro-2-ethyl5-trifluoromethyl-1 / - / - benzimidazol-1-yl azide ) phenyl] ethyl (step 5).

¹ H NMR (CDCfe) δ 8.11 (1H, s), 7.45 (2H, d, J = 8.3 Hz), 7,297.26 (2H, m), 7.23 (1H, s) , 3.11 (2H, t, J = 7.0 Hz), 2.92 (2H, t, J = 7.0 Hz), 2.79 (2H, q, J = 7.5 Hz), 1 , 36 (3H, t, J = 7.5 Hz).

STEP 7. 2-Ethyl-6-chloro-5-trifluoromethyl-1 - (4- (2-r (ÍF (4-methylphenyl) sulfoninamino) carbonyl) amino1ethyl) phenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (6-chloro-2-ethyl-5trifluoromethyl-1 / - / - benzimidazol-1-yl) phenyl ] ethylamine (step 6).

¹ H NMR (CDCI ₃ ) δ 8.09 (1H, s), 7.74 (2H, d, J = 8.4 Hz), 7.42

243/451 (2Η, d,> 8.2 Hz), 7.30-7.26 (4H, m), 7.18 (1H, s), 6.76 (1H, m), 3.59 ( 2H, q, J = 7.0 Hz), 2.96 (2H, t, J = 7.0 Hz), 2.79 (2H, q, J = 7.6 Hz), 1.34 (3H, t,> 7.6 Hz).

EXAMPLE 105

SODIUM SALT OF 6-CHLORINE-5-TRIFLUOROMETHYL 1- (4- {2r (U (4-METHYLphenyl) -SULPHONYLAMINO) CARBONYL) AMINOlETlL) -FENYL) 1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-6-chloro-5-trifluoromethyl-1- (4- {2 [({[(4-methylphenyl) sulfonyl] - amino} carbonyl) amino] ethyl} phenyl) -1 / - / - benzimidazole (Example 104).

¹ H NMR (DMSO-d ₆ ) δ 8.15 (1H, s), 7.59 (2H, d,> 8.4 Hz), 7.46-7.39 (4H, m), 7, 33 (1H, s), 7.12 (2H, d,> 8.4 Hz), 3.15 (2H, m), 2,782.71 (4H, m), 1.24 (3H, t,> 7 , 5 Hz); IV (KBr) v _max 1601, 1518, 1431, 1398, 1348, 1306, 1128, 1084 cm ^-1 .

EXAMPLE 106 4- (6-CHLORINE-2-ETHYL-5-TRIFLUOROMETHL-1H-BENZIMIDAZOL-1-IL) SULPHONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1F / benzimidazol-1-yl) phenyl] ethanol (step 4 of Example 104).

M.p .: 170-173 ° C; ¹ H NMR (CDCI ₃ ) 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,> 6.8 Hz), 3.04 (2H, t,> 6.8 Hz), 2.78 (2H, q,> 7.6 Hz), 2, 44 (3H, s), 1.35 (3H, t,> 7.6 Hz); IV (KBr) Vma _X 1746, 1518, 1342, 1232, 1159, 1132, 1086 cm “ ¹ .

EXAMPLE 107

SODIUM SALT OF 4- (6-CHLORINE-2-ETHYL-5-TRLFLUOROMETHYL-1F / -BENZIMIDAZOL-1-IL) (4-METHYLFENIDSULPHONYLCARBAMATE)

The title compound was prepared according to the procedure described in Example 2 from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1 / - / - benzimidazole-1-yl (4-methylphenyl) sulfonylcarbamate) phenethyl (Example 106).

244/451

¹ H NMR (DMSO-d _s ) δ 8.15 (1H, s), 7.59 (2H, d, J = 8.1 Hz), 7.47 (4H, s), 7.34 (1H , s), 7.15 (2H, d, J = 8.1 Hz), 3.96 (2H, t, J = 6.6 Hz), 2.86 (2H, t, J = 6.6 Hz ), 2.75 (2H, q, J = 7.4 Hz), 2.28 (3H, s), 1.24 (3H, t, J = 7.4 Hz).

EXAMPLE 108

5-CHLORINE-6-METHIL ~ 1- (4- {2-í ({[(4-METHYLPHYL) SULFONYLAMINO} CARBONYL) AMINOethyl) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2-i (4-Chloro-5-methyl-2-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-dichloro-4-methylnitrobenzene and 4-aminophenylethyl alcohol.

¹ H NMR (CDCb) δ 9.40 (1H, s), 8.20 (1H, s), 7.31 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.05 (1H, s), 3.93-3.91 (2H, m), 2.91 (2H, t, J = 6.4 Hz), 2.29 ( 3H, s).

STEP 2. 2-i (2-Amino-4-chloro-5-methylanilino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2 - [(4-chloro-5-methyl-2-nitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCb) δ 7.06 (2H, d, J = 8.6 Hz), 6.93 (1H, s), 6.76 (1H, s), 6.67 (2H, d, J = 8.6 Hz), 3.80 (2H, d, J = 6.4 Hz), 2.77 (2H, t, J = 6.4 Hz), 2.21 (3H, s).

STEP 3. 2-yl- (5-chloro-2-ethyl-6-methyl-1/7-benzimidazol-1-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2 - [(2-amino-4-chloro-5methylanilino) phenyl] ethanol (step 2) propionyl chloride.

MS (IE) m / z 370 (M ⁺ ).

STEP 4. 2-i4- (5-Chloro-2-ethyl-6-methyl-1/7-benzimidazole-1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-chloro2-ethyl-6-methyl-1/7-benzimidazol-1-yl) propionate phenyl] ethyl (step 3).

¹ H NMR (CDCb) δ 7.74 (1H, s), 7.47 (2H, d, J = 8.3 Hz), 7.27

245/451 (2Η, d, J = 8.3 Hz), 6.93 (1H, s), 4.00 (2H, t, J = 6.6 Hz), 3.02 (2H, t, J = 6.6 Hz),

2.76 (2H, q, J = 7.5 Hz), 2.39 (3H, s), 1.32 (3H, t, J = 7.5 Hz).

STEP 5. 2-R4- (5-chloro-2-ethyl-6-methyl-1 / - / - benzimidazol1-yl) phenyl1ethyl azide

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- [4- (5-chloro-2-ethyl-6-methyl1H-benzimidazol-1-yl) phenyl] ethanol ( step 4).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.27 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz),

2.76 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.33 (3H, t, J = 7.5 Hz).

STEP 6. 2- [4- (5-Chloro-2-ethyl-6-methyl-1/7-benzimidazol-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (5-chloro-2-ethyl6-methyl-1A / -benzimidazol-1-yl) phenyl azide ] ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ 7.75 (1H, s), 7.42 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3 Hz), 6.93 (1H, s), 3.10 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz),

2.76 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.33 (3H, t, J = 7.5 Hz).

STEP 7. 2-Ethyl-5-chloro-6-methyl-1 - (4-f2-rffl (4-methylphenyl) -sulfonill amino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (5-chloro-2-ethyl-6-methyl1H-benzimidazol-1-yl) phenyl] ethylamine ( step 6).

¹ H NMR (CDCI ₃ ) 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 = 6.8 Hz), 2.75 (2H, q, J = 7.6 Hz ), 2.40 (3H, s), 2.37 (3H, s), 1.30 (3H, t, J = 7.6 Hz).

EXAMPLE 109

SODIUM SALT OF 5-CHLORINE-6-METHYL 1- (4-f2-í ({r (4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETHYL} PHENYL) -1H-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-5-chloro-6-methyl-1- (4- {2 - [({[(4-methyl246 / 451 phenyl ) -sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -1 / 7-benzimidazole (Example 108).

¹ H NMR (DMSO-de) δ 7.68 (1H, s), 7.60 (2H, d, J = 8.1 Hz), 7.41-7.35 (4H, m), 7, 13 (2H, d, J = 8.1 Hz), 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 = 7.5 Hz); IV (KBr) vmax 1599, 1516, 1456, 1402, 1128, 1084, 1001 cm ^-1 .

EXAMPLE 110

6-CHLORINE-2-ETYL-1- (4- {2-r (fl (4-METlLFENIL) SULFONYL15-KMETHYLSULFONYL) AMINOl-AMINO} CARBONIL) AMINO1ETYL) PHENYL) -1 / 7-BENZlMIDAZOL

STEP 1. 2- [4- (5-Chloro-2,4-dinitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro-1,5-dinitrobenzene and 4-aminophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 9.81 (1H, s lg.), 9.07 (1H, s), 7.40 (2H, d, J = 8.3 Hz), 7.25 (2H , d, J = 8.3 Hz), 7.17 (1H, s), 3.95 (2H, t, J = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz ).

STEP 2. 2- [4- (2-Amino-5-chloro-4-nitroanilino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 40 from 2- [4- (5-chloro-2,4-dinitroanilino) phenyl] ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ 7.54 (1H, s), 7.24 (2H, d, J = 8.6 Hz), 7.11 (1H, s), 7.03 (2H, d , J = 8.6 Hz), 5.76 (1H, s lg.), 3.89 (2H, t, J = 6.4 Hz), 3.65 (2H, s lg.), 2.87 (2H, t, J = 6.4 Hz), 1.28 (1H, s).

STEP 3. 2-yl- (6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl) phenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 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 4. 2-I4-I6-C loro-2-ethyl-5-nitro-1 / - / - benzimidazol-1-yl) phenylethanol

247/451

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-amino5-chloro-4-nitroanilino) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ 8.34 (1H, s), 7.50 (2H, d, J = 8.0 Hz), 7.28 (2H, d,> 8.0 Hz), 7 , 19 (1H, s), 4.00 (2H, t, J = 6.3 Hz), 3.02 (2H, t, J = 6.3 Hz),

2.79 (2H, q, J = 7.6 Hz), 1.62 (1H, s), 1.36 (3H, t, J = 7.6 Hz).

STEP 5. 6-Chloro-1 -f4- (2-chloroethyl) phenyl1-2-ethyl-5-nitro-1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-chloro-2-ethyl-5-nitro-1/7-benzimidazol-1-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCb) δ 8.34 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7 , 19 (1H, s), 3.84 (2H, t, J = 7.0 Hz), 3.22 (2H, t, J = 7.0 Hz),

2.80 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 6. 6-Chloro-1-f4- (2-chloroethyl) phenill-2-ethyl-1/7-benzimidazol5-ylamine

The title compound was prepared according to the procedure described in step 4 of Example 89 from 6-chloro-1- [4- (2 chloroethyl) phenyl] -2-ethyl-5-nitro-1/7-benzimidazole (step 5).

¹ H NMR (CDCb) δ 7.43 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.16 (1H, s), 7 , 02 (1H, s), 3.96 (2H, s lg.), 3.81 (2H, t, J = 7.1 Hz), 3.19 (2H, t, J = 7.1 Hz) , 2.74 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz).

STEP 7. A / - (6-Chloro-1-y4- (2-chloroethyl) phenyl1-2-ethyl-1/7-benzimidazol-5-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 5 of Example 40 from 6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl-1/7-benzimidazole-5 -ylamine (step 6).

¹ H NMR (CDCb) δ 7.70 (1H, s), 7.55 (2H, d, J = 7.9 Hz), 7.50 (2H, d,> 7.9 Hz), 7, 13 (1H, s), 3.95 (2H, t, J = 7.0 Hz), 3.16 (2H, t, J = 7.0 Hz), 2.97 (3H, s), 2, 71 (2H, q,> 7.6 Hz), 1.21 (3H, t,> 7.6 Hz).

STEP 8. A / -Í1 -f4- (2-Azidoethyl) phenill-6-chloro-2-ethyl-1 H-benzimidazol-5-yl) methanesulfonamide

248/451

The title compound was prepared according to the procedure described in step 8 of Example 1 from A / - {6-chloro-1- [4- (2 chloroethyl) phenyl] -2-ethyl-1 B-benzimidazole- 5-yl} methanesulfonamide (step 7).

¹ H NMR (CDCI ₃ ) δ 7.47 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.16 (1H, s), 6.78 (1H, s), 3.63 (2H, t, J = 6.9 Hz), 2.98-3.05 (5H, m), 2.77 (2H, q, J = 7, 4 Hz), 1.35 (3H, t, J = 7.4 Hz).

STEP 9. / V- (1- [4- (2-Aminoethyl) phenyl1-6-chloro-2-ethyl-1B-benzimidazol-5-yl) methanesulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from / V- {1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-1/7-benzimidazole -5-yl} methanesulfonamide (step 8).

¹ H NMR (CDCI ₃ ) δ 8.03 (1H, s), 7.43 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.17 (1H, s), 3.33 (2H, Ig s), 3.08 (2H, t, J = 7.0 Hz), 2.96 (3H, s), 2.88 (2H , t, J = 7.0 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 10. 6-Chloro-2-ethyl-1 - (4-f2-Γ ({f (4-methylphenyl) sulfonyl1-aminoϊcarbonyl) aminoletyl) phenyl) -5-r (methylsulfonyl) amino] -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from / V- {1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1B-benzimidazole-5 -il} methanesulfonamide (step 9).

Mp: 101-123 ° C; MS (IED) m / z 590 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 8.04 (1H, s), 7.73 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.25-7.33 (4H, m), 7.16 (1H, s), 6.68 (1H, s Ig.), 3.58 (2H, t, J = 7.2 Hz), 2 , 93-2.98 (5H, m),

2.77 (2H, q, J = 7.5 Hz), 2.45 (3H, s), 1.35 (3H, t, J = 7.5 Hz); IV (KBr) v _max 1654, 1517, 1467, 1336, 1151, 1089, 972 cm ^-1 .

EXAMPLE 111

6-CHLORINE-2-ETYL-1- (442-r (f ((4-METHYLPHYL) SULFONYL1-AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1B-BENZIMIDAZOL-5-CARBOXAMIDE

STEP 1.2-Chlorine-4-f4- (2-hydroxyethyl) anilinol-5-nitrobenzonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-dichloro-5-nitrobenzonitrile (Grivsky, EM; Hitchings, GH; Ind. Chim. Belge. ', 1974, 39, 490) and aminophenyl ethyl alcohol 4249/451.

¹ H NMR (CDCl ₃ ) δ 9.81 (1H, s lg.), 8.56 (1H, s), 7.39 (2H, d, J = 8.3 Hz), 7.23 (2H , d, J = 8.3 Hz), 7.15 (1H, s), 3.93 (2H, t, J = 6.2 Hz), 2.94 (2H, t, J = 6.2 Hz ), 1.62 (1H, br s.).

STEP 2. 5-Amino-2-chloro-4-i4- (2-hydroxyethyl) aniline-1-benzonitrile

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2-chloro-4- [4- (2-hydroxy-ethyl) anilino] -5-nitrobenzonitrile (step 1).

¹ H NMR (CDCb) δ 7.23 (4H, d, J = 8.3 Hz), 6.99-7.33 (2H, m), 3.88 (2H, t, J = 6.1 Hz), 3.56 (1H, s lg.), 2.87 (2H, t, J = 6.1 Hz).

STEP 3. 2-44- (6-chloro-5-cyano-2-ethyl-1 / - / - benzimIDazole-1-iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 5-amino-2-chloro-4- [4- (2hydroxyethyl) anilino] benzonitrile (step 2) and propionyl chloride.

TLC Rf = 0.5 (hexane / ethyl acetate = 1: 2).

STEP 4. 6-Chloro-2-ethyl-1 - [4- (2-hydroxyethyl) phenill-1/7-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-chloro5-cyano-2-ethyl-1 / - / - benzimidazol-1-yl propionate ) phenyl] ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ 8.04 (1H, s), 7.52 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.19 (1H, s), 4.02 (2H, t, J = 6.5 Hz), 3.03 (2H, t, J = 6.5 Hz),

2.80 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 5. 6-Chloro-2-ethyl-1-r4- (2-hydroxyethyl) phenill-1 H-benzimidazole5-carboxamide

A 30% aqueous solution of hydrogen peroxide (1.3 mL, 11 mmol) and a 0.2 M aqueous solution of NaOH (0.7 mL, 0.14 mmol) were added to a mixture of 6-chloro- 2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 Hbenzimidazole-5-carbonitrile (step 4, 2.4 g, 7.4 mmoles) DMSO (0.7 ml, 8.8 mmoles and methanol (100 ml) The mixture was stirred at 50 ° C for 2 hours. The solvent was removed and the resulting precipitates were removed by filtration 250 / 451. The precipitates were washed with water and dried under reduced pressure. to obtain 1.9 g (76%) of the title compound as light pink solids: ¹ H NMR (DMSO-d ₆ ) δ 7.69 (1H, s lg.), 7, 61 (1H, s), 7.33-7.40 (4H, m), 6.95 (1H, s), 4.64 (1H, s lg.), 3.59 (2H, t, J = 6.4 Hz), 2.74 (2H, t, J = 6.4 Hz), 2.62 (2H, q, J = 7.4 Hz), 1.11 (3H, t, J = 7, 4 Hz).

STEP 6. 6-Chloro-1 - [4- (2-chloroethyl) phenill-2-ethyl-1 / - / - benzimidazole5-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from 6-chloro-2-ethyl-1- [4- (2hydroxyethyl) phenyl] -1 / 7-benzimidazole-5-carboxamide (step 5).

¹ H NMR (DMSO-d ₆ ) δ 7.71 (1H, s lg.), 7.62 (1H, s), 7.36-7.47 (5H, m), 6.95 (1H, s), 3.85 (2H, t, J = 7.1 Hz), 3.06 (2H, t, J = 7.1 Hz), 2.63 (2H, q, J = 7.6 Hz) , 1.11 (3H, t, J = 7.6 Hz).

STEP 7. 1 -r4- (2-Azidoethyl) phenin-6-chloro-2-ethyl-1 / - / - benzimidazole5-carboxamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-1/7-benzimidazole-5- carboxamide (step 6).

¹ H NMR (DMSO-d ₆ ) δ 7.80 (1H, s lg.), 7.71 (1H, s), 7.46-7.57 (5H, m), 7.04 (1H, s), 3.65 (2H, t, J = 6.9 Hz), 2.98 (2H, t, J = 6.9 Hz), 2.72 (2H, q, J = 7.5 Hz) , 1.21 (3H, t, J = 7.5 Hz).

STEP 8. 1-f4- (2-Aminoethyl) pheniH-6-chloro-2-ethyl-1ÁY-benzimidazole · 5-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-1 / - / - benzimidazole-5- carboxamide (step 7).

¹ H NMR (CDCI ₃ ) 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 = 7.4 Hz).

STEP 9. 6-Chloro-2-ethyl-1- (4-f2-r (ph (4-methylphenylsulfonyl1amino) carbonyl) aminoletyl) phenyl) -1 / 7-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -6251/451 chloro-2-ethyl-1F / -benzimidazole-5 -carboxamide (step 8).

Mp: 152-163 ° C; MS (IED) m / z 540 (M + H) ⁺ ; ¹ H NMR (DMSOd ₆ ) δ 7.81 (1H, s lg.), 7.72-7.75 (3H, m), 7.51 (1H, s lg.), 7.33-7, 44 (6H, m), 7.06 (1H, s), 3.26 (2H, s lg.), 2.68-2.80 (4H, m), 2.34 (3H, s), 1 , 23 (3H, t, J = 7.5 Hz); IV (KBr) v _max 3395, 1664, 1519, 1396, 1161, 1089, 991 cm ^-1 . EXAMPLE 112

6-CHLORINE-2-ETHYL-1- (4-f2 - [(fr (4-METHYLphenyl) -SULPHONYL1-AMINO) CARBONYL) AMINO1ETYL) -FENYL) -1 / 7-BENZIMlDAZOL-5-CARBOXYLIC

A mixture of 6-chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} -carbonyl) amino] ethyl} phenyl) -1H-benzimidazole-5 was stirred -carboxamide (Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol (10 mL) at 100 ° C for 1 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 (30 ml), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (10: 1) to obtain 36 mg (25%) of the title compound as white solids: Mp: 145 -150 ° C; MS (IED) m / z 541 (M + H) ⁺ ; ¹ H NMR (DMSO-d ₆ ) δ 8.10 (1H, s), 7.76 (2H, d, J = 7.9 Hz), 7.36-7.47 (6H, m), 7 , 10 (1H, s), 3.28 (2H, m), 2,692.81 (4H, m), 2.34 (3H, s), 1.24 (3H, t, J = 7.5 Hz) ; IV (KBr) v _max 3450, 1701, 1517, 1340, 1163, 1091, 900 cm ^-1 .

EXAMPLE 113 / V- [6-CHLORINE-2-ETHYL-1- (4- (2-F (f [(4-METHYLphenyl) -SULPHONYLAMINE) CARBONlL) AMlNO1ETIL) FENlL) -1 / 7-BENZIMIDAZOL-5-IL1 -ACETAMIDE

STEP 1. / V- {6-Chloro-1-F4- (2-chloroethyl) phenyl1-2-ethyl “1/7-benzimidazol-5-yl) acetamide

Acetyl chloride (0.03 mL, 0.33 mmol) was added dropwise under nitrogen at 0 ° C to a solution of 6-chloro-1- [4- (2 chloroethyl) phenyl] -2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 ml), and the reaction mixture was stirred at

252/451 room temperature for 1.5 hours. The mixture was poured into water (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with 2N aqueous NaOH solution (30 ml), brine (30 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate (1: 3) to obtain 110 mg (98%) of the title compound, as white solids: ¹ H NMR (CDCI ₃ ) δ 8.66 (1H, s), 7.56 (1H, s lg.), 7.45 (2H, d, J = 8.2 Hz ), 7.29 (2H, d, J = 8.2 Hz), 7.12 (1H, s),

3.82 (2H, t, J = 7.1 Hz), 3.19 (2H, t, J = 7.1 Hz), 2.77 (2H, q, J = 7.6 Hz), 2, 26 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 2. / V-F1-14- (2-Azidoethyl) phenin-6-chloro-2-ethyl-1/7-benzimidazol-5-yl) acetamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from A / - {6-chloro-1- [4- (2 chloroethyl) phenyl] -2-ethyl-1/7-benzimidazole -5-yl} acetamide (step 1).

¹ H NMR (DMSO-de) δ 8.66 (1H, s), 7.55 (1H, s lg.), 7.45 (2H, d, J = 8.1 Hz), 7.30 ( 2H, d, J = 8.1 Hz), 7.11 (1H, s), 3.62 (2H, t, J = 7.1 Hz), 3.02 (2H, t, J = 7.1 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

STEP 3. Λ / - {1 -í4- (2-Aminoethyl) phenyl1-6-chloro-2-ethyl-1 / - / - benzimidazoi-5-yl) acetamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from Λ / - {1 - [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-1/7-benzimIDazole -5-yl} acetamide (step 2).

¹ H NMR (CDCIs) δ 8.66 (1H, s), 7.55 (1H, s lg.), 7.42 (2H, d, J = 6.6 Hz), 7.27-7, 29 (2H, m), 7.12 (1H, s), 3.08 (2H, t, J = 6.9 Hz), 2.88 (2H, t, J = 6.9 Hz), 2, 75 (2H, q, J = 7.4 Hz), 2.26 (3H, s), 1.34 (3H, t, J = 7.4 Hz).

STEP 4. A / -f6-Chloro-2-ethyl-1- (4-f2-f (if (4-methylpheninsulfonill-amino} carbonyl) amino1ethyl} phenyl) -1 / - / - benzimidazol-5-yl) acetamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from / V- {1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1H-benzimidazole-5 -il} acetamide (step 3).

Mp: 125-133 ° C; MS (IED) m / z 554 (M + Hf; 'H NMR (CDCI ₃ ) δ

253/451

8.64 (1Η, s), 7.74 (2H, d, J = 8.4 Hz), 7.55 (1H, s lg.), 7.25-7.39 (1H, s), 7 .08 (1H, s), 3.53-3.61 (2H, m), 2.94 (2H, t, J = 7.1 Hz), 2.75 (2H, q, J = 7.4 Hz), 2.41 (3H, s), 2.27 (3H, s), 1.32 (3H, t, J = 7.4 Hz); IV (KBr) v _max 3390, 1676, 1517, 1240, 1161, 1089, 1018, 972 cm ¹ .

EXAMPLE 114

6-ETI L-5- (4-f2 - [((r (4-METILFE NI DSULFONI LIAM IN PICAR BONI DAM IN 01 ETILjFENI D-5 / - / 41,31 Dl OXO LOr4,5- / l-BENZI Ml DAZOL

STEP 1. 2- {4- [Y6-Nitro-1,3-benzodioxol-5-yl) amino1phenyl | ethanol

The title compound was prepared according to the procedure described in step 1 of Example 45 from 5-amino-6-nitro-1,3benzodioxole and 4-aminophenylethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 10.07 (1H, s lg.), 7.62 (1H, s), 7.29 (2H, d, J = 8.5 Hz), 7.20 (2H , d, J = 8.5 Hz), 6.58 (1H, s), 5.98 (2H, s), 3.90 (2H, t, J = 6.6 Hz), 2.90 (2H , t, J = 6.6 Hz).

STEP 2. 2- {4-i (6-Amino-1,3-benzodioxol-5-yl) amino1phenyl} ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(6-nitro-1,3benzodioxol-5-yl) amino] phenyl} ethanol (step 1) .

¹ H NMR (CDCI ₃ ) δ 7.26 (1H, s), 7.04 (2H, d, J = 8.2 Hz), 6.60 (2H, d, J = 8.2 Hz), 6.39 (1H, s), 5.87 (2H, s), 4.96 (1H, s lg.), 3.80 (2H, t, J = 6.4 Hz), 3.64 (2H , S lg.), 2.76 (2H, t, J = 6.4 Hz).

STEP 3. 2- [4- (6-ethyl-5H-1,3H-dixoloF4,5- / | benzimidazol-5-yl) phenyl1ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(6-amino-1,3benzodioxol-5-yl) amino] phenyl} ethanol (step 2) and propionyl alcohol.

TLC Rf = 0.5 (hexane / ethyl acetate = 1: 2).

STEP 4. 2-r4- (6-Ethyl-5H-n .31dioxolor4,5-flbenzimidazol-5-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-amino1-1,3-benzodioxol-5-yl) amino] phenyl] ethyl propionate ( step 3).

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¹ H NMR (CDCI ₃ ) δ 7.43 (2H, d, J = 8.4 Hz), 7.28 (2H, d,> 8.4 Hz), 7.19 (1H, s), 6 , 53 (1H, s), 5.94 (2H, s), 3.98 (2H, t,> 6.4 Hz), 2.99 (2H, t,> 6.4 Hz), 2.73 (2H, q,> 7.4 Hz), 1.31 (3H, t,> 7.4 Hz).

STEP 5. 5-í4- (2-Chloroethyl) fenill-6-ethyl-5/7-ri, 3 ^ ιοχοΙοί4,5- / 106ηzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-ethyl-5A7 [1.3] dioxolo [4,5 - /] benzimidazol-5-yl) phenyl] ethanol (step 4).

¹ H NMR (CDCI ₃ ) δ 7.42 (2H, d,> 8.1 Hz), 7.28 (2H, d,> 8.1 Hz), 7.19 (1H, s), 6, 54 (1H, s), 5.94 (2H, s), 3.81 (2H, t,> 7.1 Hz), 3.19 (2H, t, J = 7.1 Hz), 2.72 (2H, q,> 7.6 Hz), 1.31 (3H, t,> 7.6 Hz).

STEP 6. 2- [4- (6-ethyl-5/7-yl-1,3-dixolo (4,5- / 1-benzimidazol-5-yl) phenyl-ethyl] azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 5- [4- (2-chloroethyl) phenyl] -6-ethyl5 / - / - (1,3] dioxolo [4 , 5 - /] benzimidazole (step 5).

¹ H NMR (CDCb) δ 7.42 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.19 (1H, S), 6 , 53 (1H, s), 5.93 (2H, s), 3.60 (2H, t, J = 7.1 Hz), 3.00 (2H, t, J = 7.1 Hz), 2 , 73 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz).

STEP 7. 2- (4- (6-Ethyl-5A / - (1,31dioxolo (4,5- / 1-benzimidazol-5-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-ethyl-5 / - / [1.3] dioxolo [4,5 - /] benzimidazole azide -5-yl) phenyl] ethyl (step 6).

¹ H NMR (CDCb) δ 7.40 (2H, d, J = 8.2 Hz), 7.22-7.28 (2H, m), 7.19 (1H, s), 6.54 ( 1H, s), 5.93 (2H, s), 3.05 (2H, t, J = 6.8 Hz), 2.86 (2H, t, J = 6.8 Hz), 2.73 ( 2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz).

STEP 8. 6-Ethyl-5- (4- {2-i (n (4-methylphenyl) sulfonylamino) carbonyl) amino1ethyl) phenyl) -5 / 7- [1 ₁ 31dioxolo (4 _l 5- / | benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (6-ethyl-5H [1.3] dioxolo [4,5-f | -benzimidazol-5-yl ) phenyl] ethylamine (step 7).

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MS (IED) m / z 507 (M + H) ⁺ ; ¹ H NMR (DMSO-d ₆ ) δ 7.75 (2H, d, J = 8.1 Hz), 7.35-7.37 (6H, m), 7.16 (1H, s), 6 , 55 (1H, s), 5.97 (2H, s), 2.76 (2H, t, J = 6.9 Hz), 2.65 (2H, q, J = 7.6 Hz), 2 , 50 (2H, s lg.), 2.34 (3H, s), 1.18 (3H, t, J = 7.6 Hz).

EXAMPLE 115

SODIUM SALT OF 6-ETHYL-5- (4-f2-r (U (4-METHYLphenyl) -SULPHONYLAMINO) CARBONYL) AMINO1ETHIL} PHENYL) -5H-ri, 31DIOXOL-r4,5- / 1BENZIMIDAZOL

The title compound was prepared according to the procedure described in Example 2 from 6-ethyl-5- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -5H- [1,3] dioxolo [4,5 - /] benzimidazole (Example 114).

Mp: 140-155 ° C; IV (KBr) v _max 3384, 2873, 1600, 1519, 1460, 1155, 1128, 1085, 1037, 945, 813 cm “ ¹ .

EXAMPLE 116

2-ETIL-1- (4-f2-r (((4-METHYLFENlL) SULPHONYLAMINO} -CARBONYL) AMINOlETlL) FENIL) -6,7-DIHYDRO-1H-F1,41DIOXINOr2,3- / l-BENZIMIDAZOL

STEP 1. 7-Nitro-2,3-dihydro-1,4-benzodioxin-6-amine

Powdered iron (9.6 g, 172.5 mmoles) was added at room temperature to a mixture of 6,7-dinitro-2,3-dihydrobenzo [1,4] dioxin (Takakis, IM; Hadjimihalakis, PM; J. Heterocyclic. Chem. ', 1991, 28, 625; 13 g, 57.8 mmol) and acetic acid (150 mL), and the mixture is then 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 1: 1 to 1: 2) to obtain 3.22 g (28%) of the title compound , as an orange solid: ¹ H NMR (CDCI ₃ ) δ 7.67 (1H, s), 6.23 (1H, s), 5.85 (2H, s lg.), 4 , 19-4.33 (4H, m).

STEP 2. 2- {4-í (7-Nitro-2.3-dihydro-1,4-benzodioxin-6-yl) amino1-phenylethanol

256/451

The title compound was prepared according to the procedure described in step 1 of Example 45 from 7-nitro-2,3-dihydro-1,4benzodioxin-6-amine (step 1) and 4-bromophenyl ethyl alcohol.

¹ H NMR (CDCI ₃ ) δ 7.77 (1H, s), 7.26 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 6.64 (1H, s), 4.20-4.31 (4H, m), 3.89 (2H, t, J = 6.4 Hz), 2.88 (2H, t, J = 6, 4 Hz).

STEP 3. 2- {44 (7-Amino-2,3-dihydro-1,4-benzodioxy-6-yl) -aminophenyljetanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(7-nitro-2,3-dihydro1.4-benzodioxin-6-yl) amino] - phenyl} ethanol (step 2).

¹ H NMR (CDCI ₃ ) δ 7.02-7.05 (2H, m), 6.62-6.65 (3H, m), 6.33 (1H, s), 5.00 (1H, s lg.), 4.15-4.24 (4H, m), 3.79 (2H, t, J = 6.6 Hz), 3.53 (2H, s lg.), 2.76 (2H , t, J = 6.6 Hz).

STEP 4. 2-r4- (2-ethyl-6,7-dihydro-1H- [1,41dioxino [2,3- / lbenzimidazo-1-yl) propionate] phenyethyl

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(7-amino-2,3-dihydro1.4-benzodioxin-6-yl) amino] phenyl } ethanol (step 3) and propionyl chloride.

TLC Rf = 0.5 (hexane / ethyl acetate = 1: 2).

STEP 5. 2- [4- (2-Ethyl-6,7-dihydro-1/7-F1,41dioxinof2,3-flbenzimidazole-1-ipphenylUethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- (7-amino2,3-dihydro- [1,4] benzo dioxino-6-yl) propionate amino-phenyl} ethyl (step 4).

¹ H NMR (CDCl ₃ ) δ 7.42 (2H, d, J = 8.1 Hz), 7.25-7.28 (3H, m),

6.58 (1H, s), 4.21 - 4.27 (4H, m), 3.97 (2H, t, J = 6.6 Hz), 2.98 (2H, t, J = 6, 6 Hz), 2.74 (2H, q, J = 7.3 Hz), 1.31 (3H, t, J = 7.3 Hz).

STEP 6. 1- [4- (2-Chloroethyl) phenyl1-2-ethyl-6,7-dihydro-1 / - / - [1,41dioxinoí2,3-flbenzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-6,7-dihydro-1H257 / 451 [1.4] dioxin [2,3- / | benzimidazol-1-yl) phenyl] ethanol (step 5).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.1 Hz), 7.26-7.39 (3H, m),

6.58 (1H, S), 4.25 (4H, s), 3.80 (2H, t, J = 7.3 Hz), 3.20 (2H, t, J = 7.3 Hz), 2.74 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz).

STEP 7. 2-R4- (2-ethyl-6.7-dihydro-1B-1,4-dioxhydin2.2-flbenzimidazole-1-hyphenylethyl azide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl6,7-dihydro-1 / 7- [1, 4] dioxin [2,3 - /] benzimIDazole (step 6).

¹ H NMR (CDCI ₃ ) δ 7.40 (2H, d, J = 8.3 Hz), 7.24-7.29 (3H, m), 6.57 (1H, s), 4.21 -4.26 (4H, m), 3.59 (2H, t, J = 7.0 Hz), 2.99 (2H, t, J = 7.0 Hz), 2.73 (2H, q, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz).

STEP 8. 2- [4- (6-Ethyl-6,7-dihydro-1/7-ri ₁ 41dioxinoí2.3- / | -benzimidazole-1-iDphenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (2-ethyl-6,7dihydro-1 / - / - [1,4] dioxin [ 2,3 - /] benzimIDazol-1-yl) phenyl] ethyl (step 7).

¹ H NMR (CDCI ₃ ) δ 77.40 (2H, d, J = 8.3 Hz), 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 = 6.9 Hz), 2.72 (2H, q, J = 7.4 Hz) , 1.30 (3H, t, J = 7.4 Hz).

STEP 9. 2-Ethi I-1 - (4- {2-i (U (4-methylphenyl) sulfonyl1amino) carboniDaminoletyl) phenyl) -6.7-dihydro-1/7-yl 1,41dioxinof2,3- / lbenzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-6,7-dihydro-1 H [1.4] dioxino [2,3- / ] -benzimidazol-1-yl) phenyl] ethylamine (step 8).

MS (IED) m / z 521 (M + H) ⁺ ; ¹ H NMR (CDCI ₃ ) δ 7.76 (2H, d, J = 8.4 Hz), 7.18-7.31 (7H, m), 6.64 (1H, s lg.), 6 , 56 (1H, s lg.), 4.24 (4H, s), 3.56 (2H, t, J = 6.9 Hz), 2.90 (2H, t, J = 6.9 Hz) , 2.70 (2H, q, J = 7.6 Hz), 2.41 (3H, s), 1.27 (3H, t, J = 7.6 Hz).

EXAMPLE 117

SODIUM SALT OF 2-ETHYL-1- (4-f2-r (fr (4-METHYLphenyl) -SULPHONYLAMINOICARBONYL) AMINO1ETIDPHENYL) -6,7-DIHYDRO-1H-H, 41DIO258 / 451

XINOf2,3- / l-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) -amino] ethyl } phenyl) -6,7-dihydro-1 / 7- [1,4] dioxin [2,3 - /] benzimidazole (Example 116).

Mp: 162-173 ° C; ¹ H NMR (DMSO-dg) δ 7.83 (2H, d, J = 8.0 Hz),

7.58 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.0 Hz), 7.35 (2H, d, J = 8.6 Hz), 7, 29 (1H, s), 6.68 (1H, s), 4.42 (4H, s), 3.38 (2H, s lg.), 2.94 (2H, t, J = 6.9 Hz ), 2.86 (2H, q, J = 7.6 Hz), 2.49 (3H, s), 1.39 (3H, t, J = 7.6 Hz); IV (KBr) v _max 3360, 2875, 1596, 1516, 1468, 1335, 1167, 1130, 1064, 920 cm ¹ .

EXAMPLE 118 - Example 161

The compounds described below in this document were prepared according to the following procedure: A suspension of NaOH (0.1 mmol) in DMF (0.5 mL) was added to a solution of the sulfonamide (0.05 mmol), commercially available and required in DMF (1 mL), and stirred vigorously for 5 minutes. A solution of phenyl 2 [4- (2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylcarbamate (step 1 of Example 18 , 7 mg, 0.05 mmol) in DMF (0.5 mL) to this mixture, and the mixture was vigorously stirred at room temperature for 30 minutes. After removing the DMF in a nitrogen stream, the residue was dissolved in water (3 mL) and loaded into a 0.5 g / 3 mL BondElute SCX. The solid phase was washed with MeOH (5 ml), then eluting with 10% HCI / MeOH (3 ml). The eluent was concentrated under reduced pressure to obtain the title compound.

EXAMPLE 118

3- (4- (2-r ({í (3.4-DICLOROFENIL) -SULFONIL1 AMINO) CARBONIL) AMINO1ETYL) PHENYL) -2-ETlL-5,7-DIMETHYL-3/7-IMIDAZO [4,5- blPYRIDINE

MS (IED) m / z 546.6 (M + H) ⁺ .

EXAMPLE 119

2-ETHYL-3- {4- [2 - ((f ({3-NITROFENlL) -SULFONIL) AMINOlCARBONIL} AMINO) ETHYLFENYL) -5J-DIMETHIL-3H-IMIDAZOr4,5259 / 451

51PYRIDINE

MS (IED) m / z 523.3 (M + H) ⁺ .

EXAMPLE 120

3- (4-f2-r ({r (4-CHLOROPHENYL) SULPHONYL-AMl · NO) CARBONlL) AMINO1ETYL) PHENYL) -2-ETHYL-57-DlMETHIL-3H-IMIPAZOr4,5õlPYRIDINE HYDROCHLORATE

MS (IED) m / z 512.5 (M + H) ⁺ .

EXAMPLE 121

2-ETHYL-3T4-F2 HYDROCHLORIDE (((f ({4-NITROFENlL) -SULFONIL) AMINO1CARBONIL) AMINO) ETHYL] PHENYL} -5,7-DIMETHIL-3/7-lMIDAZOr4,5blPIRIDINE

MS (IED) m / z 523.3 (M + H) ⁺ .

EXAMPLE 122

A / -F4- «F ({2-F4- (2-ETIL-5,7-DIMETHIL-3H-IMIDAZOr4,5-blPIRIDIN-3-IL) PHENYLETHIL) AMINO) CARBONYLAMINO} -SULFONIL) CHLORIDATE

FENIL1-2.2-DIMETHILPROPANAM1DA

MS (IED) m / z 577.5 (M + H) ⁺ .

EXAMPLE 123

3- (4- {2-F (IF (2-CHLOROPHENYL) SULPHONYLAMINO} CARB0NIL) AMINO1ETYL) PHENYL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZ0F4,5- £> 1

PYRIDINE

MS (IED) m / z 512.4 (M + H) ⁺ .

EXAMPLE 124

3- (4- {2-F ((í (3-CHLOROPHENYL) -SULPHONYL] AMINO) CARBONYL) AMINO1ETYL) -2-ETHYL-5,7-DIMETHIL-3/7-IMIDAZOí4,5-h1 HYDROCHLORATE

PYRIDINE

MS (IED) m / z 512.5 (M + H) \

EXAMPLE 125

3- (4- {2-r (U (5-CHLORO-2-THENYL) -SULFONlL1 AM1NO) CARBONYL) AMINO1ETHIL} PHENYL) -2ETHYL-5,7-DIMETHIL-3H-IMIDAZ

F4,5-hlPYRIDINE

MS (IED) m / z 518.6 (M + H) ⁺ .

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EXAMPLE 126

3- (4- (2-r ((r (5-BROMO-2-THENYLENE) -SULPHONYL AMINO} CARBONYL) AMINO1ETHYL) PHENYL) -2 “ETHYL-5,7-DIMETHIL-3/7-IMIDAZE [ 4,5-blPYRIDINE

MS (IED) m / z 564.2 (M + H) ⁺ .

EXAMPLE 127

2-ETHYL-3- (4-f2 - ({f ({2-METHYL-5-NITRO-PHENYL) SULFONIL) AMINO1CARBONIL) AMINO) ETHYL1-PHENYL} -5,7-DIMETHIL-3/7-IMIDAZOÍ4,5 -1) 1PYRIDINE

MS (IED) m / z 537.3 (M + H) ⁺ .

EXAMPLE 128

3- (4- {24 ({r (3,4-DIMETOXYphenyl) -SULPHONYLAMINO | CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL-5,7-DIMETHIL-3/7-IMIDAZOr4,5-òlPIRIDINE HYDROCHLORATE

MS (IED) m / z 538.4 (M + H) ⁺ .

EXAMPLE 129

3- (4- {24 ({[(4-BUTYLPHENYL) -SULPHONYLAMINO) CARBONYL) AMINOlETYL} PHENYL) -2-ETHYL-5,7-DIMETHIL-3/7-IMIDAZO [4,5-dl

PYRIDINE

MS (IED) m / z 534.5 (M + H) ⁺ .

EXAMPLE 130

2-ETlL-3- (4T2-r ((r (4-METOXYphenyl) -SULPHONYLAMINO) CARBONYL) AMINOlETYL) PHENYL) -5,7-DIMETHYL-3H-IMIDAZO | 4,5-Õ1PIR1DINA HYDROCHLORATE

MS (IED) m / z 508.4 (M + H) ⁺ .

EXAMPLE 131

2-ETHYL-57-DIMETHYL-3-r4- (2-ph ({(5- (PHENYLSULFANYL) -2-THYLENE1SULFONYL} AMLNO) CARBONYLAMINE) -ETHYL) PHYLYL13H-IMIDAZOr4,5-51PIRIDINE HYDROCHLORATE

MS (IED) m / z 592.4 (M + Hf.

EXAMPLE 132

3- (4-í24 ({í (3,5-DICLOROFENlL) -SULFONYL CHLORIDATE)

261/451

AMINQ) CARBONIL) AMINO1ETHIL) PHENYL) -2-ETHYL-5,7-DIlMETHIL-3 / - / - IMIDAZO r4,5-hlPIRIDlNA

MS (IED) m / z 546.6 (M + H) ⁺ .

EXAMPLE 133

3- (4- (24 (ir (2-BROMOFENYL) SULFONYL-AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL-5 ₁ 7-DIMETHYL-3H-IMIDAZOF4,5blPYRIDINE

MS (IED) m / z 558.0 (M + H) ⁺ .

EXAMPLE 134

3- (4- {2 - [({f (4,5-DICLORO-2-THENYL) -SULFONlL1AMINO} CARBONYL) AMINO1ETYL) PHENYL) -2 ~ ETHYL-5,7-DIMETHIL-3HIMIDAZOKS-blPIRIDINE CHLORIDATE

MS (IED) m / z 552.6 (M + H) ⁺ .

EXAMPLE 135

3-44- (2- {r (f [2- (2,4-DICLOROPHENOXI) -FENYL SULFONYL) AMINO) CARBONYLAMINE} ETHYL) PHENYL1-2-ETHYL-5,7-DIMETHYL3H-IMIDAZE [4,5 -frlPYRIDINE

MS (IED) m / z 638.8 (M + H) ⁺ .

EXAMPLE 136

3- (4T2 - [(fF (5-CHLORINE-1,3-DIMETHIL-IH-PIRAZOL-4-IL) SULPHONYL1AMlNO) CARBONIL) AMINOLETYL) PHENYL) -2-ETHYL-7,7-DIMETHYL-3H-IMIDAZOf4, 5-b1PYRIDINE

MS (IED) m / z 530.3 (M + H) T

EXAMPLE 137

3- (4- (2-Γ «Γ (2,4-ΡΙΜΕΤΙί-1.3-THIAZOL-5-1L) SULPHONYLAMINO | CARBONYL) AMINO1ETHIL) FENlL) -2-ETlL-5,7-DIMETHIL3H-IMIDAZOf4,5 -Z) 1PYRIDINE

MS (IED) m / z 523.2 (M + H) ⁺ .

EXAMPLE 138

3- (4- {2-r ({r (4-Cyanophenyl) SULFONYL-AMINO) CARBONYL) AMINOlETYL) PHENYL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-bl

PYRIDINE

262/451

MS (IED) m / z 503.2 (M + H) ⁺ .

EXAMPLE 139

3- (4- {2-r (U (3,4-DIFLUOROFENYL) -SULPHONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL-5,7-DIMETHIL-3/7-IMIDAZOr4,5-f) HYDROCHLORATE lPJRIDINA

MS (IED) m / z 514.3 (M + H) ⁺ .

EXAMPLE 140

3- (4- {2-r ((r (2,5-DICLORO-3-THENYL)) -SULPHONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL ~ 5,7-DlMETHIL-3HIMIDAZOÍ4,5- £ > 1PYRIDINE

MS (IED) m / z 552.3 (M + H) ⁺ .

EXAMPLE 141

/ V- [5- (U ({2-r4- (2-ETlL-5,7-DIMETHIL-3H-IMIDAZOr4,5-blPIRIDIN-3-IL) PHENYLETHIL) AMINO) CARBONYLAMINO) -1SULFONIL) -1 , 3,4-THYADIAZOL-2-IL1ACETAMIDE

MS (IED) m / z 543.0 (M + H) \

EXAMPLE 142

3- <4-r2 - ({f ({4-CHLORO-3-NITROPHENYLbSULFONYL) AMINO1CARBONIL} AMINO) ETHYL1-PHENYL) -2-ETYL-57-DlMETHYL-3HIMIDAZOr4,5-Z) lPIRIDINE

MS (IED) m / z 557.2 (M + H) ⁺ .

EXAMPLE 143

3- (4- {2 - [({r (4-BUTOXYphenyl) SULFONYL-AMINO) CARBONYL) AMINO1ETHYL) PHENYL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4 ₁ 5Ò1PYRIDINE

MS (IED) m / z 550.4 (M + H) ⁺

EXAMPLE 144

344- (2-fr ({r2,6-DlCHLORO-4- (TRIFLUOROMETlL) PHENYLSULPHONYL) AMINO) CARBONYLAMINE) ETHYL) PHENYL1-2-ETHYL5,7-DlMETHIL-3 / - / - IMIDAZO [4,5- b1PYRIDINE

MS (IED) m / z 614.4 (M + H) ⁺ .

EXAMPLE 145

263/451

3-Γ4- (2 - {[(ίΓ4- (1-ΑΡΑΜΑΝΤΐηΡΕΝΙΠ-5υΐΡΟNIL} AMINO) CARBONYLAMINO) ETHYL) PHENYL1-2-ETHYL-5,7-DlMETHIL-3/7-IMIDAZOr4.5-51PYRIDINE HYDROCHLORATE

MS (IED) m / z 612.4 (M + H) ⁺ .

EXAMPLE 146

3- (4- {2-f ({r (4,5-DIBROMO-2-THENYL) -SULFONlL1AMINO) CARBONlL) AMINOlETIUFENIL) -2-ETYL-5,7-DIMETHIL-3HlMIDAZOf4,5-ò1PIRIDINE CHLORIDATE

MS (IED) m / z 642.0 (M + H) ⁺ .

EXAMPLE 147

2-ETHYL-5,7-DIMETHYL-3-F4- (2 - {[ffl5- (2-TYLENYLSULFANYL) -2-TIENYLlSULFONYL) AMINO) CARBONIL] AMINOTHYL) FENIU3H-IMIDAZO [4,5-blPIRIDINE

MS (IED) m / z 598.2 (M + H) ⁺ .

EXAMPLE 148

3- (4- {2-f ({f (4-TERC-BUTYLPHENYL) -SULPHONYLAMlNO} CARBONYL) AMINO1ETYL} PHENYL) -2-ETHYL-5,7-DIMETHIL-3WMIDAZOÍ4,5-fr | PYRIDINE

MS (IED) m / z 534.4 (M + H) ⁺ .

EXAMPLE 149

3- (4- {2-r (ir (4-AMINO-3-CHLOROPHENYL) -SULPHONYLAMINO) CARBONYL) AMINO1ETHIL} PHENYL) -2-ETHYL-5,7-DIMETLL-3HIMIDAZOr4,5-51PYRIDINE

MS (IED) m / z 527.3 (M + H) ⁺ .

EXAMPLE 150

2-ETHYL-5,7-DIMETHYL-3- (4- {2-r ({r (2,4,5-TRlCHLOROFENYL) SULFONlLAMINE) CARBONYL) AMINOLETYL | PHENYL) -3HIMIDAZOr4,5-òlPYRIDINE

MS (IED) m / z 580.4 (M + H) ⁺ .

EXAMPLE 151

3- (4- {2-r (fr (2,5-DIMETOXYphenyl) -SULPHONYL AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2-ETHYL-5,7-DIMETHYL-3/7-lMIDAZO HYDROCHLORATE

264/451

F4,5-51PYRIDINE

MS (IED) m / z 538.3 (M + H) ⁺ EXAMPLE 152

3- (4- {2-f «f (6-ETOXY-1,3-BENZOTHIAZOL-2IL) SULPHONYLAMINO) CARBONYL) AMINQ1ETHIL) PHENYL) -2-ETlL-5,7DIMETHIL-3/7-IMIDAZO [4 , 5-ò1PYRIDINE

MS (IED) m / z 579.1 (M + H) ⁺ .

EXAMPLE 153

3- (4-f2-F ({F (2-AMINO-4-CHLOROPHENYL) -SULPHONYL1AMINO) CARBONYL) AMINOlETlL) PHENYL) -2-ETHYL-5,7-DIMETHL “3 / 7IMIDAZO [4,5- 51PIRID1NA

MS (IED) m / z 527.2 (M + H) \

EXAMPLE 154

2-ETHYL-5,7-PIMETHYL-3-f4- (2-pyrethylsulfonyl) -2-THYLENYLSULPHONYL AMINO) CARBONYLAMINO | -ETHYL) PHENYL3H-IMIDAZOr4,5-dlPIRIDINE HYDROCHLORATE

MS (IED) m / z 630.2 (M + H) ⁺ .

EXAMPLE 155

3-44- (2- (f ((f2-CHLORO-5- (TRIFLUOROMETYL) PHENYLSULFONYL) AMINO) CARBONYL1AMINO) ETHYL) PHENYL-2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-blPIRIDINE

MS (IED) m / z 580.2 (M + Hf.

EXAMPLE 156

3- {4-r2- (n (2,3-DlHYDRO-1,4-BENZODIOXIN6-ILSULFONIL) AMINO1CARBONIL) AMINO) ETHYL-PHENYL) -2-ETHYL-5,7-DIMETHIL-3H-IMIDAZOr4,5 -òlPYRIDINE

MS (IED) m / z 536.2 (M + Hf.

EXAMPLE 157

2-ETHYL-5.7-DIMETHYL-3- [4- (2-nar2- (PHENYLSULFANIDFENYL1SULFONI L | AM INO) CARBONI LIAM INO | ETHYL) PHENI L1-3HIMIDAZOr4,5-Z? LPIRIDINE HYDROCHLORATE

MS (IED) m / z 586.3 (M + H) ⁺ .

265/451

EXAMPLE 158

3- (4- {2-f «f (4-CHLORO-2,5-DIMETHYLPHYL) SULPHONYLAMINO} CARBONYL) AMINO1ETHYL} PHENYL) -2-ETHYL-5,7-DIMETHYL3H-IMIDAZOf4,5-Ó1PYRIDINE HYDROCHLORATE

MS (IED) m / z 540.3 (M + H) ⁺ .

EXAMPLE 159

3- (4- {2-í (fr (3-BROMO-5-CHLORO-2-THENYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL} PHENYL) -2-ETYL-5,7-DIMETHIL3H-IMIDAZO [4,5 -51P1R1DINA

MS (IED) m / z 598.1 (M + H) ⁺ .

EXAMPLE 160

2-ETHYL-5,7-DIMETHYL-3- (4-f2 - [({f (4-VINYLFENYL) SULFONYLAMINO) CARBONlL) AMINO1ETYL) PHENYL) -3H-IMIDAZOr4.5-òl

PYRIDINE

MS (IED) m / z 504.4 (M + H) ⁺ .

EXAMPLE 161

2,4-DICLORO-5- «r ({2-í4- (2-ETyl-5,7-DlMETIL-3/7-IMIDAZOf4,5-dlPIRIDIN-3-IL) PHENYLJETYL} AMINO) CARBONIL1AMI“

NO} SUFONIL) METHYL BENZOATE

MS (IED) m / z 604.5 (M + H) ⁺ .

EXAMPLE 162 - EXAMPLE 194

The compounds described below in this document were prepared according to the following procedure: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.05 mmol, 0.5 mL) was added to an commercially available and necessary mixture of carbonic acid with dichloromethane, then adding 3-amino-4,6-dimethyl-2- (4- {2 - [({[(4methylphenyl) sulfonyl] -amino} carbonyl) amino ] ethyl} anilino) pyridine * (0.038 mmol) in dichloromethane (0.5 ml) at room temperature. The reaction mixture was stirred for 3 days at room temperature, then stirred for another 1 hour at 40 ° C. After removing the solvent, the residue was dissolved in MeOH (1 ml) and the solution was filtered through a membrane filter. The filtrate was purified by preparative LC / EM (Shiseido capcell pack UG80 C18

266/451 (4.6 χ 50 mm), eluted by MeOH / 0.1% HCOOH (volume / volume, 20/80 to 90/10), to obtain the title compound.

* 3-Amino-4,6-dimethyl-2- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} ani [ino) pyridine was prepared as Follow:

STEP 1. 3- (4 - ((4,6-Dimethyl-3-nitro-2-pyridinyl) amine1-phenippropanoic acid

Λ /, / V-diisopropylethylamine (26 g, 200 mmoles) was added to a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9 g, 96 mmoles) and 3- (4aminophenyl) propanoate methyl (19 g, 96 mmoles) in DMSO (100 ml), and the reaction mixture was heated to 140 ° C overnight. The reaction mixture was poured into water (400 ml) and ethyl acetate / toluene (volume / volume, 2: 1, 300 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate / toluene (volume / volume, 2: 1, 200 ml). The combined organic extracts were washed with brine (200 ml), dried (Na ₂ SO ₄ ), and concentrated. 2N aqueous NaOH solution (150 mL, 300 mmol) was added to a solution of residual oil in methanol (100 mL), and the resulting mixture was stirred at room temperature for 2 hours. The volatile components were removed under reduced pressure and the residue was washed with ethyl acetate (200 ml). The aqueous phase was acidified with 2N hydrochloric acid (200 ml, 400 mmoles) and extracted with ethyl acetate (3 x 200 ml). The extracts were washed with brine (200 ml), dried (Na ₂ SO ₄ ), and concentrated to obtain 23.2 g (77%) of the title compound as light brown solids.

¹ H NMR (CDCI ₃ ) δ: 9.57 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz) , 6.52 (1H, s), 2.95 (2H, t, J = 7.5 Hz), 2.66 (2H, t, J = 7.5 Hz), 2.55 (3H, s) , 2.43 (3H, s).

STEP 2. Phenyl 2- {4-f (4,6-Dimethyl-3-nitro-2-pyridinyl) amino] phenyl) ethylcarbamate

Diphenylphosphoryl azide (DPPA) (7.54 ml, 35 mmoles) and triethylamine (4.87 ml, 35 mmoles) were added to a solution, under stirring, of 3- {4 - [(4,6-dimethyl acid) -3-nitro-2-pyridinyl) amino] phenyl} propanoic (step 1, 10 g, 31.7 mmoles) in dioxane (200 ml). The reaction mixture was heated to

267/451

120 ° C for 2 hours. Phenol (6.6 g, 70 mmol) was added to the reaction mixture and the reaction mixture was refluxed. After 3 hours, an additional amount of phenol (3.3 g, 35 mmol) was added to the reaction mixture. The resulting mixture was heated under reflux temperature overnight. The volatile component was removed and the residue was poured into 10% aqueous citric acid solution (200 ml) and ethyl acetate (300 ml). The organic layer was separated and extracted with ethyl acetate (300 ml). The combined organic extracts were washed with water (200 ml) and brine (300 ml), dried (Na2SO ₄ ) and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (2: 1), to obtain 10.3 g (77%) of the title compound, as solids. Orange.

¹ H NMR (CDCI ₃ ) δ: 9.60 (1H, s), 7.61 (2H, d, J = 8.6 Hz), 7,387.32 (2H, m), 7.24-7, 16 (3H, m), 7.14-7.09 (2H, m), 6.54 (1H, s), 5.06 (1H, s lg.), 3.58-3.50 (2H, m), 2.89 (2H, t, J = 6.9 Hz), 2.56 (3H, s), 2.44 (3H, s).

STEP 3. 4,6-Dimethyl-2- (4-methyl-2 (4-methylphenyl) sulfonylamino) carbonyl) amino1ethyl) anilino) -3-nitropyridine

Sodium hydride (2.0 g, 50 mmoles) was added with stirring to a solution of phenyl 2- {4 - [(4,6-dimethyl-3-nitro-2-pyridinyl) amino] phenyl} ethylcarbamate (step 2, 10.0 g, 24.6 mmoles) and p-toluenesulfonamide (6.3 g, 36.8 mmoles) in DMF (100 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate / toluene (volume / volume, 2: 1, 2 x 300 ml). The organic extracts were washed with water (100 ml) and brine (200 ml), then dried (Na ₂ SO ₄ ). The removal of the solvent gave the crude product. Recrystallization from ethyl acetate gave 9.6 g (81%) of the title compound as brown solids. 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 obtain 1.9 g (16%) of the compound in question. title in the form of brown solids.

¹ H NMR (CDCI ₃ ) δ: 9.75 (1H, s), 7.62 (2H, d, J = 8.4 Hz). 7.59

268/451 (2Η, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 6, 62-6.50 (2H, m), 3.55-3.42 (2H, m), 2.80 (2H, t, J = 6.9 Hz), 2.56 (3H, s), 2 , 43 (3H, s), 2.39 (3H, s).

STEP 4. 3-Amino-4.6-dimethyl-2- (4- (2-í ({í (4-methylphenyl) sulfonillamino} carbonyl) amino1ethyl) anilino) pyridine

10% Pd-C (2.0 g) was added to a solution of 4,6-dimethyl2- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} anilino) -3-nitropyridine (step 3, 11.4 g, 23.6 mmoles) in methanol (250 ml). The resulting mixture was stirred under medium pressure of hydrogen (4.0 kgf / cm ² ) for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to obtain 9.0 g (85%) of the title compound as dirty white solids.

¹ H NMR (CDCI ₃ ) δ: 7.69 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.00-6.95 ( 4H, m), 6.61 (1H, s), 6.24 (1H, s lg.), 3.44-3.38 (2H, m), 2.70 (2H, t, J = 6, 7 Hz), 2.39 (3H, s), 2.33 (3H, s), 2.19 (3H, s).

EXAMPLE 162

57-DIMETHYL-3- (4- (2-r ({f (4-METlLFENIL) SULFONYLAMlNO} CARBONYL) AMINO1ETYL) PHENYL) -2-i3-OXO-3- (2-THENYL)

PROPIL1-3WMIDAZOr4,5-Z) 1 PYRIDINE

MS (IED) m / z 602.48 (M + H) ⁺ .

EXAMPLE 163

5,7-DIMETHYL-3- (4- {2-r «f (4-METHYLPHENYL) SULFONYLJAMINO) CARBONYL) AMINOLETYL) PHENYL) -2- (PHENOXYMETHYL) -3H-IMIDAZOí4,5-ÓPYRIDINE

MS (IED) m / z 570.5 (M + H) ⁺ .

EXAMPLE 164

5,7-DIMETHYL-3- (4- {2-r (U (4-METHYLphenyl) SULFONlL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2- [2- (3-PYRIDINYL) ETHYL13H-IMIDAZOr4,5-51PYRIDINE

MS (IED) m / z 569.49 (M + H) ⁺ .

EXAMPLE 165

5,7-DIMETHYL-3- (4- {24 ({((4-METHYLPHENYL) SOUL269 / 451

FQNlL1AMINO} CARBON [L) AMINO1ETIUFENIL) -2- (3-OXO3-FENILPROPIL) -3 / 7-lMIDAZO [4,5-ò1PIRIDlNA

MS (IED) m / z 596.28 (M + H) ⁺ .

EXAMPLE 166

SJ-DIMETHYL-S ^^ - Fd ^ -METHYLPHENIUSULFONILJAMINO) CARBONIL) AMINO1ETYL) FENlL) -2- (3 ~ PHENYLPROPIL) -3BIMIDAZO [4,5-b1PYRIDINE

MS (IED) m / z 528.52 (M + H) ⁺ .

EXAMPLE 167

24ETOXIMETH) -5,7-DIMETHYL-3- (4- (2-r ({[(4-METHYLphenyl) SULFON1L1AMINO) CARBONYL) AMINO1ET1L) PHENYL) -3B-IMIDAZO [4,5-blPIRIDINE

MS (IED) m / z 522.46 (M + Hf.

EXAMPLE 168

5,7-DIMETHYL-3- (442-r «r (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINOlETYL) PHENYL) -2-f (PHENYLSULFANYL) METHYL3B-IMIDAZO [4,5-51PIR1DINA

MS (IED) m / z 586.49 (M + H) ⁺ .

EXAMPLE 169

5,7-DIMETHYL-3- (442-f (ÍF (4-METHYLPHYL)) SULFONIL LIAM INO) CARBONYL) AMINO1ETYL) PHENYL) -2-PENTYL-3B-IMIDAZO [4.5-51

PYRIDINE

MS (IED) m / z 534.51 (M + H) ⁺ .

EXAMPLE 170

5,7-DIMETHYL-3- (4-f24 «r (4-METHYLphenyl) SULFONYLAMINO) CARBONYL) AMINO1ETHYL) PHENYL) -2- (2-PHENYLETHIL) -3B-IMIDAZO [4,5-òlPIRlDINA

MS (IED) m / z 568.51 (M + H) ⁺ .

EXAMPLE 171

2- (3-BUTINYL) -5.7-DIMETlL-3- (4- {2-r (ir (4-METHYLphenyl) SULFONIDAMINE) CARBONYL) AMlNOlETYL) PHENYL) -3B-IMIDAZO [4,5-òlPYRIDINE

270/451

MS (IED) m / z 516.45 (M + H) ⁺ .

EXAMPLE 172

5,7-DIMETLL-3- (4- (2-i (U (4-METHYLPHYL)) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2- (3-THYLYLMETHYL) -3HIMIDAZOr4,5-51PYRIDINE

MS (IED) m / z 560.44 (M + H) ⁺ ,

EXAMPLE 173

5,7-DIMETHYL-3- (4- {2-i (ir (4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2- (4-PENTINYL) -3H-IMIDAZOf4,5-Z? LPYRIDINE

MS (IED) m / z 530.46 (M + H) ⁺ .

EXAMPLE 174

5,7-DIMETHYL-3- (4- (2-r ((r (4-METHYLphenyl) SULFONYLAMINO) CARBONYL) AMINO1ETHYL) PHENYL) -2- (2-THYLYLMETHYL) -3 / 7IMIDAZOr4,5-51PYRIDINE

MS (IED) m / z 560.44 (M + H) ⁺ .

EXAMPLE 175

5,7-DIMETHYL-3- (4- (2-r ({f (4-METHYLphenyl) SULPHONYLAMINE} CARBONYL) AMLNO1ETYL) PHENYL) -2- (3-PYRIDINYLMETHIL) -3HIMIDAZOÍ4,5-Õ1P1RID1NA

MS (IED) m / z 555.48 (M + H) ⁺ .

EXAMPLE 176

5,7-DIMETHYL-3- (4- {2-r (ir (4-METHYLphenyl) SULFONYLAMINO} CARBONYL) AMINO1ETYL) PHENYL) -2 - [(2E) -2-PENTENYL-3HIMIDAZE [4,5- £> 1PIRID1NA

MS (IED) m / z 532.48 (M + H) ⁺ .

EXAMPLE 177

2-BENZYL-5,7-DIMETHYL-3- (4- (2-f ({f (4-METJLFENIL) SULFONYL1AMINO) CARBONYL) AM1NO1ETYL) PHENYL) -3H-IM1DAZO f4,5-h1PYRIDINE

MS (IED) m / z 554.48 (M + H) ⁺ .

EXAMPLE 178

271/451

2- (CYANOMETYL) -5,7-DIMETHYL-3- (442-i ({r (4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3WMIDAZO [4,5-dJPIRIDINE

MS (IED) m / z 503.41 (M + H) ⁺ .

EXAMPLE 179

2- (METHYLMETHYL) -5,7-DIMETHYL-3- (4T2-r (y (4-METHYLPHYL)) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZO [4,5-Z? 1PYRIDINE

MS (IED) m / z 508.44 (M + H) \

EXAMPLE 180

2-HEPTiL-5,7-DIMETHIL-3- (4- (2-r ((K4-METHYLphenyl) SULFONYL1AMINO | CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZO

F4.5-51PYRIDINE

MS (IED) m / z 562.33 (M + H) ⁺ .

EXAMPLE 181

57-DIMETHYL-3- (4- (2-f ({r (4-METHYLphenyl) SULFONYLTAMINO) CARBONYL) AMINOLETYL) FENlL) -2-OCTYL-3H-IMIDAZOr4,5-51

PYRIDINE

MS (IED) m / z 576.37 (M + H) ⁺ .

EXAMPLE 182

57-DIMETHYL-2- (4-METHYLphenyl) -3- (4-f2-i ((r (4METHYLphenyl) SULFONYL1AMINO} CARBONYL) AMINO1ETYL} PHENYL) -3H-IMIDAZOr4,5-51PlRIDINA FORMIATE

MS (IED) m / z 548.53 (M + H) ⁺ .

EXAMPLE 183

2 - [(BENZILOXI) METHYL1-5,7-DIMETHYL-3- (4- {2Í ({F (4-METHYLPHYL) SULFON1L1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3HIMIDAZO | 4,5-ôjPIRIDINE

MS (IED) m / z 584.52 (M + H) ⁺ .

EXAMPLE 184

5,7-DIMETHYL-3- (4- (2-r (f (4-METHYLphenyl) SULFONYLAMINO) CARBONlL) AMINOlETYL) PHENYL) -2- (2-PHENOXYETHIL) -3H-IMI272 / 451

DAZO [4,5-frlPIRlDINA

MS (IED) m / z 584.33 (M + H) ⁺ .

EXAMPLE 185

57-DIMETHYL-3- (4- {2-r (g (4-METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -2- [3- (2 "TIENIL) PROPIL13H-IMIDAZO [4,5-blPYRIDINE

MS (IED) m / z 588.5 (M + H) ⁺ .

EXAMPLE 186

5,7-DIMETHYL-3- (4- (2 - [((r (4-METHYLphenyl) SULFONlL1AMlNO) CARBONlL) AMINOlETYL) PHENYL) 2- (2-NAFTYLMETHIL) “3 / 7IMIDAZO | 4,5- £ > 1PYRIDINE

MS (IED) m / z 604.37 (M + H) ⁺ .

EXAMPLE 187

5,7-DIMETHYL-3- (4- {2 - [({r (4-METHYLPHYL) SULPHONYLAMINE) CARBONY) AMINO1ETlL} FENIL) 2- (4-PHENYLBUTYL) -3 / 7IMl ·

DAZOr4,5-òlPyridine

MS (IED) m / z 596.42 (M + H) ⁺ .

EXAMPLE 188

5,7-DIMETHYL-3- (4- (2-í ({r (4-METHYLPHYL) SULFONYLTAMINO) CARBONYL) AMINO1ETHY> PHENYL) -2- (5-PHENYLPENTYL) -3 / 7-IMIDAZO [4, 5-51PIR1DINA

MS (IED) m / z 610.45 (M + H) ⁺ .

EXAMPLE 189

2- (2-ETOXIETYL) -5,7-DIMETHYL-3- (4- {2 - [({[(4-METHYLFEN1L) SULFONYL1AMINO) CARBONYL) AM1NO1ETYL) PHENYL) -3H-IMIDAOÍ4.5-Ò1PYRIDINE FORMIATE

MS (IED) m / z 536.38 (M + H) ⁺ .

EXAMPLE 190

2- (2,3-DIHYDRO-1H-INDEN-2-ILMETYL) -5,7-DIMETHIL-3- (442-F (f (4-METHYLphenyl) SULFONYLAMINO) CARBONYL) AMINO1ETYL FORMIATE

FENIL) -3H-IMIDAZO [4,5 “Ò1PYRIDINE

MS (IED) m / z 594.45 (M + H) ⁺ .

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EXAMPLE 191

2- (CYCLOPROPYLMETHYL) -5J-DIMETHIL-3- (4- | 2r «r (4-METlLFENYL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -3HIMIDAZO [4,5-51PYRIDINE

MS (IED) m / z 518.45 (M + H) ⁺ .

EXAMPLE 192

5,7-DIMETHYL-3- (4- {2-rar (4-METHYLphenyl) SULFONIL] AMINO) CARBONIL) AMINOlETYL) PHENYL) -2-r2- (METHYLSULFANIL)

ETILl-3H-IMIDAZOr4,5-b] PIRIDlNA

MS (IED) m / z 538.44 (M + H) ⁺ .

EXAMPLE 193

2-HEXYL-5,7-DIMETHIL-3- (4- (2-r «r (4-METHYLPHENL L) SULFONYLTAMINO) CARBONl L) AM INOlETIL) PHENYL) -3H-IMIDAZO [4,5-51

PYRIDINE

MS (IED) m / z 548.44 (M + H) ⁺ .

EXAMPLE 194

5,7-DIMETHYL-3- (4- {2 - [((r (4-METHYLPHYL) SULFONYLAMINO) CARBONYL) AMINO1ETHYL) PHENYL) -2- (4-PENTHYL) -3HIMIDAZOÍ4,5-b] PYRIDINE

MS (IED) m / z 532.42 (M + H) ⁺ .

EXAMPLE 195

6-CHLORINE-5-CYANO-2-ETHYL 1- (4-f2 - [({((4-METHYLphenyl-SULFONYL1AMINO) CARBONYL) AMINO1ETHIL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1, 6-Chloro-1-f4- (2-chloroethyl) phenin-2-ethyl-1H-benzimidazole5-carbonitrile

The reaction was carried out according to the procedure described in step 7 of Example 1 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 / - / - benzimidazole- 5-carbonitrile (Example 111, step 4).

Δ (CDCIa) NMR: 8.07 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7, 19 (1H, s), 3.83 (2H, t, J = 7.1 Hz), 3.22 (2H, t, J = 7.1 Hz),

2.79 (2H, q, J = 7.5 Hz), 1.37 (3H, t, J = 7.5 Hz).

STEP 2. 144- (2-Azidoethyl) phenyl1-6-chloro-2-ethyl-1/7-benzimidazole274 / 451

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 (1/7-benzimidazole-5 -carbonitrile (step 1).

¹ H NMR (CDCb) δ: 8.07 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.18 (1H, s), 3.64 (2H, t, J = 7.0 Hz), 3.04 (2H, t, J = 7.0 Hz),

2.79 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 3. 144- (2-Aminoethyl) phenill-6-chloro-2-ethyl-1H-benzimidazole5-carbonitrile

The reaction was carried out according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6-chloro-2ethyl-1/7-benzimidazole-5-carbonitrile (step 2).

¹ H NMR (CDCb) δ: 8.06 (1H, s), 7.46 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.19 (1H, s), 3.09 (2H, t, J = 7.1 Hz), 2.89 (2H, t, J = 7.1 Hz),

2.79 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 4. 6-CforO5-cyano-2-ethyl-1- (4- (2-y ({f (4-metrylphenyl) sulfonamino) carbonyl) amino1ethyl) phenyl) -1 / 7-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-2ethyl-1/7-benzimidazole-5-carbonitrile (step 3).

Mp: 219-224 ° C; IV (KBr) v 3388, 2229, 1708, 1618, 1514, 1466, 1344, 1161, 1089 cm ^-1 .

MS (IED) m / z 522 (M + H) ⁺ , 520 (MH) '; ¹ H NMR (DMSO-d ₆ ) δ: 8.38 (1H, s), 7.77 (2H, d, J = 8.2 Hz), 7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H, s lg.), 3.26-3.28 (2H, m), 2.69-2.81 (4H, m), 2.35 ( 3H, s), 1.25 (3H, t, J = 7.6 Hz).

THE SYNTHETIC PROCEDURE OF EXAMPLE 196-EXAMPLE 197

The compounds described below in this document were prepared according to the following procedure: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.05 mmol, 0.5 mL) was added to an commercially available and necessary mixture of carbonic acid with dichloromethane (DCM), followed by the addition of a solution of 3-amino-4.6275 / 451 dimethyl-2- (4- {2 - [({[(4-methylphenyl) sulfonyl] -amino} carbonyl) amino] ethyl} anilino) pyridine (0.038 mmol) in DCM (0.5 mL) at room temperature. The reaction mixture was stirred for 3 days at room temperature, then stirred for another day at 40 ° C. After removing the solvent, the residue was dissolved in MeOH (1 ml) and the solution was filtered through a membrane filter. The filtrate was purified by preparative LC / EM (Shiseido capcell pack UG80 C18 (20 x 50 mm), eluting with MeOH / 0.1% HCOOH (volume / volume, 20/80 to 90/10)), to obtain the title compound.

EXAMPLE 196

Λ / -Π (2- {4-Γ5,7-DIMETHIL-2- (4-METHYLPETYL) -3HIMtDAZOr4 ₁ 5-olPYRIDIN-3-IL1FENlL) ETHYL) AMINOlCARBONIL) -4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 548.53 (M + H) ⁺ .

EXAMPLE 197

FORMAT OF /V-<f(2-(4-f5.7-DIMETlL-2-(3-OXO-3-FENILPROPIL)-3H-lMIDAZOr4,5-blPIRIDIN-3-ILlFENIL)ETlL)AMINOlCARBONILF4-METILBENZENOSSULFONAMIDA

MS (IED) m / z 596.28 (M + H) ⁺ .

THE SYNTHETIC PROCEDURE OF EXAMPLE 198-EXAMPLE 216

The compounds described below in this document were prepared according to the following procedure: Carboxylic acid (0.06 mmol) was dissolved in / V, / V-diisopropylethylamine (DIEA) (0.106 mmol) and dichloromethane (DCM) ( 0.3 mL). 1-hydroxybenzotriazole hydrate (HOBT) (0.06 mmol) in Λ /, / V-dimethylformamide (DMF) (0.02 ml) was added. 3-Amino-4,6-dimethyl-2- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} -anilino) pyridine (0.044 mmol) in DCM (0.3 mL) and DMF (0.08 mL) to the reaction, and hexafluorophosphate, O-benzotriazol-1-yl- / V, a /, / V, a /-tetramethyluronium hexafluorophosphate (HBTU) (0.13 mmol ) in DMF (0.25 ml) then. The reaction solution was stirred for 6 hours at room temperature, then heated to 40 ° C overnight. After removing the solvent, the residue was dissolved in MeOH (0.8 ml). The solution was loaded into a Varian BondElute® SCX refill device (500 mg / 3 mL) that was pre-primed with 27 mL / 451 with 2 mL of MeOH. The solid phase matrix was washed with 5 ml MeOH and then eluted with 2N ammonia / MeOH (3 ml). After removing the solvent, the product was used for the reaction in the next step.

Dissolve the intermediate product of step 1 with EtOH (2 mL) was then adding 2N aqueous NaOH solution (1 mL) in excess to the reaction solution. The reaction mixture was stirred at 40 ° C to 70 ° C overnight. After completion of the reaction, the solvent was removed. 2N aqueous HCI solution (1 mL, adjusted to pH 7.0) was added to the residue. The aqueous layer was extracted with DCM (1 ml x 3). The organic layer was concentrated to obtain the residue. The crude product was purified by preparative LC / MS (Shiseido capcellpack UG 80 C18 (20 x 50 mm), eluting with MeOH / 0.1% HCOOH (volume / volume, 20/80 to 90/10)) , to obtain the title compound in the form of a formate.

EXAMPLE 198

A / - {5-r5,7-DIMETHYL-3- (4- {2-r ((í (4-METHYLPHYL) SULFONYL1AMINO) CARBONlL) AMINO1ETHYL} PHENYL) -3 / 7-IMIDAZO [4,5- ó1PIRIDIN-2-IL | PENTILE | ACETAMIDE

MS (IED) m / z 591.33 (M + H) \

EXAMPLE 199

A / -phi (2-f4-r5,7-DIMETHIL-2- (5-OXO-5-PHENYLPENTYL) -3fy-IMIDAZOr4.5-Ó1PYRIDIN-3-ILylphenyl) ETHYL) AMINO1CARBONIL) 4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 624.37 (M + H) ⁺ .

EXAMPLE 200

A / -ff (2- (4-1,2- (2-CICLOPENTEN-1-ILMETIL) -5,7DIMETHYL-3/7-IMIDAZO [4,5-b1PIRlDlN-3-ILlFENIL) ETHYL) AMINOlCARBONILl · FORMIATE

4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 544.40 (M + H) ⁺ .

EXAMPLE 201

/ V- (f (2-f4-f2- (1-CICLOPENTEN-1-ILMETIL) -5,7DIMETHYL-3/7-IMIDAZO [4 _< 5-b1PIRIDIN-3-IL] PHENYL) PHENYL) | CARBONlL'l ·

4-MET1LBENZENOSULPHONAMIDE

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MS (IED) m / z 544.40 (M + H) ⁺ .

EXAMPLE 202

(2Z) -3-r5,7-DIMETHYL-3- (4T2-r (fr (4-METHYLphenyl) SULFONYL1AMlNO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZOr4,5-61PIRIDIN-2-1L1- / V -PROPIL-2-PROPENAMIDE

MS (IED) m / z 575.44 (M + H) ⁺ .

EXAMPLE 203

A / - (r (2-f4- [5,7-DIMETHIL-2- (1-METHYL-3-OXO-3-PHENYLPROPYL) -3H-IMIDAZOf4,5-b1PIRIDIN-3-IL1-PHENYL) ETHYL) AMINO1CARBON1U -4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 610.49 (M + H) ⁺ .

EXAMPLE 204

A / - {r (2- (4-r5,7-DIMETHIL-2- (3,3,3-TRIFLUOR-2METHYLPROPYL) -3 / - / - IMIDAZO | 4,5-frlPIRIDIN-3-ILjFENIL) FORMIATE ETHYL) AMINO1 CARBONlL) -4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 574.43 (M + H) ⁺ .

EXAMPLE 205

/ V FORMIATE - ((í2- (4- {2-í2- (DIETYLAMINE) ETHYL1-5,7-DIMETHYL-3H-IMlDAZOr4,5-õlPIRIDIN-3-IL) PHENYL) ETHYLAMINE) CARBONYL) -4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 563.49 (M + H) ⁺ .

EXAMPLE 206

A / - ((í2- (4- (2-í2- (4-FLUOROFENIL) ETIL1-57DIMETHIL-3H-IMIDAZOr4,5-ò1PIRIDlN-3-IL) PHYLMINE) ETHYLAMINE) CARBONYL) 4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 586.46 (M + H) \

EXAMPLE 207

3-f5,7-DIMETHYL-3- (4- {2 - [«r (4-METHYLphenyl) SULFONYL1AMlNO) CARBONYL) AMINO1ETYL) PHENYL) -3H-IMIDAZOr4,5-õ1PlRIDIN-3-IL1- / V, / V-DlETILPROPANAMIDA

MS (IED) m / z 591.50 (M + H) ⁺ .

EXAMPLE 208

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FQRMIATO DE A / -f ((2- [4- (5,7-DIMETHYL-2-TETRAHYDRO-3-FURANYL-3/7-IMIDAZOÍ4,5-Z) lPlRIDIN-3-IL) PHENYL1ETHIL) AMINO) CARBONIL1- 4METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 534.41 (M + H) ⁺ .

EXAMPLE 209

FQRMIATO DE / V- (í (2- (4-r5,7-DIMETHIL-2- (1-METHYLBUTYL) -3HlMIDAZOr4,5-ò1PYRIDIN-3-ILylphenyl) ETYL) AMINQ1CARBONYL} -4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 534.45 (M + H) ⁺ .

EXAMPLE 210

FQRMIATO DE / V - ([(2- (4-r2- (CYCLOPENTYLMETHYL) -5,7-DIMETHYL-3H-IMIDAZO [4,5-ò1Pyridin-3-1LlFENIL) ETHYL) AMINOLCARBONIL) -4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 546.46 (M + H) ⁺ .

EXAMPLE 211

FQRMIATO DE A / - ([(2- (4-r5,7-DIMETHIL-2- (2-METHYLCYCLOPROPlL) -3 / 7-IMIDAZOf4.5-51PIRIDIN-3-IL1FENlL) ETHYL) AMINO1CARBONIL) -4MET1LBENZENOSSULFONAMIDE

MS (IED) m / z 518.41 (M + H) ⁺ .

EXAMPLE 212

FQRMIATO DE / 74 ((244- (5,7-DIMETHIL-2- (3- [4- (Methyloxy) PHENYL1-3-OXOPROPIL) -3 / 7-IMIDAZO | 4,5-ò1PIRIDIN-3-IL) - FENIL1ETIL) AMINO)

CARBONYL1-4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 626.45 (M + H) ⁺ .

EXAMPLE 213

FQRMIATO DE / V - ((r2- (4- (2-r3- (3,4-DIMETHYLPHYL) PROPIL] -5,7DIMETHYL-3H-IMIDAZOr4,5-5lPIRIDIN-3-IL) PHENYL) ETHYLAMINO) CARBONIL) 4 -METlLBENZENOSULPHONAMIDE

MS (IED) m / z 610.28 (M + H) ⁺ .

EXAMPLE 214

FQRMIATO DE / V - ((r2- (4- (2-r (Z) -2- (4-FLUOROFENYL) ETENYL1,7,7-DIMETHYL-3H-IMIDAZOr4,5-b1PIRIDIN-3-IL) PHENYL) ETHYLAMINO) CARBO279 / 451

NID-4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 584.41 (M + H) ⁺ .

EXAMPLE 215

/ Vr «2-r4- (5,7-DIMETHYL-2 - {(Z) -2-r2- (Methyloxy) PHENYLENETHYLENE) -3H-IMIDAZOr4,5-blPIRIDIN-3-IL) PHENYL1-ETHYL} ) CARBONYL1-4-METHYLBENZENOSULPHONAMIDE

MS (IED) m / z 596.29 (M + H) ⁺ .

EXAMPLE 216

A / -fr (2- {4-1,2- (5-HEXINIL) -5,7-DIMETHIL-3H-IMl · DAZ0r4,5-òlPIRIDIN-3-IL1FENlUETIL) FORMIATE AMIN01CARB0NILM-METILBENZENOSSULFONAMIDA

MS (IED) m / z 544.33 (M + H) ⁺ .

THE SYNTHETIC PROCEDURE OF EXAMPLE 217-EXAMPLE 220

The compounds described below in this document were prepared according to the following procedure: Pyridine (0.103 mmol) in dichloromethane (DCM) (0.2 ml) was added to a solution of 3-amino4,6-dimethyl-2- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} anilino) pyridine (0.044 mmol) in DCM (0.2 mL) and DMF (0.05 mL), and excess of acid chloride (0.066 mmol - 0.088 mmol) at room temperature. The reaction mixture was stirred at room temperature until the starting compound disappeared (4-6 hours). Upon completion of the reaction, MeOH (0.2 ml) was added to the reaction mixture, and then stirred for 1 hour. The solvent was removed by vacuum centrifugation.

The residue, which was dissolved with MeOH (0.8 mL), was loaded into a Varian BondElute® SCX refill (500 mg / 3 mL) that was preconditioned with 2 mL of MeOH. The solid phase matrix was washed with 5 ml MeOH and then eluted with 2N ammonia / MeOH (3 ml). The eluate was concentrated in vacuo to obtain the intermediate product.

Dissolve the intermediate product of step 1 with EtOH (2 mL) was then adding 2N aqueous NaOH solution (1 mL) in excess to the reaction solution. The reaction mixture was stirred at 70 ° C overnight. After removing the solvent, 2N aqueous solution of

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HCI to neutralize itself. The aqueous layer was extracted with DCM (1 ml x 5 times). The organic layer was dried over sodium sulfate, then concentrated. The crude product was purified by preparative LC / MS (Shiseido capcellpack UG 80 C18 (20 x 50 mm), eluting with MeOH / 0.1% HCOOH (volume / volume, 20/80 to 90/10)) , to obtain the title compound in the form of a formate.

EXAMPLE 217

4-METHYL- / V-r ({2-r4- (2.5,7-TRIMETHIL-3H-IMIDAZOÍ4,5-b1PYRIDIN-3-IL) PHENYL1ETHIL) AMINO) CARBONYL1-4-BENZENOSULPHONAMIDE FORMIATE

MS (IED) m / z 478.31 (M + H) ⁺ .

EXAMPLE 218

/V-fr(2-{4-í2-(2.2-DIMETILPROPIL)-5.7-DIMETIL3fí-IMIDAZOr4.5-ò1PIRIDIN-3-IL1FENIL}ETIL)AMINOtCARBONIL)-4- METILBENZENOSSULFONAMIDA FORMIATE

MS (IED) m / z 534.40 (M + H) ⁺ .

EXAMPLE 219

A / -i (f2-í4- (2-CYCLOBUTYL-5.7-DIMETHIL-3H-IMIDAZO [4,5-Ó1PÍRIDIN-3-IL) PHENYL1ETHYL) AMINO) CARBONYL-4-METHYLBENZENOSULFONAMIDE FORMIATE

MS (IED) m / z 518.38 (M + H) ⁺ .

EXAMPLE 220

A / -r ({2-r4- (2-CYCLOPENTYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-Ó1PYRIDIN-3-IL) PHENYL1ETlL) AMINO) CARBONYL-4-METHYLBENZENOSULFONAMIDE

MS (IED) m / z 532.44 (M + H) ⁺ .

EXAMPLE 221

4- (6-CHLORINE-2-ETHYL-5-TRIFLUOROMETHIL-1H-BENZIMIDAZOL-1-IL) P-TOLUENOSULPHONATE (4-METHYLphenyl) SULPHONYL

A mixture of 4- (6-chloro-2-ethyl-5-trifluoromethyl-1H281 / 451 benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate) was stirred for 16 hours (Example 106, 150 mg, 0.265 mmol), p-toluenesulfonic acid (50.5 mg, 0.265 mmol) in acetone (3% in H ₂ O, 0.3 ml). The precipitated crystalline solids were filtered, washed with acetone (0.05 ml x 5), and dried in vacuo at 40 ° C for 2 hours to obtain 158 mg (81%) of the title compound, under the form of white solids.

M.p .: 234.8 ° C.

¹ H NMR (CDCI ₃ ) δ: 8.66 (1H, s lg.), 8.35 (1H, s), 7.85 (2H, d, J = 8.1 Hz), 7.81 ( 2H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.4 Hz), 7.39-7.35 (3H, m), 7.29 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 7.9 Hz), 4.35 (2H, t, J = 6.2 Hz), 3.13 (2H, q, J = 7 , 6 Hz), 3.04 (2H, t, J = 6.3 Hz), 2.42 (3H, s), 2.36 (3H, s), 1.43 (3H, t, J = 7 , 4 Hz).

EXAMPLE 222

4- (6-CHLORO-2-ETHYL-5-TRIFLUOROMETlL-1H-BENZIMIDAZOL-1-IDFENETYL BENZENOSULPHONATE OF (4-METHYLphenyl) SULPHONYL

The title compound was prepared according to the procedure described in Example 221 from 4 (6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl) phenethyl (4-methylphenyl) sulfonylcarbamate ( Example 106).

M.p .: 194.9 ° C.

¹ H NMR (CDCI ₃ ) δ: 8.83 (1H, s lg.), 8.39 (1H, s), 7.99-7.95 (2H, m), 7.81 (2H, d , J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.41-7.36 (6H, m), 7.29 (2H, d, J = 8, 4 Hz), 4.34 (2H, t, J = 6.1 Hz), 3.14 (2H, q, J = 7.6 Hz), 3.03 (2H, t, J = 6.1 Hz ), 2.41 (3H, s), 1.42 (3H, t, J = 7.4 Hz).

EXAMPLE 223

4- (6-CHLORO-2-ETHYL-5-TRIFLUOROMETHYL-1/7-BENZIMIDAZOL-1-IDFENETHIL METHANOSULPHONATE OF (4-METHYLphenyl) SULPHONYL

The title compound was prepared according to the procedure described in Example 221 from 4 (6-chloro-2-ethyl-5-trifluoromethyl-1/7-benzimidazol-1-yl (4-methylphenyl) sulfonylcarbamate) phenethyl (Example 106).

M.p .: 172.2 ° C.

¹ H NMR (CDCI ₃ ) δ: 9.03 (1H, s lg.), 8.52 (1H, s), 7.81 (2H, d,

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J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.40 (2h, d,> 8.1 Hz), 7.39 (1H, s), 7, 29 (2H, d,> 8.1 Hz), 4.35 (2H, t,> 6.3 Hz), 3.16 (2H, q,> 7.6 Hz), 3.06 (2H, t ,> 6.3 Hz), 2.94 (3H, s), 2.41 (3H, s), 1.45 (3H, t,> 7.6 Hz).

EXAMPLE 224

5-ACETYL-2-ETHYL-3- (4-f2 - [(f [(4METHYLphenyl) SULFONYL1AMINO) CARBONYL) AMINOJETYL) PHENYL) BENZIMIDAZOL P-TOLUENOSULPHONATE

A mixture of 5-acetyl-2-ethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl was stirred at room temperature for 16 hours) ) benzimidazole (Example 78, 43 mg, 0.085 mmol), p-toluenesulfonic acid (16.2 mg, 0.085 mmol) in ethanol (0.1 mL). The precipitated crystalline solids were filtered, washed with ethanol (0.05 ml x 5), and dried in vacuo at 40 ° C for 2 hours to obtain 54 mg (91%) of the title compound, under the form of white solids.

M.p .: 166.7 ° C.

¹ H NMR (CDCI ₃ ) δ: 9.85 (1H, s lg.), 8.50 (1H, s), 8.02 (1H, d,> 8.9 Hz), 7.86 (2H , d,> 8.1 Hz), 7.68 (2H, dd,> 1.8, 8.2 Hz), 7.47 (2H, d,> 8.4 Hz), 7.36-7, 31 (3H, m), 7.22 (2H, d,> 8.4 Hz), 7.17 (2H, d,> 8.4 Hz), 7.00 (1H, s lg.), 3, 47-3.39 (2H, m), 3.14 (2H, q,> 7.3 Hz), 2.88 (2H, t,> 6.3

Hz), 2.58 (3H, s), 2.35 (3H, s), 2.34 (3H, s), 1.45 (3H, t,> 7.6 Hz).

EXAMPLE 225

5-ACETYL-2-ETHYL-3- (4-f2-r «r (4-METHYLphenyl) SULFONYL1AMINO} CARBONYL) AMINO1ET1L) PHENYL) -BENZIMIDAZOL BENZENOSULPHONATE

The title compound was prepared according to the procedure described in Example 224 from 5-acetyl-2-ethyl-3- (4- {2 - [({[(4-methylphenylL) SULFonyl] amino} carbonyl) amino] ethyl} phenyl) benzimidazole (Example 78).

M.p .: 117.7 ° C.

¹ H NMR (CDCI ₃ ) δ: 9.62 (1H, s lg.), 8.52 (1H, s), 8.05-7.96 (3H, m), 7.67 (2H, d ,> 8.2 Hz), 7.49-7.43 (5H, m), 7.37-7.32 (3H, m), 7.19 (2H, d,> 8.2 Hz), 6 , 92-6.88 (1H, m), 3.48-3.42 (2H, m), 3.17 (2H, q,> 7.6 Hz), 2.89 (2H, t,> 6 , 1 Hz), 2.61 (3H, s), 2.35 (3H, s), 1.49 (3H, t,> 7.6 Hz).

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EXAMPLE 226

4-CHLORINE-2-ETHYL-6-METHYL 1- (4- (2 - [({((4-METHYLphenyl) SULFONINAMINO) CARBONIL) AMINO1ETYLJFENYL) -1H-IMlDAZOr4,5-c1PYRIDINE

STEP 1. 2- {4 - [(2-Chloro-6-methyl-3-nitro-4-pyridinyl) aminolfenylJ ethylcarbamate fer-butyl

A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine was heated at reflux for 16 hours (Chorvat, Robert J .; et al .; J. Med. Chem., 1999, 42, 833; 7.5 g, 36.2 mmoles), [2- (4-amino-phenyl) -ethyl] -carbamic acid fer-butyl ester (Stark, Peter A; et al .; J. Med. Chem., 1992, 35, 4264; 1.14 g, 4.83 mmoles) in / V, / V-diisopropylethylamine (50 ml). After cooling, the mixture was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with saturated aqueous NaHCO ₃ solution (50 ml x 2). The organic layer was dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / ethyl acetate (1: 1), gave 310 mg (16%) of the title compound as orange solids.

¹ H NMR (CDCl ₃ ) δ: 8.19 (1H, s), 7.28 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.3 Hz) , 6.69 (1H, s), 4.62 (1H, s lg.), 3.43-3.37 (2H, m), 2.84 (2H, t, J = 7.0 Hz), 2.37 (3H, s), 1.44 (9H, s).

STEP 2. 2- {4-r (3-Amino-2-chloro-6-methyl-4-pyridinyl) aminolfenyl) ethylcarbamate fer-butyl

The title compound was prepared according to the procedure described in step 1 of Example 6 from 2- {4 - [(2-chloro-6-methyl-3-nitro4-pyridinyl) amino] phenyl} ethylcarbamate butyl (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.18 (2H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.2 Hz), 6.76 (1H, s) , 6.02 (1H, s lg.), 4.61 (1H, s lg.), 3.40-3.37 (4H, m), 2.78 (2H, t, J = 7.0 Hz ), 2.33 (3H, s), 1.44 (9H, s).

STEP 3. 2- (44 (4-0loro-2-ethyl-6-methyl-1/7-imidazor4.5-c1pyridin-1yl) phenylethylcarbamate ferc-butyl

A mixture of 2- {4 - [(3-amino-2-chloro-6-methyl-4-pyridinyl) amino] phenyl} ethyl-butyl ferc-butyl (step 2, 238) was heated at reflux for 1 hour mg, 0.63 mmol), propionyl chloride (70 mg, 0.76 mmol) in to284 / 451 luene (4.6 mL) and dichloromethane (0.6 mL). After cooling, the mixture was diluted with ethyl acetate (100 ml) and washed with 1N aqueous NaOH solution (30 ml x 2) and brine (30 ml). The organic layer was dried (MgSO ₄ ), and concentrated. The residue and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) in toluene (5.0 mL) were heated at reflux for 16 hours. After cooling, the mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous NaHCO ₃ solution (30 ml) and brine (30 ml). The organic layer was dried (MgSO ₄ ), and concentrated. Purification by PTLC, eluting with hexane / ethyl acetate (1: 1), gave 90 mg (34%) of the title compound as a brown oil.

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d, J = 8.2 Hz), 7.27 (2H, d,> 8.2 Hz), 6.81 (1H, s), 4.75 (1H, s lg.), 3.52-3.44 (2H, m), 2.94 (2H, t,> 7.1 Hz), 2.82 (2H, d,> 7, 6 Hz), 2.55 (3H, s), 1.46 (9H, s), 1.32 (3H, t,> 7.6 Hz).

STEP 4. 2- (4-r (4-Chloro-2-ethyl-6-methyl-1/7-imidazof4,5-clpyridin-1ihphenylethanamine

Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added at 0 ° C under stirring to a solution of 2- {4 - [(4-chloro-2-ethyl-6-methyl-1 / 7imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl-butylcarbamate (step 3, 90 mg, 0.22 mmol) in dichloromethane (8.5 ml), and the mixture was stirred at 0 ° C for 30 minutes, and then at room temperature for 5 hours. The mixture was concentrated, and diluted with dichloromethane (50 ml), washed with saturated aqueous NaHCO ₃ solution (10 ml) and brine (10 ml). The organic layer was dried (MgSO ₄ ), and concentrated. Purification by PTLC, eluting with ethyl acetate, gave 50 mg (73%) of the title compound as a brown oil.

¹ H NMR (CDCb) δ: 7.45 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 6.81 (1H, s), 3.09 (2H, t, J = 6.9 Hz), 2.89 (2H, t, J = 6.8 Hz), 2.83 (2H, q, J = 7.4 Hz), 2, 55 (3H, s), 1.31 (3H, t, J = 7.4 Hz).

STEP 5. 4-Chloro-2-ethyl-6-methyl-1- (4-f2 - [((f (4-methylphenyl) sulfonillamino) carbonyl) amino1etil) phenyl) -1 / _7-I 5-imidazof4 clpiridina

The title compound was prepared according to the procedure 285/451 as described in step 10 of Example 1 from 2- {4 - [(4-chloro-2-ethyl-6-methyl1 / - / - imidazo [4 , 5-c] pyridin-1-yl) phenyl] ethanamine (step 4).

M.p .: 163 ° C.

MS (IED) m / z: 512 [(MH) ⁺ ], 510 [(MH) '],

¹ H NMR (CDCI ₃ ) δ: 7.73 (2H, d, J = 8.2 Hz), 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 = 7.2 Hz) , 2.52 (3H, s), 2.37 (3H, s), 1.29 (3H, t, J = 7.2 Hz).

EXAMPLE 227 (4-METHYLPHENYL) 2- [4- (2-ETHYL-4,6DIMETHYL-1 / - / - IMIDAZOf4,5-c1PYRIDIN-1-IL) SULPHONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-4,6-dimethyl-1/7-imidazo [4,5c] pyridin-yl) phenyl ] ethanol (step 4 of Example 42).

M.p .: 158 ° C.

MS (IED) m / z: 493 [(MH) ⁺ ], 491 [(MH) '].

¹ H NMR (DMSO-d ₆ ) δ: 7.72 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.0 Hz), 6.96 (1H, s), 4.18 (2H, t, J = 6.6 Hz) , 2.94 (2H, t, J = 6.4 Hz), 2.76 (3H, s), 2.74 (2H, q, J = 7.3 Hz), 2.50 (3H, s) , 2.35 (3H, s), 1.23 (3H, t, J = 7.3 Hz).

EXAMPLE 228 (4-METHYLphenyl) 2- [4- (8-ETHYL-2,6DIMETHIL-9H-PURIN-9-IDFENYL1ETHIL) SULPHONYL CARBAMATE

STEP 1. 2- {4 - [(6-Chloro-2-methyl-5-nitro-4-pyrimidinyl) aminol-phenyl} ethanol

4-Aminophenylethyl alcohol (2.47 g, 18.0 mmol) and triethylamine (3.65 g, 36.1 mmol) were added to a solution, with stirring, of 4,6dichloro-2-methyl-5-nitro -pyridine (Albert etal., J. Chem. Soc., 1954, 3832, 7.5 g, 36.1 mmoles) in THF (150 ml), and the mixture was stirred at room temperature for 1 hour. The reaction was terminated with the addition of water (10 ml), and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexa286 / 451 in ethyl acetate (gradient elution from 1: 1 to 1: 2) gave 4.0 g (72%) of the title compound as of a yellow solid.

¹ H NMR (CDCI ₃ ) δ: 9.34 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.8 Hz) , 3.89 (2H, t, J = 6.6 Hz), 2.90 (2H, t, J = 6.4 Hz), 2.57 (3H, s).

STEP 2. 2- (6-phi4- (2-Hydroxyethyl) phenyl1amino) -2-methyl-5-nitro-4pyrimidineDpropanedioate diethyl

Diethyl malonate (1.53 g, 9.54 mmoles) was added at 0 ° C with stirring to a solution of 2- {4 - [(6-chloro-2-methyl-5-nitro-4- pyrimidinyl) aminoj-phenyljetanol (step 1, 2.0 g, 6.48 mmoles) in acetone (61 ml), and then an aqueous solution of NaOH (11N, 2 ml, 22 mmoles) was added dropwise ) for 20 minutes. After the addition, the mixture was stirred at room temperature for 1 hour. The reaction was brusquely cooled with water (120 mL), and the pH value was adjusted to 8.0 by the addition of acetic acid. The whole was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. The removal of excess diethyl malonate, by azeotropic distillation with toluene, allowed 3.26 g (72%) of the title compound to be obtained, as a brown oil.

MS (IED) m / z: 432 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 10.15 (1H, s), 7.55 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz) , 5.36 (1H, s), 4.31 (4H, q, J = 7.1 Hz), 3.90 (2H, d, J = 6.6 Hz), 2.90 (2H, t, J = 6.4 Hz), 2.56 (3H, s), 1.32 (6H, t, J = 7.1 Hz).

STEP 3. 2- {4 - [(2,6-Dimethyl-5-nitro-4-pyrinriidinyl) amino1 phenyljetanol

A mixture of diethyl 2- (6 - {[4- (2-hydroxyethyl) phenyl] amino} -2-methyl-5-nitro-4-pyrimidinyl) -propanedioate was heated at reflux temperature for 5 hours ( step 2, 2.0 g, 6.48 mmoles) in 2N aqueous HCI solution (15 mL). After cooling, the reaction was terminated with saturated aqueous NaHCO ₃ solution (100 ml), and the whole was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / ethyl acetate (gradient elution 1: 1

287/451 to 0: 100), 1.33 g (71%) of the title compound was obtained as a yellow solid.

MS (IED) m / z: 288 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 9.81 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz) , 3.92-3.86 (2H, m), 2.89 (2H, t, J = 6.4 Hz), 2.76 (3H, s), 2.56 (3H, s).

STEP 4. 2- {4 - [(5-Amino-2 ₁ 6-dimethyl-4-pyrimidinyl) amino1phenyl) ethanol

The title compound was prepared according to the procedure described in step 1 of Example 6 from 2- {4 - [(2,6-dimethyl-5-nitro-4pyrimidinyl) amino] phenyl} ethanol (step 3) .

MS (IED) m / z: 258 (M ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ: 8.14 (1H, s), 7.63 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.4 Hz), 4.67 (2H, s lg.), 3.58 (2H, t, J = 7.3 Hz), 2.67 (2H, t, J = 7.2 Hz), 2.28 ( 3H, s), 2.20 (3H, s).

STEP 5. 2-yl- (8-ethyl-2,6-dimethyl-9H-purin-9-yl) phenylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(5-amino-2,6-dimethyl-4pyrimidinyl) amino] phenyl} ethanol (step 4) .

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 4.37 (2H, t, J = 6.9 Hz), 3.06 (2H, t, J = 6.8 Hz), 2.84 (3H, s), 2.82 (2H, q, J = 7.4 Hz), 2 , 70 (3H, s), 2.35 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz), 1.15 (3H, t, J = 7.6 Hz).

STEP 6. 2- [4- (8-Ethyl-2,6-dimethyl-9H-purin-9-yl) phenyl1ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (8-ethyl2,6-dimethyl-9/7-purin-9-yl) phenyl] propanoate ethyl (step 5).

¹ H NMR (CDCIs) δ: 7.46 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.3 Hz), 3.99-3.92 (2H , m), 2.99 (2H, t, J = 6.4 Hz), 2.85 (3H, s), 2.83 (2H, q, J = 7.5 Hz), 2.70 (3H , s), 1.32 (3H, t, J = 7.3 Hz).

STEP 7. 2- [4- (8-ethyl-2,6238 / 451 dimethyl-9H-purin-9-yl) phenylethyl (4-methylphenyl) sulfonicarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (8-ethyl-2,6-dimethyl-9/7-purin-9yl) phenyl] ethanol (step 6) .

M.p .: 162 ° C.

MS (IED) m / z: 494 [(MH) ⁺ ], 492 [(MH) '].

¹ H NMR (CDCI ₃ ) δ: 7.94 (2H, d, J = 8.4 Hz), 7.34 (2H, d,> 8.1 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.4 Hz), 4.36 (2H, t,> 6.4 Hz), 2.97 (2H, t,> 6.2 Hz), 2.86 (3H, s), 2.79 (2H, q,> 7.6 Hz), 2.64 (3H, s), 2.44 (3H, s), 1.28 (3H , t,> 7.6 Hz).

EXAMPLE 229 (2- (4- (4,6-DIMETHYL-2-PHENYL-1H-IMIDAZOr4,5-clPIRIDIN-1-IL) PHENYL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- (4- (4,6-dimethyl-2-phenyl-1 / - / - imidazo (4,5-c1 pyridin-1-yl) phenyl] ethyl benzoate

A mixture of 2- (4 - ((3 amino-2,6- dimethyl-4- pyridinyl) amino] phenyl} ethanol was heated at 120 ° C for 4 hours (step 2 of Example 42, 500 mg, 1 , 94 mmol), benzoic acid (4.45 g, 36.4 mmol) and benzoic anhydride (4.8 g, 21.2 mmol). After cooling, the mixture was diluted with dichloromethane (100 mL). the solution was diluted with aqueous NaHCO ₃ (50 mL), brine (50 mL), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with ethyl acetate, 813 mg (94%) of the title compound, as a white solid.

MS (IED) m / z: 447 (M ⁺ ).

¹ H NMR (CDCb) δ: 8.02-7.21 (14H, m), 6.87 (1H, s), 4.61 (2H, t, J = 7.0 Hz), 3.18 (2H, t, J = 6.8 Hz), 2.96 (3H, s), 2.61 (3H, s).

STEP 2. 2- (4- (4.6-Dimethyl-2-phenyl-1H-imidazo [4 ₁ 5-clpyridin-1-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- (4,6dimethyl-2-phenyl-1/7-imidazo [4,5-c] benzoate pyridin-1-yl) phenyl] ethyl (step 1).

’H NMR (CDCb) δ: 7.57-7.18 (9H, m), 6.87 (1H, s), 3.95 (2H,

289/451 t, J = 6.6 Hz), 2.96 (2H, t, J = 6.6 Hz), 2.94 (3H, s), 2.59 (3H, s).

STEP 3. 2-f4- (4,6-dimethyl-2-phenyl-1H-imidazor4,5-c1pyridin-1-yl) phenylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (4,6-dimethyl-2-phenyl-1H-imidazo [4,5c] pyridin-1-yl) phenyl ] ethanol (step 2).

M.p .: 194 ° C.

MS (IED) m / z: 541 [(MH) ⁺ ], 539 [(MH)].

¹ H NMR (CDCI ₃ ) δ: 7.89 (2H, d, J = 8.2 Hz), 7.46-6.95 (11H, m), 6.77 (1H, s), 4, 35 (2H, t, J = 6.0 Hz), 3.03 (3H, s), 2.96 (2H, t, J = 6.0 Hz), 2.56 (3H, s), 2, 42 (3H, s).

EXAMPLE 230 2-44- (2-BUTYL-4,6DIMETHIL-1-β-IMIDAZOf4,5-clPIRIDIN-1-IL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- [4- (2-Butyl-4.6-dimethyl-1H-imidazo f4,5-clpyridin-1-yl) pheninetyl pentanoate

The title compound was prepared according to the procedure described in step 1 of Example 229 from 2- {4 - [(3 ~ amino-2,6-dimethyl4-pyridinyl) amino] phenyl} ethanol (step 2 of Example 42).

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.2 Hz), 6.71 (1H, s) , 4.38 (2H, t, J = 6.9 Hz), 3.07 (2H, t, J = 6.9 Hz), 2.88 (3H, s),

2.78 (2H, t, J = 7.6 Hz), 2.56 (3H, s), 2.33 (2H, t, J = 7.4 Hz), 1.74-1.55 (4H , m), 1.41-1.24 (4H, m), 0.91 (3H, t, J = 7.2 Hz), 0.84 (3H, t, J = 7.2 Hz).

STEP 2. 2- [4- (2-Butyl-4.6-dimethyl-1H-imidazor4,5-clpyridin-1-yl) phenyrethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (2-butyl4,6-dimethyl-1 H-imidazo [4,5-c] pyridin pentanoate -1-yl) phenyl] ethyl (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.46 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.2 Hz), 6.72 (1H, s) , 4.00 (2H, t, J = 6.6 Hz), 3.02 (2H, t, J = 6.4 Hz), 2.88 (3H, s),

2.78 (2H, t, J = 7.6 Hz), 2.54 (3H, s), 1.76-1.64 (2H, m), 1.39-1.25 (2H, m) , 0.85 (3H, t, J = 7.4 Hz).

290/451

STEP 3. 2- [4- (2-Butyl ~ 4,6-dimethyl-1/7-imidazo [4 _l 5-clpyridin-1-yl) phenylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-butyl-4,6-dimethyl-1A7-imidazo [4,5c] pyridin-1-yl) phenyl ] ethanol (step 2).

M.p .: 162 ° C.

MS (IED) m / z: 521 [(MH) ⁺ ], 519 [(MH)].

¹ H NMR (CD ₃ OD) δ: 7.97 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.18 (2H, d , J = 8.4 Hz), 6.84 (2H, d, J = 8.4 Hz), 6.60 (1H, s), 4.34 (2H, t, J = 5.5 Hz), 3.03 (3H, s), 2.96 (2H, t, J = 5.5 Hz), 2.71 (2H, t, J = 7.5 Hz), 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 = 7.3 Hz) .

EXAMPLE 231

2- [4- (2-BUTYL-4,6-DIMETHYL-1H-IMIDAZO [4 ₁ 5-clPIRIDIN-1IUFENYL1ETYL] P-TOLUENOSULPHONATE

TsOH (1.0 eq.) Was added to a 2- [4- (2-butyl-4,6-dimethyl-1/7-imidazo [4,5-c] (4-methylphenyl) sulfonylcarbamate) solution pyridin-1-yl) phenyl] ethyl (Example 230) in methanol. The resulting mixture was stirred at room temperature for 5 minutes, and concentrated. Residual solids were removed and dried under reduced pressure at 50 ° C to obtain the title compound as white solids:

¹ H NMR (CDCI ₃ ) δ: 7.89-7.86 (4H, m), 7.49 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8 , 1 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.03 (1H, s), 4.34 ( 2H, t, J = 6.2 Hz), 3.12 (3H, s), 3.02 (2H, t, J = 6.2 Hz), 2.80 (3H, s), 2.77 ( 2H, t, J = 8.1 Hz), 2.42 (3H, s), 2.34 (3H, s), 1.78-1.68 (2H, m), 1.391.27 (2H, m ), 0.86 (3H, t, J = 7.3 Hz).

EXAMPLE 232 (2- (444,6-DIMETHIL-2- (1-METHYLETHIL) -1 / - / - 1MIDAZO [4,5-c] PIRIDIN-1-IL] PHENYL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- {4- [4,6-dimethyl-2- (1-methylethyl) 1/7-imidazo [4,5-c1pyridin-1-yl1-phenyl) ethyl 2-methylpropanoate

291/451

The title compound was prepared according to the procedure described in step 1 of Example 229 from 2- {4 - [(3-amino-2,6-dimethyl4-pyridinyl) amino] phenyl} ethanol (step 2 of Example 42).

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d,> 8.4 Hz), 7.26 (2H, d,> 8.4 Hz), 6.66 (1H, s), 4 , 38 (2H, t,> 7.0 Hz), 3.08 (2H, t,> 6.8 Hz), 3.12-3.02 (1H, m), 2.89 (3H, s) , 2.55 (3H, s), 2.61 - 2.48 (1H, m), 1.33 (6H, d,> 7.0 Hz), 1.15 (6H, d,> 7.0 Hz).

STEP 2. 2- {4-í4,6-Dimethyl-2- (1-methylethyl) -1B-imidazof4,5-clpyridin-1-illphenyl) ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4 [4,6-dimethyl-2- (1-methylethyl) -1 H-imidazo [2-methylpropanoate] 4,5-c] pyridin-1-yl] phenyl} ethyl (step 1).

¹ H NMR (CDCb) 8: 7.46 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.3 Hz), 6.68 (1H, s), 4.00 (2H, t, J = 6.6 Hz), 3.13-3.04 (1H, m), 3.02 (2H, t, J = 6.6 Hz), 2.88 (3H , s), 2.53 (3H, s), 1.33 (6H, d, J = 7.0 Hz).

STEP 3. 2- {4-y4,6-dimethyl-2 (1-methylethyl) -1H-imidazo [4,5-c1pyridin-1-infenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [4,6-dimethyl-2- (1-methylethyl) -1 / 7imidazo [4,5-c] pyridin -1-yl] phenyl} ethanol (step 2).

M.p .: 213°C.

MS (IED) m / z: 507 [(MH) ⁺ ], 505 [(MH)].

¹ H NMR (CD ₃ OD) δ: 7.80 (2H, d,> 8.4 Hz), 7.51 (2H, d,> 8.6 Hz), 7.34 (2H, d,> 8.6 Hz), 7.29 (2H, d,> 8.1 Hz), 7.01 (1H, s), 4.26 (2H, t,> 6.6 Hz), 3.15-3 .09 (1H, m), 3.00 (2H, t,> 6.4 Hz), 2.90 (3H, s), 2.58 (3H, s), 2.36 (3H, s), 1.33 (6H, d,> 6.8 Hz).

EXAMPLE 233 (2- {4-1,2- (1,1-DIMETHLETYL) -4,6-DIMETHYL-1/7-IMIDAZO [4,5-c1PIRlDIN-1-IL1FENIL) ETlLA 4-METHYLENIDSULFONYL

STEP 1 2- {4- [2- (1,1-dimethylethyl) -4,6dimethyl-1/7-imidazoyl4 ₁ 5-cyrpirin-1-yl-phenyl) ethyl 2,2-dimethylpropanoate

The title compound was prepared according to the procedure 292/451 as described in step 1 of Example 229 from 2- {4 - [(3-amino-2,6-dimethyl4-pyridinyl) amino] phenyl} ethanol ( step 2 of Example 42).

¹ H NMR (CDCI ₃ ) δ: 7.41 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 6.35 (1H, s) , 4.38 (2H, t, J = 6.6 Hz), 3.08 (2H, t, J = 6.6 Hz), 2.87 (3H, s),

2.50 (3H, s), 1.34 (9H, s), 1.17 (9H, s).

STEP 2. 2- (4- (2- (1,1-Dimethylethyl) -4,6-Dimethyl-1H-imidazo (4,5-cl pyridin-1-Phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2 {4- (2- (1,1-dimethylethyl) -4,6-dimethyl-2,2-dimethylpropanoate / - / - imidazo [4,5-c] pyridin-1-yl] phenyl} ethyl (step

1).

¹ H NMR (CDCI ₃ ) δ: 7.42 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.38 (1H, s) , 4.00 (2H, t, J = 6.4 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.87 (3H, s),

2.50 (3H, S), 1.34 (9H, s).

STEP 3. 2- (4- (2- (1,1-dimethylethyl) -4,6-dimethyl-1 / - / - imidazo (4,5-clpyridin-1-ylIfeniDetyl) 4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- (4- (2- (1,1-dimethylethyl) -4,6-dimethyl-1 Himidazo [4,5-c] pyridin-1-yl) phenyl] ethanol (step 2).

M.p .: 226 ° C.

MS (IED) m / z: 521 [(MH) ⁺ ], 519 [(MH) '].

¹ H NMR (DMSO-d ₆ ) δ: 7.71 (2H, d, J = 8.3 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.1 Hz), 6.55 (1H, s), 4.20 (2H, t, J = 7.0 Hz) , 2.95 (2H, t, J = 7.0 Hz), 2.74 (3H, s), 2.44 (3H, s), 2.36 (3H, s), 1.27 (9H, s).

EXAMPLE 234 (4-METILFENIDSULFONILCARBAMATO 2- (4- (2-cyclohexyl-4,6-dimethyl-1 H -imidazo _(4-1 5-1-clPIRIDIN ILlFENIL) ETHYL

STEP 1. 2- (4- (2-cyclohexyl-4,6-dimethyl-1H-imtdazor4.5-c1pyridin-1-iDphenylethyl cyclohexanecarboxylate

The title compound was prepared according to the procedure described in step 1 of Example 229 from 2- {4 - [(3-amino-2,6-dimethyl293 / 451

4-pyridinyl) amino] phenyl} ethanol (step 2 of Example 42).

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 6.65 (1H, s) , 4.39 (2H, t, J = 6.8 Hz), 3.08 (2H, t, J = 6.8 Hz), 2.88 (3H, s), 2.54 (3H, s) , 2.71-1.21 (22H, m).

STEP 2. 2-f4- (2-Cyclohexyl-4,6-dimethyl-1 H-imidazof4,5-pyridin1-iDphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2 [4- (2-cyclohexyl-4,6-dimethyl-1 / - / - imidazo [4,5-] cyclohexanecarboxylate c] pyridin-1-yl) phenyl] ethyl (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.46 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.2 Hz), 6.68 (1H, s) , 4.01 (2H, t, J = 6.4 Hz), 3.02 (2H, t, J = 6.4 Hz), 2.88 (3H, s), 2.72-2.70 ( 1H, m), 2.54 (3H, s), 2.30-1.15 (10H, m).

STEP 3. 2-f4- (2-cyclohexyl4.6-dimethyl-1H-imidazor4 ₁ 5-clpyridin-1-iDphenyl1ethyl 4-methylphenylsulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-cyclohexyl-4,6-dimethyl-1Himidazo [4,5-c] pyridin-1-yl) phenyl ] ethanol (step 2).

M. p .: 168 ° C.

MS (IED) m / z: 547 [(MH) ⁺ ], 545 [(MH) '].

¹ H NMR (CD ₃ OD) δ: 7.97 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.19 (2H, d , J = 8.3 Hz), 6.77 (2H, d, J = 8.2 Hz), 6.53 (1H, s), 4.33 (2H, t, J = 5.3 Hz), 3.09 (3H, s), 2.97 (2H, t, J = 5.5 Hz), 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-PHENYLPROPID-1H-IMIDAZOr4,5-clPIRIDIN-1-IL1-PHENIDETHYL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- {4-r4,6-dimethyl-2- (3-phenylpropylD1H-imidazo [4,5-c1pyridin-1-yl1-phenylDetyl) 4-phenylbutanoate

The title compound was prepared according to the procedure described in step 1 of Example 229 from 2- {4 - [(3-amino-2,6-dimethyl4-pyridinyl) amino] phenyl} ethanol (step 2 of Example 42).

¹ H NMR (CDCI ₃ ) δ: 7.39 (2H, d, J = 8.2 Hz), 7.30-7.15 (10H,

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m), 7.06 (2H, d, J = 6.4 Hz), 6.70 (1H, s), 4.37 (2H, t, J = 7.1 Hz), 3.06 (2H, t, J = 6.9 Hz), 2.88 (3H, s), 2.80 (2H, t, J = 7.6 Hz), 2.68-2.60 (4H, m), 2, 54 (3H, s), 2.36 (2H, t, J = 7.4 Hz), 2.09-1.91 (4H, m).

STEP 2. 2- {4- [4,6-Dimethyl-2- (3-phenylpropyl) -1H-imidazoyl4,5-clpyridin-1-yl1phenyl) ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- (4,6dimethyl-2- (3-phenylpropyl) -1 / - / - imidazo 4-phenylbutanoate [4,5-c] pyridin-1-yl] phenyl} ethyl (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.41 (2H, d, J = 8.2 Hz), 7.25-7.15 (5H, m), 7.07 (2H, d, J = 6 , 8 Hz), 6.72 (1H, s), 3.99 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.3 Hz), 2.88 ( 3H, s), 2.81 (2H, t, J = 7.6 Hz), 2.64 (2H, d, J = 7.6 Hz), 2.55 (3H, s), 2.11 2.00 (2H, m).

STEP 3. 2- (4- (4,6-dimethyl-2 (3-phenylpropyl) -1 / - / - Ímidazof4,5-clpiridin-1-illfenil) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- (4- (4,6-dimethyl-2- (3-phenylpropyl) -1AVimidazo [4,5-c] pyridin-1 -yl] phenyl} ethanol (step 2).

M.p .: 175 ° C.

MS (IED) m / z: 583 [(MH) ⁺ ], 581 [(MH) '].

¹ H NMR (CDCI ₃ ) δ: 7.95 (2H, d, J = 8.3 Hz), 7.30-7.14 (7H, m), 7.03 (2H, d, J = 8 , 1 Hz), 6.81 (2H, d, J = 8.0 Hz), 6.64 (1H, s), 4.33 (2H, t, J = 5.7 Hz), 3.00 ( 3H, s), 2.95 (2H, t, J = 5.7 Hz), 2.72 (2H, t, J = 7.5 Hz), 2.62 (2H, t, J = 7.4 Hz), 2.51 (3H, s), 2.41 (3H, s), 2.07-1.97 (2H, m).

EXAMPLE 236

4-METHYL-A / - P (TOLUENOSULPHONATE) - (((2- (4- [5- (METHYLoxy) -2- (1H-PIRAZOL-3-IL) -1H-BENZIMIDAZOL-1-IL1FENYL) ETHYL) AMINO1

CARBONIDBENZENOSULPHONAMIDE

STEP 1. 2- (4-F5- (Methyloxy) -2- (1H-pyrazol-3-yl) -1P-benzimidazole1-iriphenyltethanol

A mixture of 2- (44 (2-amino-4- (methyloxy) phenyl] amino} phenyl) ethanol (step 2 of Example 71, 1.95 g, 7, was heated at reflux for 2 hours). 56 mmoles), pyrazole-3-carbaldehyde (726 mg, 7.56 mmoles) in eta295 / 451 nol (45 mL). After cooling, the mixture was concentrated. Stirred at room temperature for 16 hours. mixture of the residue and lead tetraacetate (4.61 g, 8.32 mmoles) in benzene (50 ml) The reaction was brusquely cooled with saturated aqueous NaHCO ₃ solution (150 ml) and the whole was extracted with acetate ethyl acetate (150 ml x 4) The organic layer was washed with water (100 ml x 5), brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography , with elution with dichloromethane / methanol (gradient elution from 20: 1 to 10: 1), 408 mg (16%) of the title compound were obtained as an amber colored solid.

MS (IE) m / z: 334 (M ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ: 7.6 (1H, s lg.), 7.43 (2H, d, J = 7.7 Hz), 7.29-7.23 (3H, m ), 7.04 (1H, d, J = 8.8 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.34 (1H, s lg.), 3.85-3 , 81 (5H, m), 2.92 (2H, t, J = 6.6 Hz).

STEP 2. 1 - [4- (2-Chloroethyl) phenyl1-5- (methyloxy) -2- (1/7-pyrazol-3-yl) 1/7-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [5- (methyloxy) -2- (1 / 7pyrazol-3-yl) -1 / 7- benzimidazol-1-yl] phenyl} ethanol (step 1).

MS (IE) m / z: 352 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.96 (0.5H, s), 8.11 (0.5H, d, J = 2.9 Hz),

7.50 (0.5H, d, J = 2.0 Hz), 7.46-7.34 (5H, m), 7.05 (1H, dd, J = 16.5, 8.8 Hz) , 6.93 (1H, dd, J = 1.4, 9.0, 2.4 Hz), 6.71 (0.5H, dd, J = 2.9, 1.1 Hz), 5.81 (1H, s), 3.85 (3H, s), 3.82 (2H, t, J = 7.0 Hz), 3.22 (2H, t, J = 7.0 Hz).

STEP 3. 1-i4- (2-Azidoethyl) phenyl1-5- (methyloxy) -2- (1/7-pyrazol-3-iQ1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 8 in Example 1 from 1- [4- (2-chloroethyl) phenyl] -5 (methyloxy) -2- (1/7-pyrazole-3 -yl) -1 / 7-benzimidazole (step 2).

MS (IED) m / z: 359 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 14.05 (1H, s lg.), 7.53-7.50 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.01 (1H, d, J = 8.7 Hz), 6.89 (1H,

296/451 dd,> 8.7, 2.4 Hz), 5.81 (1H, s), 3.85 (3H, s), 3.61 (2H, t,> 6.9 Hz), 3 , 03 (2H, t,> 6.9 Hz).

STEP 4. 2- {4-f5- (Methyloxy) -2- (1A / -pyrazol-3-yl) -1H-benzimidazol1-yl1phenyl} ethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -5 (methyloxy) -2- (1/7-pyrazole-3- il) -1 / 7-benzimidazole (step 3).

MS (IE) m / z: 333 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.47 (1H, d,> 2.0 Hz), 7.43-7.29 (5H, m), 7.00 (1H, d,> 8.8 Hz), 6.88 (1H, dd,> 9.0, 2.4 Hz), 5.81 (1H, s), 3.80 (3H, s), 3.09 (2H, t,> 7 , 1 Hz), 2.90 (2H, t,> 6.8 Hz).

STEP 5. 4-Methyl- / V-fr (2-f4-r5- (methyloxy) -2- (1H-pyrazol-3-yl) -1Hbenzimidazol-1-illphenyl} ethyl) amino1carbonyl} benzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [5- (methyloxy) -2- (1 Hpyazol-3-yl) -1 / - / - benzimidazol-1-yl] phenyl} ethylamine (step 4).

MS (IED) m / z: 531 [(MH) ⁺ ], 529 [(MH) T

¹ H NMR (CDCI ₃ ) δ: 7.77 (2H, d, J = 8.3 Hz), 7.44 (1H, s), 7.24 (2H, d, J = 7.5 Hz) , 7.14-7.07 (5H, m), 6.98 (1H, d, J = 9.0 Hz), 6.88 (1H, d, J = 9.0 Hz), 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 6. 4-Methyl- / V- p-toluenesulfonamide mono-p-toluenesulfonate (1- (2- {4-15- (methyloxy) -2- (1/7-pyrazol-3-yl) -1 / - / - benzimidazol-1 -yljphenyl} ethyl) aminojcarbonyl} benzenesulfonamide

The title compound was prepared according to the procedure described in Example 231 from 4-methyl- / V - {[(2- {4- [5- (methyloxy) -2- (1 Hpyazol-3-i I) -1 / - / - benzimidazol-1 yl] phenyl} ethyl) amino] carbonyl} benzenesulfonamide (step 5).

¹ H NMR (CDCI ₃ ) δ: 12.65 (1H, s), 9.99 (1H, s), 7.87 (2H, d, J = 8.1 Hz), 7.78 (2H, d, J = 8.3 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 8.1 Hz), 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).

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EXAMPLE 237

2- (4-F5-METHILAXI-2- (W-PIRAZOL-3-IL) -1A / -BENZIMIDAZOL-1-IL1FEN1L1ET1LA P-TOLUENOSULPHONATE

STEP 1. 2-f4- [5- (methyloxy) -2 (1 / - / - pyrazol-3-yl) -1 / V-benzimidazole-1-ylIfeniDetila (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [5- (methyl] oxy) -2- (1/7-pyrazol-3-yl) -1Pbenzimidazole-1- il] phenyl} ethanol (step 1 of Example 236).

MS (IED) m / z: 532 [(MHf), 530 [(M-H)].

¹ H NMR (DMSO-d ₆ ) δ: 7.75 (2H, d, J = 8.1 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.33-7.21 (3H, m), 7.22 (2H, d, J = 8.1 Hz), 6.96 (1H, d, J = 8 , 1 Hz), 6.88 (1H, d, J = 8.1 Hz), 4.26-4.24 (2H, m), 3.82 (3H, s), 2.95-2.93 (2H, m), 2.34 (3H, s).

STEP 2. 2- {4- [5- (Methyloxy) -2- (1 H-pyrazol-3-yl) -1 / - / - benzimidazole- (4-methylphenyl) sulfonyl · carbamate mono-p-toluenesulfonate 1 -illfenilletila

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [5- (methyloxy) -2- (1P-pyrazol-3-yl) (4-methylphenyl) sulfonylcarbamate) -1P-benzimidazol-1-yl] phenyl} ethyl (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.88 (2H, d, J = 8.2 Hz), 7.80-7.65 (6H, m), 7.44 (2H, d, J = 8 , 1 Hz), 7.38-7.26 (3H, m), 7.17 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 7.6 Hz), 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-r6-CHLORO-2 (1,5-DIMETHIL-1/7-PIRAZOL-3-IL) -5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-IL1FENIDETYL

STEP 1. 2- (4 - {[5-chloro-2-nitro-4- (trifluoromethyl) pheninamino) phenyl) ethyl (4-methylphenyl) sulfonylcarbamate

P-Toluenesulfonyl isocyanate (574 mg, 2.91 mmol) was added to a solution, with stirring, of 2- (4 - ([5-chloro-2-nitro-4- (trifluoromethyl) fe298 / 451 nil] amino} phenyl) ethanol (step 2 of Example 104, 1.0 g, 2.77 mmoles) in dichloromethane (45 mL), and the mixture was stirred at room temperature for 2 hours. (100 ml) The organic layer was separated, the aqueous layer was extracted with dichloromethane (100 ml x 3). The combined organic layers were washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / ethyl acetate (gradient elution from 2.Ί to 1: 1), 1.51 g (98%) of the title compound was obtained under the in the form of an orange solid.

¹ H NMR (CDCI ₃ ) δ: 9.68 (1H, s), 8.58 (1H, s), 7.91 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.17 (1H, s) , 4.33 (2H, t, J = 7.0 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.45 (3H, s).

STEP 2. 2- (4-Ff2-amino-5chloro-4- (trifluoromethyl) phenyl1amino) phenyl) ethyl (4-methylphenyl) sulfonylcarbamate

5% sulfur platinum on carbon (600 mg) was added with stirring to a solution of 2- (4 - {[5 chloro-2-nitro-4- (trifluoromethyl) phenyl] amino (4-methylphenyl) sulfonylcarbamate } phenyl) ethyl (step 1, 1.51 g, 2.71 mmoles) in methanol (250 ml). 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 obtain 1.46 g (99%) of the title compound as a brown oil.

¹ H NMR (CDCI ₃ ) δ: 7.90 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.16 (1H, s) , 7.07 (2H, d, J = 8.2 Hz), 7.06 (1H, s), 6.86 (2H, d, J = 8.2 Hz), 5.40 (2H, s) , 4.26 (2H, t, J = 6.9 Hz), 2.85 (2H, t, J = 7.2 Hz), 2.44 (3H, s).

STEP 3. 2- (4-U5-chloro-2ff (1,5-dimethyl-1/7-pyrazol-3-yl) carbonyl1amino) -4- (trifluoromethyl) phenyl1amino) pheniPetyl (4-methylphenyl) sulfonylcarbamate)

A solution of 1,5-dimethyl-1 / - / - pyrazole-3-carboxylic acid (63.8 mg, 0.455 mmol) and A /, A / -diisopropylethylamine (118 mg, 0.909 mmol) in dichloromethane ( 1.7 mL) to a solution, with stirring, of 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) (4-methylphenyl) sulfonylcarbamate)

299/451 ethyl (step 2, 200 mg, 0.379 mmol) in dichloromethane (1.7 mL); then a solution of HOBt (61.5 mg, 0.455 mmol) and HBTU (431 mg, 1.14 mmol) in DMF (2.5 mL) was then added to the mixture, and the mixture was stirred at room temperature for 20 hours . The reaction was terminated by adding water (100 ml). The whole was extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with water (100 ml x 3), brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by PTLC, eluting with hexane / ethyl acetate (1: 1), gave 145 mg (59%) of the title compound as a red solid.

¹ H NMR (CDCI ₃ ) δ: 8.70 (1H, s), 7.87 (2H, d, J = 8.1 Hz), 7.79 (1H, s), 7.28 (2H, d, J = 8.1 Hz), 7.04 (2H, d, J = 8.3 Hz), 6.95 (2H, d, J = 8.3 Hz), 6.72 (1H, s) , 6.60 (1H, s), 4.22 (2H, t, J = 6.8 Hz), 3.78 (3H, s), 2.84-2.80 (2H, m), 2, 40 (3H, s), 2.30 (3H, s).

STEP 4. 2-F4-y6-chloro-2- (1,5dimethyl-1 / - / - pyrazol-3-yl) -5- (trifluoromethyl) -1H-benzimidazole-1-illfenyl (4-methylphenyl) sulfonylcarbamate ) ethyl

A mixture of 2- (4 {[5-chloro-2 - {[(1,5-dimethyl-1F / -pyrazol-3-yl) carbonyl] amino} -4- (2- (4-methylphenyl) sulfonylcarbamate) (trifluoromethyl) phenyl] amino} phenyl) ethyl (step 3, 145 mg, 0.223 mmol) in 2N NaOH (1 ml) and ethanol (2 ml) at 50 ° C for 85 hours. After cooling, the pH was adjusted to 4.0 with the addition of 2N HCI. The mixture was diluted with water (80 ml), and extracted with dichloromethane (80 ml x 3). The combined organic layer was washed with brine (50 ml), dried (MgSO ₄ ), and concentrated. Purification by PTLC, eluting with hexane / ethyl acetate (1: 3), gave 30 mg (21%) of the title compound as a red solid.

MS (IED) m / z: 632 [(MH) ⁺ ], 630 [(MH)].

¹ H NMR (CDCI ₃ ) δ: 8.15 (1H, s), 7.90 (2H, d, J = 8.4 Hz), 7,347.24 (6H, m), 7.19 (1H, s), 5.81 (1H, s), 4.40 (2H, t, J = 6.8 Hz), 3.76 (3H, s), 3.04 (2H, t, J = 6.4 Hz), 2.41 (3H, s), 2.20 (3H, s).

EXAMPLE 239 /V-í({2-{4-(2-BUTIL-4,6-DIMETlL-1/7-IMIDAZOf4.5 likeClPIRIDIN-1IL)FENIL1ETIL}AMINO)CARBONIL1-4-METILBENZENOSSULFONAMIDA

300/451

STEP 1. 2-Butyl-1-F4- (2-chloroethyl) phenyl1-4,6-dimethyl-1 H-imidazo f4,5-clpyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-butyl-4,6-dimethyl-1 / 7imidazo [4,5-c] pyridin- 1-yl) phenyl] ethanol (step 2 of Example 230).

MS (IE) m / z: 341 (M ⁺ ).

¹ H NMR (CDCb) 8: 7.45 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 6.73 (1H, s), 3.82 (2H, t, J = 7.1 Hz), 3.22 (2H, t, J = 7.1 Hz), 2.89 (3H, s), 2.79 (2H, d, J = 8.2 Hz), 2.58 (3H, s), 1.76-1.64 (2H, m), 1.39-1.25 (2H, m), 0.84 (3H, t, J = 7.2 Hz).

STEP 2. 1-F4- (2-Azidoethyl) phenyl1-2-butyl-4,6-di methyl-1/7-imidazo F4,5-clpyridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 2-butyl-1- [4- (2-chloroethyl) phenyl] 4.6-dimethyl-1W-imidazo [4,5- c] pyridine (step 1).

MS (IE) m / z: 348 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.46 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.6 Hz), 6.72 (1H, s) , 3.62 (2H, t, J = 6.8 Hz), 3.03 (2H, t, J = 6.8 Hz), 2.88 (3H, s), 2.78 (2H, d, J = 7.6 Hz), 2.55 (3H, s), 1.74-1.63 (2H, m), 1.38-1.24 (2H, m), 0.84 (3H, t , J = 7.3 Hz).

STEP 3. 244- (2-Butyl-4,6-dimethyl-1/7-imidazoF4,5-c] pyridin-1-yl) phenylethylamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -2-butyl4.6-dimethyl-1/7-imidazo [4 , 5-c] pyridine (step 2).

MS (IE) m / z: 322 (M ⁺ ).

'H NMR (CDCb) 8: 7.43 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.1 Hz), 6.72 (1H, s), 3.10-3.04 (2H, m), 2.90-2.86 (5H, m), 2.78 (2H, t, J = 7.7 Hz), 2.55 (3H, s) , 1.74-1.64 (2H, m), 1.35-1.25 (2H, m), 0.84 (3H, t, J = 7.3 Hz).

STEP 4. A / -F ({2-F4- (2-Butyl-4,6-dimethyl-1/7-imidazoF4,5-c1pyridin1-yl) phenyl1ethyl) amino) carbonill-4-methylbenzenesulfonamide

301/451

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-butyl-4,6-dimethyl-1 / 7imidazo [4,5-c] pyridin- 1-yl) -phenyl] ethylamine (step 3).

MS (IED) m / z: 520 [(MH) ⁺ ], 518 [(MH) '].

¹ H NMR (CDCI ₃ ) δ: 7.77 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.8 Hz), 7.19 (2H, d, J = 7.5 Hz), 6.76 (1H, s), 3.57-3.51 (2H, m), 2.92 ( 2H, t, J = 6.6 Hz), 2.88 (3H, s), 2.76 (2H, t, J = 7.5 Hz), 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 = 7.3 Hz).

STEP 5. / V - [((2-y4- (2-butyl-4,6d imethyl-1 / - / - imidazo [4,5-c1 pi ridin-1-yl) phenylethyl mono-p-toluenesulfonate ) amino) carboniri-4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 231 from / V - [({2- [4- (2-butyl-4,6-dimethyl-1 Himidazo [4,5-c] pyridin-1-yl) phenyl] ethyl} amino) carbonyl] -4-methylbenzenesulfonamide (step 4).

¹ H NMR (CDCI ₃ ) δ: 9.85 (1H, s lg.), 7.78 (4H, d, J = 8.1 Hz), 7.45 (2H, d, J = 7.9 Hz), 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 = 7.2 Hz).

EXAMPLE 240

2-R4- (2-ETHYL-5.7 ~ PIMETHYL-3H-1MIDAZ0r4,5-frlPYRIDIN-3-IL) PHENYL1-1-METHYLETHYL (4-METHYLPHYL) SULPHONYL CARBAMATE MONOCHLORHYDRATE

10% HCI in methanol (2 mL) was added, at room temperature, to a solution of 2- [4- (2-ethyl-5,7-dimethyl-5,7-dimethyl-3H-imidazo) (4,5-methylphenyl) sulfonylcarbamate [4,5 -ó] pyridin-3-yl) phenyl] -1-methylethyl (Example 7, 694 mg, 1.37 mmol) in methanol (4 mL). This mixture was concentrated, and treated with diethyl ether to obtain 624 mg (90%) of the title compound as a light yellow solid.

¹ H NMR (DMSO-d ₆ ) δ: 11.92 (1H, s lg.), 7.76 (2H, d, J = 7.9 Hz), 7.49-7.39 (6H, m ), 7.26 (1H, s lg.), 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 = 7.5 Hz), 1.12 (3H, d,

302/451

J = 6.1 Hz).

MS (IED) m / z: 507 [(MH) ⁺ ], 505 [(MH)].

EXAMPLE 241 /V-{{(2-f4-{5.7-DIMETIL-2-(3-FENILPROPIL)-3/7-IMIDAZO{4,5-ò1

PIRIDIN-3-IL] PHENYL) ETHYL) AMINO] CARBONYL) -4-METHYLBENZENOSULPHONAMIDE

A mixture of Á / - {[(2- {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} ethyl) amino] carbonyl was stirred at room temperature for 5 days } -4methylbenzenesulfonamide (step 4 of Example 162, 86 mg, 0.19 mmol), 4-phenylbutyric acid (37 mg, 0.23 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (40 mg , 0.21 mmol). The mixture was concentrated to obtain an orange syrup. This matter was dissolved in toluene (8 ml), p-toluenesulfonic acid monohydrate (3 mg, 0.02 mol) was added, and then stirred 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, eluting the plates with hexane / ethyl acetate (1: 3) produced 32 mg (29%) of the title compound, as a colorless solid.

¹ H NMR (CDCI ₃ ) δ: 7.85 (2H, d, J = 8.4 Hz), 7.31-7.01 (11H, m), 6.91 (1H, s), 3, 52-3.45 (2H, m), 2.83 (2H, t, J = 6.4 Hz), 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 (IED) m / z: 582 [(MH) ⁺ ], 580 [(MH) '].

EXAMPLE 242 / V-fr (2-f4-r5,7-DIMETHIL-2- (3-OXO-3-PHENYLPROPIL) -3 / 7-IMIDAZOf4,5-blPIRIDIN-3-IL1FENIL) ETHYL) AMINO1CARBONIL) -4- Methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 241 from A / - ([(2- {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (step 4 of Example 162) and 3-benzoylpropionic acid.

¹ H NMR (CDCI ₃ ) δ: 8.04-7.14 (11H, m), 6.90 (1H, s), 6.206.15 (1H, m), 3.50-3.38 (4H , m), 3.03-2.81 (4H, m), 2.56 (3H, s), 2.44 (3H,

303/451

s), 2.41 (3H, s).

MS (IED) m / z: 596 [(MH) ⁺ ], 594 [(MH) '].

EXAMPLE 243

3-PYRIDINYLSULPHONYL CARBAMATE OF 2-Y4-F6-CLQRQ-2ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-ILylphenyl) ETHYL

STEP 1. 2- (4-F6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl-phenyl) ethyl phenyl carbonate

Phenyl chloroformate (1.6 mL, 12.7 mmol) was added dropwise to a stirred solution of 2- [4- (6-chloro-2-ethyl-5-trifluoromethyl-1 / 7benzimídazol-1-yl) phenyl] ethanol (step 4 of Example 104, 3.90 g, 10.6 mmoles) in dichloromethane (20 ml) and pyridine (2 ml), and the mixture was stirred at room temperature for 16 hours. hours. The reaction mixture was diluted with dichloromethane (50 ml), and washed with water (50 ml). The organic layer was dried over Na2SO ₄ , and concentrated under reduced pressure. Purification by flash column chromatography, eluting with hexane / ethyl acetate (3: 1) yielded 4.2 g (82%) of the title compound as a colorless syrup.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.53-7.15 (10H, m), 4.56 (2H, t, J = 6.8 Hz), 3, 20 (2H, t, J = 6.8 Hz), 2.79 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

MS (IE) m / z: 488 (M ⁺ ).

STEP 2. 2-f4-F6-chloro-2-ethyl-5-trifluoromethiD-1 / - / - benzimidazole-1 -illphenylethyl 3-pyridinylsulfonylcarbamate

NaH (60% oil dispersion, 27 mg, 0.68 mmol) was added at room temperature to a solution, with stirring, of 3-pyridinesulfonamide (Rafik, Karaman; et al .; J. Am. Chem Soc., 1992, 114, 4889; 120 mg, 0.76 mmol) in DMF (3 mL). After 10 minutes, phenyl 2- (4- (2-ethyl-5,7-dimethyl-3F / -imidazole [4,5-o] pyridin-3-yl) phenif] ethylcarbamate (step 1, 313 mg, 0.64 mmol), and the mixture was stirred for 9 hours at 80 ° C. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried (Na2SO ₄ ), and concentrated. Purification by TLC, eluting with dichloromethane / methanol (6: 1) and by TLC, eluting

304/451 with dichloromethane / methanol (10: 1) yielded 67 mg (19%) of the title compound, as a colorless solid.

¹ H NMR (CDCI ₃ ) 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 (IED) m / z: 553 (MH ⁺ ), 551 ([MH] ').

EXAMPLE 244

2-PYRIDINYLSULPHONYL CARBAMATE OF 2- {4- [6-CHLORINE-2ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-ILylphenyl) ETHYL

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T .; et a / .; Chem. Pharm. Bull., 1955, 3, 38) and 2- [4- (2-ethyl-5,7-dimethyl3H-imidazo [4,5-o] pyridin-3-iI) phenyl] ethylcarbamate (step 1 of Example 243).

M.p .: 127.0-130.0 ° C.

¹ H NMR (CDCI ₃ ) 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 = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.17 (1H, s), 4.37 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 6.8 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

MS (IED) m / z: 553 (MH ⁺ ), 551 ([MH] ').

EXAMPLE 245

4-PYRIDINYLSULPHONYL CARBAMATE OF 2- {4-r6-CHLORO-2ETHYL-5- (TRtFLUOROMETHYL) -1H-BENZIMIDAZOL-1-ILylphenyl) ETHYL

The title compound was prepared according to the procedure described in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie, A. M ,; et al .; J. Chem. Soa, 1958, 3514) and 2- [4- (2-ethyl-5,7-dimethyl3 / 7-imidazo [4,5-b] pyridin-3-yl) phenyl] ethylcarbamate (step 1 of Example 243).

¹ H NMR (CDCI ₃ ) δ: 8.82 (2H, d, J = 5.2 Hz), 8.10 (1H, s), 7.87 (2H, d, J = 4.9 Hz) , 7.44 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.20 (1H, s), 4.34 (2H, t, J = 7.3 Hz), 3.04 (2H, t, J = 7.3 Hz), 2.78 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

MS (IED) m / z: 553 (MH ⁺ ), 551 ([MH]).

305/451

EXAMPLE 246 (4-METHYLPHENYL) 2-r4- (5-ACETYL-2ETiL-1 / - / - BENZIMIDAZOL-1-IL) PHENYL1-1-METHYLETH SULPHONYL

STEP 1. 1- (4-U4- (2-Hydroxypropyl) pheninamino} -3-nitrophenyl) -ethanone

The title compound was prepared according to the procedure described in step 1 of Example 162 from 1- (4-chloro-3-nitrophenyl) ethanone and 1- (4-aminophenyl) -2-propanol (step 1 of Example 6).

¹ H NMR (CDCb) δ: 9.85 (1H. S lg.). 8.83-8.82 (1H.m). 7.997.95 (1H, m), 7.33 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.18 (1H, d, J = 9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H, d, J = 6.2 Hz).

STEP 2. 1 - (3-Amino-4 - {[4- (2-hydroxypropyl) phenylamino} phenyl) -ethanone

The title compound was prepared according to the procedure described in step 4 of Example 1 from 1- (4 - {[4- (2-hydroxypropyl) phenyl] amino} -3-nitrophenyl) ethanone (step 1) .

MS (IE) m / z: 284 (M ⁺ ).

STEP 3. 2-r4- (5-acetyl-2-ethyl-1/7-benzimidazol-1yl) phenyl-1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- (3-amino-4 - {[4- (2-hydroxypropyl) phenyl] amino} phenyl) ethanone (step 2 ).

¹ H NMR (CDCl ₃ ) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m),

7.92-7.89 (1H, m), 7.43 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.12-7 .09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J = 7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J = 7.5 Hz), 1.32 (3H, d, J = 6, 2 Hz),

1.10 (3H, t, J = 7.5 Hz).

STEP 4. 1- {2-Ethyl-1-r4- (2-hydroxypropyl) phenyl1-1 / 7-benzimIDazole-5i peta nona

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-acetyl306 / 451 propanoate)

2-ethyl-1 H-benzimidazol-1-yl) phenyl] -1-methylethyl (step 3).

¹ H NMR (CDCI ₃ ) δ; 8.39 (1H, s), 7.89-7.86 (1H, m), 7.47 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8, 3 Hz), 7.13-7.10 (1H, m), 4.23-4.13 (1H, m), 2.94-2.86 (2H, m), 2.80 (2H, q , J = 7.5 Hz), 2.66 (3H, s), 1.39-1.33 (6H, m).

STEP 5. 2- [4- (5-acetyl-2-ethyl · 1-benzimidazol-1-yl) phenyl] -1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- {2-ethyl-1- [4- (2-hydroxypropyl) phenyl] -1 Hbenzimidazol-5-yl} ethanone (step 4 ).

¹ H NMR (CDCI ₃ ) δ: 8.40 (1H, d, J = 1.1 Hz), 7.91-7.86 (3H, m),

7.32-7.24 (4H, m), 7.17 (2H, d, J = 7.9 Hz), 7.07 (1H, d, J = 8.4 Hz), 5.09-5 , 03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J = 7.5 Hz), 2.67 (3H, s), 2.37 ( 3H, s),

1.33 (3H, t,> 7.5 Hz), 1.21 (3H, d,> 6.1 Hz).

MS (IED) m / z: 520 (MH ⁺ ), 518 ([MH] ').

EXAMPLE 247 (4-METHYLPHENYL) 2- {4-r6-CHLORO-2ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL-PHYLYL) -1-METHYLETHYL

STEP 1. 1- (4- {(5-Chloro-2-nitro-4- (trifluoromethyl) phenylamino) phenyl) 2-propanol

The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and 1- (4-aminophenyl) -2-propanol (step 1 of Example 6) .

¹ H NMR (CDCb) δ: 9.69 (1H, s lg.), 8.58 (1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.24 (2H , d, J = 8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 ( 1H, d, J = 4.2 Hz), 1.30 (3H, d, J = 6.2 Hz).

STEP 2. 1- (4- (r2-Amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) -2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 1- (4 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl] amino} phenyl) -2- propanol (step 1).

¹ H NMR (CDCb) δ: 7.17 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.06

307/451 (1Η, s), 6.90 (2H, d, J = 8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m) , 1.26 (3H, d, J = 6.3 Hz).

STEP 3. 2- {4-r6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-1-phenyl) -1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) -2- propanol (step 2).

MS (IE) m / z: 438 (MH ⁺ ).

STEP 4. 1- (4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 AZ-benzimidazole1- iriphenyl) -2-propanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [6-chloro2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] propanoate phenyl} -1-methylethyl (step 3).

¹ H NMR (CDCfe) δ: 8.12 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79 (2H, q, J = 7.5 Hz) , 1.56 (1H, d, J = 4.2 Hz), 1.36 (3H, t, J = 7.5 Hz), 1.34 (3H, d, J = 6.2 Hz).

STEP 5. 2- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / 7-benzimidazole-1-infenyl) -1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7benzimidazol-1-yl] phenyl} - 2-propanol (step 4).

¹ H NMR (CDCI ₃ ) δ: 8.09 (1H, s), 7.87 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz) , 7.31 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 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 = 7.5 Hz), 1.23 (3H, d , J = 6.2 Hz).

MS (IED) m / z: 580 (MH ⁺ ), 578 ([MH] ').

EXAMPLE 248 (1-S) -2-R4- (5-ACETYL-2-ETHYL-1H-BENZIMIDAZOL-1-IUFENYL-1-METHYLETHYL 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. (2S) -1- (4-Nitrophenyl) -2-propanol and (1R) 1-Methyl-2- (4-nitrophenyl) ethyl propanoate

308/451

Lipase PS / Cefite (0.5 g, Bianichi, D. et al; J. Org. Chem., 1988, 53, 5531) was added to a mixture of 1- (4-nitrophenyl) -2-propanol (Schadt , FL et al; J. Am. Chem. Soa, 1978, 100, 228; 2.5 g, 13.8 mmol) and propanoic anhydride (1.8 g, 13.8 mmol) in benzene (34 mL). 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 a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / diethyl ether (4: 1 to 1: 1), produced 1.91 g (58%) of (1 /?) - 1-methyl-2- ( 4nitrophenyl) ethyl, in the form of a very light yellow oil and 1.14 g (46%) of (2S) -1- (4-nitrophenyl) -2-propanol as a colorless solid (93% ee) . Recrystallization of 1.14 g of (2S) -1- (4-nitrophenyl) -2-propanol, from hexane / diethyl ether, provided 617 mg of colorless needles (99% ee).

(1 R) -1-Methyl-2- (4-nitrophenyl) ethyl propanoate

¹ H NMR (CDCb) δ: 8.16 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz), 5.22-5.11 (1H , m), 3.04-2.87 (2H, m), 2.30-2.19 (2H, m), 1.26 (3H, d, J = 6.1 Hz), 1.07 ( 3H, t, J = 7.5 Hz).

(2S) -1- (4-Nitrophenyl) -2-propanol

¹ H NMR (CDCI ₃ ) δ: 8.18 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 4.14-4.04 ( 1H, m), 2.92-2.79 (2H, m), 1.49 (1H, d, J = 4.0 Hz), 1.28 (3H, d, J = 6.1 Hz).

[oc] ²³ d = ⁺ 31.0 ° (c 1.00, diethyl ether).

STEP 2. (2S) -1- (4-Aminophenyl) -2-propanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from (2S) -1- (4-nitrophenyl) -2propanol (step 1).

¹ H NMR (CDCb) δ: 7.00 (2H, d, J = 8.4 Hz), 6.65 (2H, d, J = 8.4 Hz), 3.99-3.89 (1H , m), 3.60 (2H, s lg.), 2.73-2.52 (2H, m), 1.22 (3H, d, J = 6.2 Hz).

STEP 3. 1-F4- (f4-r (2S) -2-Hydroxypropylphenyl) amino) -3-nitrofe309 / 451 nillethanone

The title compound was prepared according to the procedure described in step 1 of Example 162 from 1- (4-chloro-3-nitrophenyl) ethanone and (2S) -1- (4-aminophenyl) -2-propanol (step 2).

¹ H NMR (CDCI ₃ ) δ: 9.85 (1H, s Ig.), 8.83-8.82 (1H, m), 7.997.95 (1H, m), 7.33 (2H, d , J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.18 (1H, d, J = 9.0 Hz), 4.13-4.04 (1H , m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H, d, J = 6.2 Hz).

STEP 4. 1-i3-Amino-4- (f4-i (2S) -2-hydroxypropyl1phenyl) amino) phenyl1 ethanone

The title compound was prepared according to the procedure described in step 4 of Example 1 from 1- [4 - ({4 - [(2S) -2-hydroxypropyl] phenyl} amino) -3-nitrophenyl] ethanone (step 3).

MS (IE) m / z: 284 (M ⁺ ).

STEP 5. (1S) -2- [4- (5-acetyl-2-ethyl-1B-benzimidazole-1-yl) phenyl1-1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- [3-amino-4 - ({4 - [(2S) -2hydroxypropyl] phenyl} amino) phenyl] ethanone ( step 4).

¹ H NMR (CDCI ₃ ) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m),

7.92-7.89 (1H, m), 7.43 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.12-7 .09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J = 7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J = 7.5 Hz), 1.32 (3H, d, J = 6, 2 Hz),

1.10 (3H, t, J = 7.5 Hz).

STEP 6. 1- (2-Ethyl-1 - {4-i (2S) -2-hydroxypropylphenyl} -1 B-benzimidazol-5-yl) ethanone

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1 S) -2- [4- (5acetyl-2-ethyl-1 B-benzimidazol-1-yl) propanoate phenyl] -1-methylethyl (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.39 (1H, d, J = 1.1 Hz), 7.87 (1H, dd, J = 8.6, 1.1 Hz), 7.48 ( 2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.12 (1H, d, J = 8.6 Hz), 4.22-4, 12 (1H, m), 2.94-2.89 (2H, m), 2.80 (2H, q, J = 7.5 Hz), 2.69

310/451 (3Η, s), 2.42 (1H, s lg.), 1.37 (3H, t, J = 7.5 Hz), 1.33 (3H, d, J = 6.2 Hz ).

STEP 7. (1S) -2-r4- (5-acetyl-2ethyl-1 H-benzimidazol-1-yl) phenyl] -1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- (2-ethyl-1- {4 - [(2S) -2-hydroxypropyl] phenyl} 1/7-benzimidazole-5- il) ethanone (step 6).

¹ H NMR (CDCI ₃ ) δ: 8.40 (1H, d, J = 1.1 Hz), 7.91-7.86 (3H, m),

7.32-7.24 (4H, m), 7.17 (2H, d, J = 7.9 Hz), 7.07 (1H, d, J = 8.4 Hz), 5.09-5 , 03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J = 7.5 Hz), 2.67 (3H, s), 2.37 ( 3H, s),

1.33 (3H, t, J = 7.5 Hz), 1.21 (3H, d, J = 6.1 Hz).

MS (IED) m / z: 520 (MH ⁺ ), 518 ([MH] ^- ).

M ²⁴ d = - 3.09 ° (c 0.120, methanol).

EXAMPLE 249 (1R) -2- [4- (5-ACETYL-2-ETHYL-1/7-BENZIMIDAZOL-1-IL) 4-METHYLENIDSULFONYL CARBAMATE PHENYLM-methylethyl

STEP 1. (2R) -1- (4-Nitrophenyl) -2-propanol

A 2N aqueous solution of NaOH (5 mL) was added, at room temperature, to a solution of (1 R) -1-methyl-2- (4-nitrophenyl) ethyl propanoate (step 1 of Example 248, 1.91 g , 8.05 mmol) in ethanol (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted with diethyl ether (2 x 50 ml). The organic layer was washed with brine, dried (MgSO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / diethyl ether (1: 1), produced 1.16 g (80%) of the title compound as a colorless solid (79% ee). Recrystallization from hexane / diethyl ether provided 717 mg of colorless needles (99% ee).

¹ H NMR (CDCI ₃ ) δ: 8.18 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 4.14-4.04 ( 1H, m), 2.92-2.79 (2H, m), 1.49 (1H, d, J = 4.0 Hz), 1.28 (3H, d, J = 6.1 Hz).

[cx] ²³ d = - 32.6 ° (c 1.00, diethyl ether),

STEP 2. (2 /?) - 1- (4-Aminophenii) -2-propanol

311/451

The title compound was prepared according to the procedure described in step 4 of Example 1 from (2R) -1- (4-nitrophenyl) -2propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.00 (2H, d, J = 8.4 Hz), 6.65 (2H, d, J = 8.4 Hz), 3.99-3.89 ( 1H, m), 3.60 (2H, s lg.), 2.73-2.52 (2H, m), 1.22 (3H, d, J = 6.2 Hz).

STEP 3. 1 -f4 - ({4-f (2 /?) - 2-Hydroxypropyl-phenyl) amino) -3-nitrophenillethanone

The title compound was prepared according to the procedure described in step 1 of Example 162 from 1- (4-chloro-3-nitrophenipethanone and (2R) -1- (4-aminophenyl) -2-propanol (step 2) .

¹ H NMR (CDCfe) δ: 9.85 (1H, s lg.), 8.83-8.82 (1H, m), 7.997.95 (1H, m), 7.33 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.18 (1H, d, J = 9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H, d, J = 6.2 Hz).

STEP 4. 1-r3-Amino-4 - ({4-r (2 /?) - 2-hydroxypropyl1pheniQamino) phenylethanone

The title compound was prepared according to the procedure described in step 4 of Example 1 from 1- [4 - ({4 - [(2R) -2-hydroxypropyl] phenyl} amino) -3-nitrophenyl] ethanone (step 3).

MS (IE) m / z: 284 (M ⁺ ).

STEP 5. (1R) -2-4- (5-acetyl-2-ethyl-1/7-benzimidazole-1-iPphenyl-1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- [3-amino-4 - ({4 - [(2 /?) - 2hydroxypropyl] phenyl} amino) phenyl] ethanone (step 4).

¹ H NMR (CDCI ₃ ) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m),

7.92-7.89 (1H, m), 7.43 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.12-7 .09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J = 7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J = 7.5 Hz), 1.32 (3H, d, J = 6, 2 Hz),

1.10 (3H, t, J = 7.5 Hz).

STEP 6. 1- (2-Ethyl-1- {4 - [(2R) -2-hydroxypropinphenP-1/7-benzimID312 / 451 dazol-5-yl) ethanone

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1 R) -2- [4- (5acetyl-2-ethyl-1/7-benzimidazol-1-yl propanoate ) phenyl] -1-methylethyl (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.39 (1H, d, J = 1.1 Hz), 7.87 (1H, dd, J = 8.6, 1.1 Hz), 7.48 ( 2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.6 Hz), 4.22-4, 12 (1H, m), 2.94-2.89 (2H, m), 2.80 (2H, q, J = 7.5 Hz), 2.69 (3H, s), 2.42 (1H , s lg.), 1.37 (3H, t, J = 7.5 Hz), 1.33 (3H, d, J = 6.2 Hz).

STEP 7. (1 /?) - 2- [4- (5-acetyl-2-ethyl-1 / - / - benzimidazole-1-yl) phenyl1-1-methylethyl (4-methylphenylsulfonylcarbamate)

The title compound was prepared according to the procedure described in Example 3 from 1- (2-ethyl-1- {4 - [(2R) -2-hydroxypropyl] phenyl} 1/7-benzimidazole-5- il) ethanone (step 6).

¹ H NMR (CDCI ₃ ) δ: 8.40 (1H, d, J = 1.1 Hz), 7.91-7.86 (3H, m),

7.32-7.24 (4H, m), 7.17 (2H, d, J = 7.9 Hz), 7.07 (1H, d, J = 8.4 Hz), 5.09-5 , 03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J = 7.5 Hz), 2.67 (3H, s), 2.37 ( 3H, s),

1.33 (3H, t, J = 7.5 Hz), 1.21 (3H, d, J = 6.1 Hz).

MS (IED) m / z: 520 (MH ⁺ ), 518 ([MH]).

[ct] ²⁴ D = + 6.05 ° (c 0.118, methanol).

EXAMPLE 250 ((1S) -2- {4- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL1-PHENYL) -1METHYLETHYL

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 step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2S) -1- (4-aminophenyl) -2-propanol (step 2 Example 248).

¹ H NMR (CDCI ₃ ) δ: 9.69 (1H, s lg.), 8.58 (1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.24 ( 2H, d, J = 8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 (1H, d, J = 4.2 Hz), 1.30 (3H, d, J = 6.2 Hz).

STEP 2. (2S) -1 - (4 - {[2-Amino-5-chloro-4- (trifluoromethyl) phenyl1am313 / 451 no) phenyl) -2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from (2S) -1- (4 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl] amino} phenyl ) -2-propanol (step 1).

'H (CDCb) δ NMR: 7.17 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.06 (1H, s), 6.90 (2H, d , J = 8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m), 1.26 (3H, d, J = 6.3 Hz) .

STEP 3. (1S) -2- (4- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl1-phenyl) -1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from (2S) -1- (4 - {[2-amino-5-chloro4- (trifluoromethyl) phenyl] amino} phenyl) -2-propanol (step 2).

MS (IE) m / z: 438 (M ⁺ ).

STEP 4. (2S) -1- (4-i6-Ctoro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-1-infenyl) -2-propanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1 S) -2- {4- [6 chloro-2-ethyl-5- (trifluoromethyl) -1 H- propanoate benzimidazol-1-yl] phenyl} -1-methylethyl (step 3).

¹ H NMR (CDCb) δ: 8.12 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79 (2H, q, J = 7.5 Hz) , 1.56 (1H, d, J = 4.2 Hz), 1.36 (3H, t, J = 7.5 Hz), 1.34 (3H, d, J = 6.2 Hz).

STEP 5. (1S) -2- {4-r6-chloro-2ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole-1-yl1-phenyl} -1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from (2S) -1- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) -7 1 / - / - benzimidazole -1-yl] phenyl} -2-propanol (step 4).

M.p .: 200.3 ° C.

¹ H NMR (CDCb) δ: 8.09 (1H, s), 7.87 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 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 = 7.5 Hz), 1.23 (3H, d, J = 6.2 Hz).

314/451

MS (IED) m / z: 580 (MH ⁺ ), 578 ([MH] ').

[a] ²⁴ D = + 1.31 ° (c 0.398, methanol), ee: 98%.

EXAMPLE 251

(4-METHYLPHENYL) (1S) -2- {446-CLQRO-2-ETYL-5- (TRIFLUORQMETHIL) -1 / - / - BENZIMIDAZOL-1-IUFENIL) -1-METHYLETHYL MONO-P-TOLUENOSULPHONATE

The title compound was prepared according to the procedure described in Example 231 from (1S) -2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) - (4-methylphenyl) sulfonylcarbamate - 1 / - / - benzimidazol-1-yl] phenyl} -1methylethyl (step 5 of Example 250).

¹ H NMR (DMSO-dg) δ: 11.91 (1H, s lg.), 8.23 (1H, s), 7.75 (2H, d, J = 8.3 Hz), 7.50 -7.37 (9H, m), 7.11 (2H, d, J = 8.1 Hz), 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 = 7.3 Hz), 1.14 (3H, d, J = 6.2 Hz ).

MS (IED) m / z: 580 (MH ⁺ ), 578 ([MH] “).

EXAMPLE 252 ((1 /?) - 2- (4-6-CHLORINE-2-ETHYL-5- (TRIFLUOROMETID-1 / - / - BENZIMIDAZOL-1-IL1FEN1D-1METHYLETHYL)

STEP 1. (2P) -1- (4-U5-Chloro-2-nitro-4- (trifluoromethyl) phenyl1amino} phenyl) -2-propanol

The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2 /?) - 1- (4-aminophenyl) -2-propanol ( step 2 of Example 249).

¹ H NMR (CDCI ₃ ) δ: 9.69 (1H, s lg.), 8.58 (1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.24 ( 2H, d, J = 8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 (1H, d, J = 4.2 Hz), 1.30 (3H, d, J = 6.2 Hz).

STEP 2. (2 /?) - 1 - (4- (r2-Amino-5-chloro-4- (trifluoromethyl) phenillamiηοΐ phenyl) -2-propanol

The title compound was prepared according to the procedure 315/451 as described in step 2 of Example 28 from (2R) -1- (4 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl] amino} phenyl) -2-propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.17 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.06 (1H, s), 6.90 (2H, d, J = 8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m), 1.26 (3H, d, J = 6.3 Hz ).

STEP 3. (1R) -2-f4-í6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl) -1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from (2R) -1- (4 - {[2-amino-5-chloro4- (trifluoromethyl) phenyl] amino} phenyl) -2-propanol (step 2).

MS (IE) m / z: 438 (M ⁺ ).

STEP 4. (2R) -1- {4- [6-Chloro-2-ethyl-5- (trifluoromethyl) -1 B-benzimidazol-1-yl] phenyl) -2-propanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1 /?) - 2- {4- [6chloro-2-ethyl-5- (trifluoromethyl) -1 / propanoate 7-benzimidazol-1-yl] phenyl} -1-methylethyl (step 3).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz) , 7.21 (1H, m), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79 (2H, q, J = 7.5 Hz ), 1.56 (1H, d, J = 4.2 Hz), 1.36 (3H, t, J = 7.5 Hz), 1.34 (3H, d, J = 6.2 Hz).

STEP 5. (1 /?) - 2- (4-6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole-1-yl-phenyl) -1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from (2R) -1- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) 1/7-benzimidazole-1- yl] phenyl} -2-propanol (step 4).

M. p .: 199.9 ° C.

¹ H NMR (CDCI ₃ ) δ: 10.70 (1H, s lg.), 8.10 (1H, s), 7.89 (2H, d, J = 8.3 Hz), 7.40 ( 2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.20 (1H, s), 5.32-5.00 (1H, m), 3.04-2.82 (2H, m), 2.78 (2H, q, J = 7.5 Hz), 2.40 (3H , s), 1.36 (3H, t, J = 7.5 Hz), 1.23 (3H, d, J = 6.2 Hz).

MS (IED) m / z: 580 (MH ⁺ ), 578 ([MH] ').

[a] ²⁴ D = - 2.19 ° (c 0.402, methanol).

316/451

e.e .: 97%.

EXAMPLE 253 / V- {r (2- {4-16-CHLORINE-2-ETHYL-5- (TRIFLUORQMETHYL) -1 / 7BENZIMIDAZOL-1-ILylphenyl) -1-Methylethyl) AMINOLCARBONIL} -4METHYLBENZENOSULFONAMIDE

STEP 1. 1-i4- (2-Azidopropyl) phenin-6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole

Diethyl azodicarboxylate (1.16 mg, 6.66 mmol) was added, at room temperature, to a stirred solution of 1- [4- [6-chloro-2-ethyl-5 (trifluoromethyl) -l / 7-benzimidazol-1-yl] phenyl} -2-propanol (step 8 of Example 247, 1.96 g, 5.12 mmol), triphenylphosphine (1.75 g, 6.66 mmol) and diphenylphosphoryl azide (1 , 83 mg, 6.66 mmoles) in tetrahydrofuran (15 ml). The resulting mixture was stirred at room temperature for 3 hours, and then at reflux temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO ₄ ), and concentrated. Purification by flash column chromatography, eluting with hexane / ethyl acetate (2: 1), and TLC, eluting with hexane / ethyl acetate (1: 1) yielded 769 mg (37%) of the title compound under the shape of a very light yellow syrup.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.47 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz) , 7.21 (1H, s), 3.85-3.77 (1H, m), 2.92-2.89 (2H, m), 2.80 (2H, q, J = 7.5 Hz ), 1.37 (3H, d, J = 6.6 Hz), 1.36 (3H, t, J = 7.5 Hz).

MS (IED) m / z: 408 (MH ⁺ ).

STEP 2. 2- {4-f6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol1-illfenyl) -1-methylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidopropyl) phenyl] -6chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz) , 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.95 (2H, m), 2.79 (2H, q, J = 7.5 Hz ), 1.36 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 6.2 Hz).

STEP 3. / V- {(2- {4-6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimi317 / 451 dazol-1-yl1phenyl) -1-methylethyl) amino1carbonyl) -4 -methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / 7-benzimidazole-1-yl ] phenyl} -1-methylethylamine (step 2).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.3 Hz) , 7.29-7.23 (4H, m), 7.17 (1H, s), 4.20-4.11 (1H, m), 2.992.82 (2H, m), 2.78 (2H , q, J = 7.3 Hz), 2.38 (3H, s), 1.35 (3H, t, J = 7.3 Hz), 1.24 (3H, d, J = 6.6 Hz ).

MS (IED) m / z: 579 (MH ⁺ ), 577 ([MH] ').

EXAMPLE 254

Λ / -Π ((1 S) -2- {4- [6-C LORO-2-ETHYL-5- (TRI FLUO RO METHIL) -1 / 7BENZIMlDAZOL-1-IL1FENID-1-METlLETIL) AMINO1CARBONIL) -4 -METHYLBENZENOSULPHONAMIDE

STEP 1. 1- [4 - ((2S) -2-Azidopropyl) phenyl] -6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 1 of Example 253 from (2 /?) - 1- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1/7 -benzimidazol-1-yl] phenyl} -2-propanol (step 4 of Example 252).

¹ H NMR (CDCb) δ: 8.12 (1H, s), 7.46 (2H, d, J = 7.9 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.21 (1H, s), 3.84-3.77 (1H, m), 2.92-2.89 (2H, m), 2.79 (2H, q, J = 7.6 Hz) , 1.39-1.33 (6H, m).

STEP 2. (1 S) -2- {4- [6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-1 -illphenyl-1-methylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4 - ((2S) -2-azidopropyl) phenyl] -6-chloro-2-ethyl-5- ( trifluoromethyl) -1 / 7-benzimidazole (step 1).

¹ H NMR (CDCb) δ: 8.12 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.65 (2H, m), 2.79 (2H, q, J = 7.5 Hz) , 1.36 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 6.2 Hz).

STEP 3. / V-((1S) -244- [6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl1phenyl) -1-methylethyl) amino1carbonyl) -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure 318/451 as described in step 10 of Example 1 from (1S) -2- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / - / - benzimidazole-1-yl] phenyl} -1-methylethylamine (step 2).

M.p .: 141.0-143.0 ° C.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.73 (2H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz) , 7.30 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.17 (1H, s), 6.58 (1H, d, J = 7.7 Hz), 4.22-4.14 (1H, m), 2.82-2.30 (2H, m), 2.78 (2H, q, J = 7.6 Hz), 2.39 (3H, s), 1.35 (3H, t, J = 7.5 Hz), 1.24 (3H, d, J = 6.6 Hz).

MS (IED) m / z: 579 (MH ⁺ ), 691 ([M + COOH-H]).

[ct] ²⁴ D = - 5.08 ° (c 0.394, methanol), ee: 99%.

EXAMPLE 255 / Vf [((1 /?) - 2- {4-6-CHLORINE-2-ETHYL-5- (TRIFLLIOROMETHIL) -1 / 7BENZIMIDAZOL-1-IL] PHENYL) -1-METHYLLETH) AMINO] CARBONIL) -4-METHYLBENZENOSULPHONAMIDE

STEP 1. 1-í4 - ((2 /?) - 2-Azidopropyl) phenill-6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 1 of Example 253 from (2S) -1- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl} -2-propanol (step 4 of Example 250).

¹ H NMR (CDCI ₃ ) δ; 8.12 (1H, s), 7.46 (2H, d, J = 7.9 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.21 (1H, s), 3.84-3.77 (1H, m), 2.92-2.89 (2H, m), 2.79 (2H, q, J = 7.6 Hz), 1.39-1.33 ( 6H, m).

STEP 2, (1 R) -2- {4- [6-Chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazol-1-yl] phenyl) -1-methylethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4 - ((2R) -2-azidopropyl) phenyl] -6-chloro-2-ethyl-5- ( trifluoromethyl) -1 H-benzimidazole (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz) , 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.65 (2H, m), 2.79 (2H, q, J = 7.5 Hz ), 1.36 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 6.2 Hz).

STEP 3. Λ / -Μ1 /?) - 2-f4-í6-Chloro-2-ethyl-5- (trifluoromethyl) -1 Hbenzimidazol-1-infenyl) -1-methylethyl) amino1carbonyl) -4-methylbenzenesulfone319 / 451 mida

The title compound was prepared according to the procedure described in step 10 of Example 1 from (1 /?) - 2- {4- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / - / -benzimidazole-1 -yl] phenyl} -1-methylethylamine (step 2).

M.p .: 138.0-141.0 ° C.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.3 Hz) , 7.30 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.17 (1H, s), 6.58 (1H, d, J = 7.7 Hz), 4.22-4.14 (1H, m), 2.82-2.30 (2H, m), 2.78 (2H, q, J = 7.6 Hz), 2.39 (3H, s), 1.35 (3H, t, J = 7.5 Hz), 1.24 (3H, d, J = 6.6 Hz).

MS (IED) m / z: 579 (MH ⁺ ), 691 ([M + CF ₃ COOH-H] ').

[a] ²⁴ D = + 3.43 ° (c 0.408, methanol), ee: 99%.

EXAMPLE 256 (4-METHYLFENIL) 2- {4- [6-CHLORO-2 (1B-PIRAZOL-3-IL) -5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-lLFENIL) SULPHONYL CARBAMATE

ETHYL

STEP 1. 2-f4-F6-Chloro-2- (1 H-pyrazol-3-yl) -5- (trifluoromethyl) -1 / 7benzimidazol-1-yl1phenyl) ethanol

A mixture of 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol was stirred (Example 104, step 2; 2.28 g, 5.85 mmol) and 1/7-pyrazol-3-carbaldehyde (562 mg, 2.85 mmol) in ethanol (35 ml), at reflux temperature for 1 hour. The mixture was concentrated and dissolved in benzene (40 ml). Lead tetraacetate (2.85 g, 6.44 mmol) was added at room temperature to this solution. After stirring at room temperature for 18 hours, a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and ethyl acetate were added. The organic layer was separated and washed with brine, dried (Na2SO ₄ ), and concentrated. Purification by flash column chromatography, eluting with dichloromethane / methanol (20: 1 to 10: 1), and then dichloromethane / 2propanol (5: 1) yielded 979 mg (41%) of the title compound as of a very light yellow solid,

¹ H NMR (CDCfe / CDsOD = 4/1) δ: 8.12 (1H, s lg.), 7.74 (1H, s),

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7.59 (1Η, s lg.), 7.47 (2H, d, J = 7.9 Hz), 7.34-7.30 (3H, m), 6.36 (1H, s lg.) , 3.87 (2H, t lg., J = 6.8 Hz), 2.95 (2H, t, J = 6.8 Hz).

MS (IED) m / z: 407 (MH ⁺ ), 405 ([MH] ').

STEP 2. 2- (4- [6-chloro-2- (1 Ppyazol-3-yl) -5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl) ethyl 4-methylphenylsulfonifcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (1/7-pyrazol-3-yl) -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H, s), 7.91 (2H, d, J = 8.3 Hz), 7.547.53 (1H, m), 7.34-7, 23 (8H, m), 6.31 (1H, s lg.), 4.40 (2H, t, J = 6.4 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.42 (3H, s).

MS (IED) m / z: 604 (MH ⁺ ), 602 ([MH] ').

EXAMPLE 257

2- {4-f6-CHLORO-2- (1H-PIRAZOL-3-IL) -5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-IL] MONO-P-TOLUENOSULPHONATE FENIL) ETHYL

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [6-chloro-2- (1/7-pyrazol-3-yl) -5 (4-methylphenyl) sulfonylcarbamate) - (trifluoromethyl) -1 / 7-benzimidazoM -yl] phenyl} ethyl (step 2 of Example 256).

¹ H NMR (DMSO-de) δ: 8.24 (1H, s), 7.77-7.74 (2H, m), 7,487.38 (10H, m), 7.26 (1H, s) , 7.11 (2H, d, J = 7.9 Hz), 6.44 (1H, s lg.), 4.304.20 (2H, m), 2.98-2.93 (2H, m), 2.33 (3H, s), 2.27 (3H, s).

MS (IED) m / z: 604 (MH ⁺ ), 602 ([MH] ').

EXAMPLE 258

(1S) -2-r4- (2-ETYL-5,7-DIMETHIL-3 / V-IMlDAZOr4,5-b1PIRIDIN-3-lL) (4-METHYLphenyl) SULPHONYL CARBAMATE

PHENYL1-1-METHYLTHYL

STEP 1. (2S) -1- (4 - [(4.6-Dimethyl-3-nitro-2-pyridinyl) amino] phenyl) -2propanol

The title compound was prepared according to the procedure described in step 1 of Example 162 from 2-chloro-4,6-dimethyl-3321/451 nitropyridine (step 2 of Example 1) and (2S) -1- (4-aminophenyl) -2-propanol (step 2 of Example 248).

¹ H NMR (CDCb) δ: 9.58 (1H, s lg.), 7.59 (2H, d, J = 8.6 Hz),

7.19 (2H, d, J = 8.6 Hz), 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 = 6.3 Hz).

STEP 2. (2S) -1- {4-r (3-Amino-4 ₁ 6-dimethyl-2-pyridinyl) amino1phenyl) 2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from (2S) -1- {4 - [(4,6-dimethyl-3nitro-2-pyridinyl) amino] phenyl} - 2-propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.13-7.07 (4H, m), 6.60 (1H, s), 6.21 (1H, s lg.), 4.02-3.91 (1H, m), 3.26 (2H, s lg.), 2.77-2.57 (2H, m), 2.37 (3H, s),

2.20 (3H, s), 1.24 (3H, d, J = 6.1 Hz).

STEP 3. (1S) -2- [4- (2-ethyl-5,7-dimethyl-3H-imidazoyl4,5-11pyridin-3-yl) phenyl-1-nnetylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from (2S) -1- {4 - [(3-amino-4,6dimethyl-2-pyridinyl) amino] phenyl} - 2-propanol (step 2).

MS (IE) m / z: 365 (M ⁺ ).

STEP 4. (2S) -1-r4- (2-ethyl-5.7-dimethyl-3H-imidazor4,5-òlpyridin-3yl) phenyl1-2-propanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1S) -2- [4- (2ethyl-5,7-dimethyl-3H-imidazo [4,5- propanoate] b] pyridin-3-yl) phenyl] -1-methylethyl (step 3).

¹ H NMR (CDCb) δ: 7.42 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 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. (2S) -1-44- (2-ethyl-5.7dimethyl-3 / - / - imidazoy4,5-blpiridin-3-yl) phenyl1-1-methylethyl (4-methylphenylsulfonylcarbamate)

The title compound was prepared according to the procedure described in Example 3 from (2S) -1- [4- (2-ethyl-5,7-dimethyl-3Himidazo [4,5-b] pyridin-3 -yl) phenyl] -2-propanol (step 4).

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¹ H NMR (CDCI ₃ ) δ: 7.92 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.30-7.25 ( 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 (IED) m / z: 507 (MH ⁺ ), 505 ([MH]).

STEP 6. 2- [4- (2-Ethyl-5,7-dimethyl-3/7-imidazo [4,5-]) pyridin-3-yl) phenill-1- (4-methylphenyl) sulfonylcarbamate monochloride methylethyl

The title compound was prepared according to the procedure described in Example 240 from (1S) -2- [4- (2-ethyl-5,7-dimethyl-3 / 7- (4-methylphenyl) sulfonylcarbamate) imidazo [4,5-b] pyridin-3-yl) phenyl] -1-methylethyl (step 5).

¹ H NMR (DMSO-de) δ: 11.92 (1H, s lg.), 7.76 (2H, d, J = 7.9 Hz), 7.49-7.39 (6H, m) , 7.26 (1H, s lg.), 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 = 7.5 Hz), 1.12 (3H, d, J = 6.1 Hz).

MS (IED) m / z: 507 [(MH ⁺ )], 505 [(M-H ')].

[a] ²⁴ D = -12.49 ° (c 1.014, methanol).

EXAMPLE 259 (4-METHYLphenyl) 2-j4- (6-ACETYL-2ETlL-3-phenyl-1MIDAZOF4,5-b1PIRlDIN-3-IL) SULPHONYL CARBAMATE PHENYL1-1-METHYLETHIL

STEP 1. 1-í6 - ({4- [2-Hydroxypropyl1phenyl} amine) -5-nitro-3-pyridinin ethanone

The title compound was prepared according to the procedure described in step 1 of Example 162 from 1- (6-chloro-5-nitro-3pyridinyl) ethanone (Paul, B. et al; J. Med. Chem. , 1990, 33, 2231-2239) and 1- (4aminophenyl) -2-propanol (step 1 of Example 6).

¹ H NMR (CDCI ₃ ) δ: 10.37 (1H, s lg.), 9.06-9.03 (2H, m), 7.60 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 4.10-4.00 (1H, m), 2.86-2.69 (2H, m), 2.60 (3H, s) , 1.53 (1H, d, J = 4.0 Hz), 1.28 (3H, d, J = 6.2 Hz).

MS (IE) m / z: 315 (M ⁺ ).

STEP 2. 1 -5-Amino-6 - ({4- [2-hydroxypropylphenyl) amino) -3-pyridinylethanone

10% palladium on carbon (150 mg) was added to a solution of 1- [6 - ({4- [2-hydroxypropyl] phenyl} amino) -5-nitro-3-pyridinyl] ethanone (step 1, 1.54 g, 4.88 mmoles) in tetrahydrofuran (10 ml) and ethanol (30 ml). The resulting mixture was stirred for 19 hours under a hydrogen atmosphere. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated to obtain 1.74 g (100%) of the title compound as a green syrup.

¹ H NMR (CDCI ₃ ) δ: 8.46 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 1.8 Hz), 7.50 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 6.85 (1H, s lg.), 3.76-3.67 (1H, m), 3, 38 (2H, s lg.), 2.81-2.62 (2H, m), 2.53 (3H, s), 1.26 (3H, d, J = 6.1

Hz).

STEP 3. 2-r4- (6-acetyl-2-ethyl-3H-imidazoí4.5-frlpiridin-3-yl) feniri-1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- [5-amino-6 - ({4- [215 hydroxypropyl] phenyl} amino) -3-pyridinyl] ethanone ( step 2).

MS (IE) m / z: 379 (M ⁺ ).

STEP 4. 1- (2-Etjl-3- {4-1,2-hydroxypropyl-phenyl} -3 / 7-imidazo [4,5-b1 pyridin-6-yl) ethanone

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-acetyl2-ethyl-3H-imidazo [4,5-b] -pyridine] propanoate 3-yl] -1-methylethyl (step 3).

¹ H NMR (CDCI3) δ: 8.93 (1H, d, J = 1.8 Hz), 8.59 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8.3 Hz), 4.18-4.08 (1H, m), 2.942.80 (2H, m), 2.68 (3H , s), 1.39 (3H, t, J = 7.5 Hz), 1.33 (3H, d, J = 6.2 Hz).

STEP 5. 2-r4- (6-acetyl “2-ethyl3 / - / - imidazo [4,5-b1pyridin-3-yl) phenyl1-1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- (2-ethyl-3- {4- [2-hydroxypropyl] phenyl} -3 / 7imidazo [4,5-ô] pyridin -6-yl) ethanone (step 4).

¹ H NMR (CDCI ₃ ) δ: 8.93 (1H, d, J = 1.8 Hz), 8.60 (1H, d, J = 1.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 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).

324/451

MS (IED) m / z: 521 [(MH ⁺ )], 519 [(MH)].

EXAMPLE 260 (4-METHYLphenyl) SULPHONYL CARBAMATQ OF (1S) -2-r4- (6-ACETYL-2-ETYL-3H-IMIDAZOr4,5- / 3lPYRIDIN-3-IL) PHENYLM-METHYLETHIL

STEP 1. 1 - [6 - ({4 - [(2S) -2-Hydroxypropyl1phenyl} amino) -5-nitro-3-pyridinylethanone

The title compound was prepared according to the procedure described in step 1 of Example 162 from 1- (6-chloro-5-nitro-3pyridinyl) ethanone (Paul, B. eia / .; J. Med. Chem ., 1990, 33, 2231-2239) and (2S) 1- (4-aminophenyl) -2-propanol (step 2 of Example 248).

¹ H NMR (CDCl 3) δ: 10.37 (1H, s lg.), 9.06-9.03 (2H, m), 7.60 (2H, d, J = 8.3 Hz), 7 , 29 (2H, d, J = 8.3 Hz), 4.10-4.00 (1H, m), 2.86-2.69 (2H, m), 2.60 (3H, s), 1.53 (1H, d, J = 4.0 Hz), 1.28 (3H, d, J = 6.2 Hz).

STEP 2. 1- [5-Amino-6 - ((4 - [(2S) -2-hydroxypropinphen) amino) -3pyridinillethanone

The title compound was prepared according to the procedure described in step 2 of Example 259 from 1- [6 - ({4 - [(2S) -2-hydroxypropyl] phenyl} amino) -5-nitro-3 -pyridinyl] ethanone (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.46 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 1.8 Hz), 7.50 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 6.85 (1H, s lg.), 3.76-3.67 (1H, m), 3, 38 (2H, s lg.), 2.81-2.62 (2H, m), 2.53 (3H, s), 1.26 (3H, d, J = 6.1 Hz).

STEP 3. (1S) -2- [4- (6-acetyl-2-ethyl-3 / - / - imidazo [4,5-d1-pyridin-3-yl) phenyl] -1-methylethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- [5-amino-6 - ({4 - [(2 $) - 2hydroxypropyl] phenyl} amino) -3- pyridinyl] ethanone (step 2).

MS (IE) m / z: 379 (M ⁺ ).

STEP 4. 1 - (2-Ethyl-3- (4-r (2S) -2-hydroxypropylphenyl) -3 / - / - imidazo [4.5-òlpiridin-6-yl) ethanone

The title compound was prepared according to the procedure described in step 6 of Example 1 from (1S) - [4- (6325/451 acetyl-2-ethyl-3P-imidazo [4,5-ò propanoate] ] -pyridin-3-yl) phenyl] -1-methylethyl (step 3).

¹ H NMR (CDCb) δ: 8.93 (1H, d, J = 1.8 Hz), 8.59 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8.3 Hz), 4.18-4.08 (1H, m), 2.942.80 (2H, m), 2.68 (3H , s), 1.39 (3H, t,> 7.5 Hz), 1.33 (3H, d,> 6.2 Hz).

STEP 5. (1S) -2-r4- (6-acetyl-2ethyl-3/7-imidazo [4.5-b] pyridin-3-yl) phenyl1-1-methylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- (2-ethyl-3- {4 - [(2S) -2-hydroxypropyl] phenyl} 3/7-Imidazo [4, 5-ò] pyridin-6-yl) ethanone (step 4).

¹ H NMR (CDCb) δ: 8.93 (1H, d,> 1.8 Hz), 8.60 (1H, d,> 1.8 Hz), 7.92 (2H, d,> 8, 4 Hz), 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 (IED) m / z: 521 [(MH ⁺ )], 519 [(MH)].

EXAMPLE 261

(4-METHYLPHENYL) SULPHONYLCARBAMATQ MONO-P-TOLUENOSULPHONATE (1S) -2- [4- (6-ACETYL-2-ETYL-3P-IMIDAZO [4,5-blPIRIDIN-3-IDFENYL1-1-METHYLETHYL

The title compound was prepared according to the procedure described in Example 231 from (1 S) -2- [4- (6-acetyl-2-ethyl-3H-imidazo [4 (methylphenyl) sulfonylcarbamate [4 , 5-b] pyridin-3-yl) phenyl] -1-methylethyl (step 5 of Example 260).

¹ H NMR (DMSO-d ₆ ) δ: 11.93 (1H, s lg.), 8.90 (1H, d,> 1.8 Hz), 8.63 (1H, d,> 1.8 Hz), 7.76 (2H, d,> 8.4 Hz), 7.38-7.29 (8H, m), 7.11 (2H, d,> 8.4 Hz), 4.96- 4.87 (1H, m), 2.90-2.79 (4H, m), 2.32 (3H, s), 2.27 (3H, s), 1.26 (3H, t,> 7 , 5 Hz), 1.12 (3H, d,> 6.2 Hz).

MS (IED) m / z: 521 [(MH ⁺ )], 519 [(MH)].

[a] ²⁴ D = -8.17 ° (c 1.020, methanol).

EXAMPLE 262

2- {446-CHLORO-2- (2-PYRIDINYL) -5- (TRIFLUOROMETHIL) -1 / - / - BENZIMIDAZOL-1-IL] PHENYL MONO-P-TOLUENOSULPHONATE

STEP 1, 2- {4-r6-Chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1 / 7-benzyl326 / 451 midazol-1-yl-phenyl) ethanol

A mixture of 2- (4 - {[2 amino-5- chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol (1.83 g, 5.54 mmol) was heated to reflux for 1 hour.

2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml). After cooling to room temperature, the solvent was removed. The residue was dissolved with benzene (50 ml) and treated with Pb (OAc) ₄ (3.38 g, 6.10 mmoles) at room temperature for 1 hour. The mixture was diluted with EtOAc and the solution was washed with saturated aqueous NaHCO ₃ solution and brine. The organic fraction was dried over MgSO ₄ , then filtered. After evaporation in vacuo, the residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc = 5/2, to obtain 1.20 g (52%) of the title compound.

'H (CDCb) δ NMR: 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 = 6.6 Hz), 2.99 (2H, t, J = 6.6 Hz).

MS (IED) m / z: 418 ([M + H ⁺ ]), 476 ([M + CF ₃ CO ₂ ] ').

STEP 2, 2- | 4-yl-6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1-yl-phenyl} ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (2-pyridinyl) -5 (trifluoromethyl) -1 H-benzimidazole-1-yl] il} eta nol.

¹ H NMR (CDCI ₃ ) 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,> 6.8 Hz), 2 , 98 (2H, t,> 6.8 Hz), 2.41 (3H, s).

MS (IED) m / z: 615 ([M + H ⁺ ]), 613 ([MH] ”).

EXAMPLE 263

2- {4-6-CHLORO-2- (2-PYRIDINYL) -5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL] PHENYL MONO-P-TOLUENOSULPHONATE

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [6-chloro-2- (pyridinyl) -5- (trifluoromethyl) -1 H- (4-methylphenyl) sulfonylcarbamate) benzimidazol-1-yl] phenyl} ethyl.

327/451

MS (IED) m / z: 615 ([M + H ⁺ ]).

EXAMPLE 264

MONO-P-TOLUENOSULPHONATE OF A / - (r (2- {4-r6-CHLORO-2 (2-PYRIDINYL) -5- (TRIFLUOROMETHIL) -1B-BENZIMIDAZOL-1-ILylphenyl) ETlL)

AMINO1CARBONIL) -4-METHYLBENZENQSULPHONAMIDE

STEP 1. 6-Chloro-1- [4- (2-chloroethyl) phenyl1-2- (2-pyridinyl) -5- (trifluoromethyl) -1 B-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [6-chloro-2- (pyridinyl) -5 (trifluoromethyl) -1B-benzimidazol-1-yl ] phenyl} ethanol (step 1 of Example 262).

¹ H NMR (CDCI ₃ ) δ: 8.41-3.39 (1H, m), 8.24 (1H, s), 8.11 (1H, d, J = 8.8 Hz), 7, 82-7.76 (1H, m), 7.38 (2H, d, J = 8.4 Hz), 7.35 (1H, s), 7.307.25 (3H, m), 3.31 (2H , t, J = 7.2 Hz), 3.19 (2H, t, J = 7.2 Hz).

STEP 2. 144- (2-Azidoethyl) phenill-6-chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1 B-benzimidazole

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] -2- (2-pyridinyl) -5- ( trifluoromethyl) -1 B-benzimidazole (step 1).

¹ H NMR (CDCIa) δ: 8.40-8.39 (1H, m), 8.24 (1H, s), 8.10 (1H, d, J = 7.9 Hz), 7.81 -7.75 (1H, m), 7.39 (2H, d, J = 8.4 Hz), 7.34 (1H, s), 7,297.25 (3H, m), 3.61 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 6.8 Hz).

STEP 3. 2- (4- [6-Chloro-2- (2-pyridinyl) -5- (trifluoromethi [) - 1 / - / - benzimidazole-1-infenyl} ethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1B-benzimidazole (step 2).

¹ H NMR (CDCI ₃ ) 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 = 6.8 Hz), 2.82 (2H, t, J = 6.8 Hz), 2.17 (2H, slg.).

STEP 4. A / -ff (2-f4-r6-Chloro-2- (2-pyridinyl) -5- (trifluoromethyl) -1Hbenzimidazol-1-yl1phenyl} ethinamino) carbonyl) -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure 328/451 as described in step 10 of Example 1 from 2- {4- [6-chloro-2- (2-pyridinyl) 5- (trifluoromethyl) -1 H -benzimid azo I-1 -yl] phenyl} ethylamine (step 3).

¹ H NMR (CDCI ₃ ) δ: 8.42-8.39 (1H, m), 8.24 (1H, s), 8.10 (1H, d, J = 8.1 Hz), 7, 81-7.75 (1H, m), 7.69 (2H, d, J = 8.3 Hz), 7.33-7.24 (8H, m), 6.72-6.69 (1H, m), 3.63-3.56 (2H, m), 2.93 (2H, t, J = 6.8 Hz), 2.38 (3H, s).

MS (IED) m / z: 614 ([M + H ⁺ ]), 612 ([MH]).

STEP 5. / V - ([(2- (4- [6-chloro-2- (2pyridinyl) -5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl) mono-p-toluenesulfonate ethyl] amino) carbonyl} -4methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 231 from / V - {[(2- {4- [6-chloro-2- (2-pyridinyl) -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethyl] amino) carbonyl} -4methylbenzenesulfonamide (step 4).

¹ H NMR (DMSO-d ₆ ) δ: 10.63 (1H, s lg.), 8.41-8.39 (1H, m), 8.35 (1H, s), 8.08-7 , 95 (2H, m), 7.75 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.44-7.27 (8H, m), 7.10 (2H, d, J = 7.7 Hz), 6.61-6.57 (1H, m), 3.30-3.23 (2H, m), 2.74 (2H , t, J = 7.0 Hz), 2.31 (3H, s), 2.27 (3H, s).

MS (IED) m / z: 614 [(MH ⁺ )], 612 [(MH)].

EXAMPLE 265

/ V- {r (2T4- [6-CHLORINE-2 (1H-PIRAZOL-3-IL) -5- (TRI FLUO ROM ETIL) -1H-BENZIMIDAZOL-1-IL] FENIL) MONO-P-TOLUENOSULPHONATE

ETHYL) AMINO] CARBONYL

STEP 1. 6-Chloro-1- [4- (2-chloroethyl) phenyl1-2- (1/7-pyrazol-3-yl) -5- (trifluoromethyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [6 ~ chloro-2- (1/7-pyrazol-3yl) -5- (trifluoromethyl) - 1 / - / - benzimidazol-1-yl] phenyl} ethanol (step 1 of Example 255).

¹ H NMR (DMSO-d ₆ ) 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 = 7.0 Hz), 3.16 (2H, t, J = 7.0 Hz).

STEP 2. 1- [4- (2-Azidoethyl) phenyl1-6-chloro-2- (1/7-pyrazol-3-yl) -5- (tri329 / 451 fluoromethyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2- (1/7 ~ pyrazole! -3- il) -5- (trifluoromethyl) -1 / 7-benzimidazole (step 1).

¹ H NMR (DMSO-d ₆ ) 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 = 7.0 Hz), 2.99 (2H, t, J = 7.0 Hz ).

STEP 3. 2- (4-r6-Chloro-2- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -1Hbenzimidazole-1-infenyl) ethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2- (1/7-pyrazol-3-yl) -5- (trifluoromethyl) -1 / 7-benzimidazole (step 2).

MS (IE) m / z: 405 (M ⁺ ).

STEP 4. A / - ([(2- (4-i6-Chloro-2- (1/7-pyrazol-3-yl) -5- (trifluoromethyl) 1H-benzimidazole-1-phenphenyl} ethyl1amino) carbonyl) - 4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [6-chloro-2- (1/7-pyrazol3-yl) -5- (trifluoromethyl) - 1/7-benzimidazol-1-yl] phenyl} ethylamine (step 3).

¹ H NMR (CDCh) δ: 8.17 (1H, s), 7.69 (2H, d, J = 8.4 Hz), 7.57 (1H, d, J = 2.2 Hz), 7.30-7.18 (8H, m), 6.82-6.77 (1H, m), 6.60 (1H, d, J = 2.2 Hz), 3.64-3.58 ( 2H, m), 2.91 (2H, t, J = 6.4 Hz), 2.39 (3H, s).

STEP 5. / V- (f (2- {4-F6-chloro-2- (1 / 7pyrazol-3-yl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1- mono-p-toluenesulfonate il1phenyl) ethinamino) carbonyl) -4methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 231 from / V - {[(2- {4- [6-chloro-2- (1/7-pyrazol-3-yl) -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethyl] amino) carbonyl} -4-methylbenzenesulfonamide (step 4).

¹ H NMR (DMSO-d ₆ ) δ: 10.64 (1H, s lg.), 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 = 7.9 Hz), 6.606.57 (1H, m), 6.38-6.37 ( 1H, m), 3.33-3.26 (2H, m), 2.78 (2H, t, J = 7.2 Hz), 2.32 (3H, s), 2.28 (3H, s ).

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MS (IED) m / z: 603 [(MH ⁺ )], 601 [(MH)].

EXAMPLE 266

3- (3-CHLORINE-4- <2-í ({[(4-METHYLphenyl) SULFQNIL] AMINO) CARBONYL) AMINOlETYL) PHENYL) -2-ETYL-5 _Í 7-DIMETHIL "3/7" IMIDAZO [4, 5-2nd] PYRIDINE

STEP 1.2- (2-Chloro-4-nitrophenyl) diethyl malonate

Diethylmalonate (5.2 ml, 34.2 mmoles) was added to a suspension of NaH (1.4 g, 34.2 mmoles) in 80 ml of 1,4-dioxane followed by successive addition of CuBr (4.9 g, 34.2 mmoles) and 3-chloro-4-fluoronitrobenzene (5.0 g, 28.5 mmoles). The mixture was stirred at room temperature for 0.5 hour and at reflux for 12 hours. The mixture was poured into water, and the precipitate was filtered off through a pad of Celite. The filtrate was extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to obtain a green oil. This mixture was purified by column chromatography over S1O2, eluting with hexane / ethyl acetate (10/1), to obtain 7.6 g (85%) of the title compound as a yellow oil.

¹ H NMR (CDCI ₃ ) δ: 8.30 (1H, d, J = 2.4 Hz), 8.16 (1H, dd, J = 2.2, 8.6 Hz), 7.74 ( 1H, d, J = 8.6 Hz), 5.27 (1H, s), 4.28 (2H, q, J = 7.2 Hz),

4.27 (2H, q, J = 7.2 Hz), 1.29 (6H, t, J = 7.2 Hz).

STEP 2. 2- (2-chloro-4-nitrophenyl) acetic acid

6M NaOH (12 mL) was added to a solution of 2- (2-chloro-4-nitrophenyl) diethyl malonate (step 1, 7.6 g, 24.2 mmol) in methanol (18 mL), and stirred. for 1 hour at 50 ° C. The reaction was brusquely cooled with the addition of an aqueous solution of citric acid (16 ml) and water. The organic layer was extracted with ethyl acetate (2 x 50 ml), washed with brine, dried (MgSO ₄ ) and concentrated to obtain 4.52 g (87%) of the title compound, as a light yellow solid.

¹ H NMR (CDCb) δ: 12.6 (1H, s lg.), 8.30 (1H, d, J = 2.6 Hz). 8.18 (1H, dd. J = 2.4, 8.4 Hz), 7.73 (1H, d, J = 8.6 Hz), 3.90 (2H, s).

STEP 3. 2- (2-Chloro-4-nitrophenyl) methyl acetate

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Trimethylsilyl chloride (0.3 ml) was added to a solution of 2- (2-chloro-4-nitrophenyl) acetic acid (step 2, 4.5 g, 21 mmol) in dimethyl acetate / methanol (4/1) , and stirred for 7 hours at room temperature. The solvent was removed and the residue was purified by column chromatography over SiO ₂ , eluting with hexane / ethyl acetate (10/1), to obtain 3.6 g (74%) of the title compound, under the in the form of a yellow oil.

¹ H NMR (CDCI ₃ ) δ: 8.28 (1H, d, J = 2.3 Hz), 8.11 (1H, dd, J = 2.3, 8.6 Hz), 7.50 ( 1H, d, J = 8.6 Hz), 3.88 (2H, s), 3.74 (3H, s).

STEP 4. 2- (4-Amino-2-chlorophenyl) methyl acetate

Fe (4.4 g, 78.0 mmoles) and NH ₄ CI (409 mg, 7.8 mmoles) were added to a solution of 2- (2-chloro-4-nitrophenyl) methyl acetate (step 3, 3 , 6 g, 15.6 mmoles) in ethanol / water (4/1). The mixture was stirred for 1 hour under reflux temperature. The solvent was removed and the residue was diluted with CH ₂ Cl ₂ . The mixture was washed with brine, dried (MgSO ₄ ) and concentrated to obtain 2.59 g (83%) of the title compound as an orange oil.

The title compound was prepared according to the procedure described in step 2 of Example 28 from methyl 2- (2-chloro-4-nitrophenyl) acetate (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.04 (1H, d, J = 8.2 Hz), 6.72 (1H, d, J = 2.3 Hz), 6.54 (1H, dd, J = 2.5, 8.2 Hz), 3.70 (3H, s), 3.66 (2H, s).

STEP 5. (2-Chlorine-4 - [(4,6-Dimethyl-3-nitro-2-pyridinyl) amino1phenyl) methyl acetate

Diisopropylethylamine was added to a mixture of 2- (4-amino2-chlorophenyl) methyl acetate (step 4, 2.6 g, 13.0 mmol) and 4,5-dimethyl-3-nitro-2-pyridine (step 2 of the Example 1, 2.4 g, 13.0 mmoles) in DMSO. The resulting mixture was stirred for 9 hours at 50 ° C. The mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to obtain a brown oil. This was purified by column chromatography over SiO ₂ , eluting with hexane / ethyl acetate (10/1), to obtain 1.4 g (29%) of the title compound as a yellow solid.

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¹ H NMR (CDCI ₃ ) δ: 9.55 (1H, s lg.), 7.90 (1H, d,> 2.2 Hz), 7.43 (1H, dd,> 2.2, 8 , 3 Hz), 7.24 (1H, d,> 8.3 Hz), 6.59 (1H, s), 3.76 (2H, s), 3.72 (3H, s), 2.56 (3H, s), 2.46 (3H, s).

MS (IE) m / z: 349 (M ⁺ ).

STEP 6. 2-Chlorine- {4-i (3-amino-4,6-dimethyl-2-pyridinyl) amino-phenyl) methyl acetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from {2-chloro-4 - [(4,6-Dimethyl-3-nitro-2-pyridinyl) amine] phenyl} methyl acetate ( step 5).

¹ H NMR (CDCI3) δ: 7.26 (1H, d, J = 2.2 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 2.2, 8.3 Hz), 6.64 (1H, s), 6.37 (1H, s lg.), 3.70 (3H, s),

3.27 (1H, s lg.), 2.68 (3H, s), 2.38 (3H, s), 2.20 (3H, s).

STEP 7. 2-1,2-Chloro-4- (2-ethyl-5.7-dimethyl-3-imidazof4,5-methylpyridin-3-yl) phenylethyl-methyl acetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from methyl 2-chloro- {4 - [(3-amino-4,6dimethyl-2-pyridinyl) amino] phenyl} acetate ( step 6).

¹ H NMR (CDCI ₃ ) δ: 7.50 (1H, d,> 8.3 Hz), 7.47 (1H, d,> 2.2 Hz), 7.31 (1H, dd,> 2 , 2, 8.3 Hz), 6.92 (1H, s), 3.87 (2H, s), 3.77 (3H, s), 2.85 (2H, q,> 7.5 Hz) , 2.65 (3H, s), 2.53 (3H, s), 1.31 (3H, t,> 7.5 Hz).

MS (IE) m / z: 357 (M ⁺ ).

STEP 8. 2-f2-Chloro-4- (2-ethyl-5.7-dimethyl-3/7-imidazof4,5-5lpiridin-3-yl) phenylethanol

LAH was added carefully to a solution of 2- [2-chloro-4 (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-o] pyridin-3-yl) phenylethyl-acetate methyl (step 7,

1.13 g, 3.15 mmoles), and stirred for 1 hour at room temperature. The reaction was quenched with water and the mixture was diluted with ethyl acetate (50 ml). Saturated aqueous potassium sodium tartrate solution (50 ml) was added and stirred for 2.5 hours. The organic layer was separated and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with brine, dried (MgSO ₄ ), and concentrated to obtain 1.0 g of the title compound as a white solid.

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¹ H NMR (CDCI ₃ ) 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 = 7.4 Hz), 2.82 (2H, m), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.4 Hz).

MS (IE) m / z: 329 (M ⁺ ).

STEP 9. 3- | 3-Chlorine 4 (2-chloroethyl) phenyl-2-ethyl-5,7-dimethyl-3 / - / - imidazo [4,5-frlpiridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from methyl-2- [2-chloro-4- (2-ethyl-5,7dimethyl-3i / -imidazo [4,5 -ó] pyridin-3-1) phenylethanol (step 8).

¹ H NMR (CDCI ₃ ) δ: 7.45-7.52 (2H, m), 7.23-7.31 (1H, m), 6.92 (1H, s), 3.82 (2H , t, J = 7.3 Hz), 3.29 (2H, t, J = 7.3 Hz), 2.83 (2H, q, J = 7.6 Hz),

2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.6 Hz).

STEP 10. 3-i4- (2-Azidoethyl) -3-chlorophenyl-2-ethyl-5,7-dimethyl-3 / 7imidazoí4.5-d1pyridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [3-chloro-4- (2-chloroethyl) phenyl2-ethyl-5,7-dimethyl-3 / - / -imidazo [4,5-5] pyridine (step 9).

¹ H NMR (CDCI ₃ ) δ: 7.45-7.48 (2H, m), 7.29 (1H, dd, J = 2.1, 7.9 Hz), 6.92 (1H, s), 3.62 (2H, t, J = 7.1 Hz), 3.12 (1H, t, J = 7.3 Hz), 2.83 (2H, q, J = 7.4 Hz), 2, 65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.4 Hz).

STEP 11. 2-1,2-Chloro-4- (2-ethyl-5,7-dimethyl-3A7-imidazoí4 ₁ 5-Z) 1pyridin-3-yl) ethanamine

Fe (335 mg, 6.0 mmoles) and NH ₄ CI (409 mg, 7.8 mmoles) were added to a solution of methyl-3- [4- (2-azidoethyl) -3-chlorophenyl-2-ethyl -5,7-dimethyl3H-imidazo [4,5-ó] pyridine (step 10, 430 mg, 1.2 mmol) in ethanol / water (4/1). The mixture was stirred for 1 hour under reflux temperature. The solvent was removed and the residue was diluted with CH2 Cl2. The mixture was washed with brine, dried (MgSO ₄ ) and concentrated to obtain 390 mg of the title compound as an orange oil.

¹ H NMR (CDCI ₃ ) δ: 7.44 (2H, d, J = 7.4 Hz), 7.25 (1H, m), 6.92 (1H, s), 2.92-3, 15 (6H, m), 2.83 (2H, q, J = 7.4 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.4 Hz).

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STEP 12. 242-Chlorine-4- (2-ethyl-5.7-dimethyl-3 / V-imidazo [4,5-dlpiridin-3-yl) ethanamine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [2-chloro-4- (2-ethyl-5,7dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl] ethanamine (step 11).

¹ H NMR (CDCI ₃ ) δ: 7.83 (2H, d, J = 8.4 Hz), 7.28-7.36 (4H, m),

7.14 (1H, d, J = 7.7 Hz), 6.92 (1H, s), 6.28 (1H, s lg.), 3.58 (2H, dt, J = 6.3 Hz ), 3.02 (2H, t, J = 6.4 Hz), 2.74 (2H, q, J = 7.6 Hz), 2.66 (3H, s), 2.45 (3H, s ), 2.41 (3H, s), 1.25 (3H, t, J = 7.6 Hz).

MS (IED) m / z: 526 (M ⁺ ).

EXAMPLE 267

3- (2-CHLORINE-4- {2 - [(U (4-METHYLphenyl) SULFONYLAMINO) CARBONYL) AMINO1ETHIL) FENlL) -2-ETHYL-5,7-DIMETHYL-3H-IMIDAZOr4,5-Z) 1PYRIDINE

STEP 1, 2- (3-Chloro-4-r (4,6-dimethyl-3-nitro-2-pyridinyl) amino1 phenylethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-dimethyl-3-nitro-2-pyridine (0.66 g, 3.8 mmol, step 2 of Example 1) and 4-amino-2-chloro-phenylethanol (0.72 g, 3.8 mmoles, Eur. J. Med. Chem., 1996, 31, 133).

¹ H NMR (CDCIs) δ: 9.85 (1H, s), 8.37 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 2.0 Hz), 7.14 (1H, dd, J = 2.0, 8.3 Hz), 6.60 (1H, s), 3.87 (2H, dt, J = 6.2, 6.4 Hz), 2 , 84 (2H, t, J = 6.4 Hz), 2.56 (3H, s), 2.46 (3H, s), 1.40 (1H, t, J = 6.2 Hz).

MS (IE) m / z: 321 (M ⁺ ).

STEP 2. Methyl-3-chloro- {4-f (3-amino-4,6-dimethyl-2-pyridinyl) amino1 pheniDethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {3-chloro-4 - [(4,6-dimethyl-3nitro-2-pyridinyl) amino] phenyl} ethanol (step 1).

¹ H NMR (CDCIs) δ: 7.26 (1H, d, J = 2.2 Hz). 7.20 (1H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 2.2, 8.3 Hz), 6.64 (1H, s), 6.37 (1H , s lg.), 3.70 (3H, s),

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3.27 (1H, s lg.), 2.68 (3H, s), 2.38 (3H, s), 2.20 (3H, s).

STEP 3. 2-F2-chloro-4- (2-ethyl-5,7-dimethyl-3H-imidazoy4,5-t> lpiridin-3-yl) phenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 3-chloro- {4 - [(3 amino-4,6- dimethyl-2- pyridinyl) amino] phenyl} ethyl propionate (step 2).

¹ H NMR (CDCb) δ: 7.50 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.2 Hz), 7.31 (1H, dd, J = 2.2, 8.3 Hz), 6.92 (1H, s), 3.87 (2H, s), 3.77 (3H, s), 2.85 (2H, q, J = 7, 5 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.31 (3H, t, J = 7.5 Hz).

MS (IED) m / z: 357 (M ⁺ ).

STEP 4. 2-f3-Chloro-4- (2-ethyl-5,7-dimethyl-3H-imidazof4,5-hlpyridin-3-yl) phenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from methyl-2- [2-chloro-4- (2-ethyl-5,7-dimethyl-3H-imidazo [4, 5-ò] pyridin-3-yl) phenylethyl (step 3).

¹ H NMR (CDCb) δ: 7.51 (1H, s), 7.34 (2H, s), 6.91 (1H, s), 3.96 (2H, dd, J = 6.2, 12.0 Hz), 2.96 (2H, t, J = 7.4 Hz), 2.70 (2H, m), 2.66 (3H, s), 2.51 (3H, s), 1 , 67 (1H, t lg., J = 6.2 Hz), 1.28 (3H, t, J = 7.4 Hz).

MS (IE) m / z: 329 (M ⁺ ).

STEP 5. 3-F2-Chloro-4- (2-chloroethyl) phenyl-2-ethyl-5,7-dimethyl-3H-imidazoí4,5-b1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [3-chloro-4- (2-ethyl-5,7-dimethyl3 / 7-imidazo [4,5- b] pyridin-3-yl) phenylethanol (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.49 (1H, d,> 1.3 Hz), 7.34-7.39 (2H, m), 6.91 (1H, s), 3.80 (2H, t,> 7.2 Hz), 3.17 (2H, t,> 7.0 Hz), 2.60-2.85 (2H, m),

2.66 (3H, s), 2.51 (3H, s), 1.28 (3H, t,> 7.5 Hz).

MS (IE) m / z: 347 [(M-H)].

STEP 6. 3-f4- (2-Azidoethyl) -3-chlorophenyl-2-ethyl-5 ₁ 7-dimethyl-3H-imidazoí4,5-blpiridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [2-chloro-4- (2-chloroethyl) phenyl336 / 451

2-ethyl5,7-dimethyl-3 / -7-imidazo [4,5-ô] pyridine (step 5).

¹ H NMR (CDCl ₃ ) δ: 7.49 (1H, m J = 1.8 Hz), 7.31-7.38 (2H, m), 6.91 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 2.98 (2H, t, J = 7.3 Hz), 2.60-2.80 (2H, m),

2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t, J = 7.5 Hz).

MS (IE) m / z: 354 (M) ⁺ .

STEP 7. 2- [3-Chloro-4- (2-ethyl-5,7-dimethyl-3/7-imidazor4 ₁ 5- £> lpiridin-3-yl) phenyl1ethanamine

Triphenylphosphine (116 mg, 0.4 mmol) was added at room temperature to a solution, with stirring, of 3- [4- (2-azidoethyl) -3-chlorophenyl-2ethyl-5,7-dimethyl ~ 3H -imidazo [4,5-ò] pyridine (step 6, 149 mg, 0.4 mmol) in THF (4 ml). After completion of the addition, stirring was continued for an additional 2.5 hours at the same temperature and for 3.5 hours at reflux temperature. H ₂ O (1.0 ml) was added at room temperature to the resulting mixture and the solvent was removed. The mixture was dissolved in CH ₂ Cl ₂ (100 ml), and washed with brine. The organic layer was dried (MgSO ₄ ), and concentrated to obtain a yellow oil.

MS (IE) m / z: 328 (M) ⁺ .

STEP 8. 2- [3-Chloro-4- (2-ethyl-5J-dimethyl-3H-imidazor4,5-dlpyridin-3-yl) phenyl1ethanamine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [3-chloro-4- (2-ethyl-5,7dimethyl-3tf-imidazo [4,5-b] pyridin-3-yl) phenyl] ethanamine (step 7).

¹ H NMR (CDCfe) 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, s lg.), 3.54 (2H, m), 2.78 (2H, t, J = 6.4 Hz), 2.67 (3H, s), 2.63 (3H, m), 2.42 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J = 7.5 Hz).

MS (IE) m / z: 526 (M ⁺ ).

EXAMPLE 268

2-ETYL-3- (3-METHYXY-4- (2-r (n (4-METHYLPHYL) SULFONYLAMINO) CARBONYL) AMINOLETYL} PHENYL) -5,7-DIMETHYL-3/7 “IMIDAZO [4,5-blPlRlDINA

STEP 1. 2- (2-Methoxy-4-nitrophenyl) diethyl malonate

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The title compound was prepared according to the procedure described in step 1 of Example 266 from 4-bromo-3-methoxy nitrobenzene.

¹ H NMR (CDCfe) δ: 7.78 (1H, dd, J = 2.2, 8.4 Hz), 7.75 (1H, d, J = 2.2 Hz), 7.54 (1H , d, J = 8.4 Hz), 5.15 (1H, s), 4.25 (2H, q, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz ), 3.94 (3H, s), 1.28 (6H, t, J = 7.2 Hz).

STEP 2. 2- (2-Methoxy-4-nitrophenyl) acetic acid

The title compound was prepared according to the procedure described in step 2 of Example 266 from 2- (2-methoxy-4-nitrophenyl) diethyl malonate (step 1).

¹ H NMR (CDCI ₃ ) δ: 12.4 (1H, s lg.), 7.82 (1H, dd, J = 2.2, 8.4 Hz), 7.75 (1H, dd, J = 2.2 Hz), 7.50 (1H, d, J = 8.4 Hz), 3.90 (3H, s), 3.66 (2H, s).

STEP 3. 2- (2-Methoxy-4-nitrophenyl) methyl acetate

Trimethylsilyldiazomethane (2M, 5.6 mL, 11.8 mmol) was added to a solution of 2- (2-methoxy-4-nitrophenyl) acetic acid (step 2, 1.2 g, 5.5 mmol) in methanol / dichloromethane (11 ml, 1/1), and stirred for 10 minutes at room temperature. The mixture was quenched with a saturated aqueous solution of citric acid and extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to obtain 1.2 g of the title compound as an orange solid.

'H NMR (CDCI ₃ ) §: 7.83 (1H. Dd, J = 2.2, 8.3 Hz), 7.73 (1H, dd, J = 2.2 Hz), 7.34 ( 1H, d, J = 8.1 Hz), 3.93 (3H, s), 3.71 (2H, s), 3.71 (3H, s).

STEP 4. 2- (4-Amino-2-methoxyphenyl) methyl acetate

10% Pd / C (130 mg, 0.12 mmol) was added to a solution of 2- (2-methoxy-4-nitrophenyl) methyl acetate (step 3, 1.2 g, 5.5 mmol) in methanol (10 mL), and stirred under a hydrogen atmosphere for 3 hours at room temperature. The catalyst was removed by filtration through a pad of Celite, and washed thoroughly with ethanol and ethyl acetate. The filtrate was concentrated to obtain 1.1 g of the title compound as a pink oil.

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¹ H NMR (CDCI ₃ ) δ: 6.94 (1H, d, J = 7.7 Hz), 6.26 (1H, d, J = 2.0 Hz), 6.23 (1H, s) , 3.70 (3H, s), 3.76 (3H, s), 3.67 (3H, s), 3.52 (2H, s).

STEP 5. (44 (4.6-D ^ metii-3-nitro-2-pyridyl) methyl amine-2-methoxyphenyljacetate

The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 2- (4-amino-2-methoxyphenyl) acetate (step 4).

¹ H NMR (CDCl 3) δ: 9.60 (1H, s), 7.47 (1H, d, J = 1.7 Hz), 7,067.15 (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 (IE) m / z: 345 (M ⁺ ).

STEP 6. {4-r (3-Amino-4,6-dimethyl-2-pyridinyl) aminol-2-methoxyphenyl) methyl acetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from methyl {4 - [(4,6-dimethyl-3-nitro-2pyridinyl) amino] -2-methoxyphenyl} acetate (step 5).

¹ H NMR (CDCI ₃ ) δ: 7.03 (1H, d, J = 5.1 Hz), 7.02 (1H, s), 6.60 (1H, s), 6.57 (1H, dd, J = 2.2, 8.3 Hz), 3.79 (3H, s), 3.68 (3H, s), 3.56 (2H, s), 3.25-3.35 (2H , s lg.), 2.38 (3H, s), 2.20 (3H, s).

MS (IE) m / z: 315 (M ⁺ ).

STEP 7. 2-F4- (2-Ethyl-5,7-dimethyl-3/7-imido] [4,5-ò1pyridin-3-yl) -2methoxyphenylethylacetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from methyl {4 - [(3-amino-4,6-dimethyl-2pyridinyl) amino] -2-methoxyphenyl} acetate (step 6).

¹ H NMR (CDCI ₃ ) δ: 7.36 (1H, d, J = 7.9 Hz), 6.89-6.99 (3H, m), 3.84 (2H, s), 3, 74 (3H, s), 3.71 (2H, s), 2.85 (2H, q, J = 7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.5 Hz).

MS (IE) m / z: 353 (M *).

STEP 8. 2- [4- (2-Ethyl-5,7-dimethyl-3H-imidazoí4.5-blpiridin-3-yl) -2methoxyphenylethanol

The title compound was prepared according to the procedure 339/451 as described in step 8 of Example 266 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-ò ] methyl pyridin-3-yl) -2-methoxyphenylethylacetate (step 7).

¹ H NMR (CDCb) δ: 7.33 (1H, d, J = 7.7 Hz), 6.87-6.95 (3H, m),

3.90 (2H, dt, J = 6.0, 6.2 Hz), 3.84 (3H, s), 2.98 (2H, t, J = 6.4 Hz), 2.84 (2H , q, J = 7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.76 (1H, t lg.), 1.30 (3H, t, J = 7.5 Hz).

MS (IE) m / z; 324 [(M-H)].

STEP 9. 3-i4- (2-Chloroethyl) -3-methoxyphenyl-2-ethyl-5.7-dimethyl-3Bimidazo [4.5-51pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- 3-yl) -2-methoxyphenylethanol (step 8).

¹ H NMR (CDCI ₃ ) δ: 7.33 (1H, d, J = 7.7 Hz), 6.87-6.94 (3H, m), 3.84 (3H, s), 3, 77 (3H, t, J = 7.6 Hz), 3.16 (2H, t, J = 7.3 Hz), 2.84 (2H, q, J = 7.6 Hz), 2.66 ( 3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.6 Hz).

STEP 10. 3- [4- (2-Azidoethyl) -3-methoxyphenyl-2-ethyl-5,7-dimethyl-3 / 7imidazoí4,5-ò1pyridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) -3methoxyphenyl-2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridine (step 9).

¹ H NMR (CDCI ₃ ) δ: 7.45-7.48 (2H, m), 7.29 (1H, dd, J = 2.1, 7.9 Hz), 6.92 (1H, s ), 3.62 (1H, t, J = 7.1 Hz), 3.12 (1H, t, J = 7.3 Hz), 2.83 (2H, q, J = 7.4 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J = 7.4 Hz).

STEP 11. 2-4- (2-Ethyl-5,7-dimethyl-3H-imidate [4,5-]) pyridin-3-yl-2-methoxy) phenyl1ethanamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 3- [4- (2-azidoethyl) -3methoxyphenyl-2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridine (step 10).

'H (CDCb) δ NMR: 7.30 (1H, d, J = 7.7 Hz). 6.92 (1H, dd. J = 2.0, 7.9 Hz). 6.91 (1H, s lg.). 6.86 (1H, d, J = 2.0 Hz), 3.83 (3H, s), 2.65 (3H, s), 2.99 (2H, t lg., J = 4.5 Hz), 2.85 (2H, q, J = 8.3 Hz), 2.84 (2H, q, J = 7.7 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.29 (3H, t, J = 7.7 Hz).

STEP 12. 2-Ethyl- (3-methoxy-4- (2-f ({r (4-methylphenyl) sulfonyl1amino)

340/451 carbonyl) amino1ethyl) phenyl) -5.7-dimethyl-3H-imidazole4,5- £> 1pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5,7-dimethyl-3 / - / ~ imidazo [4,5-b ] pyridin-3-yl-2-methoxy) phenyl] ethanamine (step 11).

¹ H NMR (CDCI ₃ ) δ: 7.86 (2H, d, J = 8.3 Hz), 7.30 (4H, m), 7.14 (1H, d, J = 8.1 Hz) , 7.01 (1H, d, J = 7.9 Hz), 6.92 (1H, s), 6.79 (1H, d, J = 2.0 Hz), 6.63 (1H, dd, J = 1.8, 7.7 Hz), 6.04 (1H, t lg., J = 5.1 Hz), 3.74 (3H, s), 3.51 (2H, dt, J = 6 , 0 Hz), 2.85 (2H, t, J = 6.2 Hz), 2.70 (2H, q, J = 7.5 Hz), 2.66 (3H, s), 2.44 ( 3H, s), 2.41 * 3H, s), 1.23 (3H, t, J = 7.5 Hz).

MS (IED) m / z: 522 [(M + H) ⁺ ], 520 [(MH) '].

EXAMPLE 269

2-ETIL-3- (3-METIL-4-f2-f ({[(4-METHYLphenyl) SULFONYLAMINO}

CARBONIL) AMINO] ETHYL) PHENYL) -5,7-DIMETHYL-3H-IMIDAZOr4,5-blPYRIDINE

STEP 1. 2- (2-Methyl-4-nitrophenyl) diethyl malonate

The title compound was prepared according to the procedure described in step 3 of Example 268 from 4-bromo-3-methylnitrobenzene.

¹ H NMR (CDCI ₃ ) δ: 8.10 (1H, s), 8.05-8.10 (1H, m), 7.62 (1H, d, J = 9.2 Hz), 4, 93 (1H, s), 4.26 (2H, q, J = 7.3 Hz), 4.25 (2H, q, J = 7.3 Hz), 2.46 (3H, s), 1, 28 (6H, t, J = 7.3 Hz).

STEP 2. 2- (2-Methyl-4-nitrophenyl) acetic acid

The title compound was prepared according to the procedure described in step 2 of Example 266 from 2- (2-methyl-4-nitrophenyl) diethyl malonate (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.08 (1H, s lg.), 8.02 (1H, dd, J = 8.6 Hz), 7.49 (1H, d, J = 8.4 Hz), 3.77 (2H, s), 2.35 (3H, s).

STEP 3. 2- (2-Methyl-4-nitrophenyl) methyl acetate

The title compound was prepared according to the procedure described in step 2 of Example 266 from 2- (2-methyl) -4-nitrophenyl) acetic acid (step 2).

¹ H NMR (CDCI ₃ ) δ: 8.07 (1H, d, J = 2.1 Hz), 8.02 (1H, dd, J = 2.3, 5.9 Hz), 7.36 ( 1H, d, J = 8.4 Hz), 3.74 (2H, s), 3.71 (3H, s), 2.42 (3H,

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s) STEP 4. Methyl 2- (4-Amino-2-methylphenyl) acetate

The title compound was prepared according to the procedure described in step 4 of Example 268 from methyl 2- (2-methyl-4-nitrophenyl) acetate (step 3).

¹ H NMR (CDCI ₃ ) 8: 6.97 (1H, d, J = 7.9 Hz), 6.48-6.52 (2H, m), 3.67 (3H, s), 3, 57 (2H, S lg.), 3.53 (3H, s), 2.22 (3H, s).

STEP 5. f4-f (4,6-Dimethyl-3-nitro-2-pyridinihamino1-2-methylphenyl) “methyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 2- (4-amino-2-methylphenyl) acetate (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.54 (1H, d lg., J = 8.3 Hz), 7.38 (1H, s lg.), 7.17 (1H, d, J = 8 , 39 Hz), 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 (IE) m / z: 345 (M ⁺ ).

STEP 6. Methyl (4-f (3-Amino-4 ₍ 6-dimethyl-2-pyridinyl) amino1-2-methylphenyl) acetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from methyl {4 - [(4,6-dimethyl-3-nitro-2pyridinyl) amino] -2-methylphenyl} acetate (step 5).

¹ H NMR (CDCb) 8: 7.07 (1H, d, J = 9.0 Hz), 6.91-6.93 (2H, m), 6.62 (1H, s), 6.36 (1H, S lg.), 3.79 (3H, s), 3.67 (3H, s), 3.57 (2H, s), 3.30 (2H, s lg.), 2.37 ( 3H, s), 2.26 (3H, s), 2.2 (3H, s).

STEP 7. 2-f4- (2-Ethyl-5,7-dimethyl-3H-imidazor4,5-òlpyridin-3-yl) -2-methylphenylethylacetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from methyl {4 - [(3-amino ~ 4,6-dimethyl-2pyridinyl) amino] -2-methylphenyl} acetate (step 6).

¹ H NMR (CDCb) 8: 7.39 (1H, d, J = 7.6 Hz), 7.17-7.25 (2H, m),

6.90 (1H, S), 3.74 (3H, s), 3.72 (2H, s), 2.82 (2H, q, J = 7.4 Hz), 2.65 (3H, s ), 2.52 (3H, s), 2.40 (3H, s), 1.28 (3H, t, J = 7.6 Hz).

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MS (IE) m / z: 337 (M ⁺ ).

STEP 8. 2-f4- (2-Ethyl-5,7-dimethyl-3/7-imidazo [4 ₁ 5-h1pyridin-3-yl) -2methylphenylethanol

The title compound was prepared according to the procedure described in step 8 of Example 266 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-jb] pyridin- Methyl 3-yl) -2-methylphenylethylacetate (step 7).

¹ H NMR (CDCI ₃ ) δ: 7.35 (1H, d, J = 7.9 Hz), 7.17 (1H, s), 7.16 (1H, d, J = 7.9 Hz) , 6.90 (1H, s), 3.84 (2H, dt, J = 6.8 Hz), 2.96 (2H, t, J = 7.0 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.66 (3H, s), 2.52 (3H, s), 2.40 (s, 3H), 1.91 (1H, tlg.), 1.28 (3H , t, J = 7.5 Hz).

MS (IE) m / z: 324 [(M-H) ’].

STEP 9. 3-i4- (2-Chloroethyl) -3-methylphenyl-2-ethyl-5 ₁ 7-dimethyl-3/7-imidazof4 _l 5-d1pyridine

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-ò] pyridin- 3-yl) -2-methylphenylethanol (step 8).

¹ H NMR (CDCI ₃ ) δ: 7.35 (1H, d, J = 8.4 Hz), 7.17-7.19 (2H, m),

6.90 (1H, s), 3.75 (2H, t, J = 7.6 Hz), 3.17 (2H, t, J = 7.6 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.65 (3H, s), 2.41 (3H, s), 2.36 (3H, s), 1.28 (3H, t, J = 7.5 Hz).

STEP 10. 3-i4- (2-Azidoethyl) -3-methylphenyl-2-ethyl-5,7-dimethyl-3Himidazoí4,5 - /) lpiridine

The title compound was prepared according to the procedure described in step 8 of Example 1 from 3- [4- (2-chloroethyl) -3-methylphenyl2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-ò] pyridine (step 9).

¹ H NMR (CDCl 3) δ: 7.34 (1H, d, J = 8.7 Hz), 7.19-7.26 (2H, m),

6.90 (1H, s), 3.62 (1H, t, J = 7.1 Hz), 3.56 (2H, t, J = 7.6 Hz), 2.99 (2H, t, J = 7.6 Hz), 2.81 (2H, q, J = 7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.41 (3H, s), 1.27 (3H, t, J = 7.6 Hz).

STEP 11. 2-í4- (2-Ethyl-5,7-dimethyl-3/7-imidazo [4,5-ò1pyridin-3-yl-2methydphenylethanamine

The title compound was prepared according to the procedure described in step 9 of Example 1 from 3- [4- (2-azidoethyl) -3-methylphenyl343 / 451

2-ethyl-5,7-dimethyl-3/7-imidazo [4,5-b] pyridine (step 10).

¹ H NMR (CDCI ₃ ) δ: 7.32 (1H, d, J = 7.7 Hz), 7.14-7.16 (2H, m),

6.91 (1H, s lg.), 6.90 (1H, s), 3.02 (2H, t lg., J = 7.3 Hz), 2.77-2.87 (4H, m) , 2.65 (3H, s), 2.53 (3H, s), 2.40 (3H, s), 1.28 (3H, t, J = 7.5 Hz).

STEP 12. 2-Ethyl- (3-methyl-4- (2 - [((4-methylphenyl) sulfonillamino) carbonίl) amino ^ ethyl} phenyl) -5.7-dimethyl · -3 / - / - imidazo [4.5- b ^ pyridine

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-ô] pyridin- 3-yl-2-methyl) phenyl] ethanamine (step 11).

¹ H NMR (CDCI ₃ ) δ: 7.86 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 7.9 Hz), 6.91 (1H, s), 6.85 (1H, d, J = 8.4 Hz), 6.07-6.11 (1H, m), 3.51 ( 2H, q, J = 6.4 Hz), 2.85 (2H, t, J = 6.4 Hz), 2.61 to 2.69 (2H, m), 2.69 (3H, s), 2.44 (3H, s), 2.28 (3H, s), 1.23 (3H, t, J = 7.5 Hz).

MS (IED) m / z: 506 [(M + H) ⁺ ], 504 [(MH) '].

EXAMPLE 270

6-CHLORINE-2-ETYL-1- (6- (2 - [({F (4-METHYLFENlL) SULFONYLAMINO)

CARBONIL) AMINO1ETHIL) -3-PYRIDINYL) -5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOLE

STEP 1. (4-Amino-2-pyridinyl) acetonitrile

The title compound was prepared according to the procedure described in step 2 of Example 28 from (4-nitro-2-pyridinyl) acetonitrile (8.6 g, 52.9 mmoles, Katz; RB; Voyle, M ., Synthesis, 1989, 4, 314).

¹ H NMR (CDCI ₃ ) δ: 8.04 (1H, d, J = 2.8 Hz), 7.17 (1H, d, J = 8.2 Hz), 6.99 (1H, dd, J = 2.8, 8.4 Hz), 3.81 (2H, s), 3.76 (2H, s lg.).

STEP 2. {5- [5-Chloro-2-nitro-4- (trifluoromethyl) anilino1-2-pyridinill · acetonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from (5-aminopyridine-2-yl) acetonitrile (step 1).

¹ H NMR (CDCI ₃ ) δ: 9.66 (1H, s), 8.60 (2H, m), 7.71 (TH, dd, J = 2.6, 8.4 Hz), 7, 60 (1H, d, J = 8.3 Hz), 7.13 (1H, s), 4.03 (2H, s).

MS (IE) m / z: 356 (M ⁺ ).

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STEP 3. {5-F2-Amino-5-chloro-4- (trifluoromethyl) anilino1-2-pyridinyl) acetonitrile

The title compound was prepared according to the procedure described in step 2 of Example 28 from {5- [5-chloro-nitro-4- (trifluoromet (1) ani [ino] 2-pyridinyl} acetonitrile (step 2).

¹ H NMR (CDCI ₃ ) δ: 8.25 (1H, d, J = 2.1 Hz), 7.12-7.34 (3H, m), 5.47 (1H, s lg.), 3.89 (2H, s), 3.78 (2H, s lg.).

STEP 4. {5-F6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-lill-2-pyridinyl) acetonitrile

The title compound was prepared according to the procedure described in step 5 of Example 1 from {5- [2-amino-5-chloro-4 (trifluoromethyl) anilino] -2-pyridinyl} acetonitrile (step 3) .

¹ H NMR (CDCI ₃ ) 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 = 7.6 Hz), 1.40 (3H, t, J = 7.6 Hz).

STEP 5. 2- {5-F6-Chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazole1-iH-2-pyridinyl) ethanamine

Raney-Ni was added to a solution of {5- [6-chloro-2-ethyl-5 (trifluoromethyl) -1H-benzimidazol-1-yl] -2-pyridinyl} acetonitrile (step 4, 1.0 g, 2.8 mmoles), in ammonia-ethanol (30 mL), and stirred for 8 hours under a hydrogen atmosphere (3.0 kgf / cm ² ). The catalyst was removed by filtration and the solvent was removed. The residue was diluted with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated to obtain 813 mg of the title compound as a black solid.

MS (IE) m / z: 368 (M ⁺ ).

STEP 6. 6-Chloro-2-ethyl-1- (6- {2-F (fF (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) -3-pyridinin-5- (trifluoromethyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {5- [6-chloro-2-ethyl-5 (trifluoromethyl) -1H-benzimidazol-1-yl] - 2-pyridinyl} ethanamine (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.63 (1H, d, J = 2.2 Hz), 8.14 (1H, s), 7.77 (2H, d, J = 8.3 Hz) , 7.66 (1H, dd, J = 2.6, 8.3 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.21 (1H, s), 3.73-3.80 (2H, m), 3.17 (2H, t, J = 6.2 Hz),

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2.79 (2Η, q, J = 7.5 Hz), 2.42 (3H, s), 1.38 (3H, t, J = 7.5 Hz).

MS (IED) m / z: 566 [(M + H) ⁺ ], 564 [(MH) '].

EXAMPLE 271

SODIUM SALT OF 6-CLQRO-2-ETHYL 1- (6- (2-r ({f (4-METHYLPHYL) SULFONYLTAMINO) CARBONYL) AMINOLETYL) -3-PIRIDINlL) -5- (TRIFLUOROMETID-1H-BENZIMIDAZOL

The title compound was prepared according to the procedure described in Example 2 from 6-chloro-2-ethyl-1- (6- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} -3-pyridinyl) -5- (trifluoromethyl) -1 / - / - benzimidazole (Example 270).

¹ H NMR (DMSO-d ₆ ) δ: 8.71 (1H, s lg.), 8.20 (1H, s lg.), 7.95 (1H, m), 7.43-7.64 (4H, m), 7.12 (2H, s lg.), 6.09 (1H, s lg.), 3.39 (2H, s lg.),

2.92 (2H, s lg.), 2.73 (2H, s lg.), 2.28 (3H, s lg.), 1.27 (3H, s lg.).

MS (IED) m / z: 566 [(M + H) ⁺ ], 564 [(MH) '].

EXAMPLE 272 (2- {5- [6-CHLORO-2ethyl-5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-IL1-2-P1RIDINID-ETI LA 4-METHYLFENIDSULFONYL CARBAMATE)

STEP 1. Ethyl (5-Amino-2-pyridinyl) acetate

To a solution of (5-amino-2-pyridinyl) acetic acid (1.46 g, 9.6 mmoles, Daisley; RW; Hanbali, JR, Synthetic Comunnications, 1981, 11 (9), 743) in ethanol, added Concentrated H2SO4 was added and stirred for 16.5 hours under a hydrogen atmosphere at room temperature. The mixture was neutralized with saturated aqueous NaHCO ₃ solution and the solvent was removed. The mixture was diluted with water and extracted with ethyl acetate (5 x 20 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to obtain 1.2 g of the title compound as a brown oil.

¹ H NMR (CDCl ₃ ) δ: 8.04 (1H, d, J = 2.8 Hz), 7.07 (1H, d, J = 8.2 Hz), 6.96 (1H, dd, J = 2.6, 8.2 Hz), 4.71 (2H, q,> 7.1 Hz), 3.72 (2H, s), 3.66 (2H, s lg.), 1.25 (3H, t,> 7.1 Hz).

STEP 2. Ethyl {5-r5-Chloro-2-nitro-4- (trifluoromethyl) anilino1-2-pyridinylacetate

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The title compound was prepared according to the procedure described in step 3 of Example 1 from ethyl (5-amino-2-pyridinyl) acetate (step 1).

¹ H NMR (CDCfe) δ: 9.66 (1H, s), 8.60 (2H, m), 7.71 (1H, dd, J = 2.6, 8.4 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.13 (1H, s), 4.03 (2H, s).

MS (IE) m / z: 356 (M ⁺ ).

STEP 3. Ethyl {5-f2-Amino-5-chloro-4- (trifluoromethyl) anilino1-2-pyridinylacetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from ethyl {5- [5-chloro-2-nitro-4 (trifluoromethyl) anilino] -2-pyridinyl} acetate (step 2).

¹ H NMR (CDCl 3) δ: 7.25 (1H, d, J = 1.5 Hz), 7.21 (1H, m), 7.16 (1H, s), 7.09 (1H, s ), 7.47 (1H, d, J = 8.2 Hz), 5.47 (1H, s), 4.20 (2H, q, J = 7.2 Hz), 3.80 (2H, s ), 3.77 (2H, s lg.), 1.28 (3H, t, J = 7.2 Hz).

STEP 4. f5-r6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-1yl1-2-pyridinyl} ethyl acetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from ethyl {5- [2-amino-5-chloro-4 (trifluoromethyl) anilino] -2-pyridinyl} acetate (step 3).

¹ H NMR (CDCI ₃ ) δ: 8.61 (1H, d, J = 2.0 Hz), 8.14 (1H, s), 7.71 (1H, dd, J = 2.0, 8 , 2 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.21 (1H, s), 4.27 (1H, q, J = 7.3 Hz), 4.01 ( 2H, s), 2.79 (2H, q, J = 7.6 Hz), 1.38 (3H, t, J = 7.4 Hz), 1.33 (3H, t, J = 7.1 Hz).

STEP 5. 2- {5-6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole1 -in-2-pyridinyl} ethanol

The title compound was prepared according to the procedure described in step 8 of Example 266 from {5- [6-chloro-2-ethyl-5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] - 2-pyridinyl} ethyl acetate (step 4).

¹ H NMR (CDCIs) δ: 8.57 (1H, d, J = 2.50 Hz), 8.13 (1H, s), 7.67 (1H, dd, J = 2.6, 8, 2 Hz), 7.49 (1H, d, J = 8.2 Hz), 7.20 (1H, s), 4.15 (1H, q, J = 5.6 Hz), 3.20 (2H , t, J = 5.4 Hz), 2.79 (2H, q, J = 7.4 Hz), 1.39 (3H, t, J = 7.6 Hz).

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STEP 6. 2- {5- [6-chloro-2-ethyl5- (trifluoromethyl) -1 / - / - benzimidazole-1-yl1-2-pyridinyl) ethyl (4-methylphenihsulfonylcarbamate)

The title compound was prepared according to the procedure described in Example 3 from 2- {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7benzimidazol-1-yl] -2- pyridinyl} ethanol (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.59 (1H, d,> 2.3 Hz), 8.13 (1H, s), 7.88 (2H, d,> 8.4 Hz), 7 , 65 (1H, dd,> 2.5, 8.2 Hz), 7.44 (1H, d,> 8.1 Hz), 7.32 (2H, d,> 8.1 Hz), 7, 20 (1H, s), 4.57 (2H, t,> 6.4 Hz), 3.25 (2H, t,> 6.6 Hz), 2.79 (2H, q,> 7.4 Hz ), 2.42 (3H, s), 1.38 (3H, t,> 7.4 Hz).

MS (IED) m / z: 567 [(M + H) ⁺ ].

EXAMPLE 273

2- {5-6-CHLORO-2-ETHYL (4-METHYLphenyl) SULPHONYLCHARBAMATE HYDROCHLORATE 5- (TRIFLUOROMETHYL) -1 / - / - BENZIMIDAZOL-1-ILl-2Pyridinyljetyl

The title compound was prepared according to the procedure described in Example 240 from 2 {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole (4-methylphenyl) sulfonylcarbamate -1 -yl] -2-pyridinyljetyl (Example 273).

¹ H NMR (DMSO-d ₆ ) δ: 11.9 (1H, s lg.), 8.72 (1H, s lg.), 8.18 (1H, s), 8.03-8.07 (1H, m), 7.74 (1H, d,> 7.6 Hz), 7.58 (1H, d,> 8.2 Hz), 7.43 (2H, d,> 5.1 Hz) , 7.39 (1H, s), 4.45 (2H, t,> 6.2 Hz), 3.17 (2H, t,> 6.2 Hz), 2.76 (2H, q,> 7 , 6 Hz), 2.35 (3H, s), 1.27 (3H, t,> 7.3 Hz).

MS (IED) m / z: 567 [(M + H) ⁺ ], 565 [(MH) '].

EXAMPLE 274

2-ETYL-3- (4- {2-r (([[4-PYRIDINYLSULFONYL1AMINO) CARBONY)

AMINO1ETIL) phenyl) _-5-1 7-DIMETHYL - 3H-imidazo _[4-I 5 à1PIRIDINA

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- Phenyl 3-yl) phenyl] ethylcarbamate (step 1 of Example 18) and pyridinyl-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).

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M.p .: 227.9-228.7 ° C.

¹ H NMR (CDCI ₃ ) δ: 8.63 (2H, d, J = 5.9 Hz), 7.65 (2H, d, J = 5.9 Hz), 7.36 (4H, s) , 6.96 (1H, s), 3.20 (2H, s lg.), 2.75 (2H, s lg.), 2.70 (2H, q, J = 7.6 Hz), 2, 53 (2H, s), 2.40 (3H, s), 1.20 (3H, t, J = 7.6 Hz).

MS (IED) m / z: 479 [(M + H) ⁺ ], 477 [(MH) '].

EXAMPLE 275

2-ETIL-3- (4-f2 - [((f2-PlRIDINYLSULFONYLAMINO) CARBONY)

AMINO] ETHYL) PHENYL) -5,7-DIMETHYL-3H-IMIDAZO [4,5-d] PYRIDINE

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3Wimidazo [4,5-b] pyridin-3- il) phenyl] ethyl phenylcarbamate (step 1 of Example 18) and pyridinyl-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).

¹ H NMR (CDCI ₃ ) δ: 8.51 (1H, s lg.), 8.08 (1H, s lg.), 7.94 (1H, s lg.), 7.29 (2H, s ), 7.19 (1H, s lg.), 6.91 (1H, s), 2.81 (2H, s lg.), 2.73 (2H, q, J = 7.6 Hz), 2 , 66 (3H, s), 2.78 (3H, s), 2.49 (2H, m), 1.26 (3H, t, J = 7.3 Hz).

MS (IED) m / z: 479 [(M + H) ⁺ ], 477 [(MH) '].

EXAMPLE 276

2-ETYL-3- (4- {2 - [(phy-3-PYRIDINYLSULFONY] AMINO) CARBONY)

AMINO1ETHIL} FENIL) -5,7-DIMETlL-3H-IMIDAZO [4,5-b] PYRIDINE

The title compound was prepared according to the procedure described in step 2 of Example 18 from 2- [4- (2-ethyl-5,7-dimethyl-3 / 7imidazo [4,5-b] pyridin- Phenyl 3-yl) phenyl] ethylcarbamate (step 1 of Example 18) and pyridinyl-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).

¹ H NMR (CDCI ₃ ) δ: 9.15 (1H, d, J = 1.9 Hz), 8.83 (1H, dd, J = 1.9, 5.1 Hz), 8.34 ( 1H, dd, J = 6.5 Hz), 7.50 (1H, dd, J = 4.9, 8.1 Hz), 7,127.23 (4H, m), 6.93 (1H, s), 5.92 (1H, s lg.), 3.51 (2H, q, J = 5.9 Hz), 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 (IED) m / z: 479 [(M + H) ⁺ ] _

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EXAMPLE 277 (2-f4- [6-CHLORO2-ETHYL-5- (TRIFLUOROMETYL) -1 / 7-BENZIMIDAZOL-1-ILl-2-PHENYL} ETHYL 2-CHLOROPHENIDSULFONYL CARBAMATE

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4 [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole phenyl carbonate -1-yl] phenyl} ethyl and 2-chlorophenylsulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H, s), 8.07 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 3.8 Hz) , 7.59 (1H, dd, J = 4.3, 8.1 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.31 (1H, s), 4.29 (2H, t, J = 6.2 Hz), 2.94 (2H, t, J = 6.5 Hz), 2.76 (2H, q, J = 7.6 Hz), 1.26 (3H, t, J = 7.3 Hz).

M.p .: 202.4-202.8 ° C.

MS (IED) m / z: 586 f (M + H) ⁺ ], 584 [(MH) '].

EXAMPLE 278 (244- (2-ETHYL-5,7DIMETHYL-3H-IMlDAZOY4,5-b1PYRIDIN-3-IL) 4-METHYLPHYLSULPHONYL CARBAMATE) FENlL1-1,1-DIMETHYLTHYL

STEP 1. 2-Methyl-1- (4-nitrophenyl) -2-propanol

4N LiOH (40 mL) was added to a solution of 1,1-dimethyl-2- (4-nitrophenyl) ethyl acetate (52 mmol) in MeOH (50 mL), and the mixture was stirred at 50 ° C for 2 hours . After removing the solvent, this mixture was diluted with water and extracted with EtOAc (4 x 50 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated. This crude material was purified by column chromatography over SiO ₂ , eluting with hexane / ethyl acetate (5/1), to obtain the title compound as a yellow oil (3.3 g, 33% ).

¹ H NMR (CDCI ₃ ) δ: 8.17 (2H, d, J = 8.9 Hz), 7.40 (2H, d, J = 8.6 Hz), 2.88 (2H, s) , 1.63 (1H, s lg.), 1.25 (6H, s).

STEP 2. 1- (4-Aminophenyl) -2-methyl-2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2-methyl-1- (4-nitrophenyl) -2propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.00 (2H, d, J = 8.4 Hz), 6.65 (2H, d, J = 8.4

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Hz), 3.61 (2H, s Ig.), 2.65 (2H, s), 1.39 (1H, s Ig.), 1.20 (6H, s).

STEP 3. 1- (4-f (4.6-Dimethyl-3-nitro-2-pyridinyl) amino1phenyl) -2-methyl2-propanol

The title compound was prepared according to the procedure described in step 5 of Example 266 from 1- (4-aminophenyl) -2-methyl-2propanol (step 2).

¹ H NMR (CDCI ₃ ) δ: 9.60 (1H, s), 7.59 (2H, d, J = 8.7 Hz), 7.19 (2H, d, J = 8.4 Hz) , 6.52 (1H, s), 2.75 (2H, s), 2.54 (3H, s), 2.43 (3H, s), 1.24 (6H, s).

STEP 4. 1- {4-i (3-Amino-4,6-dimethyl-2-pyridinyl) aminolfenyl) -2methyl-2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 1- {4 - [(4,6-dimethyl-3-nitro-2pyridinyl) amino] phenyl} -2-methyl- 2-propanol (step 3).

¹ H NMR (CDCfe) δ: 7.10 (4H, s), 6.61 (1H, s), 6.33 (2H, s), 3.28 (1H, Ig s), 2.70 (2H, s), 2.37 (3H, s), 2.20 (3H, s), 1.22 (6H, s).

STEP 5. 2-r4- (2-Ethyl-5.7-dimethyl-3 / - / - imidazo [4 ₁ 5-b1pyridin-3-yl) phenyl1-2-methyl-2-propanol

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- {4 - [(3-amino-4,6-dimethyl-2pyridinyl) amino] phenyl} -2-methyl- 2-propanol (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.42 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.47 Hz), 6.91 (1H, s) , 2.87 (2H, s), 2.84 (2H, q, J = 7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.31 (6H, s), 1.28 (2H, d, J = 7.6 Hz).

STEP 6. 2-f4- (2-ethyl-5,7-dimethyl-3B-imidazof4,5-d1pyridin-3-II) phenin-1,1-dimethylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5,7-dimethyl-3B-imidazo [4,5-ò] pyridin-3-yl ) phenyl] -2-methyl-2-propanol (step 5).

¹ H NMR (CDCI ₃ ) δ: 7.94 (2H, t, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.16 (4H, m) , 6.93 (1H, s), 3.10 (2H, s), 2.81 (2H, q, J = 7.6 Hz), 2.67 (3H, s), 2.54 (3H, s), 2.40 (3H, s), 2.42 (3H, s), 1.48 (6H, s), 1.28 (3H, t,

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J = 7 ₍ 6 Hz).

M.p .: 173.5-174.0 ° C.

MS (IED) m / z: 521 [(M + H) ⁺ ], 519 [(MH) T EXAMPLE 279

6-CHLORINE-2-ETYL-1- (6- {2-y (ph (4-METHYLPHYL) SULFONYLAMINO)

CARBONlL) AMINO1ETILT3-PYRIDINYL) -5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOLE

STEP 1. (6 - {[5-ChlorO2-nitro-4- (trifluoromethyl) phenine) -3-pyridinemethanol

The compound was prepared according to the procedure described in step 5 of Example 266 from 1- (6-amino-3-pyridinyl) methanol.

¹ H NMR (CDCI ₃ ) δ: 10.51 (1H, s lg.), 9.26 (1H, s), 8.60 (1H, s), 8.42 (1H, s), 7, 79 (1H, d, J = 8.1 Hz), 7.01 (1H, d, J = 8.1 Hz), 4.75 (2H, s).

STEP 2. (6- {1,2-Amino-5-chloro-4- (trifluoromethyl) phenyl1amino) -3pyridineQmethanol

The compound was prepared according to the procedure described in step 2 of Example 28 from {5- [5-chloro-2-nitro-4- (trifluoromethyl) anilino] -3-pyridinyl} methanol (step 1).

MS (IE) m / z: 317 (M ⁺ ).

STEP 3. {6-6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7benzimidazol-1-yl1-3-pyridinyl} methyl propionate

The compound was prepared according to the procedure described in step 5 of Example 1 from (6 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} -3-pyridinyl) methanol (step 2).

MS (IE) m / z: 411 (M ⁺ ).

STEP 4. {6- | 6-Chloro-2-ethyl-5- (trifluoromethyl) -1 rt-benzimidazol-1 yl1-3-pyridinyl) methanol

The compound was prepared according to the procedure described in step 6 of Example 1 from {5- [5-chloro-2-nitro-4 (trifluoromethyl) anilino] -3-pyridinyl} methyl propionate (step 3) .

¹ H NMR (CDCI _S ) δ: 8.67 (1H, s), 8.19 (1H, s), 8.09 (1H, d, J = 8.6 Hz), 7.79 (1H, d, J = 8.4 Hz), 7.65 (1H, s), 5.54 (1H, t, J = 5.6 Hz), 4.69

352/451 (2Η, d, J = 5.6 Hz), 2.95 (2H, q, J = 7.3 Hz), 1.27 (3H, t, J = 7.2 Hz).

STEP 5. 6-Chloro-1-r5- (chloromethyl) -2-pyridinyl1-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole

The compound was prepared according to the procedure described in step 7 of Example 1 from {5- [5-chloro-2-nitro-4- (trifluoromethyl) anilino] -3-pyridinyl} methanol (step 4).

¹ H NMR (CDCI ₃ ) δ: 8.72 (1H, d, J = 2.2 Hz), 8.12 (1H, s), 8.07 (1H, dd, J = 2.2, 8 , 1 Hz), 7.45-7.48 (2H, m), 4.72 (2H, s), 3.01 (2H, q, J = 7.6 Hz), 1.39 (3H, t , J = 7.6 Hz).

STEP 6. <6-f6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole-ill3-pyridinyl) acetonitrile

KCN (470 g, 7.2 mmol) was added, at room temperature, to a solution of 6-chloro-1- [5- (chloromethyl) -2-pyridinyl] -2-ethyl-5- (trifluoromethyl) 1 / - / - benzimidazole (from step 5, 550 mg, 1.5 mmoles) in DMF (5 ml) and water (1 ml), and the reaction mixture was stirred for 2 hours. The mixture was diluted with water and extracted with a solution of ethyl acetate / toluene (4/1) (3 x 30 ml). The organic layer was washed with water, dried (MgSO ₄ ), and concentrated. This was purified by column chromatography over SiO ₂ , eluting with hexane / ethyl acetate (1 /), to obtain 198 mg (37%) of the title compound, as an orange oil.

¹ H NMR (CDCI ₃ ) δ: 8.70 (1H, d, J = 2.6 Hz), 8.13 (1H, s), 8.06 (1H, dd, J = 2.6, 8 , 0 Hz), 7.52 (1H, d, J = 8.20 Hz), 7.47 (1H, s), 3.94 (2H, s), 3.01 (2H, q, J = 7 , 5 Hz), 1.40 (3H, t, J = 7.5 Hz).

STEP 7. 2-f6- [6-Chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazolill-3-pyridinyl) ethanamine

The compound was prepared according to the procedure described in step 5 of Example 270 from {6 ~ [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7benzimidazol-yl] -3-pyridinyl} acetonitrile (step 6).

MS (IE) m / z: 368 (M ⁺ ).

STEP 8. 6-Chloro-2-ethyl-1 - (6-f2-i ((í (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl} -2pyridinyl) -5- (trifluoromethyl) -1 / - / - benzimidazole the compound according to the procedure described in step

353/451 of Example 1 from 2- {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] -3-pyridinyl} ethanamine (step 7).

¹ H NMR (CDCI ₃ ) δ: 8.50 (1H, s), 8.12 (1H, s), 7.817 (1H, d, J = 6.0 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.42 (1H, s), 7.24-7.37 (3H, m), 7.21 (1H, s), 6.77 (1H, s lg.), 3.60 (2H, dt, J = 6.2 Hz), 2.94-3.01 (4H, m), 2.37 (3H, s), 1.37 (3H, t, J = 7, 5 Hz).

MS (IED) m / z: 566 [(M + H) ⁺ ], 564 [(MH) ·].

EXAMPLE 280 (4-METHYLPHENYL) 2- {4- [5-CHLORO-2ETHYL-S-ÍTRIFLUOROMETID-IH-BENZIMIDAZOL-1-ILIFENID-tl-DIMETHYLTHYL

STEP 1. 1- (4- (r5-Chloro-2-nitro-4- (trifluoromethyl) phenyl1 aminolfenyl) -2-methyl-2-propanol

The title compound was prepared according to the procedure described in step 5 of Example 266 from 1- (4-aminophenyl) -2-methyl-2propanol.

¹ H NMR (CDCI ₃ ) δ: 9.70 (1H, s lg.), 8.58 (1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.21- 7.25 (3H, m), 2.83 (2H, s), 1.28 (6H, s).

MS (IE) m / z: 388 (M ⁺ ).

STEP 2. 1- (4-ff2-Amino-5-chloro-4- (trifluoromethyl) phenyl aminolfenyl) -2-methyl-2-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 1- (4 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl] amino} phenyl) -2- methyl-2-propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.10 (4H, s), 6.61 (1H, s), 6.33 (2H, s), 3.28 (1H, s lg.), 2, 70 (2H, s), 2.37 (3H, s), 2.20 (3H, s), 1.22 (6H, s).

MS (IE) m / z: 388 (Mj.

STEP 3. 1 - (4-6-Chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazol1-yl1-phenyl) -2-methyl-2-propanol

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- (4 - {[2-amino-5-chloro4- (trifluoromethyl) phenyl] amino} phenyl) -2-methyl -2-propanol (step 2).

354/451

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.48 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz) , 7.22 (1H, s), 2.90 (2H, s), 2.80 (2H, q, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz) , 1.32 (6H, s).

MS (IE) m / z: 396 (M ⁺ ).

STEP 4. 2-f4- [5-chloro-2-ethyl-5 (trifluoromethiD-1 H-benzimidazoM -illphenyl) -1,1-dimethylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5,7-dimethyl-3/7-imidazo [4,5b] pyridin-3-yl ) phenyl] -2-methyl-2-propanol (step 3).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.94 (2H, d, J = 8.7 Hz), 7.36 (2H, d, J = 8.1 Hz) , 7.15-7.27 (5H, m), 3.16 (2H, s), 2.78 (2H, q, J = 7.6 Hz), 2.43 (3H, s), 1, 47 (6H, s), 1.37 (3H, t, J = 7.6 Hz).

M.p .: 174.6-175.3 ° C.

MS (IED) m / z: 594 [(M + H) ⁺ ], 592 [(MH) '].

EXAMPLE 281 (2.4-DIMETHYL-1,3-THIAZOL-5-IL) 2 {4- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-1LLFENYL) SULFQNILCARBAMATE

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4 [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole- 1-yl] phenyl} ethyl and 2,4-dimethyl-1,3-thiazol-5-yl sulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.41 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz) , 7.20 (1H, s), 4.45 (2H, t, J = 6.9 Hz), 3.08 (2H, t, J = 6.6 Hz), 2.79 (2H, q, J = 7.7 Hz), 2.71 (3H, s), 2.68 (3H, s), 1.36 (3H, t, J = 7.7 Hz).

M.p .: 168.3-169.0 ° C.

MS (IED) m / z: 587 [(M + H) ⁺ ], 585 [(MH) '].

EXAMPLE 282 2- (4- [6-CHLORO-2 ~ ETHYL-5-CHLORO-1,3-DIMETLL-1/7-PIRAZOL-4-IL) -AV-BENZIMIDAZOL 2- {4- [6-CHLORO-2 ~ ETHYL-5 (TRIFLUOROMETHIL) -1AV-BENZIMIDAZOL -1-1L1FENIL) ETHYL

The title compound was prepared according to the procedure 355/451 as described in step 2 of Example 243 from 2- {4 [6-chloro-2-ethyl-5- (trifluoromethyl) -1/7 phenyl carbonate -benzimidazol-1-ylphenylmethyl and 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl sulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.41 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz) , 7.20 (1H, s), 4.45 (2H, t, J = 6.9 Hz), 3.08 (2H, t, J = 6.6 Hz), 2.79 (2H, q, J = 7.7 Hz), 2.71 (3H, s), 2.68 (3H, s), 1.36 (3H, t, J = 7.7 Hz).

M.p .: 192.0-192.7 ° C.

MS (IED) m / z: 604 [(M + Hf], 602 [(M-H) J.

EXAMPLE 283 (4-METHYLPHENYL) 2- {4-5-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZYLDAZOL-1-IL1FENlL) -PROPYL

STEP 1. 2 ° (4-Aminophenyl) -1-propanol

Lithium aluminum hydride (1.96 g, 51.8 mmoles) was slowly added to a solution, with stirring, of 2- (4-aminophenyl) -propionic acid ester (5.0 g, 25.9 mmoles, Takahashi, I. et al., Heterocycles, 1996, 43, 2343-2346) in tetrahydrofuran (200 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was brusquely cooled by adding 25% ammonia solution (50 ml), while cooling in an ice bath. The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 3.88 g (99%) of the title compound as a light brown syrup.

¹ H NMR (CDCI ₃ ) δ: 7.03 (2H, d,> 8.5 Hz), 6.66 (2H, d,> 8.5 Hz), 3.70-3.57 (4H, m), 2.90-2.78 (1H, m), 1.34-1.30 (1H, m), 1.22 (3H, d,> 7.1 Hz).

MS (IE) m / z: 151 (M ⁺ ).

STEP 2. 2- (4- {f5-Chloro-2-nitro-4- (trifluoromethyl) phenyl1aminoJphenyl) 1-propanol

The title compound was prepared according to the procedure described in step 5 of Example 266 from 2- (4-aminophenyl) -1propanol (step 1).

¹ H NMR (CDCb) δ: 9.69 (1H, s lg.), 8.58 (1H, s), 7.38 (2H, d, J = 8.3 Hz), 7.21-7 , 26 (3H, m), 3.77 (2H, m), 3.03 (1H, m), 1.41 (1H, t, J = 5.7

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Hz), 1.33 (3H, d, J = 7.1 Hz).

STEP 3. 2- (4- {í2-Amino-5-chloro-4 “(trifluoromethyl) phenyl1amino} phenyl) -1-propanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- (4 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl] amino} phenyl) -1- propanol (step 2).

¹ H NMR (CDCh) δ: 7.21-7.26 (3H, m), 7.07 (1H, s), 6.93 (2H, d, J = 8.4 Hz), 5.41 (1H, s lg.), 3.68-3.69 (2H, s lg.), 2.93 (1H, m), 1.38 (1H, s lg.), 1.28 (3H, d , J = 7.1 Hz).

STEP 4, 2- (4-f6-Chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazol1-yl1phenyl} -1-propanol

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- (4 - {[2-amino-5-chloro-4 (trjfluoromethyl) phenyl] amino} phenyl) -1- propanol (step 3).

¹ H NMR (CDCh) δ: 8.12 (1H, s), 7.49 (2H, d, J = 2.3 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.22 (1H, s), 3.83 (2H, m), 3.11 (1H, m), 2.80 (2H, q, J = 7.6 Hz), 1.57 (1H, m ), 1.33-1.40 (6H, m).

STEP 5. 2- (r4- (5-chloro-2-ethyl5- (trifluoromethyl) -1 H-benzimidazole-1-ylIphenylM, 1-dimethylethyl) 4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5,7-dimethyl-3/7-imidazo- [4,5b] pyridin-3- il) phenyl] -1-propanol (step 4).

¹ H NMR (CDCh) δ: 8.11 (1H, s), 7.94 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 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 = 7.5 Hz), 2.43 (3H, s), 1.53 (3H, t, J = 7.56 Hz), 1.34 (3H, t, J = 6.9 Hz).

M.p .: 179.9-180.5 ° C.

MS (IED) m / z: 581 [(M + H) ⁺ ], 579 [(MH) '].

EXAMPLE 284 (4-METHYLphenyl) 2-r4- (5-ACETYL-2-ETHYL-1/7-BENZIMIDAZOL-1-1L) SULPHONYL CARBAMATE PHENYL-1,1-DIMETHYLETHIL

STEP 1, 1- (44F4-Hydroxy-2-methylpropyl) pheninamino) -3-nitrophenyl)

357/451 ethanone

The title compound was prepared according to the procedure described in step 5 of Example 266 from 1- (4-aminophenyl) -2-methyl-2propanol.

¹ H NMR (CDCI ₃ ) δ: 9.85 (1H, s lg.), 8.83 (1H, s), 7.97 (1H, d, J = 9.0 Hz), 7.10- 7.40 (4H, m), 2.82 (2H, s), 2.58 (3H, s), 1.28 (6H, s).

STEP 2. 1- (3-Amino-4- {f4- (2-hydroxy-2-methylpropyl) phenyl1amino) phenyl) ethanone

The title compound was prepared according to the procedure described in step 2 of Example 28 from 1- (4 - {[4-hydroxy-2methylpropyl) phenyl] amino} -3-nitrophenyl) ethanone (step 1).

¹ H NMR (CDCl 3) δ: 7.38-7.46 (2H, m), 7.16 (2H, dd, J = 8.4 Hz), 6.96 (2H, d, J = 8, 4 Hz), 5.62 (2H, s lg.), 3.60 (1H, s lg.), 2.73 (2H, s), 2.54 (3H, s), 1.39 (1H, s lg.), 1.24 (6H, s).

STEP 3. 1-f2-Ethyl-1-r4- (2-hydroxy-2-methylpropyl) phenill-1H-benzimidazol-5-yl} ethanone

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- (3-amino-4 - {[4- (2-hydroxy-2methylpropyl) phenyl] amino} phenyl) ethanone ( step 2).

¹ H NMR (CDCI ₃ ) δ: 8.40 (1H, s), 7.90 (1H, d, J = 8.6 Hz), 7.46 (2H, d, J = 8.1 Hz) , 7.30 (2H, d, J = 8.1 Hz), 7.14 (1H, d, J = 8.6 Hz), 2.96 (2H, s), 2.82 (2H, q, J = 7.6 Hz), 2.68 (3H, s), 1.63 (1H, s lg.), 1.38 (3H, t, J = 7.6 Hz), 1.32 (6H, s).

STEP 4. 2- [4- (5-acetyl-2-ethyl1 / 7-benzimIDazol-1-yl) phenyl1-1,1-dimethylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- {2-ethyl-1- [4- (2-hydroxy-2-methylpropyl) phenyl] -1 / 7-benzimidazole-5 -il} aethanone (step 3).

'H (CDCI ₃ ) δ NMR: 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 = 7.6 Hz), 2.68 (3H, s), 2.40 (3H, s), 1.45 (6H, s), 1.38 (3H, t, J = 7.6 Hz).

M. p .: 103.4-104.2 ° C.

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MS (IED) m / z: 534 [(M + Hf], 532 [(M-H)].

EXAMPLE 285

2- {4- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL] PHYLENE (5-METHYL-2-PYRIDINYL) MONOCHLORHYDRATE

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4 [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / - / - benzimidazole phenyl carbonate -1-iljphenyl} ethyl.

¹ H NMR (CDCI ₃ ) δ: 8.57 (1H, s), 8.15 (1H, s), 8.12 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 7.9 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.17-7.25 (4H, m), 4.36 (2H, t, J = 6 , 6 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.46 (3H, s), 1.36 ( 3H, t, J = 7.3 Hz).

M.p .: 205.8 ° C.

MS (IED) m / z: 567 [(M + Hf], 565 [(MH) ^- ].

EXAMPLE 286

2- {4- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHILYL) -1 / - / - BENZIMIDAZOL-1-IL] PHENYL} ETHYL (5-METHYL-2-PYRIDINYL) SULPHONYL

The title compound was prepared according to the procedure described in Example 240 from 2- {4- [6-chloro-2-ethyl-5- (trifluoromethyl) - (5-methyl-2-pyridinyl) sulfonylcarbamate monohydrochloride 1 / - / - benzimidazol-1-yl] phenyl} ethyl (Example 285).

¹ H NMR (CDCI ₃ ) δ: 8.53 (1H, s), 8.49 (1H, s), 8.08 (1H, d, J = 7.6 Hz), 7.78 (1H, d, J = 6.8 Hz), 7.53 (2H, s lg.), 7.41 (3H, s lg.), 4.38 (2H, t, J = 5.9 Hz), 3, 21 (2H, s lg.), 3.07 (2H, t, J = 5.9 Hz), 2.47 (3H, s), 1.51 (3H, s lg ·) ·

M.p .: 200.2 ° C.

MS (IED) m / z: 567 [(M + Hf], 565 [(M-H)].

EXAMPLE 287 (2-f5- [6-CHLORO-2ethyl-5- (TRIFLUOROMETYL) -1 / 7-BENZIMIDAZOL-1-IL] -3-PYRIDINYL) 4-METHYLENIDSULFONLLCARBAMATE

STEP 1. Benzyl ethyl 2- (6-Nitro-3-pyridinyl) malonate

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K ₂ CO ₃ (5.90 g, 42.7 mmoles) was added to a mixture of 5bromo-2-nitropyridine (8.66 g, 42.7 mmoles) and benzyl and ethyl malonate (9.50 g, 42.7 mmoles) in tetrahydrofuran (160 ml) and dimethylformamide (40 ml), and stirred at reflux temperature for 20 hours. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3 x 200 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give 5.26 g of the title compound as an orange oil.

¹ H NMR (CDCI ₃ ) δ: 8.61 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 2.1, 8.6 Hz), 7.29-7.38 (5H, m), 5.22 (2H, d, J = 3.6 Hz), 4.84 (1H, s), 4.22 (2H, m), 1.23 (3H, t, J = 7.1 Hz).

STEP 2. Ethyl (6-Nitro-3-pyridinyl) acetate

Palladium on carbon (530 mg) was added to a solution of

Benzyl ethyl 2- (6-nitro-3-pyridinyl) malonate (5.26 g, 15.3 mmoles) in ethanol, and stirred for 6 hours under a hydrogen atmosphere at room temperature. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to obtain the title compound as a yellowish brown oil.

¹ H NMR (CDCI ₃ ) δ: 7.95 (1H, d, J = 1.8 Hz), 7.40 (1H, dd, J = 2.4, 8.4 Hz), 6.48 ( 1H, d, J = 8.4 Hz), 4.42 (2H, s lg.), 4.14 (2H, q, J = 7.1 Hz), 3.46 (2H, s), 1, 26 (3H, t, J = 7.1 Hz).

STEP 3. 2- (6-Amino-3-pyridinyl) ethanol

LiAIH ₄ was added to a solution of ethyl (6-nitro-3-pyridinyl) acetate (468 mg, 2.60 mmol) in tetrahydrofuran, and stirred for 2 hours at room temperature. The reaction was quenched with a 25% aqueous solution of saturated NH ₃ , and the precipitate was removed. The filtrate was concentrated to give the title compound as a yellow oil.

¹ H NMR (CDCI ₃ ) δ: 7.73 (1H, d, J = 2.8 Hz), 7.23 (1H, dd, J = 8.6 Hz), 6.37 (1H, d, J = 2.6, 8.1 Hz), 5.63 (2H, s lg.), 3.49 (2H, t, J = 7.3 Hz), 2.51 (2H, t, J = 7 , 3 Hz).

MS (IE) m / z: 138 (M ⁺ ).

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STEP 4. (6- {5-Chloro-2-nitro-4- (trifluoromethyl) pheninamino} -3pyridineQethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (6-amino-3-pyridinyl) ethanol (step 3).

¹ H NMR (CDCI ₃ ) δ: 8.49 (1H, s), 8.32 (1H, d, J = 2.2 Hz), 7.64 (1H, dd, J = 2.4, 8 , 4 Hz), 7.36 (1H, s), 6.97 (1H, d, J = 8.4 Hz), 3.91 (2H, t, J = 6.5 Hz), 2.89 ( 2H, t, J = 6.5 Hz).

MS (IE) m / z: 361 (M ⁺ ).

STEP 5. (6 - {[2-Amino-5-chloro-4- (trifluoromethyl) phenylamino) -3pyridineDethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from (6 - {[5-chloro-2-nitro-4 (trifluoromethyl) phenyl!] Amino} -3-pyridinyl) ethanol (step 4).

MS (IE) m / z: 331 (M ⁺ ).

STEP 6. 2- {6- [6-chloro-2-ethyl-5- (trifluoromethyl) -1Hbenzimidazol-1-ill-3-pyridinyl) ethyl propionate

Propionic acid and propionic anhydride were added to (6 - {[2 amino-5- chloro-4- (trifluoromethyl) phenyl] amino} -3-pyridinyl) ethanol (787 mg, 2.37 mmol, from step 5), and stirred at 120 ° C for 15 hours. The reaction was quenched with the addition of NaOH to the mixture and extracted with dichloromethane (3 x 30 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give 5.26 g of the title compound as an orange oil.

¹ H NMR (CDCI ₃ ) δ: 8.58 (1H, d, J = 1.9 Hz), 8.12 (1H, s), 7.83 (1H, dd, J = 2.2, 8 , 1 Hz), 7.45 (1H, s), 7.39 (1H, d, J = 8.1 Hz), 4.40 (2H, t, J = 6.8 Hz), 4.12 ( 2H, q, J = 7.3 Hz), 3.10 (2H, t, J = 6.5 Hz), 2.99 (2H, q, J = 7.6 Hz), 2.29-2, 44 (2H, m), 1.38 (3H, t, J = 7.4 Hz), 1.15 (3H, t, J = 7.6 Hz).

STEP 7. 2-f6-r6-chloro-2-ethyl-5- (trifluoromethyl) -1 AV-benzimidazol1-yl1-3-pyridinyl} ethanol

The title compound was prepared according to the procedure described in step 8 of Example 266 from 2- {6- [6361/451 chloro-2-ethyl-5- (trifluoromethyl 1) -1 / 7- propionate benzimidazole-1-yl] -2-pyridine-jetyl (step 6).

¹ H NMR (CDCI ₃ ) δ: 8.60 (1H, d, J = 2.3 Hz), 8.11 (1H, s), 7.91 (1H, dd, J = 2.5, 8 , 0 Hz), 7.45 (1H, s), 7.38 (1H, d, J = 8.1 Hz), 4.01 (1H, t, J = 6.2 Hz), 3.72- 3.77 (2H, m), 2.94-3.04 (2H, m), 1.38 (3H, t, J = 7.4 Hz).

STEP 8. 2- (6- [6-chloro-2-ethyl-5 (trifluoromethyl) -l / - / - benzimidazole-1-in-3-pyridinylethyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {6- [6-chloro-2-ethyl-5- (trifluoromethyl) -1 / 7benzimidazol-1-yl] -2- pyrinyl} ethanol (step 7).

¹ H NMR (CDCl 3) δ: 8.33 (1H, d, J = 1.9 Hz), 8.08 (1H, s), 7.91 (2H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 2.4, 8.1 Hz), 7.29-7.42 (4H, m), 7.20 (1H, s), 4.39 (2H, t, J = 6.2 Hz), 3.00 (2H, t, J = 6.2 Hz), 2.93 (2H, t, J = 7.6 Hz), 2.43 (3H, s), 1 , 32 (3H, t, J = 7.4 Hz).

MS (IED) m / z: 567 [(M + H) ⁺ ], 565 [(MH)].

EXAMPLE 288

2- (5- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1H-BENZlMIDAZOL-1-IL1-3-P1R1DINID-ETHYL (4-METHYLphenyl) SULPHONYL CARBAMATE MONOCHLORIDRATE

STEP 1

The title compound was prepared according to the procedure described in Example 240 from 2 {5- [6-chloro-2-ethyl-5- (trifluoromethyl) -1H-benzimidazole-2 (5-methylphenyl) sulfonylcarbamate -yl] -3-pyridinyl} ethyl (Example 287).

¹ H NMR (CDCI ₃ ) δ: 8.40 (1H, s lg.), 8.49 (1H, s lg.), 8.12 (1H, s lg.), 7.82 (2H, s lg.), 7.65 (1H, s lg.), 7.25-7.28 (2H, m), 4.40 (2H, s lg.), 3.35 (1H, s), 3, 12 (2H, s lg.), 2.41 (3H, s), 2.43 (3H, s), 1.53 (3H, s lg.).

MS (IED) m / z: 567 [(M + H) ⁺ ], 565 [(MH) '].

EXAMPLE 289

2- (4- [6-CHLORINE-2-ETHYL-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL] FEN1L CARBAMATE ETHLL-5-ISOQUINOLINYLSULFONIL

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4- [6362/451 chloro-2-ethyl-5- (trifluoromethyl) -1 / - phenylcarbonate] / -benzimidazol-1-yl] phenyl} ethyl and 5-isoquinolinylsulfonamide.

¹ H NMR (CDCI ₃ ) δ: 9.39 (1H, s), 8.70 (2H, t, J = 6.3 Hz), 8.43 (1H, d, J = 6.2 Hz) , 8.29 (1H, d, J = 8.1 Hz), 8.12 (1H, s), 7.78 (1H, t, J = 7.6 Hz), 7.16-7.33 ( 5H, m), 4.32 (2H, t, J = 6.9 Hz), 2.97 (2H, t, J = 6.8 Hz), 2.77 (2H, q, J = 7.4 Hz), 1.346 (3H, t, J = 7.4 Hz).

MS (IED) m / z: 603 [(M + H) ⁺ ], 601 [(MH) '].

EXAMPLE 290

2- (4-r6-CHLORINE-2-ETHYL-5- (TRIFLUOROMETHIL) -1B-BENZIMIDAZOL-1-IL-phenyl) CARBAMATE ETHYL-5-QUINOLNILSULPHONYL

The title compound was prepared according to the procedure described in step 2 of Example 243 from 4- (6-chloro-2-ethyl-5-trifluoromethyl-1 / - / - benzimidazole (4-methylphenyl) sulfonylcarbamate) -1-yl) phenethyl and 5quinolinylsulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.43 (1H, d, J = 8.6 Hz), 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 = 6.6 Hz), 2.98 (2H, t, J = 6.3 Hz), 2.74 (2H, q, J = 7.4 Hz), 1.35 (3H, t, J = 7.4 Hz).

MS (IED) m / z: 567 [(M + H) ⁺ ], 565 [(MH) '].

EXAMPLE 291

2- {4- [6-CHLORINE-2-ETHYL-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL1-PHENYL) CARBAMATE ETHYL- [5- (DIMETHYLAMINE) -1-NAFTIL

SULPHONY

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4- [6 chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole- phenylcarbonate- 1-yl] phenyl} ethyl and 5- (di'methylamino) -naphthylsulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.61 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 7.5 Hz), 8.12 ( 1H, s), 7.58 (2H, t, J = 8.3 Hz), 7.12-7.24 (6H, m), 4.30 (2H, t, J = 6.8 Hz), 2.93 (2H, t, J = 6.8 Hz), 2.75 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz).

M. p .: 203.4 ° C.

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MS (IED) m / z: 645 [(M + H) ⁺ ], 643 [(MH)].

EXAMPLE 292

2- {4- [6-CHLORINE-2-ETlL-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL1-PHENYL CARBAMATE ETIL- (1-METHYL-1H-IMIDAZOL-4-IL) SULFON1LA

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4- [6 chloro-2-ethyl-5- (trifluoromethyl) -1 H-benzimidazole-1-phenyl carbonate -yl] phenylethyl and 1-methyl-1 HimidazoM-ylsulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.13 (1H, s), 7.72 (1H, d,> 1.5 Hz), 7.55 (1H, d,> 1.3 Hz), 7 , 41 (2H, d,> 8.2 Hz), 7.26 (2H, d,> 8.2 Hz), 7.20 (1H, s), 4.38 (2H, t,> 6.6 Hz), 3.78 (3H, s), 3.04 (2H, d,> 6.8 Hz), 2.79 (2H, q,> 7.6 Hz), 1.36 (3H, t, > 7.6 Hz).

M.p .: 204.3 ° C.

MS (IED) m / z: 556 [(M + H) ⁺ ], 554 [(MH)].

EXAMPLE 293

2- {4- [6-CHLORO-2-ETHYL-5- (TRIFLUOROMETHYL) -1HBENZIMIDAZOL-1-IL1FENILJETILA (1-METHYL-1/7-IMIDAZOL-4-IL) MONOCLORHYDRATE

The title compound was prepared according to the procedure described in Example 240 from 2- {4- [6-chloro-2-ethyl (1-methyl-1 / - / - imidazol-4-yl) sulfonylcarbamate -5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyljetyl (Example 292).

MS (IED) m / z: 556 [(M + H) ⁺ ], 554 [(MH)].

EXAMPLE 294

2- {4- [6-CHLORINE-2-ETHYL-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL] CARBAMATE- (1,2-DI METHYL-1H-1 Ml DAZOL-4-IL)

SULPHONY

The title compound was prepared according to the procedure described in step 2 of Example 243 from 2- {4- [6 chloro-2-ethyl-5- (trifluoromethyl) -1 / 7-benzimidazole- phenylcarbonate- 1-ii] phenyl} ethyl and 1,2-dimethyl-1 Himidazol-4-ylsulfonamide.

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¹ H NMR (CDCI ₃ ) 6: 8.12 (1H, s), 7.63 (1H, s), 7.41 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.19 (1H, s), 4.37 (2H, t, J = 6.8 Hz), 3.64 (3H, s), 3.04 (2H, d, J = 6.6 Hz), 2.79 (2H, q, J = 7.6 Hz), 2.42 (3H, s), 1.36 (3H, t, J = 7.6 Hz) .

M.p .: 221.2 ° C.

MS (IED) m / z: 570 [(M + H) ⁺ ], 568 [(MH) '].

EXAMPLE 295

2- (4-r6-CHLORINE-2-ETHYL5- (TRIFLUOROMETHIL) -1 / - / - BENZIMIDAZOL-1-IL] FEN1L} ETHYL- (1,2-DIMETHIL1 / 7-IMIDAZOL-4-IL-CARBAMATE DICHORHYDRATE ) SULPHONY

The title compound was prepared according to the procedure described in Example 240 from 2- {4- [6-chloro-2-ethyl- (1,2-dimethyl-1/7-imidazol-4yl) sulfonylcarbamate) 5- (trifluoromethyl) ~ 1 / - / - benzimidazol1 -yl] phenyl} ethyl (Example 294).

MS (IED) m / z: 570 [(M + H) ⁺ ], 568 [(MH) '].

EXAMPLE 296 (4-METHYLPHENYL) 2- {4- [5,7-DIMETHIL-2- (1 / - / - PIRAZOL-3-IL) -3 / - / - IMIDAZO [4.5-b] PYRIDINE-3 -IL1FENIL) -ETILA

STEP 1. 2- {4- [5,7-Dimethyl-2- (1 / - / - pírazol-3-yl) -3 / - / - imidazof4,5-ò] pyridin-3-yl-phenyl) ethanol

The title compound was prepared according to the procedure described in step 1 of Example 236 from 4 - [(3-amino-4,6-dimethyl-2pyridinyl) amino] phenylethanol.

¹ H NMR (DMSO-de) δ: 13.15 (1H, s lg.), 7.77 (3H, s), 7.35 (2H, d, J = 7.7 Hz), 7.25 (2H, d, J = 7.7 Hz), 7.02 (1H, s), 6.53 (1H, s), 4.75 (2H, t, J = 4.8 Hz), 3.71 (2H, q, J = 6.8 Hz), 2.81 (1H, t, J = 6.6 Hz), 2.58 (3H, s), 2.42 (3H, s).

STEP 2. 2- {4- [5,7-dimethyl-2 (1 B-pyrazol-3-yl) -3F / -imidazo [4,5-frlpyridine-3-yl-phenyl} ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [5,7-dimethyl-2- (1/7-pyrazol-3-yl) -3 / - / imidazo [4,5-b] pyridin-3-yl] phenyl} ethanol (step 1).

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¹ H NMR (DMSO-de) δ: 13.14 (1H, s lg.), 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 = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 2, 58 (2H, s), 2.41 (3H, s), 2.32 (3H, s).

MS (IED) m / z: 531 (MH ⁺ ), 529 ([MH] ').

EXAMPLE 297

2- (4- (5,7-DIMETHIL-2- (1H-PiRAZOL-3-IL) -3H-IMIDAZO [4,5-b1PYRIDINE-3YL-PHYLYLYLENYLETYL) SODIUM SALT

STEP 1 2- (4- (5,7-dimethyl-2- (1 / - / - pyrazol-3-yl) -3 / 7-imidazo [4,5-b] pyridin-3-yl] phenyl) ethanol

The title compound was prepared according to the procedure described in Example 2 from 2 (4 [5,7-dimethyl-2- (1tf-pyrazol-3-yl) -3 / (4-methylphenyl) sulfonylcarbamate) - / - imidazo [4,5-b] pyridin-3-yl] phenyl} ethyl (Example 296).

¹ H NMR (CDCI ₃ ) δ: 9.85 (1H, s), 8.37 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 2.0 Hz) , 7.14 (1H, dd, J = 2.0, 8.3 Hz), 6.60 (1H, s), 3.87 (2H, dt, J = 6.2, 6.4 Hz), 2.84 (2H, t, J = 6.4 Hz), 2.56 (3H, s), 2.46 (3H, s), 1.40 (1H, t, J = 6.2 Hz).

MS (IED) m / z: 531 (MH ⁺ ), 529 ([MH]).

EXAMPLE 298 / V- (f (2- (4-f5,7-DIMETHIL-2- (1 / - / - PIRAZOL-3-IL) -3 / 7-1MIDAZOf4,5-b1

PlRIDINA-3-IL] FENIL) ETIL) AMINO] CARBONIL) -4-METHYLBENZENOSULPHONAMIDE

STEP 1. 3- [4- (2-Chloroethyl) phenyl] -5 _I 7-dimethyl-2- (1 / - / - pyrazol-3-yl) 3/7-imidazo [4,5-b] pyridine

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4- [5,7-dimethyl-2- (1 / 7pyrazol-3-yl) -3 / - / -imidazo [4,5-b] -pyridin-3-yl] phenyl} ethanol (Example 297, step 1).

¹ H NMR (CDCI ₃ ) δ: 13.15 (1H, s), 7.77 (2H, s lg.), 7.43 (2H, s lg.), 7.20 (2H, s lg. ), 7.04 (1H, s), 6.54 (1H, s lg.), 3.96 (2H, t, J = 6.8 Hz), 3.15 (2H, tm, J = 6, 8 Hz), 2.60 (3H, s), 2.30 (3H, s).

STEP 2. 3- [4- (2-Azidoethyl) phenyl-5.7-dimethyl-2- (1 H-pyrazol-3-iD366 / 451

3F / -imidazo [4,5-Zj1pyridine

The title compound was prepared according to the procedure described in step 5 of Example 1 from 3- [4- (2-chloroethyl) phenyl] -5,7dimethyl-2- (1H-pyrazol-3-ii) -3H-imidazo [4,5 "b] pyridine (step 1).

¹ H NMR (DMSO-d ₆ ) δ: 13.15 (1H, s lg.), 9.85 (1H, s lg.), 7.76 (1H, s lg.), 7.41 (2H , d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.04 (1H, s), 6.53 (1H, s), 3.69 (2H , t, J = 6.6 Hz), 2.95 (2H, t, J = 6.8 Hz), 2.58 (3H, s), 2.42 (3H, s) ·

MS (IE) m / z: 358 (M ⁺ ).

STEP 3. 2- (4-f5,7-Dimethyl-2- (1 H-pyrazol-3-yl) -3H-imidazof4.5-dl pyridin-3-iHphenyl} ethanamine

The title compound was prepared according to the procedure described in step 6 of Example 1 from 3- [4- (2-azidoethyl) phenyl] -5,7dimethyl-2- (1 H-pyrazol-3-yl ) -3H-imidazo [4,5-ò] pyridine (step 2).

¹ H NMR (DMSO-d ₆ ) δ: 9.83 (1H, s lg.), 7.68 (2H, s lg.), 7,237.43 (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 (IE) m / z: 332 (M ⁺ ).

STEP 4. A / - ([(2-f4- [5.7-Dtmethyl-2- (1 / - / - pyrazol-3-yl) -3A / -imidazo [4,5-õ1pyridine-3-iriphenyl} ethyl) amino1carbonyl} -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [5,7-dimethyl-2- (1 / 7pyrazol-3-yl) -3 / 7- imidazo [4,5-b] pyridin-3-II] phenyl} ethanamine (step 3).

¹ H NMR (CD ₃ OD) δ: 7.80 (2H, d, J = 8.2 Hz), 7.58 (1H, s lg.), 7.20-7.35 (6H, m) , 7.08 (1H, s), 6.20 (1H, s lg.), 3.42 (2H, t,> 6.8 Hz), 2.84 (2H, t,> 6.9 Hz) , 2.68 (2H, s), 2.50 (3H, s), 2.34 (3H, s).

MS (IED) m / z: 530 (MH ⁺ ), 528 ([MH]).

EXAMPLE 299 (4-METHYLPHENYL) 2- [4- (5-CYAN-2-ETHYL-6-METHYL-1H-BENZIMIDAZOL-1-IDFEN1L1ET1LA SULPHONYL CARE

STEP 1.4-Chlorine-2-methyl-5-nitrobenzonitrile

KNO ₃ (7.0 g, 69.3 mmoles) was added, at 0 ° C in small por367 / 451 portions, to a solution of 4-chloro-2-methylbenzonitrile (10 g, 66 mmoles) in H ₂ SO ₄ concentrated, and the reaction mixture was stirred overnight at room temperature. It was then poured over ice and extracted with AcOEt. The combined extracts were washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ and concentrated. The resulting precipitates were removed by filtration, washed with ether, and dried under reduced pressure to obtain 5.5 g (42%) of the title compound.

¹ H NMR (CDCI ₃ ) δ: 8.19 (1H, s), 7.57 (1H, s), 2.64 (3H, s).

STEP 2. 4- {f4- (2-Hydroxyethyl) phenyl1amino) -2-methyl-5-nitrobenzonitrile

The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-bromo-6-chloro-2,4-dimethyl5-nitropyridine (step 2).

¹ H NMR (CDCI ₃ ) δ: 9.76 (1H, s lg.), 8.51 (1H, s), 7.36 (1H, d, J = 8.4 Hz), 7.22 ( 1H, d, J = 8.3 Hz), 6.96 (1H, s), 3.94 (2H, dd, J = 11.7, 6.2 Hz), 2.94 (2H, t, J = 6.4 Hz), 2.42 (3H, s).

STEP 3. 5-Amino-4-U4- (2-hydroxyethyl) pheninamino) -2-methyl-benzonitrile

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- {4 - [(5-bromo-4,6-dimethyl-3nitro-2-pyridinyl) amino] phenyl} ethanol (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.19 (1H, d, J = 8.4 Hz), 6.94-7.00 (4H, m), 5.59 (1H, s lg.), 3.84-3.90 (2H, m), 3.50 (2H, s lg.), 2.85 (2H, t, J = 6.4 Hz), 2.37 (3H, s).

STEP 5. 2- [4- (5-cyano-2-ethyl-6-methyl-1H-benzimidazo-1-yl) phenyl1ethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(3-amino-5-bromo-4,6dimethyl-2-pyridinyl) amino] phenyl} ethanol (step 4).

MS (IE) m / z: 361 (M ⁺ ).

STEP 6. 2-Ethyl-1-i4- (2-hydroxyethyl) phenin-6-methyl-1 H-benzimidazole5-carbonitrile

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The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- (4- (6bromo-2-isopropyl-5,7-dimethyl-3/7-imidazo [2-methylpropanoate] 4,5-b] pyridin-3-yl) phenyl] ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.00 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz) , 6.98 (1H, s), 4.01 (2H, t, J = 6.4 Hz), 3.03 (2H, t, J = 6.6 Hz), 2.79 (2H, q, J = 7.5 Hz), 2.56 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

STEP 7. 2- (4- (5-Cyano-2-ethyl6-methyl-1/7-benzimidazol-1-yl) phenyl1ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -6-methyl-1 Hbenzimidazole-5-carbonitrile (step 6) .

¹ H NMR (CDCI ₃ ) δ: 8.03 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz) , 7.35 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 6.96 (1H, s), 4.39 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 6.6 Hz), 2.77 (2H, q, J = 7.7 Hz), 2.57 (3H, s), 2 , 44 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

EXAMPLE 300 (4-METHYLBENZENE) SULPHONAMIDE DE / V-f ({2- (4- (5-CYAN-2THYL-6-METHYL-1H-BENZlMIDAZOL-1-IL) PHENYL1ETHIL) AMINO) -CARBONILLA1

STEP 1. 1- (4- (2-0 loroethyl) phenyl1-2-ethyl-6-methyl-1 / - / - benzirnidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-bromo-2-isopropyl5,7-dimethyl-3H-imidazo [4,5-ò] pyridin-3-yl) phenyl] ethanol (step 6).

¹ H NMR (CDCI ₃ ) δ: 8.02 (1H, s), 7.48 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz) , 6.96-6.98 (1H, m), 3.83 (2H, t, J = 7.1 Hz), 3.21 (2H, t, J = 7.0 Hz), 2.78 ( 2H, q, J = 7.5 Hz), 2.58 (3H, s), 1.35 (3H, t, J = 7.5 Hz).

STEP 2. 1-i4- (2-Azidoethyl) phenill-2-ethyl-6-methyl-1H-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-bromo-3- [4- (2 chloroethyl) phenyl] -2-isopropyl-5,7-dimethyl-3F / - imidazo [4,5-b] pyridine (step 7).

MS (IE) m / z: 412 (M ⁺ ).

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¹ H NMR (CDCI ₃ ) δ: 8.02 (1H, s), 7.48 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.2 Hz) , 6.95 (1H, s), 3.63 (2H, t, J = 6.8 Hz), 3.03 (2H, t, J = 7.0 Hz), 2.78 (2H, q, J = 7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J = 7.3 Hz).

STEP 3. 1 -4- (2-Aminoethyl) phenyl1-2-ethyl-6-methyl-1/7-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 9 of Example 1 from 2- [4- (6-bromo-2isopropyl-δJ-dimethyl-SH-imidazo ^ .õ-dlpiridin-azide) -iOfenilJetila (step 8).

¹ H NMR (CDCI ₃ ) δ: 7.49 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 6.93 (1H, s) , 6.60 (2H, s lg.), 3.32-3.00 (5H, m), 2.65 (3H, s), 2.48 (3H, s), 1.31 (6H, d , J = 6.8 Hz).

STEP 4. A / -i ({2-i4-i5-Cyano-2-ethyl-6-methyl-1/7-benzimidazol-1-yl) phenyl1ethyl} amino) carbonyl1 (4-methylbenzene) sulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from [4- (2-isopropyl-5,7-dimethyl3 / 7-imidazo [4,5-b] pyridin-3- il) phenyl] ethylamine (step 9).

¹ H NMR (CDCl ₃ ) δ: 8.00 (1H, s), 7.72 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz) , 7.28-7.32 (4H, m), 6.95 (1H, m), 3.56-3.63 (2H, m), 2.96 (2H, t, J = 7.1 Hz ), 2.78 (2H, q, J = 7.7 Hz), 2.54 (3H, s), 2.41 (3H, s), 1.34 (3H, t, J = 7.5 Hz ).

EXAMPLE 301

2-AMINO-5,7-DIMETHIL-3- (4- (2-i ((f (4-METHYLphenyl) SULFONlLamino} CARBONYL) AMINOLETYL} PHENYL) -3 / 7-IMIDAZO [4,5-blPIRLDINA

STEP 1. 2-Amino-5,7-dimethyl-3- (4- {2-i ({r (4-methylphenyl) sulfonill amino} carbonyl) amino1ethyl} phenyl) -3 / 7-imidazor4,5-iblpiridine

BrCN solution (175 mg, 1.65 mmol) in water 2 ml) was added to a solution, with stirring, of 4-methylbenzenesulfonamide of Λ / {[(2- {4 - [(3-amino-4 , 6-dimethyl-2-pyridinyl) amino] phenyl} ethyl) amino] carbonyl} (300 mg, 0.66 mmol) in THF (6 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2 Cl2 θ, washed with brine. The organic layer was dried over MgSO ₄ and filtered. After concentrating in vacuo, the residue was purified by preparative TLC (CH ₂ CI ₂ / MeOH = 10/1) to obtain 224 mg (71%) of the title compound.

¹ H NMR (DMSO-de) δ: 10.82 (1H, s), 8.54 (2H, s), 7.79 (2H, d, J = 8.3 Hz), 7.51-7 , 40 (6H, m), 7.06 (1H, s), 6.91 (1H, t, J = 5.5 Hz), 3,293.24 (2H, m), 2.80-2.76 ( 2H, m), 2.48 (3H, s), 2.38 (3H, s), 2.36 (3H, s).

MS (IED) m / z: 479 ([M + H] ⁺ ), 477 ([MH]).

STEP 2. 2-Amino-5,7-dimethyl-3- (4 ~ (2-r ({r (4-methylphenyl) sulfonyl1amino) carbonyl) amino] ethyl) phenyl) -3B-imidazo [4.5-b1piridine dihydrochloride

The title compound was prepared according to the procedure described in Example 240 from 2-amino-5,7-dimethyl-3- (4- {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl (phenyl) -3H-imidazo [4,5-ò] pyridine.

MS (IED) m / z: 479 ([M + H] ⁺ ), 477 ([MH] ·).

EXAMPLE 302

5,7-DIMETHYL 3- (4- {2 - [(([(4-METHYLphenyl) SULFONIL] AMINO |

CARBONlL) AMINO1ETlL) FENIL) -2- (METHILSULFANIL) -3B-IMIDAZO [4,5-bl

PYRIDINE

A mixture of / V - {[(2- {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (110 mg , 0.24 mmol), di-2-pyridyl thiocarbonate (68 mg, 0.29 mmol), and THF (5 mL) at room temperature for 3 days. The mixture was diluted with CH ₂ CI ₂ and washed with 0.1 M HCI and brine. The organic fraction was dried over MgSO ₄ , and filtered. The solvent was removed to obtain Λ / - [({2- {4 - [(5,7-dimethyl-2sulfanyl-3H-imidazo [4,5-ò] pyridin-3-yl) pheni!] Ethyl} amino) carbonyl} -4-methylbenzenesulfonamide [MS (IED) m / z: 496 ([M + H] ⁺ ), 494 ([MH])]. This product was dissolved in THF (2 mL), then 1M NaOMe was added in MeOH (0.49 mL) and Honey (45μΙ, 0.73 mmol) to the mixture at room temperature. After 1 hour, the mixture was evaporated in vacuo and the residue was purified by preparative TLC (CH ₂ CI ₂ / MeOH = 10/1) to obtain 31 mg (25%) of the title compound.

¹ H NMR (CDCb) δ: 7.86 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.22-7.16 (4H , m), 6.88 (1H, s), 6.02 (1H, t, J = 5.6 Hz), 3.51-3.45 (2H, m), 2.83 (2H, t, J = 6.2 Hz), 2.67 (3H, s), 2.62 (3H, s), 2.42 (3H, s), 2.417 (3H,

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s).

MS (IED) m / z: 510 ([M + H] ⁺ ), 508 ([MH] ').

EXAMPLE 303

5,7-DIMETHYL 2- (METHYLAMINE) -3- (4-f2 - [(ÍF (4-METHYLPHYL) SULFONY] AMINO) CARBONY) AMINO] ETHYL) PHENYL) -3H-IMIDAZO [4,5-b] PYRIDINE

A mixture of W - {[(2- {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (300 mg, 0.66 mmol), methyl isothiocyanate (56 μΙ, 0.86 mmol), and THF (6 mL) at room temperature for 3 days. The solvent was removed to obtain / V - {[(2 {4 - [(4,6-dimethyl - {[(methylamino) carbonothiol] amino} -2-pyridinyl) amino] phenyl} ethyl) amino] -carbonyl } -4meti! Benzenossu! Fonamide [EM (IED) m / z: 527 ([M + Hf), 525 ([MH])]. This product was dissolved in MeCN (4 mL) and treated with Honey (54 μΐ) at 0 ° C for 20 years. After concentration under reduced pressure, the residue was purified by preparative TLC (EtOAC / EtOH = 20/1) to obtain 170 mg (52%) of the title compound.

¹ H NMR (CD ₃ OD) δ: 7.72 (2H, d, J = 8.3 Hz), 7.24 (4H, d, J = 7.9 Hz), 7.15 (2H, d , J = 8.4 Hz), 6.70 (1H, s), 3.28 (2H, t, J = 7.0 Hz), 2.90 (3H, s), 2.72 (2H, t , J = 7.0 Hz), 2.41 (3H, s), 2.26 (3H, s), 2.24 (3H, s).

MS (IED) m / z: 493 ([M + H] ⁺ ), 491 ([MH]).

EXAMPLE 304

5,7-DIMETHIL-2- (METHYLAMINE) -3- (4 <2 - [({[(4-METHYLphenyl) SULPHONYL1AMINQ) CARBONlL) AMINO] ETHYL) -FENIL) 3/7-IMIDAZO [4,5 -ó1PIRIDlNA

The title compound was prepared according to the procedure described in Example 240 from 5,7-dimethyl-2 (methylamino) -3- (4- {2 - [({[(4-methylphenyl) sulfonyl) hydrochloride ] amino} carbonyl) amino] ethyl} phenyl) 3H-imidazo [4,5-ó] pyridine.

MS (IED) m / z: 493 ([M + Hf), 491 ([M-H]).

EXAMPLE 305 / V- [5,7-DIlMETHYL-3- (4- (2 - [(f [(4-METHYLphenyl) SULFONYLAMINO)

CARBONIL) AMINO] ETHYL) PHENYL) -3H-1MIDAZO [4,5-b1PlRIDIN-2-ILlACETA372 / 451

MIDA

2-Amino-5,7-dimethyl-3- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -3H-imidazo [4,5 -b] pyridine (73 mg) with pyridine (1 ml) and AC2O (0.2 ml), at room temperature for 3 hours. After evaporation in vacuo, the residue was purified by preparative TLC (hexane / acetone = 1/1) to obtain 4 mg (5%) of the title compounds.

¹ H NMR (CDCI ₃ ) δ: 7.79 (2H, d, J = 8.4 Hz), 7.34-7.22 (7H, m), 7.04 (1H, s) 6.30 (1H, s lg.), 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 (IED) m / z: 521 ([M + H] ⁺ ), 519 ([MH] ').

EXAMPLE 306

5,7-DIMETlL-2- (DIMETHYLAMlNO) -3- (4- {2-MT (4-METHYLphenyl)

SULFONIL1AMINO) CARBONIL) AMINO1ETHIL) FEN1L) -3H-IMIDAZOÍ4,5-Ò1

PYRIDINE

NaH (21 mg, 0.88 mmol) was added at room temperature to a stirred solution of 2-amino-5,7-dimethyl-3- (4- {2 - [({[(4 -methylphenyl) sulfonyl] amine} carbonyl) amino] ethyl} phenyl) -3 / 7-imidazide [4,5-b] pyridine (70 mg) in THF (1 ml). After 10 minutes, honey (27 μΙ) was added to the mixture and stirred at room temperature for 2 days. The mixture was poured into ice water and extracted with CH2 Cl2, and the organic fraction was dried over MgSO ₄ , then filtered. After removing the solvent by evaporation, the residue was purified by preparative TLC (CH ₂ Cl2 / MeOH = 10/1) to obtain 27 mg (36%) of the title compound.

¹ H NMR (CDCl 3) δ: 7.86 (2H, d, J = 8.4 Hz), 7.32-7.24 (4H, m), 7.16 (2H, d, J = 8, 4 Hz), 6.77 (1H, s), 6.04 (1H, t, J = 5.7 Hz), 3.50-3.44 (2H, m), 2.78 (2H, t, J = 6.3 Hz), 2.71 (6H, s), 2.55 (3H, s), 2.41 (3H, s), 2.34 (3H, s).

MS (IED) m / z: 507 ([M + H] ⁺ ), 505 ([MH]).

EXAMPLE 307 (4-METHYLPHENYL) 2- [4- (2-AMlNO5,7-DIMETHIL-3 / - / - IMIDAZO [4,5-b1PIRIDlN-3-IL) PHENYL] ETHYL

STEP 1. 2- (4-Methylphenyl) sulfonylcarbamate - [(4,6-dimethyl-3373/451 nitro-2-pyridinyl) amino] phenyl) ethyl

The title compound was prepared according to the procedure described in Example 3 from 2- {4 - [(4,6-dimethyl-3-nitro-2-pyridinyl) amino] phenyl} ethanol.

¹ H NMR (CDCI ₃ ) δ: 9.55 (1H, s), 7.89 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.6 Hz) , 7.32 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.4 Hz), 6.54 (1H, s), 4.28 (2H, t, J = 7.0 Hz), 2.88 (2H, t, J = 7.0 Hz), 2.55 (3H, s), 2.43 (6H, s).

MS (IED) m / z: 485 ([M + H] ⁺ ), 483 ([MH] ').

STEP 2. 2-f4 (4-methylphenyl) sulfonylcarbamate - [(3-amino-4,6dimethyl-2-pyridinyl) amino] phenyl) ethyl

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- {4 - [(4,6-dimethyl-3-nitro-2-pyridinyl) (4-methylphenyl) sulfonylcarbamate) amino] phenyl} ethyl.

¹ H NMR (CDCI ₃ ) δ: 7.82 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 8.4 Hz), 6.84 (2H, d, J = 8.4 Hz), 6.66 (1H, s), 4.22 (2H, t, J = 6.6 Hz), 2 , 77 (2H, t, J = 6.6 Hz), 2.39 (3H, s), 2.37 (3H, s), 2.22 (3H, s).

MS (IED) m / z: 455 ([M + H] ⁺ ), 453 ([MH] ').

STEP 3. 2- [4- (2-Amino-5,7-dimethi [-3 / 7-imidazoF4,5-b] pyridin-3-yl) phenyl] ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in step 127 from 2- {4 [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} (4-methylphenyl) suphonylcarbamate} ethyl.

¹ H NMR (DMSO-d _e ) δ: 7.76 (2H, d, J = 8.3 Hz), 7.42-7.35 (6H, m), 6.78 (1H, s), 6.61 (1H, s lg.), 4.22 (2H, t, J = 6.6 Hz), 2.92 (2H, d, J = 6.6 Hz), 2.373 (3H, s), 2.365 (3H, s), 2.32 (3H, s).

MS (IED) m / z: 480 ([M + H] ⁺ ), 478 ([MH] ').

EXAMPLE 308 (2- [4- [5,7-DIMETHIL-2- (METlLAMINO) -3H-IMIDAZO [4,5-blPIRIDIN-3-1-PHENYL) -ETHYL 4-METHYLPHENIUSULFONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 129 from 2 {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl} (4-methylphenyl) sulfonylcarbamate} ethyl.

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¹ H NMR (DMSO-d ₆ ) δ: 7.78 (2H, d,> 8.1 Hz), 7.43-7.33 (7H, m), 6.77 (1H, s), 6 , 43 (1H, s lg.), 4.25 (2H, t,> 6.6 Hz), 2.93 (2H, t,> 6.6 Hz), 2.88 (3H, s), 2 , 41 (3H, s), 2.37 (3H, s), 2.31 (3H, s).

MS (IED) m / z: 494 ([M + H] ⁺ ), 492 ([MH]).

EXAMPLE 309 (2- {4- [5,7-DIMETlL-2- (METHILSULFANIU-3H-IMlDAZO [4,5-b1PIRIDIN-3-IL1FENIU-ETHYL) 4-METHYLPHENIUSULFONYL-2-

The title compound was prepared according to the procedure described in Example 128 from 2 {4 - [(3-amino-4,6-dimethyl-2-pyridinyl) amino] phenyl (4-methylphenyl) sulfonylcarbamate} ethyl.

¹ H NMR (CDCI ₃ ) δ: 7.92 (2H, d,> 8.4 Hz), 7.36-7.22 (6H, m), 6.88 (1H, s), 4.32 (2H, t,> 6.6 Hz), 2.93 (2H, t,> 6.6 Hz), 2.72 (3H, s), 2.62 (3H, s), 2.48 (3H , s), 2.41 (3H, s).

MS (IED) m / z: 511 ([M + Hf), 509 ([M-H]).

EXAMPLE 310 (2- (445,7-DlMETlL-2- (METHILSULFONID-3H-1MIDAZOÍ4,5-blPIRIDIN-3-IL1FENID-ETlLA) 4-METHYLPHENIUSULFONYL CARBAMATE

A solution of KMnO ₄ (62 mg, 0.39 mmol) in water (2 ml) at room temperature was added to a solution, with stirring, of 2- {4- [5,7- dimethyl-2- (methylsulfanyl) -3H-imidazo [4,5-b] pyridin-3-yl] phenyl} ethyl (100 mg, 0.20 mmol) in AcOH (1 mL). After 1 hour, the mixture was poured into cold, saturated aqueous NaHCO _{3 solution} , and extracted with CH ₂ CI ₂ . The organic layer was dried over MgSO ₄ , and then filtered. After concentration in vacuo, the residue was purified by preparative TLC (CH ₂ CI ₂ / MeOH = 10/1) to obtain 70 mg (66%) of the title compounds.

¹ H NMR (CDCI ₃ ) δ: 7.91 (2H, d,> 8.4 Hz), 7.47 (2H, d,> 8.2 Hz), 7.34-7.26 (4H, m), 7.08 (1H, s), 4.35 (2H, t,> 6.7 Hz), 3.45 (3H, s), 2.96 (2H, t,> 6.7 Hz) , 2.68 (3H, s), 2.55 (3H, s), 2.42 (3H, s).

MS (IED) m / z: 543 ([M + H] ⁺ ), 541 ([MH] ').

EXAMPLE 311

5-ACETYL-2- (METHYLAMINE) -1- (4- (2-í (([(4-METHYLPHENIUSULFO375 / 451

NIL1AMINO) CARBONIL) AMINO1ETHIL) PHENYL) -1H-BENZIM1DAZOL

The title compound was prepared according to the procedure described in Example 129 from / V - {[(2- {4 - [(4-acetyl-2-aminophenyl) amino] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide.

¹ H NMR (CDCI ₃ ) δ: 8.06 (1H, s), 7.75-7.66 (3H, m), 7.38-7.26 (6H, m), 6.89 (1H , d, J = 8.3 Hz), 6.60 (1H, s lg.), 3.55 (2H, dd,> 12.5 and 6.6 Hz), 3.08 (3H, s), 2.91 (2H, t,> 6.6 Hz), 2.61 (3H, s), 2.38 (3H, s).

MS (IED) m / z: 506 ([M + Hf), 504 ([M-H]).

EXAMPLE 312 (2- {4-r6-CHLORO-2 (3-PYRIDINYL) -5- (TRIFLUOROMETHYL) -1 / 7-BENZIMIDAZOL-1-ILJFENYL-ETHYL (4-METHYLFENIDSULFONYL CARBAMATE)

STEP 1. 2- {4- [6-Chloro-2- (3-pyridinyl) -5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl-phenyl) ethanol

The title compound was prepared according to the procedure described in Example 138 from 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol.

¹ H NMR (CDCI ₃ ) δ: 8.70 (1H, dd, J = 2.2 and 0.7 Hz), 8.62 (1H, dd, J = 4.5 and 1.7 Hz), 8.23 (1H, s), 8.01-7.97 (1H, m), 7.45 (2H, dd, J = 6.5 and 2.2 Hz), 7.37-7.24 ( 7H, m), 3.97 (2H, t, J = 6.6 Hz), 2.99 (2H, t, J = 6.6 Hz).

MS (IED) m / z: 418 ([M + Hf), 476 ([M + CF ₃ CO ₂ ]).

STEP 2. 2- (4-r6-chloro-2- (3pyridinyl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1-yl1-phenyl) ethyl 4-methylphenylsulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4 ~ [6-chloro-2- (3-pyridinyl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1 -yl] phenyl} ethanol.

¹ H NMR (CDCI ₃ ) δ: 8.73 (1H, dd, J = 4.9 and 1.8 Hz), 8.40-8.36 (1H, m), 8.23 (1H, s ), 7.91 (1H, dd, J = 2.2 and 0.7 Hz), 7.84-7.80 (2H, m), 7,497.43 (2H, m), 7.31-7, 17 (6H, m), 4.44 (2H, t, J = 6.2 Hz), 3.02 (2H, t, J = 6.2 Hz), 2.41 (3H, s).

MS (IED) m / z: 615 ([M + H] *), 613 ([M-H] ').

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EXAMPLE 313 (2- {4- [6-CHLORO-2 (4-Pyridinyl) -5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL-phenyl-4-methylphenylsulfonylcarbonate ·

ETHYL

STEP 1. 2- {4-f6-Chloro-2- (4-pyridinyl) -5- (trifluoromethyl) -1 H-benzimidazole-1 -illphenyljetanol

The title compound was prepared according to the procedure described in Example 138 from 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol.

¹ H NMR (CDCI ₃ ) δ: 8.60 (2H, dd, J = 4.6 and 1.7 Hz), 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 = 6.4 Hz), 3.02 (2H, t, J = 6.4 Hz).

MS (IED) m / z: 418 ([M + H] ⁺ ), 476 ([M + CF ₃ CO ₂ ]).

STEP 2. 2- (4- [6-chloro-2- (4pyridinyl) -5- (trifluoromethyl) -1H-benzimidazole-1-illfenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (4-pyridinyl) -5 (trifluoromethyl) -1H-benzimidazol-1-yl] phenyl} ethanol.

¹ H NMR (CDCI ₃ ) δ: 8.60 (2H, dd, J = 4.8 and 1.5 Hz), 8.27 (1H, s), 7.89 (2H, d, J = 8 , 3 Hz), 7.44-7.18 (9H, m), 4.39 (2H, t, J = 6.4 Hz), 3.03 (2H, t, J = 6.4 Hz), 2.40 (3H, s).

MS (IED) m / z: 615 ([M + H] ⁺ ), 613 ([MH] ').

EXAMPLE 314 (2- {4- [6-CHLORINE-2 (2-METHYLPHENYL) -5- (TRIFLUOROMETID-1H-BENZIMIDAZOL-1-IL-FENID

ETHYL

STEP 1. 2- {4-16-Chloro-2- (2-methylphenyl) -5- (trifluoromethyl) -1 H-benzimidazol-1-yl] phenyl} ethanol

The title compound was prepared according to the procedure described in Example 138 from 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol.

¹ H NMR (CDCb) δ: 8.22 (1H, s), 7.47 (1H, s), 7.33-7.10 (8H,

377/451

m), 3.89 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 2.20 (3H, s).

MS (IED) m / z: 431 ([M + Hf).

STEP 2. 2- (4- [6-chloro-2- (2methylphenyl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1-iriphenyl) ethyl (4-methylphenyl) suffonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (2-methylphenyl) -5 (trifluoromethyl I) -1 / - / - benzimidazole -1 -il] phen iJeta nol.

¹ H NMR (CDCI ₃ ) δ: 8.24 (1H, s), 7.78 (2H, d, J = 8.2 Hz), 7.46 (1H, s), 7.35-7, 09 (8H, m), 7.00 (2H, d,> 8.4 Hz), 4.27 (2H, t, J = 6.8 Hz), 2.88 (2H, t, J = 6, 8 Hz), 2.41 (3H, s), 2.11 (3H, s).

MS (IED) m / z: 628 ([M + Hf), 489 ([M + CHsCOJ).

EXAMPLE 315 2- {4- [6-CHLORO-2 (1,3-THIAZOL-2-IL) -5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-ILlFENILJ (4-METHYLphenyl) SULPHONYL CARBAMATE

ETHYL

STEP 1. 2-f4- [6-Chloro-2- (1,3-thiazol-2-yl) -5- (trifluoromethyl) -1 Hbenzimidazol-1-yl1phenyl} ethanol

The title compound was prepared according to the procedure described in Example 138 from 2- (4 - {[2-amino-5-chloro-4 (trifiuoromethyl) phenyl] amino} phenyl) ethanol.

¹ H NMR (CDCI ₃ ) δ: 8.23 (1H, s), 7.75 (1H, d, J = 3.1 Hz), 7,477.45 (3H, m), 7.36-7, 27 (3H, m), 3.99 (2H, t, J = 6.4 Hz), 3.03 (2H, t, J = 6.4 Hz).

MS (IED) m / z: 424 ([M + Hf). 482 ([M + CH ₃ CO ₂ r).

STEP 2. 2- {4- [6-chloro-2- (1,3thiazol-2-yl) -5- (trifluoromethyl) -1 / 7-benzimidazole-1-iHphenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (1,3-thiazol-2-yl) -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} etanok

¹ H NMR (CDCI ₃ ) δ: 8.23 (1H, s), 7.91 (2H, d, J = 8.4 Hz), 7.74 (1H, d, J = 3.1 Hz) , 7.46 (1H, d, J = 3.1 Hz), 7.38-7.26 (7H, m), 4.40 (2H, t, J = 6.8 Hz), 3.04 ( 2H, t, J = 6.8 Hz), 2.42 (3H, s).

378/451

MS (IED) m / z: 621 ([M + H] ⁺ ), 619 ([MH]).

EXAMPLE 316 (2- {4-6-CLQRO-2 (1H-IMIDAZOL-4-IL) -5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-ILI FENYL 4-METHylphenyluscarbonate

STEP 1. 2- (4-r6-Chloro-2- (1H-imidazol-4-yl) -5- (trifluoromethyl) -1Hbenzimidazol-1-illfenyl} ethanol

The title compound was prepared according to the procedure described in Example 138 from 2- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) ethanol.

¹ H NMR (CDC1 ₃ / CD ₃ OD = 4/1) δ: 8.09 (1H, s), 7.65 (1H, s), 7.50 (2H, d, J = 8.7 Hz ), 7.33 (2H, d, J = 8.2 Hz), 7.25 (1H, s), 6.91 (1H, s), 3.93 (2H, t, J = 6.4 Hz ), 3.00 (2H, t, J = 6.4 Hz).

MS (IED) m / z: 407 ([M + H] ⁺ ), 405 ([MH] ').

STEP 2. 2- (4-6-chloro-2- (1 / - / imidazol-4-yl) -5- (trifluoromethyl) -1 / - / - benzimidazole-1-illfenyl) (4-methylphenyl) sulfonylcarbamate) ethyl

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- (1/7-imidazol-4-yl) -5 (trifluoromethyl) -1A / -benzimidazol-1-yl] phenyl} ethanol.

MS (IED) m / z: 604 ([M + H] ⁺ ), 602 ([MH] ').

EXAMPLE 317 (4-METHYLPHENIUSULFONYL CARBAMATE 244- (5,6DIMETHYL-1-p-BENZIMIDAZOL-1-IL)

STEP 1. 4- (2-hydroxyethyl) phenylboronic acid

1.5M n-BuLi in hexane (39.8 mL, 59.7 mmol) was added at -78 ° C for 30 minutes to a stirring solution of 4-bromophenethyl alcohol (5.00 g, 24, 9 mmoles) in THF (80 mL). After 1 hour, a solution of B (O / -Pr) ₃ (8.61 ml, 37.3 mmoles) in THF (20 ml) was tentatively added to the mixture at -78 ° C. The resulting mixture was warmed to room temperature, and treated with 2M HCI (100 ml) for 1 hour. The mixture was extracted with CH ₂ CI ₂ and dried over MgSO ₄ , then filtered. After evaporation in vacuo, the residue was purified by chromatography on

379/451 column on silica gel, eluting with CH ₂ CI ₂ / MeOH = 20/1, to obtain 2.61 g (63%) of the title compound.

¹ H NMR (CD ₃ OD) δ: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.2 Hz).

MS (IED) m / z: 165 ([M-H] ').

STEP 2. 4- {2-r «r (4-Methylphenyl) sulfoninamino) carbonyl) oxylethypphenylboronic acid

4- (2-hydroxyethyl) phenylboronic acid (1.00 g, 6.02 mmol) was treated with pTsNCO (1.01 mL, 6.63 mmol) and pyridine (90 mL) at room temperature for 2 hours. The mixture was poured onto ice-cold 2M HCI and extracted with EtOAc. The organic layer was dried over MgSO ₄ , and filtered. After removing the solvent, the residue was purified by column chromatography on silica gel, eluting with CH ₂ Cl ₂ / MeOH = 20/1, to obtain 2.20 g (quant.) Of the title compound.

¹ H NMR (DMSO-d ₃ ) δ: 11.95 (1H, s lg.), 7.97 (1H, s), 7.757.67 (2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 7.7 Hz), 4.18 (2H, t, J = 6.6 Hz), 2.81 (2H, t, J = 6 , 6 Hz), 2.40 (3H, s).

MS (IED) m / z: 381 ([M + NH ₄ ] ⁺ ), 362 ([MH] ').

STEP 3. 2- [4- (5,6-dimethyl-1 / 7benzimidazole-1-hyphenylethyl) (4-methylphenyl) sulfonylcarbamate

A mixture of 4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) oxy] ethyl} phenylboronic acid (100 mg, 0.28 mmol), 5,6-dimethiibenzimidazole (40 mg , 0.28 mmol), Cu (OAc) ₂ (60 mg, 0.33 mmol), triethylamine (115 μΙ, 0.83 mmol), MS4A (100 mg), and CH ₂ CI ₂ (4 mL) at temperature environment for 1 week. After filtration through a bed of Celite, the filtrate was diluted with CH ₂ CI ₂ and washed with water. The organic fraction was dried over MgSO ₄ and filtered. After concentration under reduced pressure, the residue was purified by preparative TLC (CH ₂ CI ₂ / MeOH = 10/1), to obtain 28 mg (22%) of the title compound.

¹ H NMR (CDCI ₃ ) δ: 7.82 (2H, d, J = 8.4 Hz), 7.72 (1H, s), 7.57 (1H, s), 7.33 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.07 (1H, s), 7.01 (2H, d, J = 8.4 Hz) , 4.39 (2H, t, J = 6.1 Hz), 2.49 (2H, t, J = 6.1 Hz), 2.42 (3H, s),

380/451

2.39 (3Η, s), 2.26 (3H, s).

MS (IED) m / z: 464 ([M + Hf), 462 ([M-H] ').

EXAMPLE 318

6-CHLORINE-5-CYANO-2ETHYL 1- (4- {2 - [({f (4-METHYLphenyl-SULFONl LIAM INOICARBONI L) AM INO] ETHYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 6-Chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl-1H-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 1 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 / 7-benzimidazole-5 -carbonitrile.

¹ H NMR (CDCI ₃ ) δ: 8.07 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.30 (2H, d,> 8.4 Hz), 7.19 (1H, s), 3.83 (2H, t,> 7.1 Hz), 3.22 (2H, t, J = 7.1 Hz),

2.79 (2H, q, J = 7.5 Hz), 1.37 (3H, t, J = 7.5 Hz).

STEP 2. 1- [4- (2-Azidoethyl) phenin-6-chloro-2-ethyl-1/7-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-1 / - / - benzimidazole-5 -carbonitrile (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.07 (1H, s), 7.49 (2H, d,> 8.4 Hz), 7.29 (2H, d,> 8.4 Hz), 7 , 18 (1H, s), 3.64 (2H, t,> 7.0 Hz), 3.04 (2H, t,> 7.0 Hz),

2.79 (2H, q,> 7.6 Hz), 1.36 (3H, t,> 7.6 Hz).

STEP 3. 1 - [4- (2-Aminoethyl) phenyl] -6-chloro-2-ethyl-1 H-benzimidazole5-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-1 / - / - benzimidazole-5- carbonitrile (step 2).

¹ H NMR (CDCI ₃ ) δ: 8.06 (1H, s), 7.46 (2H, d,> 8.1 Hz), 7.26 (2H, d,> 8.1 Hz), 7 , 19 (1H, s), 3.09 (2H, t,> 7.1 Hz), 2.89 (2H, t,> 7.1 Hz),

2.79 (2H, q,> 7.6 Hz), 1.36 (3H, t,> 7.6 Hz).

STEP 4. 6-Chloro-5-cyano-2-ethyl-1- (4- {2 - [(U (4-methylphenyl) sulfonyl1 amino] · carbonyl) amino] ethyl) pheni [) - 1/7-benzimidazole

The title compound was prepared according to the procedure 381/451 as described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1/7-benzimidazole- 5-carbonitrile (step 3).

Mp: 219-224 ° C; IV (KBr) v: 3388, 2229, 1708, 1618, 1514, 1466, 1344, 1161, 1089 cm ^-1 .

MS (IED) m / z: 522 (M + H) ⁺ , 520 (MH) '; ¹ H NMR (DMSO-d ₆ ) δ: 8.38 (1H, s), 7.77 (2H, d, J = 8.2 Hz), 7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H, s lg.), 3.26-3.28 (2H, m), 2.69-2.81 (4H, m), 2.35 ( 3H, s), 1.25 (3H, t, J = 7.6 Hz).

EXAMPLE 319

6-CHLORINE-5- (DIMETHYLAMINE) -2-ETYL-1- (4- {2 - [(U (4-METHYLPHYL) SULFONYL1AMINO) CARBON1L) AMINO1ETYL | PHENYL) -1H-BENZIMIDAZOLE

STEP 1. / V- {6-Chloro-1-4- (2-chloroethyl) phenyl1-2-ethyl-1/7-benzimidazol-5-yl} - / V, / V-dimethylamine

A mixture of 6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl1 / 7-benzimidazol-5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) was added and NaBH ₄ (153 mg, 4 mmoles) in THF (5 ml) to a mixture of 38% formaldehyde (0.5 ml, 5.6 mmoles) and 3M aqueous H ₂ SO _{4 solution} (0.4 ml, 0 , 12 mmol) at 0 ° C. 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 (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 2), to obtain 48 mg (46%) of the title compound as of white solids.

MS (IE) m / z: 361 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.54 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz) , 7.13 (1H, s), 3.82 (2H, t, J = 7.0 Hz), 3.19 (2H, t, J = 7.0 Hz),

2.82 (6H, s), 2.75 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 2. / V- (1- [4- (2-Azidoethyl) phenyl] -6-chloro-2-ethyl-1/7-benzimidazol-5-yl) - / V, / V-dimethylamine

The title compound was prepared according to the procedure 382/451 described in step 8 of Example 1 from / \ / - {6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl -1 / 7-benzimidazol-5-yl} - / V _J / V-dimethylamine (step 1).

¹ H NMR (CDCb) δ: 7.54 (1H, s), 7.43 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.0 Hz),

2.82 (6H, s), 2.75 (2H, q, J = 7.6 Hz), 1.34 (2H, t, J = 7.6 Hz).

STEP 3. /V-{1-F4-(2-Aminoetil)phenyl those-6- chloro-2-ethyl-1/7-benzimidazole-S-ilH/V./V-dimethylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from / V- {1- [4- (2-azidoethyl) phenyl] -6 ~ chloro-2-ethyl-1H-benzimidazole -5-yl} - / V, / V-dimethylamine (step 2).

¹ H NMR (CDCb) δ: 7.54 (1H, s), 7.41 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J-8.1 Hz), 7.13 (1H, s), 3.08 (2H, t, J = 6.9 Hz), 2.87 (2H, t, J = 6.9 Hz),

2.82 (6H, s), 2.75 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 4. 6-Chloro-5- (dimethylamino) -2-ethyl-1- (4- (2 - [(([(4- (methylphenyl) sulfoninamino) carbonyl) aminoletyl} phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from A / - {1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1/7-benzimidazole -5-il} - / \ /, / \ / - dirnetylamine (step 3).

M. p .: 108-114 ° C.

MS (IED) m / z: 540 (MH ⁺ ), 538 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.73 (2H, d, J = 8.0 Hz), 7.54 (1H, s), 7,257.39 (6H, m), 7.11 (1H, s), 6.73 (1H, s lg.), 3.58 (2H, q, J = 6.9 Hz), 2.94 (2H, t, J = 6.9 Hz), 2.71 2.82 (8H, m), 2.40 (3H, s), 1.33 (3H, t, J = 7.6 Hz).

EXAMPLE 320

6-CHLORINE-2-ETYL-5- (METHYLAMINE) -1- (4- {2 - [({[(4-METHYLPHYL) SULFQNI LIAM INO) CARBQNIL) AMINO] ETYPHENYL) -1 / 7-BENZIMIDAZOLE

STEP 1. 6-Chloro-1-14- (2-chloroethyl) phenyl] -2-ethyl-1/7-benzimidazol5-ilformamide

Formic acid (0.06 ml, 1.65 mmol), at 0 ° C under nitrogen, was added to a solution of acetic anhydride (0.14 ml) in THF (5 ml), and the mixture was stirred at 60 ° C for 2 hours. Then the mixture was cooled again and 6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl-1/7-benzimidazole383 / 451 was added

5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 hours. The volatile components were removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH solution (50 ml) and brine (50 ml) and then dried (Na2SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1:10), to obtain 68 mg (67%) of the title compound as of light yellow solids.

MS (IE) m / z: 361 (M ⁺ ).

¹ H NMR (CDCb) δ: 8.53-8.76 (1H, s lg.), 7.66 (1H, s), 7,447.48 (2H, m), 7.26-7.31 ( 2H, m), 7.18 (1H, s), 3.83 (2H, t, J = 6.9 Hz), 3.20 (2H, t, J = 6.9 Hz), 2.78 ( 2H, q,> 7.4 Hz), 1.32-1.39 (3H, m).

STEP 2. / V- (6-Chloro-1-r4- (2-chloroethyl) phenyl1-2-ethyl I-1/7-benzimidazol “5-yl) - / V-methylamine

Me ₂ SBH ₃ (0.07 ml, 0.77 mmol) was added, under hydrogen at room temperature, to a solution of 6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl- 1Hbenzimidazole-5-ylformamide (step 1, 112 mg, 0.3 mmol) in THF (15 mL). The mixture was refluxed for 1 hour. Then the mixture was cooled to room temperature and methanol (3 ml) and 2N aqueous HCI solution (12 ml) were added. The mixture was stirred at 70 ° C for 30 minutes. The volatile components were removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous NaHCO ₃ solution (50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 4), to obtain 93 mg (87%) of the title compound as of white solids.

MS (IE) m / z: 347 (M ⁺ ) ¹ H NMR (CDCb) δ: 7.42 (2H, d,> 8.2 Hz), 7.29 (2H, d,> 8.2 Hz ), 7.04 (1H, s), 7.03 (1H, s), 3.81 (2H, t,> 6.9 Hz), 3.18 (2H, t,> 6.9 Hz), 2.95 (3H, s), 2.75 (2H, q,> 7.6 Hz), 1.34 (3H, t,> 7.6 Hz).

STEP 3. / V- (1-1-4- (2-Azidoethyl) phenill-6-chloro-2-ethyl-1/7-benzimi384 / 451 dazol-5-yl) - / V-methylamine

The title compound was prepared according to the procedure described in step 8 of Example 1 from / V- {6-chloro-1- [4- (2-chloroethyl) phenyl] -2-ethyl-1H-benzimidazole -5-yl} - / V-methylamine (step 2).

¹ H NMR (CDCI ₃ ) δ: 7.42 (2H, d,> 8.3 Hz), 7.29 (2H, d,> 8.3 Hz), 7.04-7.03 (2H, m), 4.19 (1H, s lg.), 3.61 (2H, t,> 7.0 Hz), 3.00 (2H, t,> 7.0 Hz), 2.95 (3H, s), 2.75 (2H, q,> 7.6 Hz), 1.33 (3H, t,> 7.6 Hz).

STEP 4. / V-f1- [4- (2-Aminoethyl) phenyl1-6-chloro-2-ethyl-1H-benzimidazol-5-yl} -A / -methylamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from / V- {1- [4- (2-azidoethyl) phenyl] -6-chloro-2-ethyl-1 H- benzimidazol-5-yl} - / V-methylamine (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.39 (2H, d,> 8.4 Hz), 7.25 (2H, d,> 8.4 Hz), 7.06 (1H, s), 7 , 03 (1H, s), 3.64 (2H, s lg.), 3.15 (2H, t,> 7.2 Hz), 2,942.99 (5H, m), 2.73 (2H, q ,> 7.5 Hz), 1.32 (3H, t,> 7.5 Hz).

STEP 5. 6-Chloro-2-ethyl-5- (methylamino) -1- (4-f2-í ({í (4-methylphenyl) sulfonyl] amino) carbonyl) amino] ethyl) phenyl) -1 H-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from Λ / - {1 - [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1H-benzimidazoi-5 -il} - / V-methylamine (step 4).

M.p .: 95-100 ° C.

MS (IED) m / z: 526 (MH ⁺ ), 524 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 7.73 (2H, d,> 8.4 Hz), 7.23-7.36 (7H, m), 7.03 (1H, s), 3.57 (2H, t,> 6.6 Hz), 2.89-2.94 (5H, m), 2.73 (2H, q,> 7.4 Hz), 1.32 (3H, t,> 7 , 4 Hz).

EXAMPLE 321

4-CYAN-2-ETyl-1- (4- (2-í ({r (4-METlLFENIL) SULFONYLAMINO}

CARBONIL) AMINO1ET1L) PHENYL) -1H-BENZ1MIDAZOLE

STEP 1. 3-Chlorine-2-nitrobenzamide

A mixture of 3-chloro-2-nitro-benzoic acid (1 g, 4.9 mmol) and thionyl chloride (9 mL) was stirred at 80 ° C for 1 hour. Thionyl chloride was removed under reduced pressure, and the residue was dissolved in dichlorome385 / 451 tane (15 ml). The mixture was cooled to 0 ° C and 30% aqueous NH _{3 solution} (2 ml) was added dropwise. The mixture was stirred at 0 ° C 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 Na ₂ CO _{3 solution} (100 ml), and brine (100 ml). This organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, to obtain 1.2 g (quant.) Of the title compound, as light orange solids.

¹ H NMR (CDCb) δ: 7.68-7.92 (3H, m).

STEP 2. 3-Chlorine-2-nitrobenzonitrile

Thionyl chloride (2 mL, 24.8 mmol) in DMF (3 mL) was added dropwise and at room temperature to a solution of 3-chloro-2-nitrobenzamide (step 1, 1.2 g, 4, 9 mmoles) in DMF (8 mL). The mixture was stirred at 120 ° C 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 NaHCO ₃ solution (100 ml), brine (100 ml), then dried (MgSO ₄ ), and concentrated. The residue was purified by flash chromatography, eluting with hexane / ethyl acetate (3: 1/1: 2), to obtain 1 g (quant.) Of the title compound, as yellow-white solids.

¹ H NMR (CDCb) δ: 7.61-7.68 (1H, m), 7.74-7.78 (2H, m).

STEP 3. 2- [4- (3-Cyano-2-nitroanilino) phenyl1ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-2-nitrobenzonitrile (step 2) and 4-aminophenyl ethyl alcohol.

MS (IE) m / z: 283 (M ⁺ ).

¹ H NMR (CDCb) δ: 9.37 (1H, S lg.), 7.15-7.41 (7H, m), 3.91 (2H, t, J = 6.4 Hz), 2 , 91 (2H, t, J = 6.4 Hz).

STEP 4. 2-Amino-3T4- (2-hydroxyethyl) anilino1benzonitrile

The title compound was prepared according to the procedure described in step 2 of Example 40 from 2- [4- (3-cyano-2-nitroanilino) phenyl] ethanol (step 3).

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MS (IE) m / z: 253 (M ⁺ ).

¹ H NMR (CDCIs) δ: 7.22-7.28 (2H, m), 7.10 (2H, d, J = 8.4 Hz), 6.69-6.75 (3H, m) , 5.13 (1H, s lg.), 4.54 (2H, s lg.), 3.84 (2H, t, J = 6.4 Hz), 2.80 (2H, t, J = 6 , 4 Hz).

STEP 5. 2-44- (4-cyano-2-ethyl-1 / - / - benzimidazole-1ihphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-amino-3- [4- (2-hydroxyethyl) anilino] benzonitrile (step 4).

TLC, Rf = 0.6, hexane: ethyl acetate (1: 1).

STEP 6, 2-Ethyl-1-i4- (2-hydroxyethyl) phenill-1 / - / - benzimidazole-4-carbonitrile

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (4-cyano2-ethyl-1H-benzimidazol-1-yl) phenyl] ethyl propionate (step 5 ).

MS (IE) m / z: 291 (M ⁺ ).

¹ H NMR (CDCIs) δ: 7.58 (1H, d, J = 6.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.19-7.32 (4H , m), 4.01 (2H, t, J = 6.4 Hz), 3.02 (2H, t, J = 6.4 Hz), 2.86 (2H, q, J = 7.6 Hz ), 1.34 (3H, t, J = 7.6 Hz).

STEP 7, 1 -F4- (2-Chloroethyl) phenin-2-ethyl-1 H-benzimIDazole-4-cabonitrile

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2-ethyl-1- [4- (2hydroxyethyl) phenyl] -1 / - / - benzimidazole-4-carbonitrile propionate ( step 6).

¹ H NMR (DMSO-d ₆ ) δ: 7.72 (1H, dd, J = 1.2 Hz, 7.4 Hz), 7.517.60 (4H, m), 7.30-7.42 ( 2H, m), 3.97 (2H, t, J = 7.0 Hz), 3.18 (2H, t, J = 7.0 Hz), 2.79 (2H, q, J = 7.6 Hz), 1.26 (3H, t, J = 7.6 Hz).

STEP 8. 1-f4- (2-Azidoethihphenyl1-2-ethyl-1 / - / - benzimidazole-4-carbonitrile

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl1 / 7-benzimidazole-4-carbonitrile (step 7) .

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¹ H NMR (CDCI ₃ ) δ: 7.59 (1H, dd, J = 1.2 Hz, 7.3 Hz), 7.48 (2H, d, J = 8.0 Hz), 7.19 -7.32 (4H, m), 3.63 (2H, t, J = 6.6 Hz), 3.03 (2H, t, J = 6.6 Hz), 2.84 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz).

STEP 9. 1- [4- (2-Aminoethyl) phenyl1 ~ 2-ethyl-1/7-benzimidazole-4-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1 - [4- (2-azidoethyl) phenyl] -2-ethyl1H-benzimidazole-4-carbonitrile (step 8).

¹ H NMR (CDCI ₃ ) δ: 7.58 (1H, dd, J = 1.3 Hz, 7.4 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.19 -7.32 (4H, m), 3.08 (2H, t, J = 6.7 Hz), 2.81-2.93 (4H, m), 1.33 (3H, t, J = 7 , 5 Hz).

STEP 10. 4-Cyano-2-ethyl-1- (4- (2 - [((f (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -2ethyl-1/7-benzimidazole-4-carbonitrile (step 9) .

M.p .: 95-103 ° C.

IV (KBr) v: 2225, 1676, 1516, 1433, 1340, 1161, 1091, 794,

663 cm ^-1 .

MS (IED) m / z: 488 (MH ⁺ ), 486 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.72 (2H, d, J = 8.1 Hz), 7.59 (1H, d, J = 7.0 Hz), 7.42 (2H, d, J = 8.1 Hz), 7.18-7.32 (6H, m), 6.72 (1H, s lg.), 3.57 (2H, t, J = 7.1 Hz), 2, 96 (2H, t, J = 7.1 Hz), 2.85 (2H, q, J = 7.6 Hz), 2.41 (3H, s), 1.33 (3H, t, J = 7 , 6 Hz).

EXAMPLE 322

2-ETIL-1- (4- {2 - [(f [(4-METHYLphenyl) SULFONIL] AMINO) CARBONIL) AMINO] ETIL) FENlL) -1H-BENZIMIDAZOL-4-CARBOXAMEL

STEP 1. 2-ethyl-1- (4- {2 - [(U (4-methylphenyl) sulfonyl1amino) carbonyl) amino1ethyl} phenyl) -1 / 7-benzimidazole-4-carboxamide

Propionyl chloride (630 mg, 6.8 mmol) was added dropwise at 0 ° C to a stirred suspension of 2- {4 - [(3-amino-4,6-dimethyl-2- pyridinyl) amino] phenyl} ethanol (step 4, 820 mg, 3.3 mmol) in toluene (30 mL), and

388/451 the reaction mixture was refluxed for 1.5 hours. After cooling, the mixture was poured into water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH solution (50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure and the residue was dissolved with THF (20 ml) and methanol (20 ml). 4N aqueous LiOH solution (10 mL) was added to the mixture, and it was stirred at room temperature for 14 hours. The mixture was evaporated. The residue was dissolved with ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was washed with brine (50 ml), and dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 2/1: 5/0: 1), to obtain 260 mg (26%) of the title compound as white solids.

MS (IE) m / z: 309 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 9.81 (1H, s lg.), 8.13 (1H, dd, J = 2.0 Hz, 7.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.25-7.31 (4H, m), 5.99 (1H, s lg.), 4.00 (2H, t, J = 6.4 Hz), 3, 01 (2H, t, J = 6.4 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 2. 1- [4- (2-Chloroethyl) phenyl1-2-ethyl-1/7-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- [4- (6-chloro-2-ethyl-5-nitro-1Hbenzimidazol-1-yl) phenyl] ethanol ( step 1).

¹ H NMR (DMSO-d ₆ ) δ: 9.29 (1H, s lg.), 7.81-7.91 (1H, m), 7.79 (1H, s lg.), 7.49 -7.60 (4H, m), 7.24-7.33 (2H, m), 3.97 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6 , 8 Hz), 2.80 (2H, q, J = 7.5 Hz), 1.27 (3H, t, J = 7.5 Hz).

STEP 3. 1-f4- (2-Azidoethyl) phenin-2-ethyl-1 / - / - benzimidazole-4-carboxamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-1/7-benzimidazole-5- carboxamide (step 2).

¹ H NMR (DMSO-d ₆ ) δ: 9.29 (1H, s lg.), 7.89 (1H, d, J = 7.3 Hz),

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7.79 (1Η, s Ig.), 7.51-7.59 (4H, m), 7.22-7.33 (2H, m), 3.68 (2H, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.77 (2H, q, J = 7.5 Hz), 1.27 (3H, t, J = 7.5 Hz) .

STEP 4. 1- [4- (2-Aminoethyl) phenyl1-2-ethyl-1B-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-1B-benzimIDazole-4-carboxamide (step 3).

¹ H NMR (DMSO-d ₆ ) δ: 9.30 (1H, s Ig.), 7.89 (1H, d, J = 6.5 Hz), 7.81 (1H, s Ig.), 7.48-7.49 (4H, m), 7.26-7.30 (2H, m), 2.77-2.89 (6H, m), 1.28 (3H, t, J = 6 , 4 Hz).

STEP 5. 2-Ethyl-1 - (4- {2 - [({[(4-methylphenyl) sulfonyl1amino) carbonyl) aminoletyl) phenyl) -1B-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl-1B-benzimidazole-5-carboxamide (step 4).

Federal Police.; 208-214 ° C.

IV (KBr) v: 3336, 1664, 1589, 1508, 1406, 1342, 1168, 976 cm ^-1 .

MS (IED) m / z: 506 (MH ⁺ ), 504 ([MH]).

¹ H NMR (DMSO-d ₆ ) δ: 9.29 (1H, s Ig.), 7.89 (1H, dd, J = 1.3 Hz, 7.2 Hz), 7.75-7, 79 (3H, m), 7.22-7.49 (8H, m), 6.54 (1H, s Ig.), 2.75-2.83 (4H, m), 2.35 (3H, s), 1.27 (3H, t, J = 7.4 Hz).

EXAMPLE 323

6-CHLORINE-2-ETYL-1- (4- {2 - [({[(4-METHYLPHYL) SULFONYL1AMINO) CARBONYL) AMINOLETYL) PHENYL) -5- (METHYLSULFONYL) -1 B-BENZIMIDAZOLE

STEP 1. 1,5-DichlorO “2- (methylsulfinyl) -4-nitrobenzene

A mixture of sulfuric acid (4 mL) and nitric acid (smoker, 2 mL) was added dropwise to a mixture of (2,4-dichloro-phenyl) methylsulfone and sulfuric acid (conc. 14 mL) , in an ice water bath, (Ono Mitsunori, Nakamura Yoshisada, Sato Shingo, Itoh Isamu, Chem. Lett., 1988, 395-398; 3.33 g, 16 mmoles). The mixture was stirred at 55 ° C for 1 hour. The mixture was poured into ice water and neutralized with 6N aqueous NaOH solution, and then extracted with dichloromethane. Washed up

390/451 the organic layer with brine and dried (Na2SO ₄ ). 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 obtain 3 g (74%) of the title compound, in the form of white solids.

¹ H NMR (CDCI ₃ ) δ: 8.45 (1H, s), 7.65 (1H, s), 2.89 (3H, s).

STEP 2. 1,5-Dichloro-2- (methylsulfonyl) -4-nitrobenzene

3-chloroperoxybenzoic acid (1.7 g, 9.8 mmol) was added to a solution of 1,5-dichloro-2- (methylsulfinyl) -4-nitrobenzene (1.0 g, 3.9 mmol) in dichloromethane (50 mL). The mixture was stirred under nitrogen at room temperature for 3 hours. Saturated aqueous NaHCO3 solution (20 ml) was added and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), dried (Na2SO ₄ ) and concentrated. The residue was purified by flash chromatography, eluting with hexane / ethyl acetate (2: 1), to obtain 1 g (100%) of the title compound, as white solids.

MS (IE) m / z: 269 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.68 (1H, s), 7.81 (1H, s), 3.30 (3H, s).

STEP 3. 2- (4-r5-Chloro-4- (methylsulfonyl) -2-nitroanilinolfenyl} ethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 1,5-dichloro-2 (methylsulfonyl) -4-nitrobenzene alcohol and 4-aminophenylethyl alcohol (step 2).

MS (IE) m / z: 370 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 9.81 (1H, s lg.), 8.99 (1H, s), 7.39 (2H, d, J = 8.4 Hz), 7.24 ( 2H, d, J = 8.4 Hz), 7.18 (1H, s), 3.94 (2H, t, J = 6.2 Hz), 3.25 (3H, s), 2.95 ( 2H, t, J = 6.2 Hz).

STEP 4. 2- {4-1,2-Amino-5-chloro-4- (methylsulfonyl) anilino] phenyl) ethanoyl

The title compound was prepared according to the procedure described in step 2 of Example 40 from 2- {4- [5-chloro-4 (methylsulfonyl) -2-nitroanilino] phenyl} ethanol (step 3).

MS (IE) m / z: 340 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.50 (1H, s), 7.22 (2H, d, J = 8.4 Hz), 7.15

391/451 (1Η, s), 7.00 (2H, d, J = 8.4 Hz), 5.17 (1H, s lg.), 3.88 (2H, t,> 6.4 Hz) , 3.67 (2H, s lg.), 3.22 (3H, s), 2.86 (2H, t,> 6.4 Hz).

STEP 5. 244-í6-chloro-2-ethyl-5- (methylsulfonyl) -1 / 7benzimidazole-1-illfenyl) ethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4- [2-amino-5-chloro-4 (methylsulfonyl) anilino] phenyl} ethanol (step 4).

TLC, Rf = 0.7, hexane: ethyl acetate (1: 2).

STEP 6. 2- {4- [6-Chloro-2-ethyl-5- (methylsulfonyl) -1 H-benzimidazol1- yl1-phenyl> ethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [6-c! Oro2-ethyl-5- (metiIsuIfoniI) -1 / 7-benzimidazole- propionate- 1 -il] phenylethyl (step 5).

MS (IE) m / z: 378 (M ⁺ ).

¹ H NMR (CDCb) δ: 8.60 (1H, s), 7.52 (2H, d,> 8.3 Hz), 7.28 (2H, d,> 8.3 Hz), 7, 10 (1H, s), 3.97-4.04 (2H, m), 3.29 (3H, s), 3.03 (2H, t,> 6.5 Hz), 2.80 (2H, q,> 7.6 Hz), 1.36 (3H, t,> 7.6 Hz).

STEP 7. 6-Chloro-1-1,4- (2-chloroethyl) pheniri-2-ethyl-1 / 7benzimidazol-5-yl methylsulfone

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [6-chloro-2-ethyl-5 (methylsulfonyl) -1 / 7-benzimidazol-1-yl ] phenyl} ethanol (step 6).

¹ H NMR (CDCb) δ: 8.62 (1H, s), 7.50 (2H, d,> 8.4 Hz), 7.31 (2H, d,> 8.4 Hz), 7, 24 (1H, s), 3.83 (2H, t,> 7.1 Hz), 3.29 (3H, s), 3.22 (2H, t,> 7.1 Hz), 2.80 ( 2H, q,> 7.6 Hz), 1.37 (3H, t,> 7.6 Hz).

STEP 8. 1-1-4- (2-azidoethyl) phenin-6-chloro-2-ethyl1 / 7-benzimidazol-5-yl methylsulfone

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4 (2-chloroethyl) phenyl] -2-ethyl-1/7-benzimidazole- methylsulfone 5-line (step 7).

¹ H NMR (CDCI ₃ ) δ: 8.62 (1H. S), 7.50 (2H, d, J = 8.4 Hz). 7.25 (2H, d. J = 8.4 Hz), 7.23 (1H, s), 3.64 (2H, t, J = 6.9 Hz), 3.29 (3H, s), 3.04 (2H,

392/451 t, J = 6.9 Hz), 2.80 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 9. 2-f4- [6-Chloro-2-ethyl-5- (methylsulfonyl) -1 / 7-benzimidazol1-yl1phenyl) ethanamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2azidoethyl) phenyl] -6-chloro-2-ethyl-1 F / -benzimidazole-5-methylsulfone -ila (step 8).

¹ H NMR (CDCb) δ: 8.61 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.24 (1H, s), 3.29 (3H, s), 3.10 (2H, t, J = 7.1 Hz), 2.90 (2H, t, J = 7.1 Hz), 2.80 (2H, q, J = 7.5 Hz), 1.37 (3H, t, J = 7.5 Hz).

STEP 10, 6-Chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfoninamino) carbonyl) aminoletyl} phenyl) -5- (methylsulfonyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [6-chloro-2-ethyl-5 (methylsulfonyl) -1 / 7-benzimidazol-1-yl ] phenyl} ethanamine (step 9).

M.p .: 105-118 ° C.

IV (KBr) v: 2879, 1676, 1518, 1458, 1309, 1142, 1089, 993 cm ^-1 .

MS (IED) m / z: 575 (MH ⁺ ), 573 ([MH] ').

¹ H NMR (CDCb) δ: 8.59 (1H, s), 7.75 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.29-7.33 (4H, m), 7.21 (1H, s), 6.69 (1H, s lg.), 3.55-3.62 (2H, m), 3.29 ( 3H, s), 2.96 (2H, t, J = 6.9 Hz), 2.80 (3H, q, J = 7.5 Hz), 2.41 (3H, s), 1.34 ( 3H, t, J = 7.5 Hz).

EXAMPLE 324

SODIUM SALT OF 6-CHLORINE-2-ETHYL 1- (4- (2-f ({r (4-METHYLphenyl) SULFONlL1AMINO} CARBQNIL) AMINO1ETYL | PHENYL) -5- (METHILSULFONYL) -1 / 7-BENZIMIDAZOLE

The title compound was prepared according to the procedure described in Example 2 from 6-chloro-2-ethyl-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -5- (methylsulfonyl) -1 / 7-benzimidazole (Example 323).

M. p .: 175-183 ° C.

IV (KBr) v: 3375, 1604.1516, 1458, 1139, 1083, 993 cm ^-1 .

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EXAMPLE 325 (4-METHYLPHENYL) 2- {4-r6-CHLORO-2ETHYL-5- (METHYLSULFONYL) -1H-BENZIMIDAZOL-1-IL1-PHENYL SULPHONYL

STEP 1. 2-F4-F6-chloro-2-ethyl-5 (methylsulfonyl) -1 / 7-benzimidazole-1-yl-phenyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2-ethyl-5- (methylsulfonyl) -1Hbenzimidazol-1-yl] phenyl} ethanol (Example 323, step 6).

M.p .: 105-110 ° C.

IV (KBr) v: 1751, 1517, 1458, 1309, 1163, 1141, 1089 cm ^-1 .

MS (IED) m / z: 576 (MH ⁺ ), 574 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 8.60 (1H, s), 7.91-7.94 (2H, m), 7.21-7.43 (7H, m), 4.40 (2H , s lg.), 3.31 (3H, s), 3.05 (2H, s lg.), 2.78-2.81 (2H, m), 2.44 (3H, s), 1, 33 (3H, t, J = 7.6 Hz).

EXAMPLE 326

5- (AMINOSULFONYL) -6-CHLORINE-2-ETHYL-1- (4- (2-r '(4-METHYLphenyl) SULPHONYLAMINO) CARBONYL) AMINO1ETYL) PHENYL) -1H-BENZIMIDAZOLE

STEP 1. 2,4-Dichloro-5-nitrobenzenesulfonyl chloride

CISO ₃ H (8 mL, 120 mmoles) was added dropwise under a cold water bath to 2,4-dichloronitrobenzene (10 g, 52 mmoles). The mixture was stirred at 130 ° C for 26 hours. The mixture was cooled to room temperature and poured over ice water. The precipitates were removed by filtration and dried under reduced pressure, to obtain 9 g (60%) of the title compound, as brown solids.

MS (IE) m / z: 290 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.70 (1H, s), 7.90 (1H, s).

STEP 2. / V- (tert-Butyl) -2,4-dichloro-5-nitrobenzenesulfonamide

The title compound was prepared according to the procedure described in step 1 of Example 87 from 2,4-dichloro-5-nitrobenzenesulfonyl chloride (step 1) and ferc-butylamine.

¹ H NMR (CDCI ₃ ) δ: 8.65 (1H, s), 7.74 (1H, s), 5.01 (1H, s lg.),

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1.27 (9H, s).

STEP 3. / V- (tert-Butyl) -2-chloro-4- [4- (2-hydroxyethyl) anilinol-5-nitrobenzenesulfonamide

The title compound was prepared according to the procedure described in step 1 of Example 162 from / V- (ferc-butyl) -2,4-dichloro-5-nitrobenzenesulfonamide and aminophenyl ethyl alcohol (step 2).

¹ H NMR (CDCI ₃ ) δ: 9.72 (1H, s lg.), 8.95 (1H, s), 7.37 (2H, d, J = 8.3 Hz), 7.24 ( 2H, d, J = 8.3 Hz), 7.17 (1H, s), 4.79 (1H, s lg.), 3.90-3.96 (2H, m), 2.94 (2H , t,> 6.4 Hz), 1.26 (9H, s).

STEP 4. 5-Amino- / V- (ferc-butyl) -2-chloro-4-y4- (2-hydroxyethyl) anilinolbenzenesulfonamide

The title compound was prepared according to the procedure described in step 2 of Example 40 from A / - (ferc-butyl) -2-chloro-4- [4 (2-hydroxyethyl) anilino] -5-nitrobenzenesulfonamide ( step 3).

MS (IE) m / z: 397 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.51 (1H, s), 7.20 (2H, d,> 8.4 Hz), 7.14 (1H, s), 6.95 (2H, d ,> 8.4 Hz), 5.22 (1H, s lg.), 4.89 (1H, s lg.), 3.87 (2H, t,> 6.4 Hz), 2.85 (2H , t,> 6.4 Hz), 1.23 (9H, s)

STEP 5. 2-R4- (6-chloro-2-ethyl-5-nitro ~ 1 / - / - benzirnidazole-1-iDphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 5-amino-A / - (ferc-butyl) -2chloro-4- [4- (2-hydroxyethyl) anilino] benzenesulfonamide (step 4).

TLC, Rf = 0.8, hexane: ethyl acetate (1: 2).

STEP 6. / V- (ephc-Butyl) -6-chloro-2-ethyl-1-y4- (2-hydroxyethyl) phenyl1-1 Hbenzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (6-chloro2-ethyl-5-nitro-1 / - / - benzimidazol-1-yl propionate ) phenyl] ethyl (step 5).

¹ H NMR (CDCI ₃ ) δ: 8.57 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz) , 7.20 (1H, s), 4.98 (1H, s lg.), 4.00 (1H, s lg.), 3.02 (2H, t, J = 6.4 Hz), 2, 79 (2H, q, J = 7.5 Hz), 1.37 (3H, t, J = 7.5 Hz), 1.21 (9H, s).

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STEP 7. / V- (tert-Butyl) -6-chloro-1- [4- (2-chloroethyl) phenill-2-ethyl-1Hbenzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from N- (ferc-butyl) -6-chloro-2-ethyl-1 [4- (2-hydroxyethyl) phenyl] - 1 H-benzimidazole-5-sulfonamide (step 6).

¹ H NMR (CDCI ₃ ) δ: 8.58 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz) , 7.19 (1H, s), 4.96 (1H, s lg.), 3.83 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 7.0 Hz), 2.80 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz), 1.22 (9H, s).

STEP 8. 1-r4- (2-Azidoethyl) phenin - / \ / - (tert-butyl) -6-chloro-2-ethyl-1 Hbenzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from / V- (ferc-butyl) -6-chloro-1- [4- (2 chloroethyl) phenyl] -2-ethyl- 1/7-benzimidazole-5-sulfonamide (step 7).

¹ H NMR (CDCI ₃ ) δ: 8.57 (1H, s), 7.48 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz) , 7.19 (1H, s), 4.96 (1H, s lg.), 3.63 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 6.9 Hz), 2.79 (2H, q, J = 7.4 Hz), 1.37 (3H, t, J = 7.4 Hz), 1.21 (9H, s).

STEP 9. 1- [4T2-Aminoethyl) phenyl1-A / - (ferc-butyl) -6-chloro-2-ethyl-1 Hbenzimidazole-5-sulfonamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] - / V (tert-butyl) -6-chloro-2-ethyl -1 / 7-benzimidazole-5-sulfonamide (step 8).

¹ H NMR (CDCI ₃ ) δ: 8.57 (1H, s), 7.44 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz) , 7.20 (1H, s), 5.03 (1H, s lg.), 3.09 (2H, t, J = 6.9 Hz), 2.89 (2H, t, J = 6.9 Hz), 2.79 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz), 1.22 (9H, s).

STEP 10. 5-i (tert-Butylamino) sulfonyl1-6-chloro-2-ethyl 1-1 - (4- (2r ((((4-methylphenylsulfoninamino) carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] - / V (ferc-butyl) -6-chloro-2-ethyl -1 / 7-benzimidazole-5-sulfonamide (step 9).

¹ H NMR (CDCI ₃ ) δ: 8.54 (1H, s), 7.78 (2H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz) , 7.31 (2H, d, J = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.16 (1H, s), 6.61 (1H, s lg .), 5.21 (1H, s lg.), 3.54-3.60 (2H, m), 2.95 (2H, t, J = 6.9 Hz),

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2.78 (2Η, q, J = 7.5 Hz), 2.41 (3H, s), 1.35 (3H, t,> 7.5 Hz), 1.21 (9H, s).

STEP 11, 5- (Aminosulfonyl) -6-chloro-2-ethyl-1- (4-f2-i (ff (4-methylphenyl) sulfonyl | amino) carbonyl) amino1etiDphenyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 1 of Example 88 from 5 - [(tert-butylamino) suphonyl] 6-chloro-2-ethyl-1- (4- {2 - [( {[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) 1/7-benzimidazole (step 9).

M. p .: 163-170 ° C.

IV (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995 cm ^-1 .

MS (IED) m / z: 576 (MH ⁺ ), 574 ([MH]).

¹ H NMR (DMSO-d ₆ ) δ: 8.25 (1H, s), 7.77 (2H, d, J = 8.3 Hz),

7.55 (2H, s lg.), 7.37-7.48 (6H, m), 7.20 (1H, s), 6.54 (1H, s lg.), 3.27 (2H, s lg.), 2.71-2.81 (4H, m), 2.34 (3H, s), 1.23 (3H, t, J = 7.6 Hz).

EXAMPLE 327 (2- (4- [5- (AMINOSULPHONYL) -6-CHLORINE-2-ETHYL-1H-BENZIMIDAZOL-1-ILIFENID-ETHYL-4-METHYLPHYDIDSULPHONYL CARBAMATE

STEP 1. 2- (4- (5-f (ferc-butylamino) sulfonyl1-6-chloro-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl) ethyl (4-methylphenyl) sulfonifcarbamate

The title compound was prepared according to the procedure described in Example 3 from / V- (tert-butyl) -6-chloro-2-ethyl-1- [4- (2hydroxyethyl) phenyl] -1H-benzimidazoI -5-sulfonamide (Example 326, step 6).

¹ H NMR (CDCI ₃ ) δ: 8.58 (1H, s), 7.93 (2H, d, J = 8.2 Hz), 7,337.39 (4H, m), 7.20 (2H, d, J = ~ 8.2 Hz), 7.16 (1H, s), 5.07 (1H, s lg.), 4.38 (2H, t, J = 6.2 Hz), 3.03 (2H, t, J = 6.2 Hz), 2.78 (2H, q, J = 7.5 Hz), 2.44 (3H, s), 1.35 (3H, t, J = 7, 5 Hz), 1.21 (9H, s).

STEP 2. 2- {4- [5- (aminosulfonyl) -6-chloro-2-ethyl-1-H-benzimidazole-1-yl-phenyl-di-methyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in step 1 of Example 88 from 2- (4- {5 - [(ferc-butylamino) sulfonyl] -6-chloro- (4-methylphenyl) sulfonylcarbamate) 2-ethyl-1 H-benzimidazol-1-yl} phenyl) ethyl (step 1).

M.p .: 110-115 ° C.

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IV (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995 cm ^-1 .

MS (IED) m / z: 576 (MH ⁺ ), 574 ([MH]).

¹ H NMR (DMSO-d ₆ ) δ: 8.25 (1H, s), 7.76 (2H, d, J = 8.4 Hz),

7.55 (2H, s lg.), 7.47 (4H, s), 7.41 (2H, d, J = 8.4 Hz), 7.20 (1H, s), 4.29 (2H , t, J = 6.6 Hz), 2.96 (2H, q, J = 6.6 Hz), 2.75 (2H, q, J = 7.5 Hz), 2.35 (3H, s ), 1.24 (3H, t, J = 7.5 Hz).

EXAMPLE 328 (2- [4- (6-CHLORINE-5CIAN-2-ETHYL-1H-BENZIMIDAZOL-1-IL) PHENYL] 4-METHYLENIDSULFONYL CARBAMATE

STEP 1, 2- [4- (6-chloro-5-cyano-2-ethyl-1 / - / - benzimidazole-1-i-phenylethyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 Hbenzimidazole-5-carbonitrile (Example 111, step 4).

M.p .: 85-98 ° C.

IV (KBr) v: 1747, 1618, 1517, 1465, 1348, 1290, 1163, 1089 cm ^-1 .

MS (IED) m / z: 523 (MH ⁺ ), 521 ([MH]).

¹ H NMR (CDCb) δ: 8.07 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.17 (1H, s), 4.39 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 6.8 Hz), 2.78 (2H, q, J = 7.6 Hz), 2.44 (3H, s), 1, 35 (3H, t, J = 7.6 Hz).

EXAMPLE 329 / V - [({2- [4- (5-CYANO-2-ETYL-4,6-DIlMETHYL-1 / - / - BENZIMIDAZOL-1YL) PHENYL] ETHYL} AMlNO) CARBONlL] -4-METlLBENZENOSULFONAMIDE

STEP 1. 4-Cyano-3,5-dimethyl-2-nitrophenyl trifluoromethanesulfonate

Triflic anhydride (3.4 ml, 20 mmoles) and pyridine (1.5 ml, 20 mmoles) were added at 0 ° C to a solution of 4-hydroxy-2,6-dimethyl-3-nitro-benzonitrile (see Auwers; Saurwein; Forísch. Ch. Phys /, 18; Heft 2, S. 23; 2.6 g, 13.4 mmol) in dichloromethane (150 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was poured into water, and extracted with ethyl acetate (100 ml). The organic layer was washed with brine

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MS (IE) m / z: 324 (M ⁺ ).

¹ H-NMR (CDCb) δ: 7.34 (1H, s), 2.68 (3H, s), 2.61 (3H, s).

STEP 2. 2- {4 - [(4-cyano-3,5-dimethyl-2-nitrophenyl) aminolfeniDetyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-cyano-3,5-dimethyl-2-nitrophenyl trifluoromethanesulfonate (step 1).

¹ H NMR (CDCb) δ: 8.08 (1H, s lg.), 7.27 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz ), 4.30 (2H, t, J = 7.0 Hz), 2.96 (2H, t, J = 7.0 Hz), 2.65 (3H, s), 2.41 (3H, s ), 2.05 (3H, s).

STEP 3. 2- {4-í (4-Cyano-3,5-dimethyl-2-nitrophenyl) aminolfeniDetila acetate

The title compound was prepared according to the procedure described in step 3 of Example 6 from 2- {4 - [(4-cyano-3,5-dimethyl-2-nitrophenyl) amino] phenyl} ethyl acetate (step 2).

¹ H NMR (CDCb) δ: 7.14 (2H, d, J = 8.4 Hz), 6.85-6.89 (3H, m), 5.50 (1H, s lg.), 4 , 26 (2H, t, J = 7.1 Hz), 3.54 (2H, s lg.), 2.89 (2H, t, J = 7.1 Hz), 2.41 (3H, s) , 2.37 (3H, s), 2.05 (3H, s).

STEP 4. 2-R4- (5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-iDphenylethyl acetate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(4-cyano-3,5-dimethyl-2-nitrophenyl) amino] phenyl} ethyl acetate (step 3).

¹ H NMR (CDCb) δ: 7.45-7.47 (2H, m), 7.26-7.29 (2H, m), 6.79 (1H, s lg.), 4.37 ( 2H, t, J = 7.0 Hz), 3.08 (2H, t, J = 7.0 Hz), 2.83-2.89 (5H, m),

2.56 (3H, s), 2.09 (3H, s), 1.28 (3H, s lg.).

STEP 5. 2-Ethyl-1 - [4- (2-hydroxyethyl) phenyl1-4,6-dimethyl-1 H-benzimidazole-5-carbonitrile

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The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-cyano-2-ethyl-4,6-dimethyl-1/7-benzimidazole-1- acetate il) phenyl] ethyl (step 4).

MS (IE) m / z: 319 (M ⁺ ).

¹ H NMR (CDCh) 8: 7.40-7.51 (4H, m), 6.93 (1H, s), 3.68-3.75 (2H, m), 2.85 (2H, t, J = 6.7 Hz), 2.68-2.76 (5H, m), 2.50 (3H, s), 1.22 (3H, t, J = 7.4 Hz).

STEP 6. 1-f4- (2-Chloroethyl) phenin-2-ethyl-4.6-dimethyl-1H-benzimidazole-5-carbonitrite

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2-ethyl-1- [4- (2-hydroxyethyl) phenyl] 4,6 dimethyl-1H-benzimidazo! -5- carbonitrile (step 5).

¹ H NMR (CDCh) δ: 7.45 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 6.79 (1H, S), 3.83 (2H, t, J = 7.1 Hz), 3.21 (2H, t, J = 7.1 Hz), 2.88 (3H, s), 2.81 (2H, q, J = 7.6 Hz), 2.55 (3H, s), 1.29 (3H, t, J = 7.6 Hz).

STEP 7. 1- [4- (2-Azidoethyl) phenyl1-2-ethyl-4,6-dimethyl-1/7-benzimidazole-5-carbonitrile

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl4.6-dimethyl-1/7-benzimidazole-5 -carbonitrile (step 6).

MS (IE) m / z: 412 (M ⁺ ).

¹ H NMR (CDCh) δ: 7.47 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 6.78 (1H, S), 3.63 (2H, t, J = 6.8 Hz), 3.03 (2H, t, J = 6.8 Hz), 2.87 (3H, s), 2.80 (2H, q, J = 7.6 Hz), 2.55 (3H, s), 1.29 (3H, t, J = 7.6 Hz).

STEP 8. 1-i4- (2-Aminoethyl) phenill-2-ethyl-4,6-dimethyl-1/7-benzimidazole-5-carbonitrile

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -2-ethyl4.6-dimethyl-1H-benzimidazole-5-carbonitrile (step 7).

¹ H NMR (CDCI ₃ ) δ: 7.43 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 6.79 (1H, s) , 3.08 (2H, t, J = 7.0 Hz), 2.63-2.91 (7H, m), 2.55 (3H, s), 1.29 (3H, t, J = 7 , 6 Hz).

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STEP 9. / V - [({2-F4- (5-Cyano-2-ethyl-4,6-dimethyl-1/7-benzimidazol1-yl) phenyl1ethyl} amino) carbonill-4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -2ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (step 8).

M.p .: 140-145 ° C.

IV (KBr) v: 3340, 2214, 1664, 1517, 1338, 1166, 1091 cm ^-1 .

MS (IED) m / z: 516 (MH ⁺ ), 514 ([MH] ').

¹ H NMR (CDCb) δ: 7.71 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.25-7.31 (4H , m), 6.77 (1H, s), 6.73 (1H, s lg.), 3.55-3.62 (2H, m), 2.95 (2H, t, J = 7.0 Hz), 2.87 (3H, s), 2.80 (2H, q, J = 7.6 Hz), 2.52 (3H, s), 2.41 (3H, s), 1.28 ( 3H, t, J = 7.6 Hz).

EXAMPLE 330 2-f4- [5- (AMINOCARBONYL) -6-CHLORINE-2-ETHYL-1H-BENZIMIDAZOL-1-IL] -ETHYL (FETH) -ETHYL

STEP 1. 2-F4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1 / - / - benzimidazole-1 -illfenihethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 Hbenzimidazole-5-carboxamide (Example 111, step 5).

M. p .: 170-175 ° C.

IV (KBr) v: 3463, 3342, 1747, 1685, 1593, 1161, 1080, 881 cm “ ¹ .

MS (IED) m / z: 541 (MH ⁺ ), 539 ([MH]).

¹ H NMR (CDCb) δ: 8.13 (1H, s), 7.96 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.36 (2H, d, H = 8.1 Hz), 7.01 (2H, d, J = 8.1 Hz), 6.94 (1H, s), 6.55 (1 H, s lg .), 4.38 (2H, t, J = 6.1 Hz), 3.01 (2H, t, J = 6.1 Hz), 2.70 (2H, q, J = 7.5 Hz) , 2.45 (3H, s), 1.29 (3H, t, J = 7.5 Hz).

EXAMPLE 331 2- [4- (5-CYAN-2-ETHYL-4,6-DIMETHYL-1H-BENZIMIDAZOL-1-IL) PHENYL] 4-METHYLENIDSULPHONYL

STEP 1. 2- [4- (5-cyano-2-ethyl4,6-dimethyl-1 / - / - benzimidazole-1-ihphenylethyl) (4-methylphenyl) sulfonylcarbamate

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The title compound was prepared according to the procedure described in Example 3 from 2-ethyl-1- [4- (2-hydroxyethyl) -phenyl] -4,6dimethyl-1/7-benzimidazole-5-carbonitrile (Example 329, step 5).

Mp: 208-213 ° C.

IV (KBr) v: 1747.1515, 1230, 1161, 1089 cm ^-1 .

MS (IED) m / z: 517 (MH *), 515 ([M-H] ·).

¹ H NMR (DMSO-d ₆ ) δ: 7.76 (2H, d, J = 8.4 Hz), 7.40-7.48 (6H, m), 6.91 (1H, s), 4.27 (2H, t, J = 6.7 Hz), 2.96 (2H, t, J = 6.7 Hz), 2.67-2.73 (5H, m), 2.48 (3H , s), 2.36 (3H, s), 1.21 (3H, t, J = 7.6 Hz).

EXAMPLE 332 (2-f4- (5-ACETYL-2-ETHYL-1H-BENZIMIDAZOL-1-IDFENYL-1-IDYL)

STEP 1. 2-R4- (5-acetyl-2-ethyl1 H-benzimidazole-1-hyphenylethyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- {2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 Hbenzimidazol-5-yl} ethanone (Example 78 , step 4).

M. p .: 188-190 ° C.

IV (KBr) v: 1743, 1683, 1606, 1515, 1348, 1163, 1076 cm ^-1 .

MS (IED) m / z: 506 (MH ⁺ ), 504 ([MH] ').

¹ H NMR (DMSO-d ₆ ) δ: 8.33 (1H, d,> 1.4 Hz), 7.82 (1H, dd,> 1.4 Hz, 8.4 Hz), 7.76 (2H, d,> 8.4 Hz), 7.45 (4H, s), 7.40 (2H, d,> 8.4 Hz), 7.14 (1H, d,> 8.4 Hz) , 4.28 (2H, t,> 6.5 Hz), 2.97 (2H, t,> 6.5 Hz), 2.75 (2H, q,> 7.4 Hz), 2.64 ( 3H, s), 2.35 (3H, s), 1.25 (3H, t,> 7.4 Hz).

EXAMPLE 333

6-CHLORINE-2-ETHYL- / V-METlL-1- (4- {2-r (fr (4-METHYLphenyl) -SULPHONY] AMINO) CARBONY) AMINO] ETHYL) PHENYL) -1 / 7-BENZIMlDAZOL-5CARBOXAMIDE

STEP 1. 2,4-Dichloro-A / -methyl-5-nitrobenzamide

Thionyl chloride (12.4 ml, 169 mmoles) was added to a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9 mmoles) in toluene (200 ml) at room temperature. The mixture was stirred at 80 ° C for 5 hours / 45 hours. The solvent was removed and the residue was dissolved with tetrahydrofuran (60 ml). 40% methylanimal (1.4 ml, 33.9 mmol) was added at 0 ° C, 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 (100 ml), brine (100 ml), then dried (Na2SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (2: 1/1: 1/1: 2), to provide 5.3 g (63% ) of the title compound as light yellow solids.

¹ H NMR (CDCI ₃ ) δ: 8.27 (1H, s), 7.65 (1H, s), 3.15 (3H, s).

STEP 2. 2-Chloro-4-fF4- (2-hydroxyethyl) pheninamino} -A / -methyl-5-nitrobenzamide

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro - / \ / - methyl-5-nitrobenzamide (step 1).

¹ H NMR (CDCIs) 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 3. 5-Amino-2-chloro-4-U4- (2-hydroxyethyl) phenyl1aminoHV-methylbenzamide

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2-chloro-4 - {[4- (2-hydroxyethyl) phenyl] amino} - / V-methyl-5-nitrobenzamide (step 2).

¹ H NMR (CDCI ₃ ) δ: 7.28 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.08 (1H, s), 6.89 (2H, d, J = 8.4 Hz), 6.53 (1H, s lg.), 5.41 (1H, s lg.), 3.84-3.86 (2H, m), 3.66 (2H , s lg.), 3.00 (3H, d, J = 5.0 Hz), 2.83 (2H, t, J = 6.6 Hz).

STEP 4. 6-Chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl1-A / -methyl-1 / - / - benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 5 of Example 1 from 5-amino-2-chloro-4 - {[4- (2hydroxyethyl) phenyl] amino} - / V-methylbenzamide (step 3).

MS (IE) m / z: 357 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.98 (1H, s), 7.47 (2H, d, J = 8.1 Hz), 7.27

403/451 (2Η, d, J = 8.1 Hz), 7.09 (1H, s), 6.23 (1H, s lg.), 3.96-4.02 (2H, m), 3 , 05 (3H, d, J = 4.9 Hz), 3.00 (2H, t, J = 6.4 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 5. 6-Chloro-1 -F4- (2-chloroethyl) phenill-2-ethyl - / \ / - methyl-1/7-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 1 from 6-chloro-2-ethyl-1- [4- (2hydroxyethyl) phenyl] - / V-methyl-1 / 7- benzimidazole-5-carboxamide (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.98 (1H, s), 7.47 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz) , 7.10 (1H, s), 6.35 (1H, s lg.), 3.83 (2H, t, J = 6.9 Hz), 3.21 (2H, t, J = 6.9 Hz), 3.05 (3H, d, J = 4.9 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz) .

STEP 6. 1-r4- (2-Azidoethyl) phenin-6-chlorO2-ethyl- / V-methyl-1 H-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2-ethyl-A / -meti [-1H- benzimidazo! -5-carboxamide (step 5).

MS (IE) m / z: 382 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.94 (1H, s), 7.46 (2H, d, J = 8.0 Hz), 7.27 (2H, d, J = 8.0 Hz) , 7.06 (1H, s), 3.63 (2H, t, J = 7.0 Hz), 2.98-3.06 (5H, m), 2.77 (2H, q, J = 7 , 5 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 7. 1 -4- (2-Aminoethyl) phenyl1-6-chloro-2-ethyl- / V-methyl-1H-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-N-methyl-1/7-benzimidazole -5-carboxamide (step 6).

¹ H NMR (CDCI ₃ ) 6: 7.91 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz) , 7.06 (1H, s), 6.55 (1H, s lg.), 3.03-3.10 (5H, m), 2.72-2.83 (2H, m), 1.33 (3H, t, J = 7.6 Hz).

STEP 8. 6-Chloro-2-ethyl - / \ / - methyl-1- (4- {2 - [(n (4-methylphenyl) sulfonyl1 amino} carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole-5 -carboxamide

The title compound was prepared according to the procedure 404/451 as described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -6chloro-2-ethyl- / V-methyl-1 / - / - benzimidazole-5-carboxamide (step 7).

M.p .: 122-135 ° C.

IV (KBr) v: 2877, 1637, 1519, 1400, 1340, 1161, 1091 cm ^-1 .

MS (IED) m / z: 554 (MH ⁺ ), 552 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.79-7.84 (3H, m), 7.28-7.33 (4H, m), 7.12 (2H, d, J = 8.2 Hz ), 6.96 (1H, s), 6.80 (1H, s lg.), 6.70 (1H, s lg.), 3.48-3.54 (2H, m), 3.08 ( 3H, d, J = 4.8 Hz), 2.89 (2H, t, J = 6.9 Hz), 2.72 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 1.30 (3H, t, J = 7.5 Hz).

EXAMPLE 334 (4-METHYLPHENIDSULPHONYCARBAMATQ OF 2- (4- {6-CHLORINE-2ETHYL-54 (METHYLAMINE) CARBONYL1-1H-BENZIMIDAZOL-1-IL) PHENYL) ETHYL

STEP 1. 2- (4- {6-chloro-2-ethyl5 [(methylamino) carbonyl] -1 / - / - benzimidazol-1-yl} phenyl) ethyl 4-methylphenylsulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] - / Vmethyl-1/7-benzimidazole-5 -carboxamide (Example 333, step 4).

M.p .: 201-204 ° C.

MS (IED) m / z: 555 (MH ⁺ ), 553 ([MH] ').

¹ H NMR (DMSO-d ₆ ) δ: 8.27-8.29 (1H, m), 7.76 (2H, d, J = 8.1 Hz), 7.69 (1H, s), 7.40-7.48 (6H, m), 7.06 (1H, s), 4.28 (2H, t, J = 6.3 Hz), 2.96 (2H, t, J = 6, 3 Hz), 2.69-2.78 (5H, m), 2.36 (3H, s), 1.23 (3H, t, J = 7.5 Hz).

EXAMPLE 335 (2- {4- [6-CHLORO-5r (DIMETHYLAMINE) CARBONYL-2- (1-METHYLETID-1H-BENZIMIDAZOL-1-IL1-4-METHYLIDSIDSPHONYL CARBONATE)

FENIL) ETHYL

STEP 1. 2,4-Dichloro- / V ₁ / \ / - dimethyl-5-nitrobenzamide

Thionyl chloride (6 ml, 84 mmoles) was added, at room temperature, to a solution of 2,4-dichloro-5-nitrobenzoic acid (4 g, 17 mmoles) in toluene (50 ml). The mixture was stirred at 80 ° C for 2 days. The solvent was removed and the residue was dissolved in tetrahydrofuran (30 ml). 50% dimethylamine (760 mg) was added at 0 ° C to the mixture, and the mixture was stirred

405/451 at room temperature overnight. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 1), to provide 3.6 mg (82%) of the title compound, under the form of light yellow solids.

¹ H NMR (CDCI ₃ ) δ 7.90 (1H, s), 7.65 (1H, s), 3.15 (3H, s), 2.91 (3H, s).

STEP 2. 2-Chloro-4- {(4- (2-hydroxyethyl) phenyl] amino) -A / ₁ / \ / - dimethyl-5nitrobenzamide

The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro- / V, / V-dimethyl-5-nitrobenzamide (step 1).

MS (IE) m / z: 363 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 9.52 (1H, s lg.), 8.20 (1H, s), 7.34 (2H, d,> 8.2 Hz), 7.22 (2H , d, J = 8.2 Hz), 7.16 (1H, s), 3.92 (2H, m), 3.13 (3H, s), 2.89-2.94 (5H, m) .

STEP 3. 5-Amino-2-chloro-4 - {[4- (2-hydroxyethyl) phenyl1amino} - / \ /, / Vdimethylbenzamide

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2-chloro-4 - {[4- (2-hydroxyethyl) phenyl] amino} -W, / V-dimethyl-5 -nitrobenzamide (step 2).

¹ H NMR (CDCI ₃ ) δ: 7.05-7.11 (3H, m), 6.79 (2H, d, J = 8.5 Hz), 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, 4 Hz).

STEP 4. 2- {4- [6-chloro-5 - [(dimethylamino) carbonill-2- (1-methylethyl) -1 / 7-benzimidazol-1-yl-phenyl) ethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 5-amino-2-chloro-4 - {[4- (2hydroxyethyl) phenyl] amino} - / V, / V- dimethylbenzamide (step 3).

STEP 5. 6-Chloro-1- [4- (2-hydroxyethyl) phenyl1- / V, / V-dimethyl-2- (1-me406 / 451 tylethyl) -1H-benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [6-chloro5 - [(dimethylamino) carbonyl] -2- (1-methylethyl) -1 propanoate / 7-benzimídazol-1-yl] phenyl} ethyl (step 4).

MS (IE) m / z: 371 (M ⁺ ) ·

¹ H NMR (CDCI ₃ ) δ: 7.66 (1H, s), 7.46 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz) , 7.12 (1H, s), 3.95-4.00 (2H, m), 3.17 (3H, s), 3.00 (2H, d, J = 6.6 Hz), 2, 87 (3H, s), 2.78 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz).

STEP 6. 2- {4- [6-chloro-5 [(dimethylamino) carbonyl1-2- (1-methylethyl) -1H-benzimidazole-1-yl1-phenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 6-chloro-1- [4- (2-hydroxyethyl) phenyl] - / V, / \ / dimethi1-2- (1-methylethyl ) -1 / 7-benzimidazole-5-carboxamide (step 5).

M. p .: 173-176 ° C.

IV (KBr) v: 1741, 1637, 1519, 1398, 1344, 1159, 1078, 904 cm ^-1 . MS (IED) m / z: 569 (MH ⁺ ), 567 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 7.93 (2H, d, J = 8.4 Hz), 7.70 (1H, s), 7,277.34 (4H, m), 7.09-7, 12 (3H, m), 4.35 (2H, t, J = 6.6 Hz), 3.19 (3H, s), 2.98 (2H, t, J = 6.6 Hz), 2, 88 (3H, s), 2.74 (2H, q, J = 7.5 Hz), 2.42 (3H, s), 1.29 (3H, t, J = 7.5 Hz).

EXAMPLE 336 (4-METHYLphenyl) 2- (4- {6-CHLORINE-2-ETHYL-5 - [(METHYLoxide) METHYL-1H-BENZIMIDAZOL-1-IL) PHENYL) ETHYL

STEP 1. I.S-Dichloro ^ - ^ methyloxymethylM-nitrobenzene

Sodium methoxide (44 ml, 66 mmol) was added at room temperature to a solution of 1,5-dichloro-2- (chloromethyl) -4-nitrobenzene (Hagmann, William K .; Dorn, Conrad P .; Frankshun, Robert A .; O'Grady, Laura A .; Bailey, Philip J .; et al .; JMCMAR; J.Med.Chem .; EN; 29; 8; 1986; 1436-1441, 10.6 g, 44 mmoles ) in methanol (30 ml). The mixture was stirred at 80 ° C for 21 hours. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The layer was washed

407/451 organic with water (50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (6: 1/4: 1), to provide 2.8 g (27%) of the compound in title, in the form of a light yellow oil.

1 H NMR (CDCl ₃ ) δ 8.01 (1H, s), 7.09 (1H, s), 4.49 (2H, s), 3.96 (3H, s).

STEP 2. 2- [4 - ({5-Chloro-4-f (methyloxy) methyl1-2-nitrophenyl) amine) phenylethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 1,5-dichloro-2 - [(methyloxy) methyl] 4-nitrobenzene (step 1).

¹ H NMR (CDCI ₃ ) δ: 9.45 (1H, s lg.), 8.28 (1H, s), 7.17-7.33 (5H, m), 4.44 (2H, s ), 3.91 (1H, s lg.), 3.45 (3H, s), 2.91 (2H, t, J = 6.6 Hz).

STEP 3. 2-r4 - ((2-Amino-5-chloro-4 - [(methyloxy) methyl-phenyl} amino) phenylethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- [4 - ({5-chloro-4 - [(methyloxy) methyl] -2-nitrophenyl} amino) phenyl] ethanol (step 2).

¹ H NMR (CDCI ₃ ) δ: 7.07-7.01 (3H, m), 6.88 (1H, s), 6.74 (2H, d, J = 8.4 Hz), 5, 16 (1H, s lg.), 4.47 (2H, s), 3.82 (2H, t, J = 6.6 Hz), 3.71 (2H, s lg.), 3.46 (3H , s), 2.79 (2H, t, J = 6.6 Hz).

STEP 4. 2- (4- {6-Chloro-2-ethyl-5 - [(methyloxy) metin-1/7-benzimidazol-1-yl} phenyl) ethanol

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4 - ({2-amino-5-chloro-4 [(methyloxy) methyl] phenyl} amino) phenyl] ethanol (step 3).

MS (IE) m / z: 344 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.82 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz) , 7.12 (1H, s), 4.65 (1H, s), 3.99 (2H, s lg.), 3.45 (3H, s), 3.00 (3H, t, J = 7 , 6 Hz), 2.78 (2H, q, J = 7.6 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 5. 2- (4-F6-chloro-2-ethyl) (4-methylphenyl) sulfonylcarbamate408 / 451

5-i (methyloxy) methyl1-1 Z7-benzimidazole-1-ylJfeniDetila

The title compound was prepared according to the procedure described in Example 3 from 2- (4- {6-chloro-2-ethyl-5 - [(methyloxy) methyl] 1/7-benzimidazol-1-yl } phenyl) ethanol (step 4).

M.p .: 174.5 ° C.

IV (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093,

1062 cm ^-1 .

MS (IED) m / z: 542 (MH ⁺ ), 540 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.94 (2H, d, J = 8.2 Hz), 7.83 (1H, s), 7,087.33 (7H, m), 4.64 (s, 2H), 4.37 (2H, t, J = 6.4 Hz), 3.46 (3H, s), 2.97 (2H, t, J = 6.4 Hz), 2.73 (2H, q, J = 7.5 Hz), 2.42 (3H, s), 1.26 (3H, t, J = 7.5 Hz).

EXAMPLE 337 (4-METHYLPHENIUSULPHONYL CARBAMATE OF 244-I6-CHLORINE-2-ETHYL-5- (HIDRQXIMETIU-1/7-BENZIMIDAZQL-1-IL] PHENY) ETHYL

STEP 1. 2-f4-16-Chloro-5- (chloromethyl) -2-ethyl-1/7-benzimidazole-1illphenylethanol

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- [4 - ({2-amino-5-chloro-4 [(methyloxy) methyl] phenyl} amino) phenyl] ethanol (Example 336, step 3).

MS (IE) m / z: 348 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.83 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 7.27 (2H, d,> 8.2 Hz), 7.15 (1H, s), 4.84 (2H, s), 3.96-4.02 (2H, m), 3.00 (2H, t,> 6.4 Hz), 2.77 ( 2H, q,> 7.5 Hz), 1.34 (2H, t,> 7.5 Hz).

STEP 2. 6-Chloro-5- (chloromethyl) -1-f4- (24 (1,1-dimethylethyl) - (dimethyl) silyloxy) ethyl) phenin-2-ethyl-1B-benzimidazole

The title compound was prepared according to the procedure described in step 2 of Example 90 from 2- {4- [6 ~ chloro-5- (chloromethyl) 2-ethyl-1/7-benzimidazol-1-yl ] phenyl} ethanol (step 1).

MS (IE) m / z: 405 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.83 (1H, s), 7.43 (2H, d,> 8.4 Hz), 7.23 (2H, d,> 8.4 Hz), 7 , 11 (1H, s), 4.85 (2H, s), 3.91 (2H, t,> 6.4 Hz), 2.94 (2H, t,> 6.4 Hz), 2.76 (2H, q,> 7.5 Hz), 1.33 (3H, t,> 7.5 Hz), 0.87 (9H, s), 0.00

409/451 (6Η, s).

STEP 3. {6-Chloro-1-r4- (2- {F (1,1-dimethylethyl) - (dimethyl) silyloxy) ethyl) phenin-2-ethyl-1/7-benzimidazol-5-yl} methyl

Propionic acid (0.06 ml, 0.86 mmol) and NaHCO ₃ (144 mg, 1.72 mmol) were added at room temperature to a solution of 6-chloro-5 (chloromethyl) -l - [4- ( 2 - {[(1,1-dimethylethyl) (dimethyl) silyl] oxy} ethyl) phenyl] -2-ethyl-1 H-benzimidazole (step 2, 403 mg, 0.86 mmol) in N, N-dimethylformamide ( 10 ml). The mixture was stirred at 60 ° C for 7 h. Water (50 ml) was added to the mixture and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), and then dried (Na2SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (8: 1/4: 1), to obtain 235 mg (53%) of the title compound, in the form of a light yellow oil.

¹ H NMR (CDCI ₃ ) δ: 7.81 (1H, s), 7.43 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz) , 7.11 (1H, s), 5.33 (2H, s), 3.91 (2H, t, J = 6.6 Hz), 2.93 (2H, t, J = 6.6 Hz) , 2.77 (2H, q, J = 7.5 Hz), 2.42 (2H, q,> 7.5 Hz), 1.33 (3H, t,> 7.5 Hz), 1.18 (3H, t,> 7.5 Hz), 0.87 (9H, s), 0.00 (6H, s).

STEP 4. {6-Chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl11 / 7-benzimidazol-5-yl} methyl propanoate

The title compound was prepared according to the procedure described in step 6 of Example 90 from {6-chloro-1 [4- (2 - {[(1,1-dimethylethyl) (dimethyl) silicon] propanoate] oxy} ethyl) phenyl] -2-ethyl-1/7-benzimidazol-5-yl} methyl (step 3).

MS (IE) m / z: 386 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.70 (1H, s), 7.37 (2H, d,> 8.3 Hz), 7.17 (2H, d,> 8.3 Hz), 7 , 04 (1H, s), 5.21 (2H, s), 3.88 (2H, d,> 6.6 Hz), 2.91 (2H, t,> 6.6 Hz), 2.67 (2H, q,> 7.5 Hz), 2.32 (2H, q,> 7.5 Hz), 1.24 (3H, t,> 7.5 Hz), 1.08 (3H, t, > 7.5 Hz).

STEP 5. [6-Chloro-2-ethyl-1- (4-f2-i (fr (4-methylphenyl) sulfoninamino) carbonyl) oxylethyl) phenyl) -1 / - / - benzimidazol-5-ylmethyl propanoate

The title compound was prepared according to the procedure described in Example 3 from {6-chloro-2-ethyl-1- [4- (2410/451 hydroxyethyl) phenyl] -1 H-benzimidazole-5 propanoate -ilJmetila (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.92 (2H, d, J = 8.3 Hz), 7.81 (1H, s), 7,327.36 (4H, m), 7.21-7, 25 (2H, m), 7.10 (1H, s), 5.32 (2H, s), 4.38 (2H, t, J = 6.7 Hz), 3.02 (2H, t, J = 6.7 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.37-2.49 (5H, m), 1.33 (3H, t, J = 7.6 Hz ), 1.18 (3H, t, J = 7.6 Hz).

STEP 6. 2- {6-chloro-2-ethyl-5 (hydroxymethyl) -1H-benzimidazol-1-yl-phenyl) -ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in step 6 of Example 1 from [6-chloro-2-ethyl1- (4- {2 - [({[(4-methylphenyl) sulfonyl] propanoate] amino} carbonyl) oxy] ethyl} phenyl) -1 H-benzimidazol5-yl] methyl (step 5).

M.p .: 172.7 ° C.

IV (KBr) v: 1745, 1519, 1240, 1160, 1089, 1058 cm ^-1 .

MS (IED) m / z: 528 (MH ⁺ ), 526 ([MH] ').

¹ H NMR (DMSO-d ₆ ) 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 = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz), 2.72 (2H, q, J = 7, 5 Hz), 2.34 (3H, s), 1.23 (3H, t, J = 7.5 Hz).

EXAMPLE 338 / V - ({í2- (4- {6-CHLORINE-2-ETHYL-5-F (METHYLoxy) METHYL1-1H-BENZIMIDAZOL-1-IL) PHENYL) ETHLLAMINO} CARBONYL) -4-METHYL-BENZENOSULFONAMIDE

STEP 1. 1- [4- (2-Azidoethyl) phenyl1-6-chloro-2-ethyl-5-yl (methyloxy) -methyl1 H-benzimidazole

The title compound was prepared according to the procedure described in step 5 of Example 26 from 2- (4- {6-chloro-2-ethyl-5 [(methyloxy) methyl] -1H-benzimidazole-1- yl} phenyl) ethanol (Example 336, step 4).

MS (IE) m / z: 369 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.82 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz) , 7.11 (1H, s), 4.65 (2H, s), 3.62 (2H, t, J = 7.0 Hz), 3.45 (3H, s), 3.02 (2H, t, J = 7.0 Hz), 2.77 (2H, q, J = 7.7 Hz), 1.34 (3H, t, J = 7.7 Hz).

STEP 2. 2- (4- {6-Chloro-2-ethyl-5-yl (methyloxy) methyl1-1H-benzimidazol-1-yl) phenyl) ethanamine

411/451

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2-ethyl-5 - [(methyloxy) -methyl] -1 / 7-benzimidazole (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.82 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7,247.29 (2H, m), 7.12 (1H, s), 4.65 (1H, s), 3.45 (3H, ds), 3.08 (2H, t, J = 6.7 Hz), 2.88 (2H, t, J = 6.7 Hz), 2.77 (2H, q, J = 7.6 Hz), 1.34 (3H, t, J = 7.6 Hz).

STEP 3. A / - '2- (4- {6-Chloro-2-ethyl-5-yl (methyloxy) methyl1-1 / 7-benzimidazol-1-yl) phenyl) ethyl1amino) carbonyl) -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- (4- {6-chloro-2-ethyl-5 [(methyloxy) methyl] -1 / 7-benzimidazole- 1 -il} phenyl) ethanamino (step 2).

M.p .: 134.6°C.

IV (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093,

1062 cm ^-1 .

MS (IED) m / Z: 541 (MH ⁺ ), 539 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.82 (1H, s), 7.72 (2H, d, J = 8.4 Hz), 7,247.39 (4H, m), 7.09 (1H, s), 6.72 (1H, s lg), 4.65 (2H, s), 3.57 (2H, m), 3.45 (3H, s), 2.93 (2H, d, J = 6.8 Hz), 2.77 (2H, q, J = 7.5 Hz), 2.40 (3H, s), 1.32 (3H, t, J = 7.5 Hz).

EXAMPLE 339 (4-METHYLPHENYL) 2- {4-6-CHLORINE-2r3- (4PYRIDINIDPROPILl-5- (TRIFLUOROMETlD-1H-BENZIMIDAZOL-1-IL1)

PHENIDETHYL

STEP 1. 2- (4- {f5-chloro-2-nitro-4- (trifluoromethyl) phenin amino} phenyl) ethyl acetate

Acetyl chloride (1.6 ml, 22.4 mmoles) was added to a mixture of 2- (4 - {[5-chloro ~ 2-nitro-4- (trifluoromethyl) phenyl] amino} phenyl) ethanol (Example 104, step 1, 8.1 g, 22.4 mmoles) and pyridine (1.8 ml, 22.45 mmoles) in dichloromethane (200 ml), at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes. Water was added to the mixture (50 ml) and extracted with dichloromethane (300 ml). The organic layer was washed with brine (100 ml), then dried (Na2SO4). After removing the solvent, the crude product was purified by

412/451 flash column chromatography eluting with hexane / ethyl acetate (2: 1) providing 8.6 g (95%) of the title compound as yellow solids.

¹ H NMR (CDCI ₃ ) δ: 9.68 (1H, s lg.), 8.57 (1H, s), 7.35 (2H, d, J = 8.4 Hz), 7.22 ( 2H, d, J = 8.4 Hz), 7.17 (1H, s), 4.33 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 7.0 Hz), 2.06 (3H, s).

STEP 2. 2- (4-phi2-amino-5-chloro-4- (trifluoromethyl) phenyl1amino} phenyl) ethyl acetate

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- (4 - {[5-chloro-2nitro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate ( step 1).

¹ H NMR (CDCb) δ: 7.13-7.16 (3H, m), 7.06 (1H, s), 6.89 (2H, d, J = 8.4 Hz), 5.43 (1H, s lg.), 4.26 (2H, t, J = 7.2 Hz), 3.69 (2H, s lg.), 2.89 (2H, d, J = 7.2 Hz) , 2.04 (3H, s).

STEP 3. 2- (4- {(5-chloro-2-ff4- (4-pyridinyl) butanoyl1 amino) -4- (trifluoromethyl) pheninamino) phenyl) ethyl acetate

A mixture of 2- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate (step 2, 250 mg, 0.67 mmol), 4- (4 pyridinyl acid) was stirred ) butanoic (200 mg, 1 mmol), and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) at room temperature for 1.5 hours. Water was added to the mixture (5 ml) and extracted with diloromethane (30 ml). The organic layer was washed with brine (5 ml), then dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure to provide the title compound as a light brown amorphous.

MS (IE) m / z: 519 (M ⁺ )

STEP 4. 2- {4í6-Chloro-2-f3- (4-pyridinyl) propin-54trifluoromethyl) 1/7-benzimidazol-1-illfeniljetanol

A mixture of 2- (4 - {[5-chloro-2 - {[4- [4-pyridinyl) butanoyl] amino) -4- (trifluoromethyl) phenyl] amin ^o } phenyl) ethyl was stirred (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) at 40 ° C for 7 hours. The solvent was removed and water (50 ml) was added to the residue. The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with

413/451 brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography eluting with dichloromethane: methanol (20: 1) to provide 105 mg (54%) of the title compound as a brown oil. clear.

¹ H NMR (CDCI ₃ ) δ: 8.40-8.42 (2H, m), 8.10 (1H, s), 7.43 (2H, d, J = 8.3 hz), 7, 16-7.19 (3H, m), 7.02 (2H, d, J = 6.0 Hz), 4.00 (2H, t, J = 6.2 Hz), 3.00 (2H, t , J = 6.2 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.68 (2H, t, J = 7.3 Hz), 2.11 - 2.19 (2H , m).

STEP 5. 2- (4- [6-chloro-2- [3- (4pyridinyl) propin-5- (trifluoromethyl) -1 / 7-benzimidazole-1-yl1-phenyl} ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- [3- (4-pyridinyl) propyl] -5 (trifluoromethyl) 1B-benzimidazole- 1-yl] phenyl} ethanol (step 4).

M.p .: 80-87 ° C.

IV (KBr) v: 1743, 1610, 1517, 1431, 1346, 1161 cm ^-1 .

MS (IED) m / z: 657 (MH ⁺ ), 655 ([MH])

¹ H NMR (CDCI ₃ ) δ: 8.32 (2H, d, J = 6.0 Hz), 8.09 (1H, s), 7.99 (2H, d, J = 8.2 Hz) , 7.34 (2H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.15 (1H, s), 6.94-7.02 ( 4H, m), 4.48 (2H, t, J = 5.4 Hz), 3.01 (2H, t, J = 5.4 Hz), 2.74 (2H, t, J = 6.0 Hz), 2.54 (2H, t, J = 7.9 Hz), 2.44 (3H, s), 2.16-2.21 (2H, m).

EXAMPLE 340 (2- <4-r6-CHLORINE-2-3- (3-PYRIDINIDPROPIL1-5- (TRIFLUOROMETID-1B-BENZIMIDAZOL-1-IL1

PHENIDETHYL

STEP 1. 2- (4-f [5-chloro-2-U4- (3Pyridinyl) butanoyl1 amino) -4- (trifluoromethyl) phenyl] amino) phenyl) ethyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 339 from 2- (4 - {[2-amino5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate ( Example 339, step 2).

¹ H NMR (CDCI ₃ ) δ: 8.43 (2H, s Ig.), 7.50-7.71 (2H, m), 7,157.28 (6H, m), 6.96 (2H, d , J = 8.3 Hz), 6.43 (1H, s Ig.), 4.26 (2H, t, J = 7.0 Hz),

2.90 (2H, t, J = 7.0 Hz), 2.70 (2H, t, J = 7.3 Hz), 2.41 (2H, t, J = 7.3 Hz), 2, 03414/451

2.08 (5Η, m).

STEP 2. 2- (4-F6-Chloro-2- [3- (3-pyridinyl) propyl] -5- (trifluoromethyl) 1 H-benzimidazole-1 -illiphenipethanol

The title compound was prepared according to the procedure described in step 4 of Example 339 from 2- (4 - {[5-chloro2 - {[4- (3-pyridinyl) butanoyl] amino} -4 acetate] - (trifluoromethyl) phenyl] amino} phenyl) ethyl (step 1).

MS (IE) m / z: 459 (M ⁺ ).

¹ H NMR (CDCIs) δ: 8.33 (1H, d, J = 4.4 Hz), 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 = 5.6 Hz), 2.99 (2H, t, J = 5.6 Hz) , 2.74 (2H, t, J = 7.5 Hz), 2.64 (2H, t, J = 6.6 Hz), 2.04-2.13 (2H, m).

STEP 3. 2-f4- [6-Chloro-2-3- (3pyridinyl) propill-5- (trifluoromethyl) -1 / - / - benzimidazole-1-illfeniltethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- [3- (3-pyridinyl) propyl] -5 (trifluoromethyl-1 / - / / -benzimidazol-1-yl] phenyl} ethanol (step 2).

M.p .: 90-95 ° C.

IV (KBr) v: 1743, 1517, 1431, 1346, 1301, 1161, 1130, 1085 cm ^-1 .

MS (IED) m / z: 657 (MH ⁺ ), 6.55 ([MH] ')

¹ H NMR (CDCl ₃ ) δ: 8.59 (1H, dd, J = 1.7 Hz, 5.1 Hz), 8.08 (1H, s), 7.95 (2H, d, J = 8.3 Hz), 7.86 (1H, d, H = 1.7 Hz), 7.54-7.58 (1H, m), 7,277.34 (5H, m), 7.20 (1H, s), 7.12 (2H, d, J = 8.4 Hz), 4.46 (2H, t, J = 5.1 Hz), 3.00 (2H, t, J = 5.1 Hz) , 2.77-2.82 (2H, m), 2.62 (2H, t, J = 7.0 Hz), 2.43 (3H, s), 1.85-1.91 (2H, m ).

EXAMPLE 341 2- (4-METHYLPHENYL) SULPHONYL CARBAMATE OF 2- {4-6-CHLORINE-2f3-OXO-3- (3-PYRIDINYL) PROPIL1-5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-1L1FENIL) ETHYL

STEP 1. 2- (4 - ([5-Chloro-2- {Î ± -oxo-4- (3-pyridinyl) butanoyl acetate (4- trifluoromethyl) phen) lyophen) phenyl) ethyl acetate

The title compound was prepared according to the procedure 415/451 as described in step 3 of Example 339 from 2- (4 - {[2-amino5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl acetate ) ethyl (Example 339, step 2).

¹ H NMR (CDCb) δ: 9.19 (1H, d, J = 2.2 Hz), 8.80 (1H, dd, J = 1.8 Hz, 3.9 Hz), 8.20 ( 1H, d, J = 7.9 Hz), 7.64 (2H, s lg.), 7.44 (1H, dd, J = 5.8 Hz, 7.9 Hz), 7.28 (1H, s), 7.19 (2H, d, J = 8.3 Hz), 7.05 (2H, d, J = 8.3 Hz), 6.70 (1H, s lg.), 4.27 ( 2H, t, J = 7.1 Hz), 3.49 (2H, t, J = 5.5 Hz), 2.92 (2H, t, J = 7.1 Hz), 2.78 (2H, t, J = 5.8 Hz), 2.05 (3H, s).

STEP 2. 3-6-Chloro-1-4- (2-hydroxyethinphen-H-5- (trifluoromethyl) -1 Hbenzimidazole-2-in-1 - (3-pyridinyl) -1-propanone

The title compound was prepared according to the procedure described in step 4 of Example 339 from 2- (4 - {[5-chloro2 - {[4-oxo-4- (3-pyridinyl) butanoyl] acetate] amino} -4- (trifluoromethyl) phenyl] amino} phenyl) ethyl (step 1).

¹ H NMR (CDCb) δ: 9.05-9.06 (1H, m), 8.77-8.79 (1H, m), 8.24-8.28 (1 H, m), 8 , 06 (1H, s), 7.54 (2H, d, J = 8.5 Hz), 7.40-7.46 (3H, m), 3.97-4.04 (2H, m), 3.66 (2H, t, J = 7.0 Hz), 3.19 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 6.4 Hz).

STEP 3. 2- (4- [6-chloro-2-r3oxo-3- (3-pyridinyl) propyl1-5- (trifluoromethyl) -1 / - / - benzimidazole-1-illphenyl) (4-methylphenyl) sulfonylcarbamate ethyl

The title compound was prepared according to the procedure described in Example 3 from 3- [6-chloro-1- [4- (2-hydroxyethyl) phenyl] -5 (trifluoromethyl) -1 / 7-benzimidazole- 2-yl] -1 - (3-pyridinyl) -1-propanone (step 2).

M.: 89-95°C.

IV (KBr) v: 2972,1747, 1693, 1517, 1346, 1230, 1161, 1085 cm ^-1 .

MS (IED) m / z: 671 (MH ⁺ ), 669 ([MH] ').

¹ H NMR (CDCb) 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 = 8.2 Hz), 7.33-7.48 (7H, m), 7.21 (1H, s), 4.43 (2H, t, J = 6.3 Hz), 3.47 (2H, t, J = 7.1 Hz), 3.25 (2H, t, J = 7.1 Hz), 3.04 (2H, t, J = 6 , 3 Hz), 2.43 (3H, s).

EXAMPLE 342 (2-f4- [6-CHLORINE-2 [3-OXO-3- (2-PYRIDINYL) PROPIL] -5- (4-METHYLFENIDSULFONYL CARBAMATE) -5- (TRIFLUOROMETID-1H-BENZIMIDA416 / 451

ZOL-1-IL1FENILIETILA

STEP 1. 2- (4- (r5Cloro-2-U4-oxo-4- (2-pyridinyl) butanylamino) -4- (trifluoromethyl) phenylamino) phenyl) ethyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 339 from 2- (4 - {[2 ~ amino5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate ( Example 339, step 2).

MS (IE) m / z: 533 (M ⁺ )

STEP 2. 3- [6-Chloro-1-r4- (2-hydroxyethyl) phenyl1-5- (trifluoromethyl) -1Hbenzimidazole-2-ill-1- (2-pyridinyl) -1-propanone

The title compound was prepared according to the procedure described in step 4 of Example 339 from 2- (4 - {[5-chloro2 - {[4-oxo-4- (2-pyridinyl) butanoyl] acetate] amino} -4- (trifluoromethyl) phenyl] amino} phenyl) ethyl (step 1).

¹ H NMR (CDCI ₃ ) 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 = 6.9 Hz), 3.15 (2H, t, J = 6.9 Hz), 3.01 (2H, t, J = 6.4 Hz).

STEP 3. 2- {4- [6-chloro-2-yloxy-3- (2-pyridinyl) propyl1-5- (trifluoromethyl) -1 H-benzimidazole-l-illfenillethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 3- [6-chloro-1- [4- (2-hydroxyethyl) phenyl] -5 (trifluoromethyl) -1 / 7-benzimidazole- 2-yl] -1 - (2-pyridinyl) -1-propanone (step 2).

M.p .: 233.6 ° C.

IV (KBr) v: 1743, 1703, 1515, 1481, 1336, 1203, 1120, 1087,

995 cm ¹ .

MS (IED) m / z: 671 (MH ⁺ ), 669 ([MH])

¹ H NMR (DMSO-d ₆ ) δ: 8.74-8.76 (1H, m), 8.13 (1H, s), 7.908.03 (2H, m), 7.77 (2H, d , J = 8.1 Hz), 7.66-7.70 (1H, m), 7.49-7.58 (4H, m), 7.42 (2H, d, J = 8.1 Hz) , 7.34 (1H, s), 4.30 (2H, t, J = 6.4 Hz), 3.83 (2H, t, J = 6.4 Hz), 3.09 (2H, t, J = 6.4 Hz), 2.98 (2H, t, J = 6.4 Hz), 2.50 (3H, s).

EXAMPLE 343 (4-METHYLphenyl) 2-f4-f6-CHLORINE-2r3- (2-PYRIDINIL) PROPIL] -5- (TRIFLUOROMETHIL) -1 / 7-BENZIMIDAZOL-1-IL1

417/451

PHENIDETHYL

STEP 1. 2- (4 - {[5-chloro-2-phen- (2-pyridinyl) butanoyl] amine) -4- (trifluoromethyl) phenyl] amino) phenyl) ethyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 339 from 2- (4 - {[2-amino-5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate ( Example 339, step 2).

¹ H NMR (CDCI ₃ ) δ: 9.26 (1H, s lg.), 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 = 8.4 Hz), 4.27 (2H, t,> 7.1 Hz), 2.98 (2H, t, J = 6.3 Hz),

2.91 (2H, t,> 7.1 Hz), 2.33 (2H, t,> 5.9 Hz), 2.05 (3H, s).

STEP 2. 2-f4-í6-Chloro-2-í3- (2-pyridinyl) propyl1-5- (trifluoromethyl) 1 / - / - benzimidazole-1 -illphenylethanol

The title compound was prepared according to the procedure described in step 4 of Example 339 from 2- (4 - {[5-chloro2 - {[4- (2-pyridinyl) butanoyl] amine} -4 acetate - (trifluoromethyl) phenyl] amino} phenyl) ethyl (step 1) ·

¹ H NMR (CDCI ₃ ) δ: 8.43- 8.45 (1H, m), 8.09 (1H, s), 7.53-7.59 (1H, m), 7.45 (2H , d,> 8.2 Hz), 7.22-7.25 (3H, m), 7.05-7.13 (2H, m), 3.98 (2H, t,> 6.3 Hz) , 3.00 (2H, t,> 6.3 Hz), 2.84 (4H, t,> 7.5 Hz), 2.18-2.22 (2H, m), 1.81-1, 90 (2H, m).

STEP 3. 2- {4- [6-chloro-2-r3- (2pyridinyl) propyl1-5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [6-chloro-2- [3- (2-pyridinyl) propyl] -5 (trifluoromethyl) -1/7 -benzimidazol-1-yl] phenyl} ethanol (step 2).

M.p .: 193 ° C.

IV (KBr) v: 1747, 1626, 1517, 1433, 1350, 1159, 1120, 1085 cm ^-1 .

MS (IED) m / z: 657 (MH ⁺ ), 655 ([MH])

¹ H NMR (CDCI ₃ ) δ: 8.47-8.49 (1H, m), 8.08 (1H, s), 7.90 (2H, d,> 8.4 Hz), 7.60 -7.66 (1H, m), 7.36 (2H, d,> 8.4 Hz), 7.11-7.22 (7H, m), 4.44 (2H, t,> 6.0 Hz), 3.01 (2H, t,> 6.0 Hz), 2.82-2.88 (4H, m), 2.45 (3H, s), 1.84-1.94 (2H, m).

418/451

EXAMPLE 344 (4-METHYLPHENYL) 2- (4-r6-CHLORO-2-r3- (2-PYRIDINYL) PROPIL1-5- (TRIFLUOROMETHYL) -1 / 7-BENZIMLDAZQL-1-IL1FILYL

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [6-chloro-2- [3- (2-pyridyl) propyl] -5- (4-methylphenyl) sulfonylcarbamate (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethyl (Example 343).

M. p .: 108-110 ° C.

IR (KBr) v: 3062, 1745, 1456, 1232, 1163, 1010 CRRI ^1.

EXAMPLE 345

A / - (í (2-f4-f2-ETHYL-5- (1-HYDROXYETHIL) -1 / 7-BENZIMIDAZOL-1-1 LI PHENYL) ETHYL) AMINO1 CARBONYL} -4-METHYLBenzenesulfone

STEP 1. / V - {[(2-f4- [2-Ethyl-5- (1-hydroxyethyl) -1F / -benzimidazol-1-ill phenyl) ethyl) amino1carbonyl | -4-methylbenzenesulfonamide

A mixture of NaBH ₄ (178 mg, 0.47 mmol) and 2N NaOH (0.1 ml) in ethanol (4 ml) was added at room temperature to a mixture of / V - [({2- [4- (5-acetyl-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] ethyl} amino) carbonyl] -4methylbenzenesulfonamide (Example 78, 238 mg, 0.47 mmol) and 2N NaOH (0.1 ml ) in ethanol (10 ml). The mixture was stirred at room temperature for 4 hours. Water (10 ml) was added and neutralized with NH ₄ CI. The mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 4/1: 6) / CH ₂ CI ₂ : methanol (10: 1) to provide 198 mg (83%) of the title compound, as white solids.

M.p .: 190 ° C.

IV (KBr) v: 3384, 2979, 1716, 1514, 1404, 1159, 1087 cm ^-1 .

MS (IED) m / z: 507 (MH ⁺ ), 505 ([MH])

¹ H NMR (CDCh) δ: 7.73-7.76 (3H, m), 7.21-7.34 (7H, m), 7.20 (1H, d, J = 8.5 Hz) , 6.66 (1H, s lg.), 5.02 (1H, q, J = 6.4 Hz), 3.52-3.59 (2H, m),

419/451

2.91 (2Η, t, J = 7.0 Hz), 2.75 (2H, q, J = 7.5 Hz), 2.39 (3H, s), 1.54 (3H, d, J = 6.4 Hz), 1.30 (3H, t, J = 7.5 Hz).

EXAMPLE 346

/ V-TOLUENOSULPHONATE - {[(2- {4-r2-ETYL-5- (1-HYDROXYETHYL) -1H-BENZIMIDAZOL-1-ILylphenyl} ETYL) AMINOl-CARBONYL} -4-MET1LBENZENOSULFONAMIDE

The title compound was prepared according to the procedure described in Example 231 from / V - {[(2- {4- [2-ethyl-5- (1-hydroxyethyl) -1 / 7benzimidazol-1-yl ) phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (Example 345).

M.p .: 110-115 ° C.

IV (KBr) v: 3062, 1708, 1519, 1340, 1163 cm ^-1 .

EXAMPLE 347

A / - «[2- (4- {2-ETIL-5- [1- (METILQXI) ETIL1-1 / - / - BENZIMIDAZQL-1IL | PHENYL) ETHIL] AMINQ) CARBONYL) -4-METHYL-BENZENOSULPHONAMIDE

STEP 1, A / - (ff2- (4-f2-Ethyl-5- [1- (methyl) oxy) etif1-1H-benzimidazol-1yl) phenyl) ethylamino1carbonyl) -4-methylbenzenesulfonamide

Thionyl chloride (0.1 ml, 1.5 mmol) was added to a solution of A / - {[(2- {4- [2-ethyl-5- (1-hydroxyethyl) -1 H-benzimidazole- 1-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (Example 345, 151 mg, 0.3 mmol) in CH2 Cl2 (15 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was dissolved with methanol (15 ml). Triethylamine (0.08 ml, 0.6 mmol) was added to the mixture and stirred at room temperature for 5 hours. The solvent was removed and the residue was extracted with CH2 Cl2 (50 ml). The organic layer was washed with water (10 ml), brine (10 ml), then dried (NasSCU). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (1: 6) / CH ₂ CI ₂ : methanol (10: 1) to provide 139 mg (89 %) of the title compound as white solids.

MS (IED) m / z: 521 (MH ⁺ ), 519 ([MH] ')

¹ H NMR (CDCb) δ: 7.65-7.75 (3H, m), 7.27-7.37 (6H, m),

420/451

7.16-7.20 (1Η, m), 7.07 (1H, d, J = 8.3 Hz), 6.69 (1H, s lg.), 4.42 (1H, q, J = 6.5 Hz), 3.54-3.62 (2H, m), 3.22 (3H, s), 2.93 (2H, t, J = 7.0 Hz), 2.93 (2H, t, J = 7.0 Hz), 2.78 (2H, q, J = 7.6 Hz), 2.39 (3H, s), 1.49 (3H, d, J = 6.5 Hz) , 1.32 (3H, t, J = 7.6 Hz).

EXAMPLE 348

Λ / - ({Γ2- (4- {2-ΕΤΙί-5-Γ1- (ΜΕTlLÓXI) ETYL-1/7-BENZIMIDAZOL-1-lL) PHENYL) ETHYL1AMINO} CARBONYL) -4METHYLBENZENOSULFONAMIDE

The title compound was prepared according to the procedure described in Example 231 from / V - ({[2- (4- {2-ethyl-5- [1 - (methyloxy) ethyl] -1 / 7benzimidazole- 1-yl} phenyl) ethyl] amino} carbonyl) -4-methylbenzenesulfonamide (Example 347).

M.p .: 110-115 ° C.

IV (KBr) v: 3064, 1710, 1519, 1452, 1340, 1163, 1033 cm ^-1 .

EXAMPLE 349

A / - P-TOLUENOSULPHONATE ((2- (4-f2-ETHYL-5- (1-HYDROXY-1-METHYLTHYL) -1H-BENZIMIDAZOL-1-YLFENYL) ETHYL) AMINOL-CARBONYL) -4METHYLBELSENFULAMON

STEP 1. <V-ff (2- (4- [2-Ethyl-5- (1-hydroxy-1-methylethyl-1H-benzimidazol-1-infenyl) ethyl) amino1carbonyl) -4-methylbenzenesulfonannide

MeMgl (1.2 ml, 0.99 mmol) was added dropwise to a solution of A / - [({2- [4- (5-acetyl-2-ethyl-1 P-benzimidazole-1 -yl) phenyl] ethyl] amin o) carbonyl] -4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrofuran (15 ml) under an atmosphere of nitrogen at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and then stirred at room temperature for 30 minutes. Water was added to the mixture (10 ml) and extracted with CH2 Cl2 (50 ml). The organic layer was washed with brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with CH ₂ CI ₂ : methanol (30: 1/20: 1/10: 1) to provide 100 mg (97%) of the title compound, in the form of white solids.

MS (IED) m / z: 521 (MH ⁺ ), 519 ([MH] ')

421/451

¹ H NMR (CDCI ₃ ) δ: 7.87 (1H, s), 7.76 (2H, d, J = 7.9 Hz), 7,177.38 (7H, m), 7,00 (1H, d, J = 8.5 Hz), 6.69 (1H, s lg.), 3.52 (2H, s lg.), 2.88 (2H, s lg.), 2.73 (2H, s 1.36 (3H, s), 1.62 (6H, s), 1.27 (3H, m).

STEP 2. A / - (i (2- {4-r2-ethyl-5- (1-hydroxy-1-methylethyl) -1H-benzimidazol-1-yl-phenyl) ethyl) amino1carbonyl} -4-methylbenzenesulfonamide p-Toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from A / - {[(2- {4- [2-ethyl-5- (1-hydroxy-1methylethyl) -1 / 7-benzimidazole -1-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (STEP 1).

M.p .: 146-150 ° C.

IV (KBr) v: 2871, 1685, 1519, 1448, 1340, 1124 cm ^-1 .

EXAMPLE 350

2-ETIL-4,6-DIMETlL-1- (442-r ({[(4-METHYLPHYL) SULFONYL1AMINQ) CARBONYL) AMINO1ETYL} PHENYL) -1 / 7-BENZIMIDAZQL-5-CARBOXAMIDE

STEP 1. 1 -r4- (2-Chlorethyl) phenill-2-ethyl-4,6-dimethyl-1 H-benzimidazole-5-carboxamide

A solution of 1- [4- (2-chloroethyl) phenyl] -2-ethyl-4,6-dimethyl1 / 7-benzimidazole-5-carbonitrile (Example 329, step 6, 997 mg, 2.95 mmoles) was stirred ) in concentrated H2SO4 (50 ml) at 80 ° C for 15 hours. The mixture was poured over ice and neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300 ml), then dried (Na ₂ SO ₄ ). The solvent was removed to provide 871 mg (83%) of the title compound, as white solids.

MS (IED) m / z: 355 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.43 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 6.73 (1H, s) , 6.56 (1H, s lg.), 5.88 (1H, s lg.), 3.82 (2H, t, J = 7.0 Hz), 3.19 (2H, t, J = 7 , 0 Hz), 2.82 (2H, q, J = 7.6 Hz), 2.72 (3H, s), 2.41 (3H, s), 1.26 (3H, t, J = 7 , 6 Hz).

STEP 2. 1-i4- (2-Azidoethyl) pheniH-2-ethyl-4,6-dimethyl-1A7-benzimide ~ zol-5-carboxamide

422/451

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- [4- (2-chloroethyl) phenyl] -2-ethyl4.6-dimethyl-1 / - / - benzimidazole- 5-carboxamide (step 1).

¹ H NMR (CDCb) δ: 7.44 (2H, d, J = 8.4 Hz), 7.27-7.30 (2H, m), 6.73 (1H, s), 5.97 (1H, s lg.), 5.72 (1H, s lg.), 3.62 (2H, t, J = 7.1 Hz), 3.02 (2H, t, J = 7.1 Hz) , 2.80 (2H, q, J = 7.5 Hz), 2.73 (3H, s), 2.42 (3H, s), 1.26 (3H, t, J = 7.5 Hz) .

STEP 3. 1- [4- (2-Aminoethyl) phenyl1-2-ethyl-4,6-dimethyl-1 / - / - benzimIDazole-5-carboxamide

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- [4- (2-azidoethyl) phenyl] -2-ethyl4.6-dimethyl-1H-benzimidazole-5-carboxamide (step 2).

¹ H NMR (CDCb) δ: 7.41 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 6.74 (1H, s), 6.00 (1H, s lg.), 5.76 (1H, s lg.), 3.07 (2H, t, J = 7.1 Hz), 2.87 (2H, t, J = 7, 1 Hz), 2.81 (2H, q, J = 7.5 Hz), 2.74 (3H, s), 2.43 (3H, s), 1.26 (3H, t, J = 7, 5 Hz).

STEP 4. 2-Ethyl-4,6-dimethyl-1- (442 - [(U (4-methylphenyl) sulfonillamino) carbonyl) aminoletyl) phenyl) -1 / - / - benzimidazole-5-carboxamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 1- [4- (2-aminoethyl) phenyl] -2ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide (step 3).

MS (IED) m / z: 534 (MH ⁺ ), 532 ([MH] ').

¹ H NMR (CD ₃ OD) δ: 7.88 (1H, s), 7.80 (2H, d, J = 8.3 Hz), 7.25-7.42 (6H, m), 6 , 74 (1H, s lg.), 3.42 (2H, t, J = 6.8 Hz), 2.86 (2H, t, J = 6.8 Hz), 2.79 (2H, q, J = 7.6 Hz), 2.65 (3H, s), 2.37 (3H, s), 2.34 (3H, s), 1.21 (3H, t, J = 7.6 Hz) .

STEP 5. 2-Ethyl-4,6-dimethyl-1- (4- {2 - [(U (4methylphenyl) sulfonyl1amino} carbonyl) amino1ethyl) phenyl) -1 / 7-benzimidazole-5-carboxamide p-Toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from 2-ethyl-4,6-dimethyl-1- (4- {2 [({[(4 (methylphenyl) sulfonyl] amino} carbonyl) amino ] ethyl} phenyl) -1 / - / - benzimidazole-5-carbo423 / 451 xamide (step 4).

EXAMPLE 351

A / -U (2- {4-r2-ETHYL-5- (TRIFLUOROACETYL) -1H-BENZlMIDAZOL-1-ILylphenylJETYL) AMINOl-CARBONYL) -4METHYLBENZENQSSULFONAMIDE

STEP 1. 2,2,2-Trifluoro-1- (4-U4- (2-hydroxyethyl) pheninamino) -3-nitrophenyl) ethanone

The title compound was prepared according to the procedure described in step 1 of Example 45 from 1- (4-amino-3-nitrophenyl) 2,2,2-trifluoroethanone.

¹ H NMR (CDCI ₃ ) δ: 9.47 (1H, s lg.), 8.10 (1H, d, J = 2.6 Hz), 7.16 = 7.33 (6H, m), 3.87-3.94 (2H, m), 2.91 (2H, t, J = 6.4 Hz), 1.43 (1H, t, J = 5.6 Hz).

STEP 2. 1- (3-Amino-4 - {[4- (2-hydroxyethyl) phenylamino} phenyl) -2,2,2trifluoroethanone

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2,2,2-trifluor-1- (4 - {[4- (2hydroxyethyl) phenyl] amino} -3-nitrophenyl ) ethanone (step 1).

¹ H NMR (CDCb) δ: 7.05-7.09 (3H, m), 6.57-6.70 (4H, m), 3.82 (2H, t, J = 6.6 Hz) , 2.78 (2H, t, J = 6.6 Hz).

STEP 3. 2- {4- [2-ethyl-5- (trifluoroacetyl) -1 / 7-benzimidazol-1-yl-phenyl) ethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 1- (3-amino-4 - {[4- (2-hydroxyethyl) phenyl] amino} phenyl) -2,2, 2-trifluoroethanone (step 2).

¹ H NMR (CDCb) δ: 7.65 (1H, s), 7.45 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.06 (2H, s), 4.38 (2H, t, J = 6.9 Hz), 3.07 (2H, t, J = 6.9 Hz),

2.79 (2H, q, J = 7.4 Hz), 2.35 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.4 Hz), 1, 14 (3H, t, J = 7.5 Hz).

STEP 4. 1- (2-Ethyl-144- (2-hydroxyethyl) phenyl-1/7-benzimidazole-5yl) 2,2,2-trifluoroethanone

The title compound was prepared according to the procedure 424/451 as described in step 6 of Example 1 from 2- {4- [2-ethyl-5 (trifluoroacetyl) -1 / - / - benzimidazole-1 propanoate -il] phenyl} ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.65 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz) , 7.06 (2H, s), 3.96-4.03 (2H, m), 3.01 (2H, t, J = 6.6 Hz),

2.79 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 5. 1- {1-r4- (2-Chloroethyl) phenin-2-ethyl-1H-benzimidazol-5-yl)

2.2.2- trifluoroethanone

The title compound was prepared according to the procedure described in step 7 of Example 1 from 1- {2-ethyl-1- [4- (2hydroxyethyl) phenyl] -1 / - / - benzimidazol-5-yl } 2,2,2-trifluoroethanone (step 4).

¹ H NMR (CDCI ₃ ) δ: 7.66 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz) , 7.07 (2H, s), 3.82 (2H, t, J = 7.0 Hz), 3.20 (2H, t, J = 7.0 Hz),

2.79 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 6. 1- {1- [4- (2-Azidoethyl) phenyl1-2-ethyl-1/7-benzimidazol-5-yl)

2.2.2- trifluoroethanone

The title compound was prepared according to the procedure described in step 8 of Example 1 from 1- {1- [4- (2-chloroethyl) phenyl] -2ethyl-1/7-benzimidazol-5-yl} 2,2,2-trifluoroethanone (step 5).

¹ H NMR (CDCI ₃ ) δ: 7.65 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz) , 7.06 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.02 (2H, t, J = 7.0 Hz),

2.79 (2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz).

STEP 7. 141 -f4- (2-Aminoethyl) phenyl1-2-ethyl-1 / - / - benzimidazol-5-yl)

2.2.2- trifluoroethanone

The title compound was prepared according to the procedure described in step 9 of Example 1 from 1- {1- [4- (2-azidoethyl) phenyl] -2ethyl-1 / - / - benzimidazol-5-yl } 2,2,2-trifluoroethanone (step 6).

¹ H NMR (CDCI ₃ ) δ: 7.65 (1H, s), 7.43 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz) , 7.07 (2H, s), 3.09 (2H, t, J = 6.7 Hz), 2.89 (2H, t, J = 6.7 Hz),

2.79 (2H, q, J = 7.4 Hz), 1.35 (3H, t, J = 7.4 Hz).

STEP 8. A / 4 [(24442-Ethyl-5- (trifluoroacetih-1 / - / - benzimidazol-1 ylphenyl) ethyl) amino1carbonyl) -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure 425/451 as described in step 10 of Example 1 from 1- {1- [4- (2-aminoethyl) phenyl] -2ethyl-1/7-benzimidazole-5 -il} 2,2,2-trifluoroethanone (step 7).

MS (IED) m / z: 547 (MH ⁺ ), 545 ([MH] ').

¹ H NMR (CDCb) δ: 7.72 (2H, d, J = 8.4 Hz), 7.64 (1H, s), 7.39 (2H, d, J = 8.4 Hz), 7.27-7.29 (4H, m), 7.02-7.04 (2H, m), 6.75 (1H, s lg.), 3.55-3.62 (2H, m), 2.94 (2H, t, J = 6.9 Hz), 2.79 (2H, q, J = 7.5 Hz), 2.39 (3H, s), 1.33 (3H, t, J = 7.5 Hz).

STEP 9. / V - ([(2- (4- [2-ethyl-5- (trifluoroacetyl) -1 / 7-benzimidazol-1-yl1-phenylJetyl) amino] carbonylJ-4-methylbenzenesulfonamide p-Toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from A / - {[(2- {4- [2-ethyl-5- (trifluoroacetyl) -1 / 7benzimidazol-1-yl] phenyl } ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (step 8).

M.p .: 194.1 ° C.

IV (KBr) v: 3589, 1701, 1627, 1521, 1458, 1330, 1091 cm ^-1 .

EXAMPLE 352

2- {4-r2-ETHYL-5- (TRIFLUOROACETYL) -1P-BENZIMIDAZOL-1-IL1FEN ILJETI LA P-TOLUENOSULPHONATE

STEP 1. 2- {4- [2-Ethyl-5- (trifluoroaceti D-1/7-benzimidazole-1 -illphenyljetyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 1- {2-ethyl-1 - [4- (2-hydroxyethyl) phenyl] -1 Hbenzimidazol-5-yl} 2,2, 2-trifluoroethanone (Example 351, step 4).

MS (IED) m / z: 548 (MH ⁺ ), 546 ([MH] ').

¹ H NMR (CDCb) δ: 7.93 (2H, d,> 8.4 Hz), 7.64 (1H, s), 7,287.35 (4H, m), 7.20 (2H, d, > 8.4 Hz), 7.05-7.07 (2H, m), 4.37 (2H, t,> 6.6 Hz), 3.00 (2H, t,> 6.6 Hz), 2.76 (2H, q,> 7.6 Hz), 2.43 (3H, s), 1.31 (3H, t,> 7.6 Hz).

STEP 2. 244-f2-ethyl-5- (trifluoroacetyl) -1 / 7-benzimidazole-1 -illphenyljetila (4-methylphenyl) sulfonylcarbamate jp-toluenesulfonate

426/451

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [2-ethyl-5- (trifluoroacetyl) -1 H-benzimidazol-1-yl] (4-methylphenyl) sulfonylcarbamate phenyl} ethyl (step 1).

M.p .: 92-97 ° C.

IV (KBr) v: 1745, 1519, 1458, 1350, 1222, 1163, 1122 cm ^-1 .

EXAMPLE 353

2- (4-F5-ACETYL-2- (1H-PIRAZOL-3-IL) -1H-BENZIMIDAZOL-1-IL1-PHENYL) Ethyl P-TOLUENOSULPHONATE

STEP 1. 1- [1-í4- (2-Hydroxyethyl) phenill-2- (1 / - / - pyrazol-3-yl) -1 / 7-benzimidazole-5-inethanone

The title compound was prepared according to the procedure described in step 1 of Example 236 from 1- (3-amino-4 - {[4- (2hydroxyethyl) phenyl] amino} phenyl) ethanone (Example 78, step 2).

MS (IED) m / z: 345 (M ⁺ ).

¹ H NMR (CDCb) δ: 8.53 (1H, s), 7.94 (1H, d, J = 8.4 Hz), 7,487.53 (3H, m), 7.37 (2H, d , J = 8.2 Hz), 7.27 (1H, s), 7.18 (1H, d, J = 8.4 Hz), 6.03 (1H, s lg.), 4.02 (2H , t, J = 6.6 Hz), 3.05 (2H, t, J = 6.6 Hz), 2.69 (3H, s).

STEP 2. 244-f5-acetyl-2- (1Hpyrazol-3-tl) -1H-benztmidazol-1-yl-phenyl) (4-methylphenyl) sulfonylcarbamate)

The title compound was prepared according to the procedure described in Example 3 from 1- [1- [4- (2-hydroxyethyl) phenyl] -2- (1/7-pyrazol3-yl) ~ 1/7 -benzimidazol-5-yl] ethanone (step 1).

MS (IED) m / z: 544 (MH ⁺ ), 542 ([MH] ⁺ ).

¹ H NMR (DMSO-de) δ: 8.41 (1H, s), 7.77-7.89 (4H, m), 7,387.42 (7H, m), 7.12 (1H, d, J = 8.5 Hz), 6.65 (1H, s lg.), 4.29 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.6 Hz) , 2.66 (3H, s), 2.35 (3H, s).

STEP 3. 2- (4-5-Acetyl-2- (1P-pyrazol-3-ih-1 P-benzimidazot-1-ylphenylethyl) p-benzimidazot-1-ylphenylethyl jp-toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [5-acetyl-2- (1H-pyrazol-3-yl) -1H-benzimidazole (4-methylphenyl) sulfonylcarbamate -1-yl] phenyl} ethyl (step 2).

427/451

M. p .: 204 ° C.

IV (KBr) v: 3249, 1755, 1676, 1595, 1517, 1440, 1332, 1207, 1161, 1008 cm ^-1 .

EXAMPLE 354

P-TOLUENOSULPHONATE OF / V- {r (2-f446-CHLORINE-2-ri- (MET! Loxy) ETYL-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL] PHENY} ETHYL)

AMINO1CARBONILM-MET1LBENZENOSULPHONAMIDE

STEP 1. 2- (4-U5-chloro-2-f (2-hydroxypropanoyl) amino1-4- (trifluoromethyl) phenyl] amino) phenyl) ethyl acetate

The title compound was prepared according to the procedure described in step 3 of Example 339 from 2- (4 - {[2-amino5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate ( Example 339, step 2).

MS (IE) m / z: 444 (M ⁺ )

STEP 2. 2- {4- [6-chloro-2- (1-hydroxyethyl) -5- (trifluoromethyl) -1 H-benzimidazole-1 -illphenylethyl acetate

The title compound was prepared according to the procedure described in step 4 of Example 339 from 2- (4 - {[5-chloro2 - [(2-hydroxypropanoyl) amino] -4- (trifluoromethyl) phenyl acetate ] amino} phenyl) ethyl (step 1).

¹ H NMR (CDCl ₃ ) δ: 8.14 (1H, s), 7.48 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz) , 7.24 (1H, s), 4.88-4.98 (1H, m), 4.38 (2H, t, J = 7.0 Hz), 3.66 (1H, d, J = 8 , 1 Hz), 3.08 (2H, t, J = 7.0 Hz), 2.09 (3H, s), 1.57 (3H, d, J = 6.6 Hz).

STEP 3. 1 -r6-Chloro-1 -4- (2-hydroxyethyl) phenin-5- (trifluoromethyl) -1 / 7benzimidazole-2-illethanol

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [6-chloro-2- (1hydroxyethyl) -5- (trifluoromethyl) -1 / 7- acetate benzimidazol-1-yl] phenyl} ethyl (step 2).

MS (IED) m / z: 384 (M ⁺ )

¹ H NMR (CDCI ₃ ) δ: 8.14 (1H, s), 7.49 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz) , 7.25 (1H, s), 4.89-4.96 (1H, m), 3.98 (2H, t, J = 6.2 Hz), 3.36 (1H, d, J = 5 , 5 Hz), 3.01 (2H, t, J = 6.2 Hz), 1.54 (3H, m).

STEP 4. 1-r6-Chloro-144- (2-fr (T1-dimethylethyl) (diphenyl) silyloxy) 428/451 ethyl) phenyl1-5- (trifluoromethyl) -1/7 “benzimidazol-2-yl1ethanol

A mixture of 1- [6-chloro-1- [4- (2-hydroxyethyl) phenyl] -5- (trifluoromethyl) -1 / 7-benzimidazol-2-yl] ethanol was stirred (step 3, 461 mg, 1.19 mmol), ferc-butyldiphenylsilyl chloride (0.35 ml, 1.3 mmol), triethylamine (0.2 ml, 1.4 mmol) and N, Ndimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (11 ml) under a nitrogen atmosphere at room temperature for 4 hours. Water (50 ml) was added and extracted with dichloromethane (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (3: 1/1: 1), to provide 590 mg (80%) of the title compound, in the form of white amorphous.

¹ H NMR (CDCb) 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 = 6.4 Hz), 3.29 (1H, d, J = 8.1 Hz ), 2.97 (2H, t, J = 6.4 Hz), 1.52 (3H, d, J = 6.6 Hz), 1.03 (9H, s).

STEP 5. 6-Chloro-1- [4- (2 - {[(1 .l-dimethylethylDidifeniDsililloxyethyl) phen i IΊ-2-Γ1 - (methyloxy) ethyl1-5- (trifluoromethyl) -1 H-benzimidazole

NaH (45 mg, 1.13 mmol) was added to a solution of 1- [6 chloro-1- [4- (2 {[(1,1-dimethylethyl) diphenyl) silyl] oxy} ethyl) phenyl] -5 - (trifluoromethyl) -1 / 7-benzimidazol-2-yl] ethanol (step 4, 590 mg, 0.95 mmol) in DMF (10 ml). Then Mel (0.08 ml, 1.23 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Water (30 ml) was added to the mixture and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (3: 1), to provide 550 mg (91%) of the title compound as a colorless oil.

¹ H NMR (CDCb) δ: 8.17 (1H, s), 7.20-7.70 (15H, m), 4.54 (1H, q, J = 6.6 Hz), 3.95 (2H, t, J = 6.6 Hz), 3.22 (3H, s), 2.97 (2H, t, J = 6.6 Hz), 1.55 (3H, d, J = 6, 6 Hz), 1.03 (9H, s).

STEP 6. 2- {4-f6-Chloro-2- [1 - (methyloxy) ethin-5- (trifluoromethyl) -1/7429/451 benzimidazole-1 -illphenylethanol

The title compound was prepared according to the procedure described in step 6 of Example 90 from 6-chloro-1- [4- (2 - {[(1,1 dimethylethyl) (diphenyl) silyl] oxy} ethyl] ) phenyl] -2- [1- (methyloxy) ethyl] -5- (trifluoromethyl) -1I / -benztmidazole (step 5).

MS (IED) m / z: 398

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz) , 7.24 (1H, s), 4.58 (1H, q, J = 6.6 Hz), 4.00 (2H, s lg.), 3.24 (3H, s), 3.02 ( 2H, t, J = 6.5 Hz), 1.55-1.60 (3H, m).

STEP 7. 6 Chloro-1-- (2-chloroethyl) phenill-241- (methyloxy) ethyl1-5- (trifluoromethyl) -1 / 7-benzimidazole

The title compound was prepared according to the procedure described in step 7 of Example 1 from 2- {4- [6-chloro-2- [1 (methyloxy) ethyl] -5- (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethanol (step 6).

MS (IED) m / z: 416 (M ⁺ )

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H, s), 7.48 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz) , 7.23 (1H, s), 5.57 (1H, q, J = 6.6 Hz), 3.83 (2H, t, J = 7.1 Hz), 3.19-3.24 ( 5H, m), 1.57 (3H, d, J = 6.6 Hz).

STEP 8. 1 - [4- (2-Azidoethyl) phenyl1-6-chloro-2-r 1 - (methyloxy) etii1-5- (trifluoromethyl) -1 / - / - benzimidazole

The title compound was prepared according to the procedure described in step 8 of Example 1 from 6-chloro-1- [4- (2-chloroethyl) phenyl] 2- [1 - (methyloxy) ethyl] -5 - (trifluoromethyl) -1 / - / - benzimidazole (step 7).

MS (IED) m / z: 423 (M ⁺ )

¹ H NMR (CDCl ₃ ) 8: 8.18 (1H, s), 7.48 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz) , 7.22 (1H, s), 4.57 (1H, q, J = 6.6 Hz), 3.63 (2H, t, J = 6.9 Hz), 3.23 (3H, s) , 3.04 (2H, t, J = 6.9 Hz), 1.56 (3H, d, J = 6.6 Hz).

STEP 9. 2- {4-r6-Chloro-2-y1- (methyloxy) ethyl-5- (trifluoromethyl) -1Hbenzimidazole-1-ylphenyl} ethanamine

The title compound was prepared according to the procedure described in step 7 of Example 37 from 1- [4- (2-azidoethyl) phenyl] -6chloro-2- [1- (methyloxy) ethyl] -5- (trifluoromethyl) -1 / - / - benzimidazole (step 8).

430/451

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz) , 7.24 (1H, s), 4.57 (1H, q, J = 6.6 Hz), 3.23 (3H, s), 3.10 (2H, s lg.), 2.90 ( 2H, t, J = 6.6 Hz), 1.57 (3H, d, J = 6.6 Hz).

STEP 10. A / - <(2- (4- [6-Chloro-2- [1- (methyloxy) ethyl] -5- (trifluoromethyl) 1/7-benzimidazol-1-yl-phenyl) ethyl) amino1-carbonyl} - 4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in step 10 of Example 1 from 2- {4- [6-chloro-2- [1- (methyloxy) ethyl] -5- (trifluoromethyl) -1 / - / - benzimidazole-1-yl] phenyl} ethanamine (step 9).

MS (IED) m / z: 595 (MH ⁺ ), 593 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 8.18 (1H. S). 7.73 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.27-7.34 (4H, m), 7.21 (1H , s), 6.76 (1H, s lg.), 4.57 (1H, q, J = 6.6 Hz), 3.56-3.63 (2H, m), 3.23 (3H, s), 2.96 (2H, t, J = 7.1 Hz), 2.41 (3H, s), 1.56 (3H, d, J = 6.6 Hz).

STEP 11. / V - {[(2- {4-6-chloro-2- [1- (methyloxy) ethyl1-5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl-phenyl} ethyl p-Toluenesulfonate ) amino1carbonyl} -4methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 231 from / V - {[(2- {4- [6-chloro-2- [1- (methyloxy) ethyl] -5 (trifluoromethyl) -1 / 7-benzimidazol-1-yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (step 10).

IV (KBr) v: 2873, 1712,1517, 1454, 1342, 1122, 1033, 1010 cm ^-1 . EXAMPLE 355

(4-METHYLPHENYL) 2-F4-Y2-ETHYL-5- (1-HYDROXYETHYL) -1B-BENZIMlDAZOL-1YL-PHYLYLENYLETHIL P-TOLUENOSULPHONATE

STEP 1. 2- {4-r2-ethyl-5- (1-hydroxy-ethyl) -1 / 7-benzimidazole-1-infenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 345 from 2 [4- (5-acetyl-2-ethyl-1 / - / - benzimidazol-1-yl) (4-methylphenyl) sulfonylcarbamate) phenyl] ethyl (Example 332).

MS (IED) m / z: 508 (MH ⁺ ), 506 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.94 (2H, d, J = 8.3 Hz), 7.77 (1H, s), 7.03431 / 451

7.35 (8Η, m), 5.04 (1H, q, J = 6.4 Hz), 4.36 (2H, t, J = 6, Hz), 2.97 (2H, t, J = 6.6 Hz), 2.74 (2H, q, J = 7.5 Hz), 2.43 (3H, s), 1.56 (3H, d, J = 6.4 Hz), 1.28 (3H, t, J = 7.5 Hz).

STEP 2. 2- {4- [2-ethyl-5- (1-hydroxyethH) -1 B-benzimidazole-1 -illphenyljetyl p-toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [2-ethyl-5- (1-hydroxyethyl) -1 B-benzimidazole-1 - (4-methylphenyl) sulfonylcarbamate il] phenyljetyl (step 1).

M.p .: 96-110 ° C.

IV (KBr) v: 1743, 1519, 1456, 1163, 1033, 1010 cm “ ¹ .

EXAMPLE 356

2- {4-r2-ETHYL-4-METHYL-5- (METHYLOXY) -1B-BENZIMIDAZOL1-IL1FENILJET1LA P-TOLUENOSULPHONATE

STEP 1. 2- (4-fl3-Methyl-4- (methyloxy) -2-nitrophenir | amino) phenipethanol

The title compound was prepared according to the procedure described in step 3 of Example 1 from 1-chloro-3-methyl-4- (methyloxy) -2nitrobenzene.

MS (IE) m / z: 302 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.11-7.20 (3H, m), 6.89-6.96 (3H, m), 6.53 (1H, s Ig.), 3.83 (5H, Ig's), 2.81 (2H, t, J = 6.4 Hz), 2.25 (3H, s).

STEP 2. 2- (4-f [2-Amino-3-methyl-4- (methyloxy) phenyl1amino) phenyl) ethanol

The title compound was prepared according to the procedure described in step 4 of Example 1 from 2- (4 - {[3-methyl-4- (methyloxy) -2nitrophenyl] amino} phenyl) ethanol (step 1) .

MS (IE) m / z: 272 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 7.03 (2H, d, J = 8.6 Hz), 6.92 (1H, d, J = 8.6 Hz), 6.57 (2H, d, J = 8.6 Hz), 6.32 (2H, d, J = 8.6 Hz), 5.01 (1H, s Ig.), 3.77-3.90 (7H, m), 2, 76 (2H, t, J = 6.4 Hz), 2.09 (3H, s).

STEP 3. 2- {4-f2-ethyl-4-methyl-5- (methyloxy) -1B432 / 451 benzimidazol-1-yl] phenyl) ethyl propanoate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- (4 - {[2-amino-3-methyl-4 (methyloxy) phenyl] amino} phenyl) ethanol (step 2).

MS (IE) m / z: 366 (M ⁺ ).

STEP 4. 2- {4- [2-Ethyl-4-methyl-5- (methyloxy) -1 / - / - benzimidazole-1illfenilletanoi

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- {4- [2-ethyl-4methyl-5- (methyloxy) -1 / 7-benzimidazole-1- propanoate il] phenyl} ethyl (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.42 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz), 6.84 (2H, s) , 3.97 (2H, t, J = 6.4 Hz), 3.86 (3H, s), 2.99 (2H, t, J = 6.4 Hz), 2.81 (2H, q, J = 7.7 Hz), 2.58 (3H, s), 1.26 (3H, t, J = 7.7 Hz).

STEP 5. 2- {4- [2-ethyl-4-methyl-5 (methyloxy) -l / - / - benzimidazole-1-yl-phenyl-di-methyl (4-methylphenyl) sulfonylcarbamate)

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-4-methyl-5- (methyloxy) -1 / - / benzimidazol-1-yl] phenyl } ethanol (step 4).

MS (IED) m / z: 508 (MH ⁺ ), 506 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 7.98 (2H, d, J = 8.3 Hz). 7.33 (2H, d, J = 8.9 Hz). 6.88-6.91 (6H, m), 4.28 (2H, t, J = 6.0 Hz), 3.89 (3H, s), 2.84 (2H, t, J = 6, 0 Hz), 2.74 (2H, q, J = 7.5 Hz), 2.56 (3H, s), 2.43 (3H, s), 1.05 (3H, t, J = 7, 5 Hz).

STEP 6. 2-F4-F2-ethyl-4-methyl-5- (methyloxy) -1 A / -benzimidazol-1-yl] phenyl) ethyl 4-methylene-4-toluenesulfonate

The title compound was prepared according to the procedure described in Example 231 from 2 {4- [2-ethyl-4-methyl-5- (methyloxy) -1 / 7-benzimidazole (4-methylphenyl) sulfonylcarbamate) -1 -il] phenyl} ethyl (step 5).

M. p .: 94-103 ° C.

IV (KBr) v: 1747, 1458, 1232, 1163, 1120 cm ^-1 .

EXAMPLE 357 (2- [4- (2-ETiL-5-PHENYL-1H-BENZIMIDAZOL-1-IDFEN1DETYL) 4-METHYLFILIDSULPHONYL

433/451

STEP 1. 2- {4 - [(4-Bromo-2-nitrophenyl) amino] phenyl} ethanol

The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,5-dibromonitrobenzene.

¹ H NMR (CDCI ₃ ) δ: 9.43 (1H, s lg.), 8.34 (1H, d,> 2.4 Hz), 7.43-7.39 (1H, m), 7 , 30 (2H, d,> 8.3 Hz), 7.20 (2H, d,> 8.3 Hz), 7.08 (1H, d,> 9.2 Hz), 3.94-3, 88 (2H, m), 2.90 (2H, d,> 6.4 Hz), 1.43 (1H, t,> 5.7 Hz).

STEP 2. 2- (4-f (2-Amino-4-bromophenyl) amino1phenyl} ethanol

The title compound was prepared according to the procedure described in step 2 of Example 28 from 2- {4 - [(4-bromo-2-nitrophenyl) amino] phenyl} ethanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 7.08 (2H, d, J = 8.4 Hz), 6.97-6.93 (2H, m), 6.84 (1H, dd, J = 8 , 3, 2.2 Hz), 6.69 (2H, d, J = 8.6 Hz), 5.04 (1H, s lg.), 3.80 (2H, s lg.), 3.82 (2H, t, J = 6.4 Hz), 2.79 (2H, t, J = 6.4 Hz).

STEP 3. 2-r4- (5-bromo-2-ethyl-1 / - / - benzimidazole-1 ihphenylethyl propionate

The title compound was prepared according to the procedure described in step 5 of Example 1 from 2- {4 - [(2-amino-4-bromophenyl) amino] phenyl} ethanol (step 2).

MS (IE) m / z 401 (M ⁺ ).

STEP 4. 2-i4- (5-Bromo-2-ethyl-1 / - / - benzimidazole-1-iDfenilletanoi

The title compound was prepared according to the procedure described in step 6 of Example 1 from 2- [4- (5-bromo2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] ethyl propionate (step 3).

¹ H NMR (CDCI ₃ ) δ: 7.90 (1H, s), 7.45 (2H, d,> 8.1 Hz), 7,267.30 (3H, m), 6.96 (1H, d ,> 8.4 Hz), 3.98 (2H, m), 3.00 (2H, t,> 6.4 Hz), 2.78 (2H, q,> 7.6 Hz), 1.34 (3H, t,> 7.6 Hz).

STEP 5. 2- [4- (2-Ethyl-5-phenyl-1H-benzimidazole-1-iDfenilletanoi

PhB (OH) ₂ (141 mg, 1.16 mmol), K ₂ CO ₃ (240 mg, 1.75 mmol) and Pd (PPh ₃ ) ₄ (67 mg, 0.06 mmol) were added to a solution of 2- (4- (5bromo-2-ethyl-1 / - / - benzimidazol-1-yl) phenyl] ethanol (step 4, 116 mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 This mixture was stirred at 95 ° C for 11 hours, the reaction mixture was diluted with water and extracted with CH ₂ CI ₂ (4

434/451 x 10 ml). The organic layer was dried (MgSO ₄ ) and concentrated to provide brown oil. This mixture was purified by preparative TLC over SiO ₂ (hexane / ethyl acetate = 1/5) to provide 52 mg (27%) of the title compound.

MS (IE) m / z 342 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.00 <1H, d, J = 1.6 Hz), 7.65 (2H, dd, J = 1.6, 8.4 Hz), 7.42- 7.48 (5H, m), 7.32-7.35 (3H, m), 7.15 (2H, d, J = 8.4 Hz), 4.00 (2H, t lg.), 3 , 01 (2H, t, J = 6.5 Hz), 2.82 (2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

STEP 6. 2- [4- (2-ethyl-5-phenyl1 / V-benzimidazole-1-iOphenylethyl) (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- [4- (2-ethyl-5-phenyl-1 / V-benzimidazol-1yl) phenyl] ethanol (step 5).

MS (IED) m / z 540 [M + H] ⁺ , 538 [MH] '.

¹ H NMR (CDCI ₃ ) δ: 8.00 (1H, s), 7.94 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.6 Hz) , 7.43-7.48 (3H, m), 7.29-7.36 (7H, m), 7.15 (2H, d, J = 8.4 Hz), 4.39 (2H, t , J = 6.8 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.70 (2H, q, J = 7.4 Hz), 2.43 (s, 3H), 1.35 (3H, t, J = 7.6 Hz).

EXAMPLE 358 (2-F4- [2-ETHYL-5-5-PYRIMIDINID-1 / V-BENZIMIDAZOL-1-IL1FENYL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- {4- [2-Ethyl-5- (4,4,5,5, -tetramethyl-1,3.2-dioxaborolan-2il) -1 / V-benzimidazole-1 -illphenylethanol

KOAc (2.13 g, 21.7 mmol), 1.1'-bis (diphenylphosphino) ferrocene (241 mg, 0.43 mmol) and Pd (dppf) CI ₂ CH ₂ CI ₂ (362 mg, 0.44 mmol) to a solution of 2- [4- (5-bromo-2-ethyl-1 / V-benzimidazol-1 yl) phenyl] ethanol (Example 357, step 4, 2.5 g, 7.24 mmoles) and bis (pinacolate) diboro (1.84 g, 7.24 mmoles) in DMSO. This mixture was stirred at 80 ° C for 7 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 80 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated, to provide black oil.

435/451

This mixture was purified by neutral S1O2 chromatography, eluting with hexane / ethyl acetate (1: 4), to provide 1.38 g (35%) of the title compound, as pink solids.

MS (IE) m / z 391 [MH] ⁺ .

¹ H NMR (CDCI ₃ ) δ: 8.25 (1H, s), 7.64 (2H, dd, J = 0.8, 8.1 Hz), 7.45 (2H, d, J = 8 , 4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.08 (1H, d, J = 8.1 Hz), 3.99 (2H, t, J = 6.5 Hz), 3.00 (2H, t, J = 6.5 Hz), 2.81 (2H, q, J = 7.6 Hz), 1.36 (12H, s), 1.32 (3H, t, J = 7.8 Hz).

STEP 2. 2- {4-1,2-Ethyl-5- (5-pyrimidinyl) -1 / - / - benzimidazole-1-illphenyl) ethanol

Saturated aqueous solution of NaHCO ₃ (1.2 ml) and Pd (PPh ₃ ) ₄ (60 mg, 0.05 mmol) were added to a solution of 2- {4- [2-ethyl-5- (4, 4,5,5, tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / - / - benzimidazol-1-yl] phenyl} ethanol (step 1, 100 mg, 0.26 mmol) and 5- bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml). This mixture was stirred at 70 ° C for 17 hours. The reaction mixture was diluted with water and extracted with CH ₂ CI ₂ (3x10 ml). The organic layer was dried (MgSO ₄ ) and concentrated to provide light brown oil. This mixture was purified by preparative TLC over SiO ₂ (CH ₂ Cl2 / methanol = 10/1) to provide 45 mg (50%) of the title compound.

MS (IE) m / z 344 (M) ⁺ .

¹ H NMR (CDCI ₃ ) δ: 9.19 (1H. S). 9.00 (2H, s), 7.99 (1H, s), 7.49 (2H, d, J = 8.2 Hz), 7.31-7.42 (3H, m), 7.23 (1H , d, J = 8.4 Hz), 4.00 (2H, q, J = 6.1 Hz), 3.02 (2H, t, J = 6.4 Hz), 2.83 (2H, q , J = 7.6 Hz), 1.39 (3H, t, J = 7.6 Hz).

STEP 3. 2-f4- [2-ethyl-5- (5-pyrimidinyl) -1 / - / - benzimidazole-1-illphenylethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-5- (5-pyrimidinyl) -1 Hbenzimidazol-1-yl] phenyl} ethanol (step 2 ).

MS (IED) m / z 542 [M + H] ⁺ , 540 [MH] '.

¹ H NMR (CDCIs) δ: 9.20 (1H, s), 8.97 (2H, s), 7.30-7.42 (4H,

436/451

m), 7.24 (2H, d,> 8.2 Hz), 7.14 (2H, d,> 8.2 Hz), 4.41 (2H, t,> 6.4 Hz), 3, 03 (2H, t,> 6.1 Hz), 2.89 (2H, q,> 7.4 Hz), 2.43 (3H, s), 1.34 (3H, t,> 7.4 Hz ).

EXAMPLE 359 (2- {4-1,2-ETHYL-5- (4-PYRIMIDINID-1H-BENZIMfDAZOL-1-IL1FENIDETYL) 4-METHYLENIDSULFONYL CARBAMATE

STEP 1. 2- {4-1,2-Ethyl-5- (4-pyridinyl) -1 / - / - benzimidazol-1-illphenyl) ethanol

The title compound was prepared according to the procedure described in step 1 of Example 358 from 4-bromopyridine hydrochloride (step 2).

MS (IE) m / z 343 (M) ⁺ .

¹ H NMR (CDCIa) δ: 8.66 (2H, d, J = 6.1 Hz), 8.07 (1H, d, J = 1.2 Hz), 7.57 (2H, d, J = 6.1 Hz), 7.45-7.52 (3H, m), 7.34 (2H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.4 Hz ), 4.00 (2H, s lg.), 3.03 (2H, t, J = 6.6 Hz), 2.83 (2H, q, J = 7.4 Hz), 1.39 (3H , t, J = 7.4 Hz).

STEP 2. 2- {4- [2-ethyl-5- (4-pyridinyl) -1H-benzimidazol-1-yl1phenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-5- (4-pyridinyl) -1 / - / - benzimidazol-1-yl] phenyl} ethanol (step 1).

MS (IED) m / z 541 [M + H] ⁺ , 539 [MH].

¹ H NMR (CDCI ₃ ) δ: 8.52 (2H, d,> 5.8 Hz), 8.00 (1H, s), 7.94 (2H, d,> 8.1 Hz), 7 , 48 (2H, d,> 5.8 Hz), 7.23-7.40 (5H, m), 7.20 (2H, d,> 8.1 Hz), 7.00 (2H, d, > 8.2 Hz), 4.41 (2H, t,> 5.8 Hz), 3.02 (2H, t,> 5.8 Hz), 2.76 (2H, q,> 7.4 Hz ), 2.39 (3H, s), 1.32 (3H, t,> 7.4 Hz).

EXAMPLE 360 (2- {4- [2-ETHYL-5- (3PYRIDINID-1H-BENZIMIDAZOL-1-IL1FENIDETHYL 4-METHYLFENIDSULFONYL CARBAMATE)

STEP 1. 2- (4- [2-Ethyl-5- (3-pyridinyl) -1H-benzimidazole-1-infenyl) ethanol

The title compound was prepared according to the procedure 437/451 as described in step 1 of Example 358 from 3-bromopyridine.

MS (IE) m / z 343 (M) ⁺ .

¹ H NMR (CDCb) δ: 8.91 (1H, d, J = 1.8 Hz), 8.55-8.61 (1H, m), 8.00 (1H, s), 7.90 -7.97 (1H, m), 7.48 (2H, d, J = 8.2 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.4 Hz), 4.00 (2H, m), 3.02 (2H, t, J = 6.5 Hz), 2 , 83 (2H, q, J = 7.6 Hz), 1.92 (1H, s), 1.39 (3H, t, J = 7.6 Hz).

STEP 2. 2- {4-r2-ethyl-5- (3-pyridinyl) -1 / 7-benzimidazole · 1 -illphenyljetyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-5- (3-pyridinyl) -1 Hbenzimidazol-1-yl] phenyl} ethanol (step 1 ).

MS (IED) m / z 541 [M + H] ⁺ , 539 [MH] “.

¹ H NMR (CDCI ₃ ) 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 = 8.2 Hz), 7.00 (1H, d, J = 8.2 Hz), 4 , 42 (2H, s lg.), 3.01 (2H, s lg.), 2.74 (2H, q,> 7.4 Hz), 2.43 (3H, s), 1.31 (3H , t,> 7.4 Hz).

EXAMPLE 361 (2- (4- [2-ETHYL-5-2-PYRIDINID-1H-BENZIMIDAZQL-1-IL1-PHENYLJETILLA 4-METHYLIDSIDSULFONYL CARBAMATE)

STEP 1. 2- {4-r2-Ethyl-5- (2-pyridinyl) -1A / -benzimidazole-1-iHphenyl} ethanol

The title compound was prepared according to the procedure described in step 1 of Example 358 from 2-bromopyridine.

MS (IE) m / z 343 (M) ⁺ .

¹ H NMR (CDCb) δ: 8.70 (1H, dd, J = 1.5, 5.3 Hz), 8.32 (1H, d, J = 1.5 Hz), 8.00 (1H , dd, J = 1.5, 8.4 Hz), 7.76-7.80 (2H, m), 7.48 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.16-7.23 (2H, m), 3.93 ^, 05 (2H, m), 3.01 (2H, t, J = 6.6 Hz) , 2.83 (2H, q, J = 7.6 Hz), 1.91 (1H, s), 1.38 (3H, t, J = 7.6 Hz).

STEP 2. 2- {4-Γ2-θΐίΙ-5- (2pyridinyl) -1 / 7-benzimidazole-1-iljfen iljeti (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-5- (2-pyridinyl) -1 / 7-benzi438 / 451 midazol-1-yl] phenyl} ethanol (step 1).

MS (IED) m / z 541 [M + Hf, 539 [M-H].

¹ H NMR (CDCI ₃ ) δ: 8.68 (1H, d, J = 4.6 Hz), 8.31 (1H, s), 7.887.98 (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 = 6.3 Hz), 2 , 90 (2H, t, J = 6.4 Hz), 2.73 (2H, q, J = 7.6 Hz), 2.36 (3H, s), 1.28 (3H, t, J = 7.6 Hz).

EXAMPLE 362 (2-f4- [2-ETHYL-5- (4PYRIDINYL) -1 / 7-BENZIMIDAZOL-1-IL1FEN1DETHIL 4-METHYLFENIDSULFONYL CARBAMATE

STEP 1. 2- (4- [2-Eti 1-5- (1-methyl-1/7-pyrazol-4-yl) -1F / -benzim idazol1-yl1phenyl) ethanol

The title compound was prepared according to the procedure described in step 1 of Example 358 from 4-bromo-1-methyl-1/7-pyrazole (Huettel et al., LiebigsAnn. Chem., 1955, 593, 179).

MS (IE) m / z 343 (Mf.

¹ H NMR (CDCb) δ: 7.86 (1H, s), 7.78 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.28-7.35 (3H, m), 7.09 (2H, d, J = 8.2 Hz), 3.99 (2H, m), 3.01 (2H, t, J = 6.4 Hz), 2.81 (2H, q, J = 7.6 Hz), 1.36 (3H, t, J = 7.6 Hz).

STEP 2. 2- (4-1,2-ethyl-5- (1-methyl-1 / - / - pyrazol-4-yl) -1 / - / - benzimidazol-1-yl] phenyljet (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3 from 2- {4- [2-ethyl-5- (1-methyl-1 / - / - pyrazol ~ 4-yl) -1 Hbenzimidazole -1-yl] phenyl} ethanol (step 1).

MS (IED) m / z 544 [Μ + H f, 542 [Μ - H] '.

¹ H NMR (CDCI ₃ ) 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 = 7.7 Hz), 4.39 (2H, t, J = 6.0 Hz), 3.97 (3H, s), 3.02 (2H, q, J = 6.3 Hz), 2.78 (2H, q, J = 7.4 Hz), 2.44 (3H, s), 1.35 (3H, t, J = 7.4 Hz).

EXAMPLE 363 (2- (4- [6-CHLORO-2 [3-OXO-3- [1-PIRROLIDINlL) PROPILT5- (TRIFLUOROMETID-1/7-BENZIMIDAZOL-1-IL1FENIDENETHIL 4-METHYLFENIDSULFONYL CARBAMATE)

439/451

The title compound was prepared according to the procedure described in Example 339 from 2- (4 - {[2-amino-5-chloro-4 (trifiuoromethyl) phenyl] amino} phenyl) ethyl acetate (Example 339 , step 2) and 4-oxo-4 (1-pyrrolidinyl) butanoic acid (McCasland; Proskow, J. Org. Chem., 1957, 22, 122).

M.p .: 98-105 ° C.

IV (KBr) v: 2875, 1747, 1624, 1517, 1400, 1346, 1130, 1085 cm ^-1 .

MS (IED) m / z: 663 (MH ⁺ ), 661 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 8.08 (1H, s), 7.92 (2H, d, J = 8.2 Hz), 7,227.36 (7H, m), 4.38 (2H, t, J = 6.6 Hz), 3.49 (2H, t, J = 6.8 Hz), 3.43 (2H, t, J = 6.8 Hz), 2.97-3.07 (4H, m), 2.88 (2H, m), 2.44 (3H, s), 1.94-1.98 (2H, m), 1.821.86 (2H, m).

EXAMPLE 364 (2- {4-r6-CHLORO-2 [3-OXO-3- (1-PIPERIDINYL) PROPIL1-5- (TRIFLUOROMETID-1/7-BENZIMIDAZOL-1-IL1FENIL1ETYL) 4-METHYLENIDSULFONYL CARBAMATE

The title compound was prepared according to the procedure described in Example 339 from 2- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) ethyl 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).

M.:210°C.

IV (KBr) v: 1753, 1649, 1515, 1433, 1406, 1366, 1161, 1118,

1091 cm ¹ .

MS (IED) m / z: 677 (MH ⁺ ), 675 ([MH]).

¹ H NMR (CDCl ₃ ) δ: 8.14 (1H, s), 7.78 (2H, d, J = 8.4 Hz), 7,477.56 (4H, m), 7.42 (2H, d, J = 8.4 Hz), 7.31 (1H, s), 4.29 (2H, t, J = 6.6 Hz), 3.37-3.40 (4H, m), 2, 92-2.99 (6H, m), 2.36 (3H, s), 1.50-1.56 (4H, m), 1,351.36 (2H, m).

EXAMPLE 365 (2- {4- [6-CHLORO-2í3- (2-OXO-1-PIRROLIDINIL) PROPIL1-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL1FENIDETHIL (4-METHYLFENIDSULFONYLCARBAMATE)

440/451

The title compound was prepared according to the procedure described in Example 339 from 2- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate (Example 339 , step 2) and 4- (2-oxo1-pyrrolidinyl) butanoic acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, J. Heterocycf. Chem., 1982, 19, 1465) .

M.p .: 85-90 ° C.

IV (KBr) v: 1745, 1624, 1517, 1433, 1348, 1299, 1161, 1130,

1085 cm ¹ .

MS (IED) m / z: 663 (MH ⁺ ), 661 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 8.09 (1H, s), 7.91 (2H, d, J = 8.5 Hz), 7,197.33 (7H, m), 4.42 (2H, t, J = 6.0 Hz), 3.38 (2H, t, J = 7.0 Hz), 3.27 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 6.0 Hz), 2.70-2.75 (2H, m), 2.42 (3H, s), 2.37-2.40 (2H, m), 1.93-2.04 (4H, m).

EXAMPLE 366 (4-METHYLPHENYL) 2- {4-r6-CHLORINE-2'3- (2-OXO-1-PIPERIDINYL) PROPIL] -5- (TRIFLUOROMETHYL) -1 / 7-BENZIMIDAZOL-1-IL1FENIL) ETHYL

The title compound was prepared according to the procedure described in Example 339 from 2- (4 - {[2-amino-5-chloro-4 (trifluoromethyl) phenyl] amino} phenyl) ethyl acetate (Example 339 , step 2) and 4- (2-oxo1-piperidinyl) butanoic acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, J. Heterocycf. Chem., 1982, 19, 1465) .

M.p .: 98-105 ° C.

IV (KBr) v: 1745, 1618, 1433, 1348, 1301, 1230, 1161, 1130,

1085 cm ¹ .

MS (IED) m / z: 677 (MH ⁺ ), 675 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 8.08 (1H, s), 7.89 (2H, d, J = 8.0 Hz), 7.167.29 (7H, m), 4.40 (2H, t, J = 5.9 Hz), 3.35 (2H, t, J = 7.2 Hz), 3.25-3.27 (2H, m), 2.98 (2H, t, J = 5 , 9 Hz), 2.73 (2H, t, J = 7.2 Hz), 2.35-2.40 (5H, m), 1,921.99 (2H, m), 1.73-1.76 (4H, m).

EXAMPLE 367 / V - {[(2-f4-r6-CHLORINE-2- (1-HiDROXIETYL) -5- (TRlFLUOROMETYL) 441/451

1-benzimidazql-1-ilylphenyl) ethyl) aminoylcarbonyl} -4-methylbenzenesulfonamide

STEP 1. 1- [6-Chloro-144- (2-chloroethyl) phenyl1-54trifluorOmethyl) -1 / - / benzimidazole-2-iriethanol

The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5, from 4 chloro - / \ / ² - [4- (2-chloroethyl) phenyl] -5- ( trifluoromethyl) -1,2-benzenediamine and lactic acid.

¹ H NMR (CDCI ₃ ) δ: 8.14 (1H, s), 7.49 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz) , 4.90-4.96 (1H, m), 3.83 (2H, t, J = 6.8 Hz), 3.75 (1H, d, J = 8.1 Hz), 3.22 ( 2H, t, J = 6.8 Hz), 1.57 (3H, d, J = 6.9 Hz).

STEP 2. / V - {[(2- {4-r6-Chloro-2- (1-hydroxoethyl) -5- (trifluoromethyl) 1 / - / - benzimidazol-1-illphenyl} ethyl) amino1carbonyl} -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 1, from 1- [6-chloro-1- [4- (2-chloroethyl) phenyl] -5 (trifluoromethyl) -1 / 7-benzimidazole -2-yl] ethanol (step 1).

M.:220°C.

IV (KBr) v: 3348, 1706, 1533, 1519, 1434, 1344, 1328, 1126 cm ^-1 .

MS (IED) m / z: 581 (MH ⁺ ), 579 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 8.23 (1H, s), 7.78 (2H, d, J = 8.1 Hz), 7.327.50 (7H, m), 6.58 (1H, s lg.), 5.66 (1H, s lg.), 4.78 (1H, s lg.), 3.30-3.32 (2H, m), 2.79-2.82 (2H, m), 2.34 (3H, s), 1.51 (3H, d, J = 6.8 Hz).

EXAMPLE 368 / V-U (2- {4-r2-ACETYL-6-CHLORINE-5- (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL | FENlL) ETHYL) AMINOlCARBONlL) -4METHYLBENZENOSULFONAMIDE

STEP 1. 1 -Í6-Chloro-1 -r4- (2-chloroethyl) phenyl1-5- (trifluoromethyl) -1 / 7benzimidazole-2-illethanone

MnO ₂ (2.7 g, 32 mmol) was added to a solution of 1- [6 chloro-1 [4- (2-chloroethyl) phenyl] -5- (trifluoromethyl) -1 / - / - benzimidazole-2 -yl] ethanol (Example 367, step 1, 400 mg, 1 mmol) in CH ₂ CI ₂ . The mixture was stirred at room temperature for 24 hours. The product was purified directly

442/451 by flash column chromatography of the mixture, eluting with hexane / ethyl acetate (4: 1), to provide 350 mg (88%) of the title compound as white solids.

¹ H NMR (CDCI ₃ ) δ: 8.31 (1H, s), 7.44 (2H, d, J = 8.1 Hz), 7,237.28 (3H, m), 3.82 (2H, t, J = 7.3 Hz), 3.21 (2H, t, J = 7.3 Hz), 2.80 (3H, s).

STEP 2. / V- {r (2- (4- [2-Acetyl-6-chloro-5- [trifluoromethyl) -1 / 7-benzimidazol-1-iHfeniDetyl) amino1carbonyl} -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 1, from 1- [6-chloro-1- [4- (2-chloroethyl) phenyl] -5 (trifluoromethyl) -1H-benzimidazole-2 -il] ethanone (step 1).

M.p .: 225 ° C.

IV (KBr) v: 3350, 1697, 1519, 1326, 1294, 1134, 1083 cm ^-1 .

MS (IED) m / z: 579 (MH ⁺ ), 577 ([MH] ').

¹ H NMR (CDCIs) δ: 8.31 (1H, s), 7.74 (2H, d, J = 8.4 Hz), 7,217.39 (7H, m), 6.70 (1H, s lg.), 3.55-3.62 (2H, m), 2.94 (2H, t, J = 7.2 Hz), 2.81 (3H, s), 2.40 (3H, s) .

EXAMPLE 369

A / - (f (2- (4-í6-CHLORINE-2- (1 -Η IDROXY-1 -METHYLETH L) -5- (TRI FLUOROMETHIL) -1H-BENZIMIDAZOL-1-IL1FENYL) ETHYL) AMINO1CARBONILM-METHYLBENZENOSULFONAMIDE

STEP 1. 2-r6-Chloro-1-r4- (2-chloroethyl) phenyl1-5- (trifluoromethyl) -1 / - / benzimidazole-2-ill-2-propanol

The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5, from 2-hydroxy-isobutyric acid and 4-chloro- / V ² - [4- (2- chloroethyl) phenyl] -5- (trifluoromethyl) -1,2 benzenediamine.

¹ H NMR (CDCIs) δ: 8.13 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.00 (1H, s), 3.84 (2H, t, J = 7.0 Hz), 3.38 (1H, s), 3.22 (2H, t, J = 7.00 Hz), 1.53 (6H, s).

STEP 2. A / Tf (2-f4-r6-Chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1H-benzimidazole-1-iHphenyl) ethyl) amino1carbonyl) -4-methylbenzenesulfonamide

443/451

The title compound was prepared according to the procedure described in Example 1, from 2- [6-chloro-1- [4- (2-chloroethyl) phenyl] -5 (trifluoromethyl) -1 / - / - benzimidazol-2-yl] -2-propanol (step 1).

¹ H NMR (CDCI ₃ ) δ: 8.13 (1H, s), 7.73 (2H, d, J = 8.2 Hz), 7.307.39 (6H, m), 6.99 (1H, s), 6.68 (1H, s lg.), 3.55-3.66 (2H, m), 2.95 (2H, t, J = 6.6 Hz), 2.42 (3H, s ), 1.13 (6H, d, J = 6.2 Hz).

EXAMPLE 370

MONO P-TOLUENOSULPHONATE OF A / 4í (2-f4-r6-CHLORO-2 (1-HYDROXY-1-METI LETIL) -5- (TRIFLUOROMETHIL) -1 / - / - - BENZIMIDAZOL-1ILLFENIL) ETIL) AMINO1CARBONIL) -4 -METHYLBENZENOSULPHONAMIDE

The title compound was prepared according to the procedure described in Example 231 from A / - {[(2- {4- [6-chloro-2- (1-hydroxy-1methylethyl) -5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl} ethyl) amino] carbonyl} -4methylbenzenesulfonamide (Example 369).

M.p .: 146-150 ° C.

IV (KBr) v: 1685, 1515, 1448, 1340, 1124, 1089, 1010 cm ^-1 .

EXAMPLE 371 / V-f1- [6-CHLORINE-1- (4- {2-r (U (4-METHYLphenyl) SULFONlL1-AMINO) CARBONYL) AMINO1ETHYL) PHENYL) -5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-2 -IL1ETIDACETAM1DA

STEP 1. 1,1-Dimethylite 1-r6-Chloro-1- [4- (2-hydroxyethyl) phenyl1-5- (trifluoromethyl) -1 / 7benzimidazole-2-illethylcarbamate

The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5, from N (tert-butoxycarbonyl) -alanine and 2- (4 - {[2.amino -5-chloro-4- (trifluoromethyl) phenyl] amino} phenyl) ethyl (Example 339, step 2).

MS (IE) m / z: 483 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.12 (1H, s), 7.50 (2H, d, J = 8.6 Hz), 7,357.37 (2H, m), 7.24 (1H, s), 5.46 (1H, s lg.), 4.92-4.98 (1H, m), 3.95-4.02 (2H, m), 3.00 (2H, t, J = 6.5 Hz), 1.43 (3H, s), 1.40 (9H, s).

STEP 2. 1-i6-Chloro-t- (4- {2-f (U (4-methylphenyl) sulfoninamino) carbonyl) amino1ethyl} phenyl) -5- (trifluoromethyl) -1 / 7-benzimidazole-2-inethylcarbamate

444/451

1,1-dimethylethyl

The title compound was prepared according to the procedure described in Example 1, from 1- [6-chloro-1- [4- (2-hydroxyethyl) phenyl] -5 (trifluoromethyl) -1W-benzimidazole-2 -il] 1,1-dimethylethyl ethyl carbamate ( ¹ H DRMN step (CDCl ₃ ) δ: 8.13 (1H, s), 7.79 (2H, d, J = 8.2 Hz), 7,157.35 (7H, m), 6.50 (1H, s lg.), 5.55 (1H, d, J = 8.6 Hz), 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 3. Λ / - (Γ (2- (4-Γ2- (1-Aminoethyl) -6-chloro-5- (trif [uoromethyl) -1 Hbenzimidazol-1-yl1phenyl) ethyl) aminolcarbonyl) -4-methylbenzenesulfonamide

Trifluoroacetic acid (1 ml) was added to a solution of 1- [6chloro-1- (4- {2 - [({[(4-methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -5- 1,1-dimethylethyl (trifluoromethyl) -1H-benzimidazol-2-yl] ethylcarbamate (step 2, 190 mg, 0.28 mmol) in CH ₂ CI ₂ (2 ml), and stirred at room temperature for 2 hours. Water (10 ml) was added to the mixture, and extracted with CH2 Cl2 (20 ml). The organic layer was washed with brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with CH ₂ CI ₂ / MeOH (10: 1/5: 1) to provide 160 mg (99%) of the title compound under the form of white solids.

MS (IED) m / z: 580 (MH ⁺ ), 578 ([MH]).

STEP 4. / V- (1-í6-Chloro-1- (4- {2-í (([(4-methylphenyl) sulfonyl1amino) carbonyl) amino] ethyl) phenyl) -5- (trifluoromethyl) -1 / - / -benzimidazole-2-inethyl} acetarnide

Acetyl chloride (0.01 ml, 0.18 mmol) was added to a mixture of / V - {[(2- {4 ~ [2- (1-aminoethyl) -6-chloro-5- (trifluoromethyl) -1H-benzimidazol-1yl] phenyl} ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (step 3, 100 mg, 0.17 mmol) in CH ₂ CI ₂ (12 ml), and stirred at room temperature for 5 hours. Water (10 ml) was added to the mixture, and it was extracted with CH2 Cl2 (20 ml). The organic layer was washed with brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with ΟΗ ₂ 0 ₂ / ΜθΟΗ (10: 1) to provide 59 mg (53%) of the title compound as solids.

445/451 whites.

MS (IED) m / z: 622 (MH ⁺ ), 620 ([MH]).

¹ H NMR (CDCl 3) δ: 8.14 (1H, s), 7.80 (2H, d, J = 8.2 Hz), 7,257.40 (7H, m), 7.00 (1H, s lg.), 6.03 (1H, s lg.), 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 = 6.9 Hz).

EXAMPLE 372

A / -f1-r6-CHLORINE-1- (4-f2 [(ff (4-METHYLPHYL) SULPHONYLAMINE) CARBONYL) AMINOLETYL) -PHENYL) -5 (TRIFLUOROMETHIL) -1H-BENZIMIDAZOL-2-ILLETH ) -ACETAMIDE

The title compound was prepared according to the procedure described in Example 231, from / V- {1- [6-chloro-1- (4- {2 - [({[(4methylphenyl) sulfonyl] amino} carbonyl) amino] ethyl} phenyl) -5- (trifluoromethyl) -1 / 7benzimidazol-2-yl] ethyl} acetamide (Example 371).

M.p .: 135-142 ° C.

IV (KBr) v: 3267, 1676, 1517, 1456, 1236, 1163, 1122, 1010 cm ¹ .

EXAMPLE 373 (2- {4- [2-ETlL-5 (PHENYLCARBONID-1 / - / - BENZIMIDAZOL-1-IL1FENIDETHIL 4-METHYLFENIDSULFONYL

STEP 1. (3Amino-4- {f4- (2-hydroxyethyl) phenyl1amino} phenyl) (phenyl) methanone

The title compound was prepared according to the procedure described in Example 78, from (4-chloro-3-nitrophenyl) (phenyl) methanone.

¹ H NMR (CDCI ₃ ) δ: 7.77 (2H, d, J = 6.9 Hz), 7.42-7.55 (3H, m), 7.36 (1H, S), 7, 14-7.25 (4H, m), 6.97 (2H, d, J = 8.5 Hz), 5.64 (1H, s), 3,833.89 (2H, m), 3.64 (2H , s lg.), 2.84 (2H, t, J = 6.6 Hz), 1.47 (1H, s lg.).

STEP 2. (2-Ethyl-1-f4- (2-hydroxyethyl) phenill-1H-benzimidazol-5-yl) (phenyl) methanone

The title compound was prepared according to the procedure described in Example 1, from (3-amino-4 - {[4- (2-hydroxyethyl) phenyl] amino} phenyl) - (phenyl) meta nona (step 1).

¹ H NMR (CDCI ₃ ) 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 = 8.4 Hz), 3.98-4.03 (2H, m), 3.02

446/451 (2Η, t, J = 6.3 Hz), 2.81 (2H, q, J = 7.6 Hz), 1.89 (1H, t, J = 5.4 Hz), 1, 37 (3H, t, J = 7.6 Hz).

STEP 3. 2- {4- [2-ethyl-5- (phenylcarbonyl) -1B-benzimidazole ~ 1-infenyl) ethyl (4-methylphenyl) sulfonylcarbamate

The title compound was prepared according to the procedure described in Example 3, from {2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1 / 7benzimidazol-5-yl} (phenyl) methanone (step 2).

MS (IED) m / z: 568 (MH ⁺ ), 566 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 8.21 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7,797.84 (3H, m), 7.44-7, 58 (3H, m), 7.23-7.36 (6H, m), 7.15 (1H, d, J = 8.6 Hz),

4.37 (2H, t, J = 6.6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.79 (2H, q, J = 7.6 Hz), 2, 42 (3H, s), 1.34 (3H, t, J = 7.6 Hz).

EXAMPLE 374

MONO P-TOLUENOSULPHONATE OF 2- {4- [2-ETHYL-5- (PHENYLCARBONYL) -1P-BENZIMIDAZOL-1-IL1-PHENYL) ETHYL

The title compound was prepared according to the procedure described in Example 231, from 2 {4- [2-ethyl-5- (phenylcarbonyl) -1 H-benzimidazole-1-yl (4-methylphenyl) sulfonylcarbamate) ] phenyljetyl (Example 373).

M.p .: 102-107 ° C.

IV (KBr) v: 1747, 1654, 1517, 1448, 1033, 1008 cm ^-1 .

EXAMPLE 375 / V-f [(2-f4- [2-ETYL-5- (PHENYLCARBONYL) -1 / 7-BENZIMIDAZOL-1YLFENYL) ETlL) AMINO] CARBONYL) -4-METHYLBENZENOSULFONAMIDE

STEP 1. A / -n (2-f4-r2-Ethyl-5- (phenylcarbonyl) -1P-benzimidazol-1yl] phenyl) ethyl) amino] carbonyl) -4-methylbenzenesulfonamide

The title compound was prepared according to the procedure described in Example 78, from {2-ethyl-1- [4- (2-hydroxyethyl) phenyl] -1Pbenzimidazol-5-yl} (phenyl) methanone (Example 373, step 2).

MS (IED) m / z: 567 (MH ⁺ ), 565 ([MH] ').

¹ H NMR (CDCI ₃ ) δ: 8.20 (1H, s), 7.72-7.83 (5H, m), 7.28-7.60 (9H, m), 7.15 (1H , d, J = 8.6 Hz), 6.74 (1H, s lg.), 3.59 (2H, m), 2.94 (2H, t,

447/451

J = 7.1 Hz), 2.82 (2H, q, J = 7.4 Hz), 2.39 (3H, s), 1.35 (3H, t, J = 7.4 Hz).

EXAMPLE 376

A / -ph (2-f4-F2-ETYL-5- (PHENYLCARBONYL) -1H-BENZIMIDAZOL-1-IL1FENIDETYL) AMINO1-CARBONYL | 4-METHYLBENZENOSULFONAMIDE MONO P-TOLUENOSULPHONATE

The title compound was prepared according to the procedure described in Example 231, from / V - {[(2- {4- [2-ethyl-5- (phenylcarbonyl) -1 Hbenzimidazol-1-yl] phenyl } ethyl) amino] carbonyl} -4-methylbenzenesulfonamide (Example 375).

M.p .: 198 ° C.

IV (KBr) v: 1697, 1660, 1596, 1519, 1446, 1319, 1035 cm ^-1 .

EXAMPLE 377 (2- {4-1,2-H- (ACETYLAMINO) -1-METHYLETHYL-6-CHLORO-5- (TRIFLUOROMETHYL) -1H-BENZIMIDAZOL-1-IL1-PHENIDETYL

STEP 1. 2- {4- [6-chloro-2- (1-chloro-1-methylethyl) -5 (trifluoromethyl) -1 / - / - benzimidazole-1-illfenillethyl acetate

Thionyl chloride (0.07 ml, 1.02 mmol) was added to a solution of 2- {4- [6-chloro-2- (1-hydroxy-1-methylethyl) -5- (trifluoromethyl) -1 Hbenzimidazol-1-yl] phenyl} ethyl (300 mg, 0.68 mmol) in dichloromethane (15 ml), and the reaction mixture was heated to reflux overnight. The reaction mixture was poured into water (10 ml), and the reaction mixture was extracted with dichloromethane (30 ml). The organic layer was washed with brine (10 ml), then dried (Na ₂ SO ₄ ). The solvent was removed to provide 273 mg (87%) of the title compound as white amorphous.

MS (IE) m / z: 458 (M ⁺ ).

STEP 2. 24442- (1-azido-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1 H-benzimidazole-1 -illphenylethyl acetate

A mixture of 2- {4- [6-chloro-2- (1-chloro-1methylethyl) -5- (trifluoromethyl) -1 / - / - benzimidazol-1-yl] phenyl} ethyl acetate (step 1.273 mg, 0.68 mmol), sodium azide (88 mg, 1.36 mmol), Kl (112 mg, 0.68 mmol) in DMF (8 mL) under a nitrogen atmosphere at room temperature du448 / 451 for 5.5 hours. The reaction mixture was poured into water (5 ml) and the aqueous mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with hexane / ethyl acetate (2/1), to provide 133 mg (42%) of the title compound as a yellow oil.

MS (IE) m / z: 465 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.17 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz) 7.02 (1H, s), 4.39 (2H, t, J = 7.0 Hz), 3.09 (2H, t, J = 7.0 Hz), 2.08 (3H, s), 1.70 (6H, s).

STEP 3. 2-F4-r2- (1-amino-1-methylethyl) -6-chloro-5- (trifluoromethyl) -1 / - / - benzimidazole-1-ylIphenyldetyl acetate

A mixture of 2- {4- [2- (1-azido-1-methylethyl) 6-chloro-5- (trifluoromethyl) -1 / 7-benzimidazol-1-II] phenyl} ethyl acetate was stirred (step 2, 133 mg, 0.28 mmol) and Lindlar catalyst (13 mg) in methanol (5 ml) under H ₂ atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration through a pad of Celite, and the filtrates were concentrated to provide the title compound as a yellow oil (121 mg, 98%).

MS (IE) m / z: 439 (M ⁺ ).

STEP 4. 2- {4-r241- (acetylamino) -1-methylethyl-6-chloro5- (trifluoromethyl) -1 / - / - benzimidazole-1 -illphenylethyl acetate

Acetyl chloride (0.02 ml, 0.3 mmol) was added to a 2- {4- [2- (1-amino-1-methylethyl) -6-chloro-5- (trifluoromethyl) acetate solution ) -17 / benzimidazol-1-yl] phenyl} ethyl (step 3, 121 mg, 0.27 mmol), in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 7 hours. Water (5 ml) was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by flash column chromatography, eluting with CH ₂ CI ₂ / methanol (10/1), to provide 76 mg (57%) of the title compound as of white amorphous.

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MS (IE) m / z: 481 (M ⁺ ).

¹ H NMR (CDCI ₃ ) δ: 8.14 (1H, s), 7.42 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.4 Hz) 6.91 (1H, s), 4.38 (2H, t, J = 6.6 Hz), 3.07 (2H, t, J = 6.6 Hz), 2.06 (3H, s), 1.75 (6H, s), 1.68 (3H, s).

STEP 5. A / - (1- [6-Chloro-1- [4- (2-hydroxyethyl) phenyl1-5- (trifluoromethyl) 1 H-benzimidazol-2-yl] 1-methylethylacetamide

The title compound was prepared according to the procedure described in step 6 of Example 1, from 2- {4- [2- [1 (acetylamino) -1-methylethyl] -6-chloro-5- acetate (trifluoromethyl) -1H-benzimidazol-1-yl] phenyl} ethyl (step 4).

¹ H NMR (CDCI ₃ ) δ: 8.13 (1H, s), 7.44 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz) , 6.92 (1H, s), 5.95 (1H, s lg.), 3.98 (2H, t, J = 6.4 Hz), 2.99 (2H, t, J = 6.4 Hz), 1.68-1.75 (9H, m).

STEP 6. 2-f4- [2- [1- (acetyl · amino) -1-methylethin-6-chloro-5- (trifluoromethyl) -1 / - / - benzimidazole-1-yl (4-methylphenyl) sulfonylcarbamate ] phenyl} ethyl

The title compound was prepared according to the procedure described in Example 3, from / V- {1- [6-chloro-1- [4- (2-hydroxyethyl) phenyl] -5 (trifluoromethyl) -1 / - / - benzimidazol-2-yl] -1-methylethyl} acetamide (step 5).

MS (IED) m / z: 637 (MH ⁺ ), 635 ([MH] ').

¹ H NMR (CD ₃ OD) δ: 8.04 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz ), 7.34 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 6.93 (1H, s), 4.32 (2H, t , J = 6.4 Hz), 3.02 (2H, t, J = 6.4 Hz), 2.37 (3H, s), 1.75 (6H, s), 1.53 (3H, s ).

EXAMPLE 378

2- {4- [2- [1- (ACETYLAMINE) -1-Methylethyl] -6-CHLORO-5 (TRIFLUOROMETHIL) -1P-BENZIMIDAZOL-1-IL1FENIL) E-P-TOLUENOSULPHONATE

The title compound was prepared according to the procedure described in Example 231, from A / - {[(2- {4- [6-chloro-2- [1- (methyloxy) ethyl] -5 (trifluoromethyl) () -1H-benzimidazol-1-yl] phenyl} ethyl) amino] carbonylp4-methylbenzenesulfonamide (Example 377).

IV (KBr) v: 1751, 1508, 1450, 1340, 1161, 1122 cm ^-1 .

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EXAMPLE 379

6-CHLORINE-2-ETHYL-1- (4- (2-rMETHIL ((f (4-METHYLPHYL) SULFONYL1AMINO} CARBONYL) AMINOLETYL)

STEP 1. 2- (4- [5- (aminocarbonyl) -6-chloro2-ethyl-1F / -benzimidazole-1-illphenyljetyl methanesulfonate

A mixture of 6-chloro-2-ethyl-1- [4- (2-hydroxyethyl) phenyl] 1 H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol) was stirred, triethylamine (293 mg, 2.90 mmoles) and methanesulfonyl chloride (322 mg, 2.9 mmoles) in dichloromethane (20 ml) 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 (50 ml), then dried (Na2SO ₄ ). After removing the solvent, the crude product was purified by TLC with hexane / ethyl acetate (1: 1), to provide 304 mg (50%) of the title compound, as white solids.

MS (IED) m / z: 422 ([M + Hf).

¹ H NMR (CDCI ₃ ) δ: 7.54 (1H, s), 7.44 (2H, d, J = 8.3 Hz). 7.29 (2H, d, J = 8.3 Hz), 7.13 (1H, s), 3.82 (2H, t, J = 7.0 Hz), 3.19 (2H, t, J = 7.0 Hz), 2.82 (BH, s), 2.75 (2H, q, J = 7.6 Hz), 1.35 (3H, t, J = 7.6 Hz).

STEP 2. 6-Chloro-2-ethyl-1 - {4- [2- (methylamino) ethyl1phenyl} -1 A7-benzimidazole-5-carboxamide

A mixture of 2- {4- [5- (aminocarbonyl) -6-chloro-2-ethyl-1/7-benzimidazol-1-yl] phenyl} ethyl methanesulfonate (step 1, 304 mg, 0, 72 mmol), a solution of methylamino (40% in methanol, 10 ml) and water (5 ml), at 100 ° C in a sealed tube, overnight. The reaction mixture was fractionated by pouring over dichloromethane (30 ml) and water (30 ml). The organic layer was separated, and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (50 ml) and dried (Na ₂ SO ₄ ). After removing the solvent, the crude product was purified by TLC with dichloromethane / methanol (10: 1) to provide 154 mg (60%) of the title compound as yellow solids.

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¹ H NMR (CDCl 3) δ: 7.54 (1H, s), 7.43 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.0 Hz), 2.82 (6H, s), 2.75 (2H, q, J = 7.6 Hz), 1.34 (2H, t, J = 7.6 Hz).

STEP 3. 6-Chloro-2-ethyl-1- (4- {2- [metiK {[((4-methylphenyl) sulfonill 5 amino) carbonyl) amino] ethyl} phenyl) -1B-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} -1B-benzimidazole- 5-carboxamide (step 2).

MS (IED) m / z: 554 (MH ⁺ ), 552 ([MH]).

¹ H NMR (CDCI ₃ ) δ: 8.09 (1H, s), 7.97-7.94 (2H, d, J = 8.4 Hz),

7.40-7.31 (4H, m), 7.16-7.13 (2H, d, J = 8.4 Hz), 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 = 7.6 Hz), 2, 42 (3H, s), 1.34-1.28 (3H, t, J = 7.6 Hz).

EXAMPLE 380

SODIUM SALT OF 6-CHLORINE-2-ETHYL-1- (4- {2- [METHYL ({r (4-MET1LFENIL) SULFONYL1AMINO) CARBONYL) AMINO1ETYL) PHENYL) -1B-BENZIMlDAZOL-5-CARBOXAMlDA

The title compound was prepared according to the procedure described in Example 2, from 6-chloro-2-ethyl-1- (4- {2- [methyl ({[(420 methylphenyl) sulfonyl] amino} carbonyl ) amino] ethyl} phenyl) -1 / 7-benzimidazole-5-carboxamide (Example 379).

MS (IED) m / z: 554 (MH ⁺ ), 552 ([MH]).

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Claims (5)

1. Compound, characterized by the fact that it has the formula συ or its salts in which Y ¹ , Y ² , Y ³ and Y ⁴ are selected independently from N, CH or C (L); R ¹ is ethyl; A is a benzene ring optionally substituted with up to 3 substituents, or a pyridine ring optionally substituted with up to 3 substituents, wherein said substituents are selected from halo, C _1-4 alkyl, C _1-4 alkyl substituted with halo, hydroxy, _C1-4 alkoxy, _C1-4 alkoxy substituted with halo, _C1-4 alkylthio, nitro, amino, mono- or di- (C _1-4 alkyl) amino, cyano, HO-C _1-4 alkyl , alkoxy C _1-4 -alkyl C _1-4 alkyl, C _1-4 -sulfonila, aminossulfonila, acetyl, R ³ N (R ⁴⁾ C (= O) -, HO (O =) C-, C1- 4-O (O =) C-, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) - and NH2 (HN =) C-; B is a C _2-6 alkylene, C _3-7 cycloalkylene group, C ₂₆ alkenylene or C _2-6 alkynylene group, optionally substituted with a C _1-3 alkyl group; W is NH; P is H, a protecting group, or Q ³ -OC (= O); Q ³ is a 6- to 10-membered monocyclic or bicyclic aromatic ring optionally substituted with halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, nitro, cyano, C1-4 alkylsulfonyl, C1- alkyl 4-C (= O) -, HO (O =) C- or C1-4-O (O =) C- alkyl; L is halo, _C1-4 alkyl, _C1-4 alkyl substituted with halo, hydroxy, _C1-4 alkoxy, _C1-4 alkoxy substituted with halo, _C1-4 alkylthio, nitro, amino, mono- or di- ( C _1-4 alkyl) amino, cyano, HO-C _1-4 alkyl, C _1-4 alkoxy C _1-4 -alkyl, C _1-4 alkyl -sulfonila, aminossulfonila, C _1-4 alkyl - C (= O) -, HO (O =) C-, C _1-4 alkyl O (O =) C-, C _1-4 alkylsulfonylamino, C _3-7 cycloalkyl, R ³ -C (= O) N (R ⁴ ) -, 2/2 NH ₂ (HN =) C-, R ³ N (R ⁴ ) C (= O) - or R ³ N (R ⁴ ) S (O) _m -, or two adjacent L groups optionally bond to each other forming a alkylene chain having 3 or 4 members, in which one or two carbon atoms (non-adjacent) are optionally replaced by oxygen atoms; 5 m is 0, 1 or 2; and R ³ and R ⁴ are selected independently from H and C _1-4 alkyl.