WO2002100851A2 - Thiophene derivatives as antiviral agents for flavivirus infection - Google Patents

Thiophene derivatives as antiviral agents for flavivirus infection Download PDF

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Publication number
WO2002100851A2
WO2002100851A2 PCT/CA2002/000876 CA0200876W WO02100851A2 WO 2002100851 A2 WO2002100851 A2 WO 2002100851A2 CA 0200876 W CA0200876 W CA 0200876W WO 02100851 A2 WO02100851 A2 WO 02100851A2
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WO
WIPO (PCT)
Prior art keywords
carboxylic acid
phenyl
acid compound
thiophene
amino
Prior art date
Application number
PCT/CA2002/000876
Other languages
French (fr)
Other versions
WO2002100851A3 (en
Inventor
Chun Kong Laval Chan
Jean Bédard
Sanjoy Kumar Das
Nghe Nguyen Ba
Oswy Z. Pereira
Thumkunta Jagadeeswar Reddy
M. Arshad Siddiqui
Wuyi Wang
Constantin Yannopoulos
Original Assignee
Shire Biochem Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AT02742563T priority Critical patent/ATE438637T1/en
Priority to EA200400022A priority patent/EA007484B1/en
Priority to BR0210357-5A priority patent/BR0210357A/en
Priority to MXPA03011452A priority patent/MXPA03011452A/en
Priority to JP2003503618A priority patent/JP4544857B2/en
Priority to APAP/P/2003/002932A priority patent/AP1753A/en
Priority to SK1520-2003A priority patent/SK288015B6/en
Priority to KR1020037016240A priority patent/KR100900304B1/en
Application filed by Shire Biochem Inc. filed Critical Shire Biochem Inc.
Priority to CA2450007A priority patent/CA2450007C/en
Priority to SI200230851T priority patent/SI1401825T1/en
Priority to DK02742563T priority patent/DK1401825T3/en
Priority to DE60233227T priority patent/DE60233227D1/en
Priority to AU2002344854A priority patent/AU2002344854B2/en
Priority to EP02742563A priority patent/EP1401825B1/en
Publication of WO2002100851A2 publication Critical patent/WO2002100851A2/en
Publication of WO2002100851A3 publication Critical patent/WO2002100851A3/en
Priority to NO20035485A priority patent/NO331721B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds and a method for the treatment or prevention of Flavivirus infections using novel compounds .
  • Hepatitis is a disease occurring throughout the world. It is generally of viral nature, although there are other causes known. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans are affected by hepatitis each year, and out of t ose more than 150,000 are infected with the hepatitis C virus ("HCV”) .
  • HCV hepatitis C virus
  • HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV) . HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm.
  • BVDV bovine viral diarrhea virus
  • the HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co and post-translationally by cellular and two viral proteinases into mature viral proteins (core, El, E2 , p7, NS2 , NS3 , NS4A,
  • NS4B NS5A, NS5B
  • structural proteins El and E2
  • the major glycoproteins are embedded into a viral lipid envelope and form stable heterodimers.
  • structural core protein interacts with the viral RNA genome to form the nucleocapsid.
  • the nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
  • the main source of contamination with HCV is blood.
  • the magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers dn western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors .
  • IFN- ⁇ interferon- ⁇
  • ALT alanine aminotransferase
  • RIBA ribavirin
  • the present invention provides novel compounds represented by formula I :
  • X is chosen from:
  • M is chosen from:
  • R 4 is C ⁇ g alkyl
  • R 8 is chosen from H, C ⁇ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 12 heteroaralkyl , C 6 _ 16 aralkyl; and R 15 is chosen from H or C 1 _ 6 alkyl;
  • W is chosen from O, S or NR 7 , wherein R 7 is chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 ⁇ 12 heterocycle, C 3 _ 12 heteroaralkyl , C 6 _ 16 aralkyl; and R 6 is chosen from H, C x _ 12 alkyl, C 6 _ 14 aryl or C 6 _ 15 aralkyl;
  • Y 1 is chosen from a bond, C ⁇ _ ⁇ alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl;
  • Y is chosen from COOR 16 , C0C00R 5 , P(0)OR a OR b , S(0)OR 5 , S(0) 2 OR 5 tetrazole, CON(R 9 )CH(R 5 ) COOR 5 , CONR 10 R 1X , CON(R 9 ) -S0 2 -R 5 , CONR 9 OH or halogen, wherein R g , R 5 , R 10 and R are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl, C 6.18 aralkyl; or R 10 and R 11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
  • R a and P ⁇ are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl and C 6.18 aralkyl; or R a and R ⁇ are taken together with the oxygens to form a 5 to 10 membered heterocycle;
  • R 16 is chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3.12 heterocycle, C 3.18 heteroaralkyl and C 5.18 aralkyl; provided that R 16 is other than methyl or ethyl;
  • R x is chosen from C 2 _ 12 alkyl, C 2.12 alkenyl, C 2 _ 12 alkynyl, C 6.14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl or C 6 _ 18 aralkyl;
  • R 2 is chosen from C 2 _ 12 alkyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3.12 heterocycle, C 3 . 18 heteroaralkyl, or C 6 _ 18 aralkyl;
  • R 3 is chosen from H, C x _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C s _ 14 aryl, C 3 _ 12 heterocycle, C 3.18 heteroaralkyl or C 6 _ 18 aralkyl;
  • Z is chosen from H, halogen, C h al y!; with the proviso that:
  • the compounds of the present invention are useful in therapy, particularly as antivirals .
  • a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.
  • a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a combination comprising at least one compound of formula (I) and at least one further therapeutic agent.
  • a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient .
  • Another aspect of the invention is the use of a compound according to formula (I) , for the manufacture of a medicament for the treatment of viral infections .
  • a method for inhibiting -or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula (I) .
  • compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.
  • the present invention provides novel compounds of formula (la) :
  • X is chosen from:
  • M ' is chosen from:
  • R 4 is C 1-6 alkyl
  • R 8 is chosen from H, C x _ 12 alkyl, C 2 _ 12 alkenyl, C 2.12 alkynyl, C 6 _ 14 aryl, C 3 . 12 heterocycle, C 3 _ 12 heteroaralkyl, C 6 _ 16 aralkyl; and
  • R 15 is chosen from H or C _ e alkyl
  • W is chosen from 0, S or NR 7 , wherein R 7 is chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C ' '22 2 -12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 12 heteroaralkyl, C 6 . 16 aralkyl; and R 6 is chosen from H, C x _ 12 alkyl, C e _ u aryl or C 6 _ 16 aralkyl;
  • Y 1 is chosen from a bond, C., alkyl, C , alkenyl or C 2 , alkynyl;
  • Y is chosen from C00R 16 , C0C00R 5 , P(0)0R a 0R b , S(0)0R 5 , S(0) 2 OR 5 _ tetrazole, C0N(R 9 ) CH(R 5 ) C00R 5 , CONR 10 R U , CON (R 9 ) -S0 2 -R 5 , C0NR 9 0H or halogen, wherein R 9 , R 5 , R 10 and R X1 are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2.12 alkynyl, C 3 _ 12 heterocycle, C 3.18 heteroaralkyl, C 6.18 aralkyl; or R 10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle; R a and ⁇ are each independently chosen from H, C x _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl
  • R 16 is chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3.18 heteroaralkyl and C 6 _ 18 aralkyl; provided that R 16 is other than methyl or ethyl;
  • R 1 is chosen from C 2 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 . 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl or C 6 _ 18 aralkyl;
  • R 2 is chosen from C 2 _ 12 alkyl, C 2.12 alkynyl, C ⁇ _ u aryl, C 3 _ 12 heterocycle, C 3 _ 1B heteroaralkyl, or C 6 _ 18 aralkyl;
  • R 3 is chosen from H, C H2 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl or C 6 _ 18 aralkyl;
  • Z is chosen from H, halogen, C ⁇ alkyl
  • the present invention provides novel compounds represented by formula II :
  • M is chosen from:
  • Y 1 is chosen from a bond, C x _ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl;
  • Y is chosen from COOR ls , CO-COOR 5 , P0 3 R a R b , S0 3 R 5 , tetrazole,
  • R 1 is chosen from C t _ 6 alkyl, C 2.6 alkenyl, C 2 _ 6 alkynyl, C 6 _ 12 aryl, C heterocycle, C 3 _ 10 heteroaralkyl, C aralkyl, or a halogen;
  • R 2 is chosen from C 6 _ 12 aryl, C 3 _ 10 heterocycle, C 6 _ 12 aralkyl or C 3 _ 10 heteroaralkyl;
  • R 3 is chosen from H or C _ 6 alkyl; C 6 _ 12 aralkyl or C 3.10 heteroaralkyl ;
  • R 4 is chosen from H or C 1-6 alkyl
  • R 15 is chosen from H or C x _ 6 alkyl
  • R 2 is 4-chloro-2, 5-dimethyl-phenyl, R ⁇ is phenyl, and R 3 is H, and Y 1 is a bond, then Y is other than CONH 2 ; compound #580
  • R 2 is 4-methylphenyl, R is 4-chloro-phenyl, and R 3 is H, and Y 1 is a bond, then Y is other than CONH 2 ; compound #563
  • R 2 is 4-methylphenyl
  • R 1 is 4- f luoro-phenyl
  • R 3 is H
  • Y 1 is a bond, then Y is other than CONH 2 ;
  • R 2 is 4-methylphenyl, R 1 is 4-methoxy-phenyl, and R 3 is H, and Y 1 is a bond, then Y is other than CONH 2 ; compound #565
  • the present invention provides novel compounds of formula (Ha) :
  • M is chosen from:
  • Y 1 is chosen from a bond, C 1 _ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl;
  • Y is chosen from C00R 1S , CO-COOR 5 , P0 3 R a R t)/ S0 3 R 5 , tetrazole,
  • each R 5 R 9 , R 10 , R u , R 16 , R a , and R b are independently chosen from H or C ⁇ _ 6 alkyl, ;
  • R 1 is chosen from C ⁇ _ 6 alkyl, C 2.6 alkenyl, C 2 _ 6 alkynyl, C 6 _ 12 aryl, C 3 _ 10 heterocycle, C 3 _ 10 heteroaralkyl, C 6 _ 12 aralkyl, or a halogen;
  • R 2 is chosen from C , 12 aryl, C 3 ,_ heterocycle, C , 12 aralkyl or C, heteroaralkyl ;
  • R 3 is chosen from H or C j _ 6 alkyl; C 6 _ 12 aralkyl or C 3 _ 10 heteroaralkyl ;
  • R 4 is chosen from H or C _ e alkyl
  • R 15 is chosen from H or C x _ 6 alkyl
  • R 2 is 4-chloro-2 , 5-dimethyl-phenyl , R is phenyl , and R 3 is H, and Y 1 is a bond, then Y is other than CONH 2 ; compound #580
  • R 2 is 4-methylphenyl
  • R x is 4 -chloro -phenyl
  • R 3 is H
  • Y 1 is a bond, then Y is other than CONH 2 ; compound #563
  • R 2 is 4-methylphenyl, R 1 is 4-fluoro-phenyl, and R 3 is H, and Y 1 is a bond, then Y is other than CONH 2 ; compound #564
  • R 2 is 4-methylphenyl
  • R 1 is 4-methoxy-phenyl
  • R 3 is H
  • Y 1 is a bond, then Y is other than CONH 2 ; compound #565.
  • X is:
  • X is:
  • Z is chosen from H, halogen, _ 6 alkyl .
  • Z is H
  • Z is C _ 6 alkyl
  • Z is chosen from methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, hexyl or cyclohexyl.
  • Ri is chosen from C 2 - ⁇ 2 alkyl, C2-12 alkenyl, C2-12 alkynyl, C ⁇ - ⁇ aryl, C 3 _i2 heterocycle, C 3 ⁇ s heteroaralkyl or C ⁇ -is aralkyl .
  • Ri is chosen from a C2- 1 2 alkyl, C 6 - ⁇ aryl or C 3 _ ⁇ 2 heterocycle.
  • Ri is a C2-12 alkyl .
  • Ri is a C 3 _i2 heterocycle.
  • Ri ' is chosen from t-butyl, isobutyl, allyl, ethynyl, 2- phenylethenyl, isobutenyl, benzyl, phenyl, phenethyl, benzodioxolyl, thienyl, thiophenyl, pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl, or benzothiophenyl any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S0 2 Ri2/ P0 3 RcRd, CONR ⁇ 3 R ⁇ 4 , C ⁇ -6 alkyl, C-6 alkenyl, C 2 -6 alkynyl, C6-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C 2 -6 alkenyloxy, C
  • Ri is chosen from thienyl, t-butyl, phenyl or pyridinyl.
  • R x is isoxazolyl substituted by at least one methyl.
  • Ri is pyridinyl .
  • R x is chosen from a C _ 6 alkyl, C 6 _ 12 aryl or C 3 _ 10 heterocycle.
  • Ri is chosen from t-butyl, isobutyl, allyl, ethynyl, 2-phenylethenyl, isobutenyl, benzyl, phenyl, phenethyl, benzodioxolyl, thienyl, thiophenyl, pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl, or benzothiophenyl, any of which can be substituted by at least one substituent chosen from C ⁇ _ s alkyl, C- 6 alkenyl, C 2 -6 alkynyl, C 3 - ⁇ o heterocycle, halogen, nitro, CONR ⁇ 3 R ⁇ 4 , NR ⁇ 3 R ⁇ 4 , amidino, guanido, Cyano, S0-C ⁇ _ 6 alkyl, C(0)0R ⁇ 2 ,
  • R x is chosen from thienyl, t-butyl, phenyl, thiophenyl, pyridinyl, isoxazolyl, any of which can be substituted by at least one substituent chosen from a halogen, C _ s alkyl, C x _ ⁇ alkyloxy, C 2.6 alkenyl, C 2 _ 6 alkynyl, nitro, cyano, S0 2 - C x _ 6 alkyl, NO- ⁇ alkyl .
  • R x is phenyl .
  • R is phenyl substituted with fluoride.
  • R x is phenyl substituted with at least one fluoride
  • R x is phenyl di-substituted with fluoride.
  • R x is phenyl substituted with chloride.
  • R 1 is phenyl substituted with at least one chloride
  • R x is phenyl di-substituted with chloride.
  • R x is phenyl substituted with fluoride and chloride.
  • R x is phenyl substituted with nitro.
  • R x is phenyl substituted with at least one nitro.
  • R x is phenyl substituted with methoxy.
  • R x is phenyl substituted with OCF 3 .
  • R 1 is phenyl substituted with CF 3 .
  • R is phenyl substituted with methyl.
  • R is phenyl substituted with at least one methyl.
  • R is phenyl substituted with CN.
  • R is phenyl substituted with S0 2 -CH 3 .
  • R x is phenyl substituted with NH(C0)-CH 3 .
  • R x is thiophenyl .
  • R is thiophenyl substituted by at least one halogen.
  • R 1 is thiophenyl substituted by at least one chloride.
  • R ⁇ is thiophenyl substituted by at least one methyl.
  • R is thiophenyl substituted by at least one methyl and one chloride.
  • R x is thienyl.
  • R ⁇ is thienyl substituted by at least one halogen.
  • R 1 is thienyl substituted by at least one chloride.
  • R 1 is thienyl substituted by at least one methyl.
  • R ⁇ is thienyl substituted by at least one methyl and one chloride.
  • R is isoxazole di-substituted with CH 3 .
  • R x is pyridine.
  • M is chosen from:
  • M is :
  • M is:
  • J is chosen from :
  • W is as defined above.
  • J is
  • J is
  • Y is chosen from C00R 16 , C0C00R 5 , P(0)0R a 0R b , S(0) 2 0R 5 tetrazole, C0N(R 9 )CH(R 5 ) C00R 5 , CONR 10 R , C0NR 9 0H.
  • any of R 5 , Ra, Rb, R 9 , R 10 , R 11 and R 16 are each independently chosen from H or C x _ 6 alkyl; provided that R 16 is other than methyl or ethyl .
  • Y is chosen from COOR 16 , CONR 10 R U or CON (R 9 ) CH (R 5 ) -COOR 5 .
  • any of R 5 , R 9 , R 10 , Rn and R 16 are each independently chosen from H or C 1-6 alkyl; provided that R 16 is other than methyl or ethyl .
  • Y is chosen from COOR ⁇ 6 , CONR 10 R 1:L or CON R 9 CH 2 COOR 5 .
  • Y is chosen from COOR 5 , CONR 5 R 5 or
  • Y is COOH
  • Y is CONH 2 . In a further embodiment, Y is CONHCH 2 COOH.
  • Y is COOCH 3 .
  • R 3 is chosen from H, C 1-12 alkyl, C 6-18 aralkyl , C 3-12 heterocycle or C 3-18 heteroaralkyl .
  • R 3 is chosen from H, C 1.12 alkyl, C s _ 18 aralkyl or C 3 _ 12 heterocycle.
  • R 3 is C J . JJ alkyl .
  • R 3 is C 6.18 aralkyl . . R 3 is C 3 _ 12 heterocycle. R 3 is chosen from H, methyl, ethyl, i-propyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, dioxolanyl, azepanyl or benzyl; any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S0 3 R 12 , P0 3 RcRd, CONR 13 R 14 , C ⁇ alkyl, C 2 _ 6 alkenyl, C 2.6 alkynyl, C 6.12 aralkyl , C 6 _ 12 aryl, C ⁇ alkyloxy, C 2 _ 6 alkenyl
  • R 3 is chosen from H or Methyl, isopropyl, piperidinyl, piperidinylmethyl, dioxolanyl or cyclohexyl.
  • R 3 is H or methyl.
  • R 3 is H.
  • R 3 is methyl
  • R 3 is benzyl, thiophenylmethyl, furanylmethyl .
  • R 2 is C 2 _ 12 alkyl, C 6.14 aryl or C 3 _ 12 heterocycle
  • R 2 is C 3.6 heterocycle.
  • R 2 is chosen from thienyl, furanyl, pyridinyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl, piperazinyl, pyrrolidinyl or quinolinyl any of which can be optionally substituted by one or ' more substituent chosen from halogen, nitro, nitroso, S0 3 R 12 , P0 3 RcRd, CONR 13 R 14 , C ⁇ alkyl, C 2.6 alkenyl, C 2 _ 6 alkynyl, C 6 _ 12 aralkyl , C 6 _ 12 aryl, C x _ 6 alkyloxy, C 2.6 alkenyloxy, C 2 _ 6 alkynyloxy, C 6 _ 12 aryloxy, alkyl, C (0) C 2
  • C 3 . 18 heteroaralkyl , C 6 _ 18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to
  • R 2 is a heterocycle chosen from thienyl, furanyl, pyridinyl, pyrrolyl, indolyl, piperazinyl or benzothienyl.
  • R 2 is C 2 _ 12 alkyl .
  • R 2 is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl cyclohexyl, cycloheptyl, 2- (cyclopentyl) -ethyl, methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl any of which can be optionally - substitute.d by one or more substituent chosen from halogen, nitro, nitroso, S0 3 R 12 , P0 3 RcRd, CONR 13 R 14 , C x _ 6 alkyl, C 2.6 alkenyl, C 2 .
  • C 3 _ 18 heteroaralkyl, C 6 _ 18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to
  • R 13 and R 14 are taken together with the nitrogen to form a 3 to
  • R 2 is an aryl chosen from indenyl, naphthyl or biphenyl.
  • R 2 is phenyl substituted by one or more substituent chosen from halogen, nitro, nitroso, S0 3 R 12 , P0 3 RcRd, CONR 13 R 14 , C _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 6.12 aralkyl , C 6 _ 12 aryl, C x _ e alkyloxy, C 2.6 alkenyloxy, C 2 _ 6 alkynyloxy, C 6 _ 12 aryloxy, C (0) C x _ ⁇ alkyl, C(0)C 2 _ 6 alkenyl, C (O) C 2 .
  • R 12 , Rc, Rd, R 13 and R 14 are each independently chosen from H, C _ 12 alkyl, C 2 .
  • Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R 13 and R 14 are taken together with the nitrogen to form a 3 to • 10 membered heterocycle.
  • R 2 is phenyl substituted by one or two substituents chosen from halogen, nitro, nitroso, S0 3 R 12 , P0 3 RcRd, C0NR 13 R 14 , C _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 6 . 12 aralkyl, C 6 _ 12 aryl , C ⁇ alkyloxy, C 2.6 alkenyloxy, C 2 . 6 alkynyloxy, C 6 _ 12 aryloxy, C (O) C 1 _ 6 alkyl, C(0)C 2 _ s alkenyl, C (0) C 2 .
  • R 2 is phenyl substituted by one or more substituent chosen from halogen, nitro, CONR 13 R 14 , C _ e alkyl, C 2 _ 6 alkenyl, C x _ 6 alkyloxy, C (0) C 1.6 alkyl, C G .
  • R 2 is phenyl substituted by one or two substituents chosen from halogen, nitro, CONR 13 R 14 , C ⁇ alkyl, C 2.6 alkenyl, C x _ 6 alkyloxy, C (0)C X _ 6 alkyl, C 6 _ 12 aryl, C 3 _ 10 heterocycle, hydroxyl, NR 13 R 14 , C(0)OR 12 , cyano, azido, wherein R 12 , R 13 and R 14 are each independently chosen from H, C ⁇ alkyl, C 2 _ 12 alkenyl , C 2 _ 12 alkynyl , C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl , C 6 _ 18 aralkyl ; or R 13 and R 14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
  • R 2 is phenyl substituted by one or two substituents chosen from halogen, C ⁇ alkyl, NR 13 R 14 , nitro, CONR 13 R 14 , C (O) OC x.6 alkyl, COOH or C x _ 6 alkyloxy C(0)OR 12 , cyano, azido, wherein R 12 , R 13 and R 14 are each independently chosen from H, C W! alkyl, C 2 _ 12 alkenyl , C 2 _ 12 alkynyl, C 6 _ 14 aryl , C 3 _ 12 heterocycle, C 3.18 heteroaralkyl , C 6 _ 18 aralkyl ; or R 13 and R 14 are taken together with the nitrogen to form a 3 to
  • R 2 is chosen from C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 6 _ 12 aralkyl or C 3 _ 10 heteroaralkyl .
  • R 2 is chosen from a C 6 _ 12 aryl or C 3 _ 10 heterocycle.
  • R 2 is a C 6 aryl or a C 3 _ 6 heterocycle.
  • R 2 is chosen from phenyl, pyridinyl, thiophenyl, benzofuran, thiazole, pyrazole, substituted with at least one substituent chosen from a halogen, C. ⁇ alkyl, C _ s alkyloxy, CF 3 , COOH, COOC ⁇ alkyl , cyano, NH 2 , nitro, NH(C 1.6 alkyl), N(C 1.6 alkyl) 2 or a C 3 _ 8 heterocycle.
  • R 2 is chosen from thienyl, furanyl, pyridyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl or quinolinyl any of which can be substituted by at least one substituent chosen from C ⁇ alkyl, amino, halogen, nitro, amido, CN, COOC ⁇ alkyl , or C ⁇ alkyloxy.
  • R 2 is methylphenyl .
  • R is dichlorophenyl .
  • R 2 is chosen from:
  • Rw is H, 0 or methyl
  • Rw is H
  • Rw is methyl; Ry is H;
  • Ry is methyl; and wherein, Xa is S, N, 0 or carbon.
  • each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, C ⁇ - 6 alkyl, 0C ⁇ _6 alkyl, CF 3 , COOH, COOCi_ 6 alkyl, CN, NH 2 , N0 2 , NH(C ⁇ _ 6 alkyl), N(C ⁇ - 6 alkyl ) 2 .
  • each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl , CF 3 , COOH, COOCH 3 , CN, NH 2 , N0 2 , NH(CH 3 ) or N(CH 3 ) 2 .
  • each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl,
  • each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, methyl, O-methyl, CF 3 , COOH, COOCH 3 , CN, NH 2 , or N0 2 .
  • each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, F, methyl, CF 3 or O-methyl.
  • Rf is H or methyl. In another embodiment, Rf is H. In another embodiment, Rf is methyl.
  • each of Ra, Rb, Rc, Rd and Re is independently chosen from, H or Cl .
  • each of Ra, Rb, Rc, Rd and Re is H.
  • Ra is chosen from Cl, F, methyl or O-methyl
  • Rb is H
  • Rc is chosen from Cl, F, methyl or O-methyl
  • Rd is H; Re is chosen from Cl, F, methyl or O-methyl.
  • Ra is methyl; Rb is H; Rc is Cl; Rd is H; Re is methyl .
  • each of Rs, Rt, Ru are independently chosen from, H, Cl, Br, I, F, Ci_ 6 alkyl, OC ⁇ _ 6 alkyl, CF 3 , COOH, COOC ⁇ -6 alkyl, CN, NH 2 , N0 2 , NH(d- 6 alkyl), N(C ⁇ _ 6 alkyl) 2 .
  • each of Rs, Rt, Ru are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF 3 , COOH, C00CH 3 , CN, NH 2 , N0 2 , NH(CH 3 ) or N(CH 3 ) 2 .
  • each of Rs , Rt, Ru are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF 3 , COOH, COOCH 3 , CN, NH 2 , or N0 2 .
  • each of Rs, Rt, Ru are independently chosen from, H, Cl , Br, I, F, methyl, O-methyl, CF 3 , COOH, COOCH 3 , CN, NH 2 , or N0 2 .
  • each of Rs, Rt, Ru are independently chosen from, H, Cl, methyl, O-methyl, CF 3 , COOH, COOCH 3 , CN, NH 2 , or N0 2 .
  • each of Rs, Rt, Ru are independently chosen from, H, Cl, F, methyl, CF 3 or O-methyl.
  • each of Rs, Rt, Ru are independently chosen from, H or Cl .
  • each of Rs, Rt, Ru are H.
  • Rs and Ru are Cl and Rt is H.
  • Rs is Cl, Rt and Ru are H.
  • the viral infection is chosen from Flavivirus infections .
  • the Flavivirus infection is chosen from Hepatitis C virus (HCV) , bovine viral diarrhea virus (BVDV) , hog cholera virus and yellow fever virus .
  • the Flavivirus infection is Hepatitis C viral infection.
  • a method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III)
  • X is chosen from:
  • M is chosen from:
  • R 4 is chosen from H or C x _ 6 alkyl
  • R 8 is chosen from H, C ⁇ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C aryl, C 3 _ 12 heterocycle, C 3 _ 12 heteroaralkyl, C 6 _ 16 aralkyl; and
  • R 15 is chosen from H or C 1-6 alkyl
  • J is chosen from: ⁇
  • W is chosen from 0, S or NR 7 , wherein R 7 is chosen from H, C 1 . 12 alkyl, C 2 _ 12 alkenyl, C 2 . 12 alkynyl, C 6 _ 12 aryl, C 3.12 heterocycle, C 3.12 heteroaralkyl, C 6 _ 16 aralkyl; and R 6 is chosen from H, C 1 . 12 alkyl, C 6 _ 12 aryl or C 6.16 aralkyl;
  • Y 1 is chosen from a bond, C x _ 6 alkyl, C 2 _ 6 alkenyl or C 2 . 6 alkynyl;
  • Y is chosen from COOR 16 , C0C00R 5 , P(0)OR a OR b , S(0)OR 5 , S(0) 2 OR 5 tetrazole, CON(R 9 ) CH(R 5 ) COOR 5 , CONR 10 R U , CON(R 9 ) -S0 2 -R 5 , CONR 9 OH or halogen, wherein R 9 , R 5 , R 10 and R X1 are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 . 12 heterocycle, C 3 _ 18 heteroaralkyl, C 6 .
  • R 10 and R X1 are taken together with the nitrogen to form a 3 to 10 membered heterocycle
  • R a and R ⁇ are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2.12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl and C 6.18 aralkyl
  • R a and ⁇ are taken together with the oxygens to form a 5 to 10 membered heterocycle
  • R 16 is chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2.12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3.18 heteroaralkyl and C 6 . 18 aralkyl;
  • R is chosen from C _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 . 12 heterocycle, C 3.18 heteroaralkyl, C 6.18 aralkyl, or halogen;
  • R 2 is chosen from C 1.12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3.12 heterocycle, C 3 _ 1B heteroaralkyl, or C 6.18 aralkyl;
  • R 3 is chosen from H, C 1.12 alkyl, C 2 _ 12 alkenyl, C 2.12 alkynyl, C 6.14 aryl, C 3.12 heterocycle, C 3 _ 18 heteroaralkyl or C 6.18 aralkyl;
  • Z is chosen from H, halogen, C ⁇ _ 6 alkyl.
  • a method for treating or preventing Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III) ,_further comprising at ⁇ least one antiviral agent.
  • the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
  • the antiviral agent is chosen from interferon and ribavirin.
  • said compound of formula (III) and said antiviral agent are administered sequentially.
  • said compound of formula (III) and said antiviral agent are administered simultaneously.
  • a method for treating or preventing Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III) and at least one additional agent chosen from immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
  • the additional agent is chosen from silybum marianum, interleukine-12 , amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
  • the compound of formula (III) and the additional agent are administered sequentially.
  • the compound of formula (III) and the additional agent are administered simultaneously.
  • the present invention further provides A pharmaceutical composition comprising at least one compound having the formula III or pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable carrier or excipient .
  • the pharmaceutical composition is further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
  • the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
  • the antiviral agent is chosen from interferon and ribavirin.
  • the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N- acetyl cysteine or cyclosporin.
  • the invention further provides the use of a compound having the formula III for the manufacture of a medicament for treating or preventing a viral Flaviridea infection in a host '
  • the invention provides the use of a compound having the formula III for treating or preventing Flaviviridae viral infection in a host.
  • the use of a compound having the compound of formula III for treating or preventing Flaviviridae viral infection in a host is further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
  • the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
  • the antiviral agent is chosen from interferon ⁇ and ribavirin.
  • the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N- acetyl cysteine or cyclosporin.
  • the compound of formula III and the additionnal agent are administered sequentially.
  • the compound of formula III and the ⁇ additionnal agent are administered simultaneously.
  • a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula (III) .
  • the method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula
  • (III) is further comprising one or more viral polymerase inhibitor.
  • the viral polymerase is a Flaviviridae viral polymerase.
  • the viral polymerase is a RNA-dependant RNA-polymerase.
  • the viral polymerase is HCV polymerase.
  • the invention provides a method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula III .
  • the invention provides a method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound chosen from:
  • the viral helicase is a flaviviridea helicase.
  • the viral helicase is HCV helicase.
  • a compound having the formula III for inhibiting or reducing the activity of ' viral polymerase in a host, further comprising one or more viral polymerase inhibitor.
  • the viral polymerase is Flaviviridae viral polymerase.
  • the viral polymerase is RNA-dependant RNA-polymerase.
  • the viral polymerase is HCV polymerase.
  • the invention provides the use of a compound having the formula III for inhibiting or reducing the activity of viral helicase in a host.
  • the invention provides the use of a compound chosen from:
  • the invention provides the use of a compound having the formula III for inhibiting or reducing the activity of viral helicase in a host further comprising one or more viral helicase inhibitor.
  • the viral helicase is Flaviviridae viral helicase.
  • the viral helicase is HCV helicase.
  • the present invention provides a combination comprising a compound having the formula III and one or more additionnal agent chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
  • the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine, cyclosporin, interferon ⁇ and ribavirin.
  • the compound of formula (III) and the additionnal agent are administered sequentially.
  • the compound of formula (III) and the additionnal agent are administered simultaneously.
  • the present invention provides_a process for preparing a compound of formula A:
  • Y 1 is chosen from a bond, C _ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl;
  • Y is chosen from C00R 16 , C0C00R 5 , P(0)0R a 0R b , S(0)OR 5 , S(0) 2 OR 5 _ tetrazole, CON(R 9 ) CH(R 5 ) COOR 5 , CONR 10 R U , CON(R 9 ) -S0 2 -R 5 , CONR 9 OH or halogen, wherein R 9 , R 5 , R 10 and R u are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl, C 6 _ 18 aralkyl; or R 10 and R u are taken together with the nitrogen to form a 3 to 10 membered heterocycle; R a and R b are each independently chosen from H, C 1 _ 12 alkyl, C 2 _ 12 alkenyl,
  • R 16 is chosen from H, C 1 _ 12 alkyl, C 2.12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl and C 6 _ 18 aralkyl;
  • R x is chosen from C 1 _ 12 alkyl, C 2.12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl, C 6 _ 18 aralkyl or halogen;
  • R 2 is chosen from C ⁇ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl, or C 5 . 18 aralkyl;
  • R 3 is chosen from H, C x _ 12 alkyl, C 2 _ 12 alkenyl, C 2 _ 12 alkynyl, C 6 _ 14 aryl, C 3 _ 12 heterocycle, C 3 _ 18 heteroaralkyl or C 6 _ 18 aralkyl;
  • Z is chosen from H, halogen, C 1-6 alkyl.
  • the compounds of formula (I) or (la) can contain a chiral centre on the general formula* (I) .
  • the compounds of formula (I) or (la) thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers) . All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the single optical isomer or enantiomer can be obtained by method well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary.
  • the compounds of formula (I) or (la) include:
  • THIOPHENE-2-CARBOXYLIC ACID Compound 89 5- (4-METHANESULFONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
  • THIOPHENE-2-CARBOXYLIC ACID Compound 236 5- (4-AC ⁇ TYL-PHENYL) -3- (2 , 4-DIMETHYL-B ⁇ NZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
  • THIOPHENE-2-CARBOXYLIC ACID Compound 320 3- (2 , 4-DIM ⁇ THYL-BENZENESULFONYLAMINO) -5- (4-HYDROXYMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
  • the compounds of the present invention are provided in the form of a single enantiomer at least 95%, more preferrably at least 97% and most preferably at least 99% free of the corresponding enantiomer .
  • the compound of the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer . More preferably the compound of the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.
  • the compound of the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.
  • the compound of the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.
  • the compound of the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.
  • the compound of the present invention are in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.
  • salts of the present invention are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases .
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric,, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, ' citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts .
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR4+ (where R is C ] __4 alkyl) salts.
  • alkali metal e.g. sodium
  • alkaline earth metal e.g. magnesium
  • ammonium NR4+ (where R is C ] __4 alkyl) salts.
  • References hereinafter to a compound according to the invention includes compounds of the general formula (I) or (la) and their pharmaceutically acceptable salts .
  • alkyl represents a straight chain, branched chain or cyclic hydrocarbon moiety which mayoptionallybesubstitutedby one or more of: halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido;
  • R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle;
  • alkyls include isopropyl, ethyl, fluorohexyl or cyclopropyl.
  • alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an oxygen, (e.g. a benzoyl) or an halogen, more preferably, the halogen is fluoro (e.g. CF3- or CF3CH2-) .
  • alkenyl and alkynyl represent an alkyl containing at least one unsaturated group (e.g. allyl, acetylene, • ethylene) .
  • aryl represents a carbocyclic moiety containing at least one benzenoid-type ring which may optionally be substituted by one or more of halogen, nitro, nitroso, S03R12, P03RcRd, C0NR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxy
  • R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
  • aryl include phenyl and naphthyl .
  • aralkyl represents an aryl group attached to the adjacent atom by a Cl-6alkyl, Cl-6alkenyl, or Cl-6alkynyl (e.g. , benzyl) .
  • heterocycle represents a saturated or unsaturated, cyclic moiety wherein said cyclic moeity is interrupted by at least one heteroatom, (e.g. oxygen, sulfur or nitrogen) which may optionally be substituted halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R
  • heterocyclic ring represents a mono or polycyclic (e.g., bicyclic) ring.
  • heterocyclic rings include but are not limited to epoxide; furan; benzofuran; isobenzofuran; oxathiolane; dithiolane; dioxolane; pyrrole; pyrrolidine; imidazole; pyridine; pyrimidine; indole; piperidine; morpholine; thiophene and thio orpholine.
  • heteroarylkyl represents an heterocycle group attached to the adjacent atom by a C h lky!, C ⁇ alkenyl, or C _ 6 alkynyl.
  • the sulfur atom can be at different oxidation levels, ie. S, SO, or S02. All such oxidation levels are within the scope of the present invention.
  • hydride donating agent means a suitable ionic or covalent inorganic compound of hydrogen with another element (e.g. boron, sodium, lithium or aluminum) allowing the process to occur under the reaction conditions without causing adverse effect on the reagents or product.
  • hydride donating agent include but are not limited to sodium borohydride (NaBH 4 ) , sodium cyanoborohydride (NaCNBH 3 ) , sodium triacetoxyborohydride (Na(OAc) 3 BH) and borane-pyridine complexe (BH 3 -Py) .
  • resin or polymer supported hydride donating agent on a may be used.
  • organic carboxylic acid include but is not limited to aliphatic acid (e.g. acetic, formic, trifluoroacetic), aromatic acid (e.g. benzoic and salicylic) , dicarboxylic acid (e.g. oxalic and phthalic) . It will be apparent to one of ordinary skill that resin supported organic carboxylic acid may also be used.
  • enol ether as used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . Enol ethers may be obtained commercially or prepared by well-known methods . Non-limiting examples of preparation include alkylation or silylation of enolates obtained from carbonyl compounds such as aldehydes, ketones, esters .
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 ⁇ M, preferably about 2 to 50 ⁇ M, most preferably about ' 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising compounds of formula (I) or (la) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers ' therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier (s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. '
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual) , transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • composition suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents .
  • the tablets may be coated according to methods well known in the art. Oral liquid.
  • preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non- aqueous vehicles (which may include edible oils) , or preservatives .
  • the compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing an/or dispersing agents .
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds according to the invention may be formulated as ointments , creams or lotions, or as a transdermal patch.
  • Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents .
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents , or colouring agents .
  • Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier (s) followed by chilling and shaping in moulds .
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops .
  • Drops may be formulated with an aqueous or non- aqueous base also comprising one more dispersing agents, solubilising agents or suspending agents .
  • Liquid sprays are conveniently delivered from pressurized packs.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the above described formulations adapted to give sustained release of the active ingredient may be employed.
  • the compounds of the invention may also be used in combination with other antiviral agents or in combination with any additional agents useful in therapy and may be administered sequentially or simultaneously.
  • the compounds of the invention may be employed together with at least one other antiviral agent chosen from protease inhibitors, polymerase inhibitors, and helicase inhibitors .
  • the compounds of the invention may be employed together with at least one other antiviral agent chosen from Interferon- and Ribavirin.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.
  • each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

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Abstract

The present invention provides novel compounds represented by formula (I): or pharmaceutically acceptable salts thereof useful for treating flaviviridae viral infection.

Description

COMPOUNDS AND METHODS FOR THE TREATMENT OR
PREVENTION OF FLAVIVIRUS INFECTIONS
FIELD OF THE INVENTION '
The present invention relates to novel compounds and a method for the treatment or prevention of Flavivirus infections using novel compounds .
BACKGROUND OF THE INVENTION
Hepatitis is a disease occurring throughout the world. It is generally of viral nature, although there are other causes known. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans are affected by hepatitis each year, and out of t ose more than 150,000 are infected with the hepatitis C virus ("HCV") .
HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV) . HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm. The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co and post-translationally by cellular and two viral proteinases into mature viral proteins (core, El, E2 , p7, NS2 , NS3 , NS4A,
NS4B, NS5A, NS5B) . It is believed that the structural proteins, El and E2 , the major glycoproteins are embedded into a viral lipid envelope and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
The main source of contamination with HCV is blood. The magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers dn western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors .
The only treatment currently available for HCV infection is interferon-α (IFN-α). However, according to different clinical studies, only 70% of treated patients normalize alanine aminotransferase (ALT) levels in the serum and after discontinuation of IFN, 35% to 45% of these responders relapse. In general, only 20% to 25% of patients have long-term responses to IFN. Clinical studies have shown that combination treatment with IFN and ribavirin (RIBA) results in a superior clinical response than IFN alone. Different genotypes of HCV respond differently to IFN therapy, genotype lb is more resistant to IFN therapy than type 2 and 3.
There is therefore a great need for the development of anti-viral agents.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel compounds represented by formula I :
Figure imgf000003_0001
or pharmaceutically acceptable salts thereof;
wherein, X is chosen from:
R,
N R2
I or
\|^ ISL
R, \T ^R3
wherein,
M is chosen from:
Figure imgf000004_0001
Figure imgf000004_0002
wherein,
R4 is C ^g alkyl;
R8 is chosen from H, C ^12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl , C 6_16 aralkyl; and R15 is chosen from H or C 1_6 alkyl;
J is chosen from:
Figure imgf000005_0001
wherein W is chosen from O, S or NR7, wherein R7 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3^12 heterocycle, C3_12 heteroaralkyl , C 6_16 aralkyl; and R6 is chosen from H, C x_12 alkyl, C 6_14 aryl or C 6_15 aralkyl;
Y1 is chosen from a bond, Cα_β alkyl, C 2_6 alkenyl or C 2_6 alkynyl;
Y is chosen from COOR16, C0C00R5, P(0)ORaORb, S(0)OR5, S(0)2OR5 tetrazole, CON(R9)CH(R5) COOR5 , CONR10R1X, CON(R9) -S02-R5 , CONR9OH or halogen, wherein Rg, R5, R10 and R are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl; or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and P^ are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to 10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl and C5.18 aralkyl; provided that R16 is other than methyl or ethyl;
Rx is chosen from C 2_12 alkyl, C 2.12 alkenyl, C2_12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl or C 6_18 aralkyl;
R2 is chosen from C 2_12 alkyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl, or C 6_18 aralkyl;
R3 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl or C 6_18 aralkyl;
Z is chosen from H, halogen, Chal y!; with the proviso that:
i) when X is 4-Chloro-2 , 6-dimethyl-benzenesulfonamide and, Rx is phenyl, and R3 is H, and Y1 is a bond, then Y is other, than CONH2; compound #580
ii) when X is Toluene-4-sulfonamide and Rx is 4-chloro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #563
iii) when X is Toluene-4-sulfonamide and Rx is 4-fluoro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #564
iv) when X is Toluene-4-sulfonamide and R± is 4-methoxy-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #565
v) when X is Benzamide and Ri is phenyl Y1 is a bond and Y is COOH then R3 is other than hydrogen.
The compounds of the present invention are useful in therapy, particularly as antivirals .
In another aspect, there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.
In still another aspect, there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a combination comprising at least one compound of formula (I) and at least one further therapeutic agent.
In another aspect, there is provided a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient . Another aspect of the invention is the use of a compound according to formula (I) , for the manufacture of a medicament for the treatment of viral infections .
In another aspect, there is provided a method for inhibiting -or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula (I) .
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.
In one embodiment, the present invention provides novel compounds of formula (la) :
Figure imgf000007_0001
(la)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
M.. R,
N R, or I
R, R3 wherein,
M 'is chosen from:
Figure imgf000008_0001
Figure imgf000008_0002
wherein,
R4 is C 1-6 alkyl;
R8 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and
R15 is chosen from H or C _e alkyl;
J is chosen from:
Figure imgf000008_0003
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C ' '222-12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6.16 aralkyl; and R6 is chosen from H, C x_12 alkyl, C e_u aryl or C 6_16 aralkyl;
Y1 is chosen from a bond, C., alkyl, C , alkenyl or C 2, alkynyl;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)2OR5_ tetrazole, C0N(R9) CH(R5) C00R5 , CONR10RU, CON (R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and RX1 are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 3_12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl; or R10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle; Ra and ^ are each independently chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; or Ra and R,, are taken together with the oxygens to form a 5 to 10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6_18 aralkyl; provided that R16 is other than methyl or ethyl;
R1 is chosen from C 2_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl or C 6_18 aralkyl;
R2 is chosen from C 2_12 alkyl, C2.12 alkynyl, C β_u aryl, C 3_12 heterocycle, C3_1B heteroaralkyl, or C 6_18 aralkyl;
R3 is chosen from H, C H2 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_18 heteroaralkyl or C 6_18 aralkyl;
Z is chosen from H, halogen, C^ alkyl;
with the proviso that:
i) when X is 4-Chloro-2 , 6-dimethyl-benzenesulfonamide and, R1 is phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #580
ii) when X is Toluene-4-sulfonamide and R1 is 4-chloro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than C0NH2; compound #563
iii) when X is Toluene-4-sulfonamide and R± is 4-fluoro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than C0NH2; compound #564
iv) when X is Toluene-4-sulfonamide and Ri is 4-methoxy-phenyl, and R3 is H, and Y1 is a bond, then Y is other than C0NH2; compound #565 v) when X is Benzamide and Ri is phenyl Y1 is a bond and Y is COOH then R3 is other than hydrogen.
In a further aspect, the present invention provides novel compounds represented by formula II :
Figure imgf000010_0001
and pharmaceutically acceptable salts thereof,
wherein,
M is chosen from:
Figure imgf000010_0002
Y1 is chosen from a bond, Cx_6 alkyl, C 2_6 alkenyl or C 2_6 alkynyl;
Y is chosen from COORls, CO-COOR5, P03RaRb, S03R5, tetrazole,
CON(R9)CH(R5)-COOR5, CON R10R1X or CONR9OH, wherein each R5 R9, R10, R , R1S, Ra, and Rj, are independently chosen from H or C ., alkyl , ;
R1 is chosen from C t_6 alkyl, C 2.6 alkenyl, C2_6 alkynyl, C 6_12 aryl, C heterocycle, C3_10 heteroaralkyl, C aralkyl, or a halogen; R2 is chosen from C 6_12 aryl, C 3_10 heterocycle, C 6_12 aralkyl or C3_ 10 heteroaralkyl;
R3 is chosen from H or C _6 alkyl; C 6_12 aralkyl or C3.10 heteroaralkyl ;
R4 is chosen from H or C 1-6 alkyl; R15 is chosen from H or C x_6 alkyl
with the proviso that:
i) when M is
Figure imgf000011_0001
and R2 is 4-chloro-2, 5-dimethyl-phenyl, Rλ is phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #580
ii) when M is O
—S
II o and R2 is 4-methylphenyl, R is 4-chloro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #563
iii ) when M is
Figure imgf000011_0002
and R2 is 4-methylphenyl , R1 is 4- f luoro-phenyl , and R3 is H, and Y1 is a bond, then Y is other than CONH2 ; compound #564
iv) when M is O
-s-
II- o and R2 is 4-methylphenyl, R1 is 4-methoxy-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #565
In still a further embodiment, the present invention provides novel compounds of formula (Ha) :
Figure imgf000012_0001
wherein,
M is chosen from:
Figure imgf000012_0002
7, a bond
CH ■
R< R ~A.
0
Y1 is chosen from a bond, C1_6 alkyl, C 2_6 alkenyl or C 2_6 alkynyl;
Y is chosen from C00R1S, CO-COOR5, P03RaRt)/ S03R5, tetrazole,
C0N(R9)CH(R5)-C00R5, CON R10RX1 or C0NR90H, wherein each R5 R9, R10, Ru, R16, Ra, and Rb are independently chosen from H or C α_6 alkyl, ;
R1 is chosen from C χ_6 alkyl, C 2.6 alkenyl, C2_6 alkynyl, C 6_12 aryl, C 3_10 heterocycle, C3_10 heteroaralkyl, C 6_12 aralkyl, or a halogen; R2 is chosen from C ,12 aryl, C 3,_ heterocycle, C ,12 aralkyl or C, heteroaralkyl ;
R3 is chosen from H or Cj_6 alkyl; C 6_12 aralkyl or C3_10 heteroaralkyl ;
R4 is chosen from H or C _e alkyl; R15 is chosen from H or C x_6 alkyl;
with the proviso that:
i ) when M is O
-S-
II o and R2 is 4-chloro-2 , 5-dimethyl-phenyl , R is phenyl , and R3 is H, and Y1 is a bond, then Y is other than CONH2 ; compound #580
ii ) when M is O
-S-
II o and R2 is 4-methylphenyl , Rx is 4 -chloro -phenyl , and R3 is H, and Y1 is a bond, then Y is other than CONH2 ; compound #563
iii ) when M is
Figure imgf000013_0001
and R2 is 4-methylphenyl, R1 is 4-fluoro-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #564
iv) when M is O
—S —
II o and R2 is 4-methylphenyl, R1 is 4-methoxy-phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #565.
In one embodiment, X is:
N R2
Ra
In a further embodiment, X is:
Figure imgf000014_0001
In one embodiment, Z is chosen from H, halogen, _6 alkyl .
In further embodiments , Z is H
Z is halogen
Z is fluoride
Z is C _6 alkyl
Z is chosen from methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, hexyl or cyclohexyl.
In further embodiments;
Ri is chosen from C2-ι2 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cε-ι aryl, C3_i2 heterocycle, C3~ιs heteroaralkyl or Cε-is aralkyl .
Ri is chosen from a C2-12 alkyl, C6-ι aryl or C3_ι2 heterocycle.
Ri is a C2-12 alkyl .
Figure imgf000014_0002
Ri is a C3_i2 heterocycle.
Ri'is chosen from t-butyl, isobutyl, allyl, ethynyl, 2- phenylethenyl, isobutenyl, benzyl, phenyl, phenethyl, benzodioxolyl, thienyl, thiophenyl, pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl, or benzothiophenyl any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S02Ri2/ P03RcRd, CONRι3Rι4, Cι-6 alkyl, C-6 alkenyl, C2-6 alkynyl, C6-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C (0) Cι_6 alkyl, C (O) C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-ι2 aryl, C(0)Cδ-i2 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0Rι2, cyano, azido, amidino or guanido; ' wherein Rι2, Rc, Rd, R3 and R14 are each independently chosen from H, Cι_i2 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-ι4 aryl, C3-12 heterocycle, C3_i8 heteroaralkyl, Cβ-is aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
Ri is chosen from thienyl, t-butyl, phenyl or pyridinyl. Rx is isoxazolyl substituted by at least one methyl.
Ri is pyridinyl .
In one embodiment, Rx is chosen from a C _6 alkyl, C6_12 aryl or C3_10 heterocycle.
In one embodiment, Ri is chosen from t-butyl, isobutyl, allyl, ethynyl, 2-phenylethenyl, isobutenyl, benzyl, phenyl, phenethyl, benzodioxolyl, thienyl, thiophenyl, pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl, or benzothiophenyl, any of which can be substituted by at least one substituent chosen from Cι_s alkyl, C-6 alkenyl, C2-6 alkynyl, C3-ιo heterocycle, halogen, nitro, CONRι3Rι4, NRι3Rι4, amidino, guanido, Cyano, S0-Cι_6 alkyl, C(0)0Rι2, Cι_6 alkyloxy, C2- 6 alkenyloxy, C2-6 alkynyloxy, or C6-i2 aryloxy; wherein R1 , Rι3 and Rι4 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-i4 aryl, C3-12 heterocycle, C3_ is heteroaralkyl, C6-18 aralkyl; or R13 and Rι4 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
In one embodiment, Rx is chosen from thienyl, t-butyl, phenyl, thiophenyl, pyridinyl, isoxazolyl, any of which can be substituted by at least one substituent chosen from a halogen, C _s alkyl, Cx_β alkyloxy, C2.6 alkenyl, C2_6 alkynyl, nitro, cyano, S02- Cx_6 alkyl, NO- ^ alkyl .
In further embodiments ;
Rx is phenyl .
R is phenyl substituted with fluoride. '
Rx is phenyl substituted with at least one fluoride
Rx is phenyl di-substituted with fluoride. Rx is phenyl substituted with chloride.
R1 is phenyl substituted with at least one chloride
Rx is phenyl di-substituted with chloride.
Rx is phenyl substituted with fluoride and chloride.
Rx is phenyl substituted with nitro.. Rx is phenyl substituted with at least one nitro.
Rx is phenyl substituted with methoxy.
Rx is phenyl substituted with OCF3.
R1 is phenyl substituted with CF3.
R is phenyl substituted with methyl. R is phenyl substituted with at least one methyl.
R is phenyl substituted with CN.
R is phenyl substituted with S02-CH3.
Rx is phenyl substituted with NH(C0)-CH3.
In further embodiments ,
Rx is thiophenyl .
R is thiophenyl substituted by at least one halogen.
R1 is thiophenyl substituted by at least one chloride.
Rλ is thiophenyl substituted by at least one methyl. R is thiophenyl substituted by at least one methyl and one chloride.
In further embodiments , Rx is thienyl. Rα is thienyl substituted by at least one halogen.
R1 is thienyl substituted by at least one chloride.
R1 is thienyl substituted by at least one methyl.
Rλ is thienyl substituted by at least one methyl and one chloride.
R is isoxazole di-substituted with CH3.
Rx is pyridine.
In one embodiment, M is chosen from:
Figure imgf000017_0001
In a further embodiment , M is :
Figure imgf000017_0002
In an alternative embodiment, M is:
Figure imgf000017_0003
In one embodiment , J is chosen from :
>
W O o
wherein, W is as defined above.
In an alternative embodiment, J is
Figure imgf000017_0004
In a further embodiment, J is
Figure imgf000018_0001
In one embodiment, Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)20R5 tetrazole, C0N(R9)CH(R5) C00R5 , CONR10R , C0NR90H. In a further embodiment, any of R5, Ra, Rb, R9, R10, R11 and R16 are each independently chosen from H or Cx_6 alkyl; provided that R16 is other than methyl or ethyl .
In one embodiment, Y is chosen from COOR16, CONR10RU or CON (R9) CH (R5) -COOR5. In a further embodiment, any of R5, R9, R10, Rn and R16 are each independently chosen from H or C1-6 alkyl; provided that R16 is other than methyl or ethyl .
In a further embodiment, Y is chosen from COORα6, CONR10R1:L or CON R9CH2COOR5.
In a further embodiment, Y is chosen from COOR5, CONR5R5 or
CON (Rs) CH (R5) .COOR5.
In a further embodiment, Y is COOH.
In a further embodiment, Y is CONH2. In a further embodiment, Y is CONHCH2COOH.
In a further embodiment, Y is COOCH3.
In a further embodiment, Y1 is chosen from CH2, C=CH, CH-CH2 or a bond.
In further embodiments ;
R3 is chosen from H, C1-12 alkyl, C6-18 aralkyl , C3-12heterocycle or C3-18 heteroaralkyl .
R3 is chosen from H, C1.12 alkyl, Cs_18 aralkyl or C3_12 heterocycle. R3 is CJ.JJ alkyl .
R3 is C6.18 aralkyl . . R3 is C3_12 heterocycle. R3 is chosen from H, methyl, ethyl, i-propyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, dioxolanyl, azepanyl or benzyl; any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, C^ alkyl, C2_6 alkenyl, C2.6 alkynyl, C6.12 aralkyl , C6_12aryl, C^ alkyloxy, C2_6 alkenyloxy, C2.6 alkynyloxy, C5_12 aryloxy, C (0) Cx_6 alkyl, C (O) C2_6 alkenyl, C(0)C2.6 alkynyl, C (0) C6_12 aryl, C (0) C6_12 aralkyl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C1.12 alkyl, C2_12 alkenyl, C2_12 alkynyl , C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
R3 is chosen from H or Methyl, isopropyl, piperidinyl, piperidinylmethyl, dioxolanyl or cyclohexyl.
In a further embodiment, R3 is H or methyl.
In a further embodiment, R3 is H.
In a further embodiment, R3 is methyl.
In a further embodiment, R3 is benzyl, thiophenylmethyl, furanylmethyl .
In additional embodiments;
R2 is C2_12 alkyl, C6.14 aryl or C3_12 heterocycle;
R2 is C3.6 heterocycle. R2 is chosen from thienyl, furanyl, pyridinyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl, piperazinyl, pyrrolidinyl or quinolinyl any of which can be optionally substituted by one or ' more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, C^ alkyl, C2.6 alkenyl, C2_6 alkynyl, C6_12 aralkyl , C6_12aryl, Cx_6 alkyloxy, C2.6 alkenyloxy, C2_6 alkynyloxy, C6_12 aryloxy, alkyl, C (0) C2.6 alkenyl, C (0) C2.6 alkynyl, C (0) Cs.12 aryl,
C (0)C6_12 aralkyl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cx_12 alkyl, C2_12 alkenyl , C2_12 alkynyl , C6_14aryl, C3.12 heterocycle,
C3.18 heteroaralkyl , C6_18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to
10 membered heterocycle; ' or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
R2 is a heterocycle chosen from thienyl, furanyl, pyridinyl, pyrrolyl, indolyl, piperazinyl or benzothienyl.
R2 is C2_12 alkyl .
R2 is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl cyclohexyl, cycloheptyl, 2- (cyclopentyl) -ethyl, methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl any of which can be optionally - substitute.d by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cx_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6.12 aralkyl , C6.12aryl, C _6 alkyloxy, C2_6 alkenyloxy, C2_s alkynyloxy, C6_12 aryloxy, C (0) Cx_6 alkyl, C(0)C2_6 alkenyl , C (0) C2_s alkynyl , C (0) CG_12 aryl , C (0) C6.12 aralkyl , C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from
H, C1_12 alkyl, C2_12 alkenyl , C2.12 alkynyl , C6_14aryl, C3.12 heterocycle,
C3_18 heteroaralkyl, C6_18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to
10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to
10 membered heterocycle.
Figure imgf000020_0001
R2 is an aryl chosen from indenyl, naphthyl or biphenyl. R2 is phenyl substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, C _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C6.12 aralkyl , C6_12aryl, Cx_e alkyloxy, C2.6 alkenyloxy, C2_6 alkynyloxy, C6_12 aryloxy, C (0) Cx_β alkyl, C(0)C2_6 alkenyl, C (O) C2.6 alkynyl , C (0) C6_12 aryl, C (0) C6_12 aralkyl, C3.10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido ; . wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C _12 alkyl, C2.12 alkenyl , C2_12 alkynyl , C6.14aryl, C3_12 heterocycle, C3_18 heteroaralkyl , C6_1B aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to • 10 membered heterocycle. R2 is phenyl substituted by one or two substituents chosen from halogen, nitro, nitroso, S03R12, P03RcRd, C0NR13R14, C _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C6.12 aralkyl, C6_12 aryl , C^ alkyloxy, C2.6 alkenyloxy, C2.6 alkynyloxy, C6_12 aryloxy, C (O) C1_6 alkyl, C(0)C2_s alkenyl, C (0) C2.6 alkynyl, C (0) C6_12 aryl, C (0) C6_12 aralkyl , C3.10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C^ alkyl, C2_12 alkenyl , C2.12 alkynyl , C6_14aryl, C3.12 heterocycle, C3_18 heteroaralkyl , C6_18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle. R2 is phenyl substituted by one or more substituent chosen from halogen, nitro, CONR13R14, C _e alkyl, C2_6 alkenyl, Cx_6 alkyloxy, C (0) C1.6 alkyl, CG.12aryl, C3.10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, Cx_12 alkyl , C2_12 alkenyl , C2_12 alkynyl , C6.14aryl, C3_12 heterocycle, C3_18 heteroaralkyl , C6.18 aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
R2 is phenyl substituted by one or two substituents chosen from halogen, nitro, CONR13R14, C^ alkyl, C2.6 alkenyl, Cx_6 alkyloxy, C (0)CX_6 alkyl, C6_12aryl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)OR12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, C^^ alkyl, C2_12 alkenyl , C2_12 alkynyl , C6_14aryl, C3_12 heterocycle, C3_18 heteroaralkyl , C6_18 aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
R2 is phenyl substituted by one or two substituents chosen from halogen, C^ alkyl, NR13R14, nitro, CONR13R14, C (O) OCx.6 alkyl, COOH or Cx_6 alkyloxy C(0)OR12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, CW! alkyl, C2_12 alkenyl , C2_12 alkynyl, C6_14 aryl , C3_12 heterocycle, C3.18 heteroaralkyl , C6_18 aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to
10 membered heterocycle.
In one embodiment, R2 is chosen from C 6_14 aryl, C 3_12 heterocycle, C 6_12 aralkyl or C3_10 heteroaralkyl .
In a further embodiment, R2 is chosen from a C6_12 aryl or C3_10 heterocycle.
In a further embodiment, R2 is a C6 aryl or a C3_6 heterocycle.
In a further embodiment, R2 is chosen from phenyl, pyridinyl, thiophenyl, benzofuran, thiazole, pyrazole, substituted with at least one substituent chosen from a halogen, C.^ alkyl, C _s alkyloxy, CF3, COOH, COOC^ alkyl , cyano, NH2, nitro, NH(C1.6 alkyl), N(C1.6 alkyl) 2 or a C3_8 heterocycle.
R2 is chosen from thienyl, furanyl, pyridyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl or quinolinyl any of which can be substituted by at least one substituent chosen from C^ alkyl, amino, halogen, nitro, amido, CN, COOC^ alkyl , or C^ alkyloxy. R2 is methylphenyl . R is dichlorophenyl . In a further embodiment, R2 is chosen from:
Figure imgf000023_0001
wherein :
Rw is H, 0 or methyl ;
Ry is H or methyl ;
Rw is H;
Rw is methyl; Ry is H;
Ry is methyl; and wherein, Xa is S, N, 0 or carbon.
In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, Cι-6 alkyl, 0Cι_6 alkyl, CF3, COOH, COOCi_6 alkyl, CN, NH2, N02, NH(Cι_6 alkyl), N(Cι- 6 alkyl ) 2.
In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl , CF3, COOH, COOCH3, CN, NH2 , N02, NH(CH3) or N(CH3)2.
In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl,
CF3, COOH, COOCH3, CN, NH2 , or N02.
In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, methyl, O-methyl, CF3, COOH, COOCH3, CN, NH2, or N02.
In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, F, methyl, CF3 or O-methyl.
In one embodiment, Rf is H or methyl. In another embodiment, Rf is H. In another embodiment, Rf is methyl.
In a further embodiment, each of Ra, Rb, Rc, Rd and Re is independently chosen from, H or Cl .
In a further embodiment, each of Ra, Rb, Rc, Rd and Re is H.
In one embodiment :
Ra is chosen from Cl, F, methyl or O-methyl;
Rb is H;
Rc is chosen from Cl, F, methyl or O-methyl;
Rd is H; Re is chosen from Cl, F, methyl or O-methyl. In one embodiment: Ra is methyl; Rb is H; Rc is Cl; Rd is H; Re is methyl .
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, Br, I, F, Ci_6 alkyl, OCι_6 alkyl, CF3, COOH, COOCι-6 alkyl, CN, NH2, N02, NH(d-6 alkyl), N(Cι_6 alkyl) 2.
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF3, COOH, C00CH3, CN, NH2, N02, NH(CH3) or N(CH3)2.
In a further embodiment, each of Rs , Rt, Ru, are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF3, COOH, COOCH3, CN, NH2, or N02.
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl , Br, I, F, methyl, O-methyl, CF3, COOH, COOCH3, CN, NH2, or N02.
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, methyl, O-methyl, CF3, COOH, COOCH3, CN, NH2, or N02.
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, F, methyl, CF3 or O-methyl.
In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H or Cl .
In a further embodiment, each of Rs, Rt, Ru, are H. In one embodiment : Rs and Ru are Cl and Rt is H. Rs is Cl, Rt and Ru are H.
In one embodiment, the viral infection is chosen from Flavivirus infections .
In one embodiment, the Flavivirus infection is chosen from Hepatitis C virus (HCV) , bovine viral diarrhea virus (BVDV) , hog cholera virus and yellow fever virus .
In another embodiment, the Flavivirus infection is Hepatitis C viral infection.
In one embodiment, there is provided a method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III)
Figure imgf000026_0001
(III)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
Figure imgf000026_0002
wherein,
M is chosen from:
Figure imgf000027_0001
Figure imgf000027_0002
wherein,
R4 is chosen from H or C x_6 alkyl;
R8 is chosen from H, C ^12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and
R15 is chosen from H or C 1-6 alkyl;
J is chosen from: ■
Figure imgf000027_0003
wherein
W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_12 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1.12 alkyl, C 6_12 aryl or C 6.16 aralkyl;
Y1 is chosen from a bond, Cx_6 alkyl, C 2_6 alkenyl or C 2.6 alkynyl;
Y is chosen from COOR16, C0C00R5, P(0)ORaORb, S(0)OR5, S(0)2OR5 tetrazole, CON(R9) CH(R5) COOR5 , CONR10RU, CON(R9) -S02-R5 , CONR9OH or halogen, wherein R9, R5, R10 and RX1 are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl; or R10 and RX1 are taken together with the nitrogen to form a 3 to 10 membered heterocycle; Ra and R^ are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; or Ra and ^ are taken together with the oxygens to form a 5 to 10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6.18 aralkyl;
R is chosen from C _12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3.12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl, or halogen;
R2 is chosen from C1.12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3.12 heterocycle, C3_1B heteroaralkyl, or C6.18 aralkyl;
R3 is chosen from H, C1.12 alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl or C6.18 aralkyl;
Z is chosen from H, halogen, Cι_6 alkyl.
In one embodiment, there is provided a method for treating or preventing Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III) ,_further comprising at ■ least one antiviral agent.
In one embodiment, the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
In a further embodiment, the antiviral agent is chosen from interferon and ribavirin.
In a further embodiment, said compound of formula (III) and said antiviral agent are administered sequentially.
In a further embodiment, said compound of formula (III) and said antiviral agent are administered simultaneously. In one embodiment, there is provided a method for treating or preventing Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (III) and at least one additional agent chosen from immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
In another embodiment, the additional agent is chosen from silybum marianum, interleukine-12 , amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
In further embodiments;
The compound of formula (III) and the additional agent are administered sequentially. The compound of formula (III) and the additional agent are administered simultaneously.
In one embodiment, the present invention further provides A pharmaceutical composition comprising at least one compound having the formula III or pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable carrier or excipient .
In a further embodiment, the pharmaceutical composition, is further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
In one embodiment, the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
In one embodiment, the antiviral agent is chosen from interferon and ribavirin.
In one embodiment, the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N- acetyl cysteine or cyclosporin. In one embodiment, the invention further provides the use of a compound having the formula III for the manufacture of a medicament for treating or preventing a viral Flaviridea infection in a host '
In one embodiment, there is provided the use of a compound having the formula III or pharmaceutically acceptable salts thereof in therapy
In one embodiment, the invention provides the use of a compound having the formula III for treating or preventing Flaviviridae viral infection in a host.
In one embodiment, the use of a compound having the compound of formula III for treating or preventing Flaviviridae viral infection in a host is further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
In one embodiment, the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
In one embodiment, the antiviral agent is chosen from interferon α and ribavirin.
In one embodiment, the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N- acetyl cysteine or cyclosporin.
In one embodiment, the compound of formula III and the additionnal agent are administered sequentially.
In one embodiment, the compound of formula III and the ■ additionnal agent are administered simultaneously.
In one embodiment, there is provided a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula (III) . In one embodiment, the method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound of formula
(III) is further comprising one or more viral polymerase inhibitor.
In further embodiments;
The viral polymerase is a Flaviviridae viral polymerase.
The viral polymerase is a RNA-dependant RNA-polymerase.
The viral polymerase is HCV polymerase.
In one embodiment, the invention provides a method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula III .
In one embodiment, the invention provides a method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound chosen from:
Compound #14 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5- (4- chloro-phenyl) -thiophene-2-carboxylic acid
Compound #19 3- (4-Chloro-2, 5-dimethyl-benzenesulfonylamino) -5- (4- isobutyl- henyl) -thiophene-2-carboxylic acid
Compound #223 3- (4-Bromo-2-fluorobenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #224 3- (4-Bromo-2-methylbenzenesulfo-nylamino) -5- (4- isobutylp enyl) -thiophene-2-carboxylic acid
Compound #225 5- (4-Isobutylphenyl 3- (3-methoxy-benzenesulfonylamino) -thiophene-2-carboxylic acid
Compound #581 5- (4-Isobutyl-phenyl) -3- [5- (5-trifluoromethyl- isoxazol-3-yl) -thiophene-2-sulfonylamino] -thiophene- < 2-carboxylic acid
Compound #227 3-[2, 5-Bis- (2, 2, 2-trifluoroethoxy) - benzenesulfonylamino]-5- (4-isobutyl-phenyl) - thiophene-2-carboxylic acid Compound #228 3- (2-Chloro-4-cyanobenzenesulfonylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid Compound #582 5- (4-Isobutyl-phenyl) -3- (2, 3 , 4-trifluoro-
. benzenesulfonylamino) -thiophene-2-carboxylic acid or pharmaceutically acceptable salts thereof.
In further embodiments ;
The viral helicase is a flaviviridea helicase.
The viral helicase is HCV helicase.
In a further embodiment, there is provided the use of a compound having the formula III for inhibiting or reducing the activity of viral polymerase in a host.
In still a further embodiment, there is provided the use of a compound having the formula III for inhibiting or reducing the activity of 'viral polymerase in a host, further comprising one or more viral polymerase inhibitor. In further embodiments; The viral polymerase is Flaviviridae viral polymerase. The viral polymerase is RNA-dependant RNA-polymerase. The viral polymerase is HCV polymerase.
In one embodiment, the invention provides the use of a compound having the formula III for inhibiting or reducing the activity of viral helicase in a host.
In one embodiment, the invention provides the use of a compound chosen from:
Compound #14 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5- (4- chloro-phenyl) -thiophene-2-carboxylic acid
Compound #19 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5- (4- isobutyl-phenyl) -thiophene-2-carboxylic acid
Compound #223 3- (4-Bromo-2-fluorobenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #224 3- (4-Bromo-2-methylbenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #225 5- (4-Isobutylphenyl 3- (3-methoxy-benzenesulfonyl- amino) -thiophene-2-carboxylic acid
Compound #581 5- (4-Isobutyl-phenyl) -3- [5- (5-trifluoromethyl- isoxazol-3-yl) -thiophene-2-sulfonylamino] -thiophene- 2-carboxylic acid
Compound #227 3-[2, 5-Bi's- (2, 2, 2-trifluoroethoxy) - benzenesulfonylamino]-5- (4-isobutyl-phenyl) - thiophene-2-carboxylic acid
Compound #228 3- (2-Chloro-4-cyanobenzenesulfonylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #582 5- (4-Isobutyl-phenyl) -3- (2, 3 , -trifluoro- benzenesulfonylamino) -thiophene-2-carboxylic acid or pharmaceutically acceptable salts thereof for inhibiting or reducing the activity of viral helicase in a host.
In one embodiment, the invention provides the use of a compound having the formula III for inhibiting or reducing the activity of viral helicase in a host further comprising one or more viral helicase inhibitor.
In further embodiments ; The viral helicase is Flaviviridae viral helicase. The viral helicase is HCV helicase.
In one embodiment, the present invention provides a combination comprising a compound having the formula III and one or more additionnal agent chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
In a further embodiment, the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine, cyclosporin, interferon α and ribavirin. In further embodiments ; The compound of formula (III) and the additionnal agent are administered sequentially.
The compound of formula (III) and the additionnal agent are administered simultaneously.
In still a further embodiment, the present invention provides_a process for preparing a compound of formula A:
Figure imgf000034_0001
said process comprising the steps of adding:
• an enol ether;
• an hydride donating agent; and
• an organic carboxylic acid;
to a compound of formula B:
Figure imgf000034_0002
wherein;
Y1 is chosen from a bond, C _6 alkyl, C 2_6 alkenyl or C 2_6 alkynyl;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)OR5, S(0)2OR5_ tetrazole, CON(R9) CH(R5) COOR5 , CONR10RU, CON(R9) -S02-R5 , CONR9OH or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl; or R10 and Ru are taken together with the nitrogen to form a 3 to 10 membered heterocycle; Ra and Rb are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and Cs.18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to 10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2.12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl;
Rx is chosen from C1_12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl or halogen;
R2 is chosen from C^12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C3_12 heterocycle, C3_18 heteroaralkyl, or C5.18 aralkyl;
R3 is chosen from H, Cx_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl or C6_18 aralkyl;
Z is chosen from H, halogen, C1-6alkyl.
It will be appreciated by those skilled in the art that the compounds of formula (I) or (la) can contain a chiral centre on the general formula* (I) . The compounds of formula (I) or (la) thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers) . All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. The single optical isomer or enantiomer can be obtained by method well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary.
In accordance with the present invention, the compounds of formula (I) or (la) include:
Compound 1 3- [ (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYL) - (3-IODO-BENZYL) - AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 2 3- [ (3-BENZOFURAN-2-YL-BENZYL) - (4-CHLORO-2 , 5-DIMETHYL- BENZENESULFONYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 3 3- (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYLAMINO) ■ •5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 4 3- { (2 , 4-DICHLORO-BENZOYL) - [5- (3-TRIFLUOROMETHYL-PHENYL) -FURAN- 2-YLMΞTHYL] -AMINO}-5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 5 3- [ (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYL) -METHYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 6 5- (4-FLUORO-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 7 3- (2 , 4-DICHLORO-BENZΞNESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 8 3- (4-CHLORO-2 , 5-DIMΞTHYL-BENZENESULFONYLAMINO) -5- (4-FLUORO- PHΞNYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 9 3- [ (2 , 4-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 10 5- TERT -BUTYL-3-(4-CHLORO-BENZENESULFONYLAMINO)-THIOPHENE-2- CARBOXYLIC ACID Compound 11 4- (TOLUENE-4-SULFONYLAMINO) -[2,3'] BITHIOPHENYL-5-CARBOXYLIC ACID
Compound 12 3- [ (5-BENZ0FURAN-2-YL-THI0PHEN-2-YLMETHYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THI0PHENE-2-CARB0XYLIC ACID
Compound 13 5-PHENYL-3- (TOLUΞNE-4-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 14 3- (4-CHL0R0-2, 5-DIMΞTHYL-BENZENESULFONYLAMINO) -5- (4-CHLORO- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 15 5-PHENYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 16 5-PHENYL-3- (TOLUENE-3-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 17 3-BΞNZENΞSULFONYLAMINO-5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 18 3- (4-CHLORO-BENZΞNΞSULFONYLAMINO) -5-PHENYL-THI0PHΞNE-2- CARBOXYLIC ACID
Compound 19 3- (4-CHLORO-2, 5-DIMETHYL-.BENZΞNESULFONYLAMINO) -5- (4-ISOBUTYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 20 5-TERT-BUTYL-3- (4-CHLORO-2 , 5-DIMETHYL-BENZΞNESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 21 3- (2, 5-DIMETHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 22 3- (4-METHOXY-2 , 3 , 6-TRIMETHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 23 5-PHΞNYL-3- (THIOPHENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 24 4- (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYLAMINO) - [2,3'] BITHIOPHΞNYL-5-CARBOXYLIC ACID
Compound 25 5- (3, 5-BIS-TRIFLUOROMETHYL-PHENYL) -3- (4-CHLORO-2 , 5-DIMETHYL- BENZENESULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 26 8-CHLORO-3- (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYLAMINO) -4H- 1,5-DITHIA-CYCL0PENTA[ A ]NAPHTHALENE-2-CARBOXYLIC ACID
Compound 27 3- (2 , 4-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 28 3- [3- (2, 6-DICHLORO-PYRIDIN-4-YL) -UREIDO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 29 3- (2-CHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THI0PHENE-2- CARBOXYLIC ACID
Compound 30 3- (2-FLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 31 5-PHENYL-3- (2-TRIFLUOROMΞTHOXY-BENZENΞSULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 32 3- (4- TERT -BUTYL-BENZENESULFONYLAMINO)-5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 33 3- (4-CHLORO-PHENOXYCARBONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 34 3- (3 , 4-DICHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 35 5-PHENYL-3- (2-TRIFLUOROMETHYL-BENZENESULFONYLAMINO) -THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 36 3- (5-BROMO-6-CHLORO-PYRIDINΞ-3-SULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 37 3- (5-CHLORO-THIOPHENE-2-SULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 38 3-(5-CHLORO-3-METHYL-BENZO[ B ] THIOPHENE-2-SULFONYLAMINO) -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 39 3- (4-BROMO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 40 3- (3-CHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 41 3- (5-CHLORO-l, 3-DIMETHYL-1H-PYRAZOLE-4-SULFONYLAMINO) -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 42 3- (3-BROMO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 43 3- (4-ISOPROPYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 44 3- (2 , 6-DICHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 45 3- (2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 46 5-PHENYL-3- (5- [1 , 2 , 3 ] HIADIAZOL-4-YL-THIOPHENE-2- SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 47 5-PHENYL-3- (PYRIDINE-2-SULFONYLAMINO) -THI0PHENE-2-CARBOXYLIC ACID
Compound 48 3- (2 , 4-DICHLORO-BENZYLAMINO) -5-PHENYL-THI0PHENE-2-CARB0XYLIC ACID
Compound 49 3- (3-FLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 50 5-PHENYL-3- (3-TRIFLUOROMETHYL-BENZΞNESULFONYLAMINO) -THIOPHENE-
2-CARBOXYLIC ACID
Compound 51 3- (2-CARBOXY-BENZOYLAMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC
ACID METHYL ESTER
Compound 52 5-PHΞNYL-3- (4-TRIFLUOROMETHYL-BENZENESULFONYLAMINO) -THIOPHENE-
2-CARBOXYLIC ACID
Compound 53 3- (2 , 5-DIFLUORO-BENZENESULFONYLAMINO) -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 54 3- (2-CYANO-BENZΞNESULFONYLAMINO) -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID Compound 55 3- (2 , 5-DICHLORO-THIOPHENE-3-SULFONYLAMINO) -5-PHΞNYL-THIOPHENE-
2-CARBOXYLIC ACID
Compound 56 4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5-CARBOXYLIC
ACID
Compound 57 5 ' -CHLORO-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5-
CARBOXYLIC ACID
Compound 58 5- (2 , 4-DICHLORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 59 5- (4-NITRO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID Compound 60 3- (TOLUENE-2-SULFONYLAMINO) -5- (4-TRIFLUOROMETHOXY-PHΞNYL) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 61 5-QUINOLIN-8-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 62 5-PHENYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 63 5- (3-NITRO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 64 3- (TOLUENE-2-SULFONYLAMINO) -5-M-TOLYL-THIOPHENE-2-CARBOXYLIC ACID Compound 65 5- (3-CHLORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 66 5- (4-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 67 5- (3-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID Compound 68 5- (4-CHLORO-PHΞNYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 69 5- (3 , 5-DIFLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 70 5- (3 , 4-DIFLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 71 3- (TOLUENE-2-SULFONYLAMINO) -5-VINYL-THIOPHENE-2-CARBOXYLIC
ACID
Compound 72 3- (4-CHLORO-BENZOYLAMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 73 3- [ (4-CHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 74 5-PHENYL-3- [ (THIOPHENE-2-CARBONYL) -AMINO] -THIOPHENE-2-
CARBOXYLIC ACID
Compound 75 3- [METHYL- (THIOPHENE-2-CARBONYL) -AMINO] -5-PHENYL-THIOPHENE-2
CARBOXYLIC ACID
Compound 76 3- (2-BROMO-BENZΞNESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 77 3- (2 , 4-DIFLUORO-BENZOYLAMINO) -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 78 3- [ ( , 4-DIFLUORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 79 3- (TOLUENE-2-SULFONYLAMINO) -5-TRIMETHYLSILANYLETHYNYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 80 5-ETHYNYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC
ACID
Compound 81 3- (TOLUENE-2-SULFONYLAMINO) -5- (3-TRIFLUOROMETHOXY-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 82 5-BENZOYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 83 5- (4-CYANO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 84 5- (3-CHLORO-4-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 85 5- (3 , -DICHLORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNΞ-
2-CARBOXYLIC ACID
Compound 86 5-PYRIDIN-4-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 87 5-PYRIDIN-3-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 88 3- (TOLUENE-2-SULFONYLAMINO) -5- (4-TRIFLUOROMETHYL-PHENYL) -
THIOPHENE-2-CARBOXYLIC ACID Compound 89 5- (4-METHANESULFONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 90 5- (3-ACETYLAMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 91 5- (3-CHLORO-4-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 92 3- (4-METHYL-BENZOYLAMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 93 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 94 3- (3 , 5-DIMETHYL-ISOXAZOLE-4-SULFONYLAMINO) -5-PHENYL-THIOPHΞNE-
2-CARBOXYLIC ACID
Compound 95 3- [ (2-CHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 96 3- (2-METHYL-BENZOYLAMINO) -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 97 3- [METHYL- (2-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 98 5-PHENYL-3- ( 5-TRIFLUOROMETHYL-PYRIDINE-2-SULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 99 5-PHENYLETHYNYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 100 3- (2 , 5-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-NITRO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 101 5- ( 2-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 102 5- (2-CYANO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 103 5- (2-ETHOXYCARBONYL-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 104 5- (2-METHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 105 3 ' -METHYL-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5- CARBOXYLIC ACID Compound 106 3- (TOLUENE-2-SULFONYLAMINO) -5- (2-TRIFLUOROMETHYL-PHENYL) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 107 3- (2 , 5-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-FLUORO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 108 5-STYRYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 109 3- (2 , 4-DIFLUORO-BENZENΞSULFONYLAMINO) -5- (4-NITRO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 110 3- (2 , 4-DIFLUORO-BΞNZENESULFONYLAMINO) -5- (4-FLUORO-PHENYL) - THIOPHENΞ-2-CARBOXYLIC ACID Compound 111 3- [ [5- (3-CHLORO-4-FLUORO-PHENYL) -THIOPHEN-2-YLMETHYL] -(2,4- DICHLORO-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 112 3-[ ( 4-OXO-l-PHENYL-l, 3, 8-TRIAZA-SPIRO [4.5 ] DECANE-8-CARBONYL) AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 113 3-{ [4- (2-0X0-2, 3-DIHYDRO-BENZOIMIDAZOL-l-YL) -PIPERIDINE- CARBONYL] -AMINO} -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 114 3-{ [4- (4-NITRO-PHENYL) -PIPERAZINE-1-CARBONYL] -AMINO} -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 115 5- (2-CARBOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 116 5- (4-CHLORO-PHENYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 117 5- (3-CYANO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 118 3- (2 , 5-DIMETHYL-BENZENESULFONYLAMINO) -5-P-TOLYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 119 3- (2 , 4-DIFLUORO-BENZENΞSULFONYLAMINO) -5-P-TOLYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 120 5-PHENETHYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 121 5- (3-ETHOXYCARBONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID Compound 122 5- (4-METHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2-
CARBOXYLIC ACID
Compound 123 5- (3-METHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 124 5- ( ' -BROMO-BIPHΞNYL-4-YL) -3- (TOLUΞNE-2-SULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 125 5- ( 4-HYDROXYMΞTHYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 126 5-FURAN-3-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 127 5-BENZOFURAN-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 128 5-PYRIDIN-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 129 5- (4-NITRO-PHENYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 130 3- [ (BENZOFURAN-2-CARBONYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 131 3- [ (2, 4-DIMETHYL-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 132 3- [ [5- (2-CYANO-PHENYL) -THIOPHEN-2-YLMETHYL] - (2 , -DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 133 5- (4-FLUORO-PHENYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 134 5- [2- ( -CHLORO-PHENYL) -VINYL] -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID
Compound 135 3-BENZENESULFONYLAMINO-5- (4-FLUORO-PHENYL) -THIOPHENE-2- CARBOXYLIC ACID
Compound 136 3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 137 5-PHENYL-3- (2-VINYL-BENZENESULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID Compound 138 3- (4-BROMO-2, 5-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 139 3- (2-ACETYLAMINO-4-METHYL-THIAZOLE-5-SULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 140 3- (4-ACETYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 141 3- (4-FLUORO-2-TRIFLUOROMETHYL-BENZENΞSULFONYLAMINO) -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 142 3- (2-METHOXY-4-METHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 143 3- (3 , 4-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 144 4- (2-CARBOXY-5-PHΞNYL-THIOPHEN-3-YLSULFAMOYL) -5- (4-CHLORO- PHENYD-2-METHYL-FURAN-3-CARBOXYLIC ACID ETHYL ESTER
Compound 145 3- (4-FLUORO-3-TRIFLUOROMΞTHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 146 3- (2-AMINO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 147 3- (3-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 148 3- (4-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 149 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 150 5- (3-CYANO-BENZYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 151 5-PHENYL-3- (2 , 4, 6-TRIFLUORO-BENZENESULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 152 3- (4-METHOXY-2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID ' Compound 153 5-PHΞNYL-3- (2,3, 4-TRICHLORO-BENZENESULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 154 5- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -2-METHYL-FURAN- 3-CARBOXYLIC ACID METHYL ESTER
Compound 155 4- (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YLSULFAMOYL) -2-METHYL-l, 5- DIPHENYL-1H-PYRROLΞ-3-CARBOXYLIC ACID ETHYL ESTER
Compound 156 5-PHΞNYL-3-{ [4- (3-TRIFLUOROMETHYL-PHENYL) -PIPERAZINΞ-1- CARBONYL] -AMIN}-THIOPHENE-2-CARBOXYLIC ACID
Compound 157 3-{ [4- (4-FLUORO-PHENYL) -PIPERAZINΞ-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 158 3-{ [4- (2 , 6-DIMETHYL-PHENYL) -PIPΞRAZINE-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 159 3-{ [4- (2-CHLORO-PHENYL) -PIPERAZINE-1-CARBONYL] -AMINO}-5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 160 3-{ [4- (3-CHLORO-PHENYL) -PIPERAZINE-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 161 4,4' -BIS- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5 , 5 ' ■ DICARBOXYLIC ACID
Compound 162 3- [ALLYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 163 5- (l-DIMETHYLSULFAMOYL-lH-PYRAZOL-4-YL) -3- (TOLUENE-2- SULFONYLAMINO) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 164 5- (3-AMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 165 5- (4-AMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 166 5- (4-ACETYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 167 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -2 , 5-DIMETHYL-1H- PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER
Compound 168 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -5- (4-CHLORO-
PHENYL)-3-METHYL-l-PHENYL-lH-PYRROLΞ-2-CARBOXYLIC ACID ETHYL ESTER
Compound 169 3- (3 , 5-DICHLORO-4-HYDROXY-BENZENESULFONYLAMINO) -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 170 5- (1H-PYRAZOL-4-YL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 171 5- (3-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 172 3- [METHYL- (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID Compound 173 3- { [2- (4-FLUORO-PHENYL) -ACETYL] -METHYL-AMINO} -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 174 3- (4-PENTYL-BENZΞNESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 175 3- (MΞTHYL-PHENYLACETYL-AMINO) -5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 176 3- [2 , 5-BIS- (2 , 2 , 2-TRIFLUORO-ΞTHOXY) -BENZENESULFONYLAMINO] -5-
PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 177 3- (4-METHYL-2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 178 5-THIAZOL-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 179 5-PHENYL-3- [3- (3-PHENYL- ROPYL) -UREIDO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 180 3- [ (3 , 4-DIHYDRO-1H-ISOQUINOLINE-2-CARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 181 3-{ [4- ( -METHOXY-PHENYL) -PIPΞRAZINE-1-CARBONYL] -AMINO}-5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 182 3-{ [4- (6-METHYL-PYRIDIN-2-YL) -PIPΞRAZINE-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID HYDROCHLORIDE
Compound 183 3-{ [4- (4-CHLORO-BENZYL) -PIPERAZINE-1-CARBONYL] -AMINO}- PHENYL-THIOPHENE-2-CARBOXYLIC ACID HYDROCHLORIDE
Compound 184 5- (5-METHYL-PYRIDIN-2-YL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 185 3- [ETHYL- (4-MΞTHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 186 3- [ (3-CHLORO-THIOPHENE-2-CARBONYL) -METHYL-AMINO] -5-PHΞNYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 187 3- [ (2-BROMO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THI0PHΞNΞ-2- CARBOXYLIC ACID
Compound 188 3- [ (4-BUTYL-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 189 3- (2-CHLOROMETHYL-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 190 5- (4-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 191 5- (5-CHLORO-PYRIDIN-2-YL) -3- (TOLUENE-2-SULFONYLAMINO) -
THIOPHENΞ-2-CARBOXYLIC ACID
Compound 192 5- (4-CHLORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 193 5- (4-CYANO-PHENYL) -3- [METHYL- (4-METHYL-BΞNZOYL) -AMINO] • THIOPHENE-2-CARBOXYLIC ACID Compound 194 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (4-NITRO-PHENYL).- THIOPHENE-2-CARBOXYLIC ACID
Compound 195 5- (4-HYDROXYMETHYL-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) - AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 196 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (3-NITRO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 197 5- (4-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 198 5- (4-METHOXY-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 199 3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] -5-P-TOLYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 200 5- (4-AMINO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 201 3- [CYCLOPENTYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 202 5-BENZO [1, 3] DIOXOL-5-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-
2-CARBOXYLIC ACID
Compound 203 3- [ (2-HYDROXY-ETHYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 204 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOBUTYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 205 3- [ (2-METHOXY-4-METHYL-BENZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 206 5- (3-CYANO-PHENYL) -3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 207 5- (2-CHLORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 208 3-[ (2 , 4-DICHLORO-BENZOYL) -PHENYL-AMINO] -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 209 3- [4- (TRIFLUOROMΞTHYL-BENZOYL)METHYLAMINE] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 210 3- [ (4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 211 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 212 5- (3 , 5-DIFLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 213 5- (3-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 214 5- (2 , 4-DIFLUORO-PHΞNYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID Compound 215 5- (4-HYDROXY-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 216 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (4-TRIFLUOROMETHOXY- PHENYL) -THIOPHΞNE-2-CARBOXYLIC ACID
Compound 217 5- (2-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID Compound 218 3- [ (2-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 219 3- [ (3 , 5-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHΞNE-
2-CARBOXYLIC ACID
Compound 220 3- (4-BROMO-2-METHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-
2-CARBOXYLIC ACID
Compound 221 3- (5-CARBOXY-4-CHLORO-2-FLUORO-BΞNZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 222 5-PHENYL-3- (2,3, 4-TRIFLUORO-BENZENESULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 223 3- (4-BROMO-2-FLUORO-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL-
PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 224 3- (4-BROMO-2-METHYL-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL-
PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 225 5- (4-ISOBUTYL-PHENYL) -3- (3-METHOXY-BENZENESULFONYLAMINO) -
THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 226 3- [ (4-FLUORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 227 3- [2 , 5-BIS- (2,2, 2-TRIFLUORO-ETHOXY) -BENZENESULFONYLAMINO] -5- (4-ISOBUTYL-PHENYL) -THIOPHΞNE-2-CARBOXYLIC ACID Compound 228 3- (2-CHLORO-4-CYANO-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 229 5 ' -ACETYL-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5-
CARBOXYLIC ACID
Compound 230 5-BΞNZO [B] HIOPHEN-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-
2-CARBOXYLIC ACID
Compound 231 5- ( -BUTYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 232 5- (4-ETHYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 233 3- [BENZYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHΞNYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 234 3- [ (4-CHLORO-2-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-
THIOPHENΞ-2-CARBOXYLIC ACID
Compound 235 3- [ (2 , 4-DIMΞTHYL-BENZENESULFONYL) -METHYL-AMINO] -5-PHΞNYL-
THIOPHENE-2-CARBOXYLIC ACID Compound 236 5- (4-ACΞTYL-PHENYL) -3- (2 , 4-DIMETHYL-BΞNZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 237 5- (4-ACΞTYL-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 238 5- (4-ACETYL-PHENYL) -3- (4-CHLORO-BENZΞNESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 239 5- (4-CARBOXY-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID TERT-BUTYL ESTER
Compound 240 3- [ (2 , 4-DIMETHYL-BENZENESULFONYL) -ISOPROPYL-AMINO] -5-PHENYL-
THIOPHENΞ-2-CARBOXYLIC ACID
Compound 241 3- [ACETYL- (4-CHLORO-BENZYL) -AMINO] -5-PHΞNYL-THI0PHENE-2-
CARBOXYLIC ACID
Compound 242 3-ETHANESULFONYLAMINO-5-PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 243 3- [ISOPROPYL- (4-TRIFLUOROMETHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 244 3- [ (2, 4-DICHLORO-BENZOYL) - (3-METHYL-BUT-2-ENYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 245 3- [ (2 , 6-DICHLORO-PYRIDINE-3-CARBONYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 246 3- [ (6-CHLORO-PYRIDINE-3-CARBONYL) -ISOPROPYL-AMINO] -5-PHΞNYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 247 3- [ (4-TERT-BUTYL-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 248 5- (4-CARBOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID
Compound 2 9 5- ( 4-ETHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 250 3-[ (2, 6-DICHLORO-PYRIDINE-3-CARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 251 3- [ (BENZO [B] THIOPHENE-2-CARBONYL) -METHYL-AMINO] -5-PHENYL-
THIOPHENΞ-2-CARBOXYLIC ACID
Compound 252 3- [METHYL- (NAPHTHALΞNE-2-CARBONYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 253 3- [ (3 , 4-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 254 3- [ (3 , 5-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 255 3- [ (4-BROMO-3-METHYL-BΞNZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 256 3- [ (3-CHLORO-BENZO [B]THIOPHENE-2-CARBONYL) -METHYL-AMINO] -5-
PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 257 3- [METHYL- (4-MΞTHYL-3-NITR0-BENZ0YL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 258 5- (4-CARBAMOYL-PHENYL) -3- (2 , 4-DIMETHYL-BENZENΞSULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 259 5- (4-CARBAMOYL-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 260 5- (1H-INDOL-5-YL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-
CARBOXYLIC ACID
Compound 261 3- [ SEC -BUTYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 262 3- [ (2 , 4-DIMETHYL-BΞNZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 263 5- (4-AZIDO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- - CARBOXYLIC ACID
Compound 264 3- [ (2 , -DICHLORO-BENZOYL) - (1-PHENYL-ETHYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 265 5- (4-CARBAMOYL-PHENYL) -3- (4-CHLORO-BΞNZENESULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID
Compound 266 5- (2-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 267 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- O -TOLYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 268 3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] -5-M-TOLYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 269 5- (3-CHLORO-PHENYL) -3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 270 5- (3 , 4-DIFLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 271 5- (3-AMINO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENE-2-CARBOXYLIC ACID
Compound 272 5- (3-ACΞTYL-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -
THIOPHENΞ-2-CARBOXYLIC ACID
Compound 273 5- (3-HYDROXY-PHENYL) -3- [METHYL- (4-METHYL-BΞNZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 274 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (3-TRIFLUOROMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound ' 275 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (4-TRIFLUOROMETHYL-
PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 276 3- [ (3 , 4-DIMETHOXY-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 277 3- [METHYL- (2 , 4, 6-TRIFLUORO-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-
2-CARBOXYLIC ACID Compound 278 3- [ (2 , 3-DIFLUORO-4-TRIFLUOROMETHYL-BENZOYL) -METHYL-AMINO] -5- PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 279 3- [ (3-FLUORO-4-TRIFLUOROMΞTHYL-BENZOYL) -METHYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 280 3- [ (2 , 3-DIFLUORO-4-METHYL-BENZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 281 3- [ (2-FLUORO-4-TRIFLUOROMETHYL-BENZOYL) -METHYL-AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 282 5- (4-CARBAMOYL-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 283 5- (4-FLUORO-PHENYL) -3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID
Compound 284 3- [ (2-BROMO-4-CHLORO-BΞNZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound • 285 3- (2 , 6-DIMETHYL-BΞNZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 286 3- [METHYL- (4-METHYL-CYCLOHEXANΞCARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 287 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID METHYL ESTER
Compound 288 5- (4-CYANO-PHENYL) -3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 289 3- (4-CHLORO-BENZENΞSULFO YLAMINO) -5- (4-CYANO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 290 5- (4-CYANO-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 291 5 ' -ACETYL-4- (2 , -DIMETHYL-BENZENESULFONYLAMINO) -
[2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID
Compound 292 5 ' -ACETYL-4- (2 , 6-DIMETHYL-BENZΞNESULFONYLAMINO) - [2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID
Compound 293 3- [METHYL- (4-METHYL-THIOPHENΞ-2-CARBONYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 294 5- (3-CHLORO-PHENYL) -3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 295 5 ' -CYANO-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5- CARBOXYLIC ACID Compound 296 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-PYRIDIN-2-YL-THIOPHENE-
2-CARBOXYLIC ACID
Compound 297 3- [ (2 , 4-DICHLORO-THI BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 298 5-PHENYL-3- (2,4, 6-TRIMETHYL-BENZENESULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 299 3- [ (1-CARBOXY-ETHYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 300 3- [ (4-METHYL-BENZOYL) - (3-MΞTHYL-BUT-2-ENYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 301 3- [ (2-HYDROXY-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 302 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-PYRIDIN-3-YL-THIOPHENE-
2-CARBOXYLIC ACID
Compound 303 5 ' -ACETYL-4- [METHYL- (4-METHYL-BENZOYL) -AMINO] - [2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID
Compound 304 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5- (3-TRIFLUOROMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 305 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5-M-TOLYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 306 3- [ (2-BROMO-4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 307 3- [ (4-CHLORO-2-FLUORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 308 3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) -4-METHYL-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 309 3- [ (2-BROMO-4-MΞTHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 310 3-[ (4-CHLORO-2-IODO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 311 3- [' (4-CYANO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 312 3- [ALLYL- (4-METHYL-BΞNZOYL) -AMINO] -5- [4- (2-CARBOXY-VINYL) -
PHENYL] -THIOPHENE-2-CARBOXYLIC ACID
Compound 313 3- [ (4-CHLORO-2-HYDROXY-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 314 3- [ (2 , 4-DICHLORO-BΞNZOYL) -ISOPROPYL-AMINO] -4-METHYL-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 315 5- TERT -BUTYL-3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 316 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 317 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 318 5- [4- (2-CARBOXY-ETHYL) -PHENYL] -3- [ (4-METHYL-BENZOYL) -PROPYL-
AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 319 5-BENZOFURAN-2-YL-3- (2 , -DIMETHYL-BENZENESULFONYLAMINO) -
THIOPHENE-2-CARBOXYLIC ACID Compound 320 3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) -5- (4-HYDROXYMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 321 3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) -5- (4-MΞTHANESULF0NYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 322 5- [4- (2-CARBOXY-VINYL) -PHENYL] -3- (2 , 4-DIMETHYL-
BENZΞNΞSULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 323 3- [ALLYL- (4-METHYL-BΞNZOYL) -AMINO] -5- [3- (2-CARBOXY-VINYL) -
PHENYL] -THIOPHΞNE-2-CARBOXYLIC ACID
Compound 324 3- [ISOPROPYL- (2 , 4, 6-TRIMETHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 325 5- [3- (2-CARBOXY-ETHYL) -PHENYL] -3- [ (4-METHYL-BENZOYL) -PROPYL- AMINO]-THIOPHΞNE-2-CARBOXYLIC ACID
Compound 326 3- [ (2-FLUORO-4-TRIFLUOROMETHYL-BENZOYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 327 3- [ TERT -BUTYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 328 3- [ (2-AMINO-4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 329 3- [ (4-CHLORO-2-NITRO-BΞNZOYL) -ISOPROPYL-AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 330 3- [ (4-METHYL-BENZOYL) - (3-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 331 3- [ (3-FLUORO-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 332 5- (4-CARBOXY-PHENYL) -3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) - THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 333 3- [CYCLOPROPYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 334 3- [ (3-TERT-BUTYL-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 335 3- [ (3-CHLORO-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 336 3- [ (2 , 4-DIFLUORO-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 337 3- [ (4-CHLORO-2 , 5-DIFLUORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 338 3- [ (2 , -DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (2-METHYL-ALLYL)-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 339 3- {ALLYL- [2- (4-CHLORO-PHENYL) -ACΞTYL] -AMINO} -5-PHENYL-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 340 3- [BENZYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID Compound 341 3- [ (4-CHLORO-BENZYL) - (4-MΞTHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 342 3- [ (4-METHYL-BENZOYL) - (4-NITRO-BΞNZYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 343 3- [ (4-METHYL-BENZOYL) - (2-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 344 3- [ (3-METHOXY-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 345 3- [ (2-CHLORO-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 346 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-ISOBUTYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 347 3- [ALLYL- (2-NAPHTHALΞN-2-YL-ACETYL) -AMINO] -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 348 3- {ALLYL- [2- (2 , 4-DICHLORO-PHENYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 349 3-{ALLYL- [2- (2-CHLORO-4-FLUORO-PHENYL) -ACETYL] -AMINO}-5-
PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID
Compound 350 3- {ALLYL- [2- (3 , 4-DICHLORO-PHENYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 351 3- {ALLYL- [2- (2 , 4-DIFLUORO-PHENYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 352 3- {ALLYL- [2- (4-TRIFLUOROMETHYL-PHENYL) -ACETYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 353 3-{ALLYL- [2- (2 , 6-DICHLORO-PHENYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 354 3- [ALLYL- (2-M-TOLYL-ACETYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 355 5- (4-ACΞTYL-PHENYL) -3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 356 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4-FLUORO- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 357 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-M-TOLYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 358 5 ' -ACETYL-4- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] - [2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 359 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (3-
TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 360 4- [ (2 , -DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5 ' -METHYL- [2,2'] BITHIOPHΞNYL-5-CARBOXYLIC ACID
Compound 361 3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-METHOXY-PHENYL) THIOPHENE-2-CARBOXYLIC ACID Compound 362 3- (CYCLOHEXANECARBONYL-ISOPROPYL-AMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 363 3-{ (2 , 4-DICHLORO-BENZOYL) - [1- (2 , 4-DICHLORO-BENZOYL) -PIPERIDIN- 4-YL] -AMINO} -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 364 4- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (4-METHYL-BENZOYL) - AMINO] -PIPERIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER Compound 365 4- [ (2-CARBOXY-5-PHΞNYL-THIOPHΞN-3-YL) - (2 , 4-DICHLORO-BENZOYL) -
AMINO] -PIPΞRIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER
Compound 366 3- [ (4-METHYL-BENZOYL) -PIPERIDIN-4-YL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 367 5 ' -ACETYL-4- (2 , 4-DIMETHYL-BENZENΞSULFONYLAMINO) - [2,3'] BITHIOPHENYL-5-CARBOXYLIC ACID
Compound 368 3- [ (2, 4-DICHLORO-BENZOYL) -PIPERIDIN-4-YL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 369 5- (4-METHANESULFONYLAMINO-PHENYL) -3- {TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 370 3- (4-FLUORO-2-METHYL-BENZΞNESULFONYLAMINO) -5-PHENYL-THIOPHENE-
2-CARBOXYLIC ACID
Compound' 371 3- [ (3-METHYL-CYCLOHEXANΞCARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 372 3- (4-CHLORO-2-METHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 373 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4- MΞTHANESULFONYL-PHENYL)-THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 374 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4-
MΞTHANESULFINYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 375 5- (4-CARBOXY-PHENYL) -3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 376 5-BENZOFURAN-2-YL-3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] THIOPHENE-2-CARBOXYLIC ACID
Compound 377 3- [ (2-ACETOXY-4-MΞTHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 378 3- [ISOPROPYL- (2-METHYL-CYCLOHΞXANECARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 379 3- [ISOPROPYL- (2-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 380 3- (CYCLOHEPTANECARBONYL-ISOPROPYL-AMINO) -5-PHΞNYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 381 3- [ISOPROPYL- {4-METHYL-CYCLOHΞXANΞCARBONYL) -AMINO] -5- (3- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 382 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-METHYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 383. 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- (3-NITRO- PHΞNYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 384 3- [ (3-CYCLOPENTYL-PROPIONYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 385 3- (BUTYRYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 386 3- (METHYL-PENT-4-ENOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC
ACID
Compound 387 3- [ISOPROPYL- (5-METHYL-3-OXO-3H-ISOINDOL-1-YL) -AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 388 3- [METHYL- (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 389 3- (METHYL-PENTANOYL-AMINO) -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 390 3- [METHYL- (4-METHYL-PΞNTANOYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 391 3- (CYCLOPENTANECARBONYL-ETHYL-AMINO) -5-PHΞNYL-THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 392 3- [ (3-CYCLOPENTYL-PROPIONYL) -ETHYL-AMINO] -5-PHENYL-THIOPHENE-
2-CARBOXYLIC ACID
Compound 393 3- (CYCLOBUTANECARBONYL-ETHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 394 3- (BUT-2-ENOYL-ΞTHYL-AMINO) -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 395 3- [ISOPROPYL- (4-METHYL-2-VINYL-BENZOYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 396 3- [ISOPROPYL- (4-METHYL-CYCLOHEX-l-ΞNECARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 397 3- (ALLYL-HEXANOYL-AMINO) -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 398 3- (ALLYL-CYCLOBUTANECARBONYL-AMINO) -5-PHΞNYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 399 3- (ALLYL-PENTANOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 400 3- [ALLYL- (4-METHYL-PENTANOYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 401 3- [ALLYL- (2-CYCLOPENTYL-ACETYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 402 3- [ (2-HYDROXY-4-METHYL-CYCLOHΞXANECARBONYL) -ISOPROPYL-AMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 403 3- [ (2 , 4-DICHLORO-BENZOYL) - (1-PHENYL-ETHYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 404 3- [ (2, 4-DICHLORO-BENZOYL) - (1-PHENYL-ETHYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 405 3- [ISOPROPYL- (3-METHYL-CYCLOPENT-3-ENECARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 406 3-[ (2-BENZYLOXY-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5- (3- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 407 3- [ (2 , 4-DIMETHYL-CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 408 3- [ISOPROPYL- (3-METHYL-CYCLOPENTANECARBONYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 409 3- [ (2-HYDROXY-4-METHYL-CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] ■ 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 410 5-PHENYL-3- [PROPIONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID
Compound 411 3- [ISOBUTYRYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 412 3- [ (3-METHYL-BUTYRYL) - (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 413 3- [CYCLOPROPANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 414 3- [CYCLOBUTANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 415 3- [BUTYRYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 416 3- [ (2-CYCLOPENTYL-ACETYL) - (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 417 3-[ (4-TΞRT-BUTYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 418 3- [ (4-NITRO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENΞ-2-
CARBOXYLIC ACID
Compound 419 3- [ (3-METHYL-BUTYRYL) - (4-NITRO-BENZYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 420 3- [CYCLOPROPANECARBONYL- (4-NITRO-BENZYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 421 3- [ (2-CHLORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 422 3- [ (2-CHLORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 423 3- [ (2-CHLORO-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 424 3- [ (ADAMANTANΞ-1-CARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 425 3- [ (2-CHLORO-BENZYL) -CYCLOBUTANΞCARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 426 3- [ACETYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNΞ-2- CARBOXYLIC ACID
Compound 427 3- [ (2-METHYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 428 3- [ (2-HYDROXY-4-MΞTHYL-BENZOYL) -ISOPROPYL-AMINO] -5- (3- TRIFLUOROMΞTHYL-PHENYL) -THIOPHΞNE-2-CARBOXYLIC ACID Compound 429 3- [ (l-ACETYL-PIPERIDIN-4-YL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 430 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- [4- (1 H - TETRAZOL-5-YL) -PHENYL] -THIOPHENE-2-CARBOXYLIC ACID
Compound 431 3- [ (2-CYANO-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 432 3- [CYCLOBUTANECARBONYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 433 3- [BUTYRYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 434 3- [ACETYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 435 3- [CYCLOBUTANECARBONYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 436 3- [CYCLOHEXANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 437 3- [ (4-TERT-BUTYL-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 438 3- [ (4-TΞRT-BUTYL-BΞNZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 439 3- [ (4-TΞRT-BUTYL-BENZYL) -CYCLOBUTANΞCARBONYL-AMINO] -5-PHΞNYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 440 3-[ (4-TERT-BUTYL-BENZYL) -BUTYRYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 441 3-[ (4-TERT-BUTYL-BENZYL) -CYCLOHEXANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 442 3- [ (4-TERT-BUTYL-BENZYL) - (2-CYCLOPENTYL-ACETYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 443 3- [ (2-CYCLOPENTYL-ACETYL) - (4-NITRO-BENZYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 444 3- [ (.2-CHLORO-BENZYL) -CYCLOHEXANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 445 3- [ (2-CYCLOPENTYL-ACETYL) - (3-METHYL-BENZYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 446 3- [BUTYRYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID Compound 447 3- [BUTYRYL- (2-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 448 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- M - TOLYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 449 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-THIAZOL-2-YL- THIOPHENE-2-CARBOXYLIC ACID Compound 450 3- (ACETYL-BENZYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 451 3- (BΞNZYL-PROPIONYL-AMINO) -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 452 3- [BENZYL- (2-METHOXY-ACETYL) -AMINO] -5-PHENYL-THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 453 3- [BENZYL- (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 454 3- (BENZYL-CYCLOPROPANECARBONYL-AMINO) -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 455 3- [ACETYL- (4-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 456 3-[ (4-CHLORO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 457 3- [ (4-CHLORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 458 3- [ (4-CHLORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHΞNYL-
THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 459 3-[ (4-CHLORO-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 460 5- (4- CETYL-PHENYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANECARBONYL) -AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 461 3- [ (4-CHLORO-BENZYL) -CYCLOBUTANECARBONYL-AMINO] -5-PHENYL- THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 462 3- [BUTYRYL- (4-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 463. 3- [ (4-CHLORO-BENZYL) - (2-CYCLOPENTYL-ACETYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 464 3- [ACETYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-PHENYL-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 465 3- [ISOBUTYRYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 466 3- [CYCLOPROPANECARBONYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 467 3- [ (4-METHYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHΞNE-2-
CARBOXYLIC ACID Compound 468 3- [ISOBUTYRYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 469 3- [CYCLOPROPANECARBONYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 470 3- [BUTYRYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 471 3- [ (3-METHOXY-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 472 3- [ (3-METHOXY-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 473 3- [CYCLOBUTANECARBONYL- (3-METHOXY-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 474 3- [ (2-CARBAMOYL-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 475 3- [BUTYRYL- (3-METHOXY-BΞNZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 476 3- [ACETYL- (3-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 477 3-[ (3-CHLORO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 478 3- [ (3-CHLORO-BENZYL) - (2-METHOXY-ACETYL) -AMINO] -5-PHΞNYL-
THIOPHΞNE-2-CARBOXYLIC ACID
Compound 479 3- [ (3-CHLORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 480 3- [ (3-CHLORO-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 481 3- [ (3-CHLORO-BENZYL) -CYCLOBUTANECARBONYL-AMINO] -5-PHΞNYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 482 3- [BUTYRYL- (3-CHLORO-BΞNZYL) -AMINO] -5-PHENYL-THIOPHΞNE-2-
CARBOXYLIC ACID
Compound 483 3- [ACETYL- (2 , 4-DIFLUORO-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNE-2-
CARBOXYL1C ACID
Compound 484 3- [ (2 , 4-DIFLUORO-BENZYL) - (2-METHOXY-ACETYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 485 3- [ (2 , 4-DIFLUORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID Compound 486 3- [ (2 , 4-DIFLUORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-
THIOPHENE-2-CARBOXYLIC ACID
Compound 487 3- [BENZYL- (2-CYCLOPENTYL-ACETYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 488 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (1H-INDOL-5-YL) -
THIOPHENE-2-CARBOXYLIC ACID Compound 489 3- (BENZYL-CYCLOBUTANECARBONYL- MINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 490 3- [CYCLOHEXANECARBONYL- (2 , 4-DIFLUORO-BΞNZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 491 3- {ALLYL- [2- (4-METHOXY-PHENYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 492 3- (ETHYL-HEXANOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 493 3- (BUTYRYL-ETHYL-AMINO) -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 494 3- [ETHYL- (4-METHYL-PENTANOYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 495 3- [CYCLOBUTANECARBONYL- (2 , -DIFLUORO-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 496 3- [BUTYRYL- (2, 4-DIFLUORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 497 3- (CYCLOPENTANECARBONYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 498 3- (CYCLOHEXANECARBONYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 499 3-[ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -PYRROLIDINΞ-1-CARBOXYLIC ACID TERT-BUTYL ESTER
Compound 500 3- [ (1 , 4-DIMETHYL-CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 501 5- (4-ETHYL-PHENYL) -3- [ (2-HYDROXY-4-METHYL-BENZOYL) -ISOPROPYL- AMINO] -THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 502 3- [ (2-HYDROXY-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5- M -TOLYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 503 3- [ (2 , 4-DICHLORO-BENZOYL) -PYRROLIDIN-3-YL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 504 4-{5-CARBOXY-4- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] - THIOPHΞN-2-YL}-3,6-DIHYDRO-2H-PYRIDINE-l-CARBOXYLIC ACID
BENZYL ESTER
Compound 505 3- { [2- (HYDROXYIMINO-MΞTHYL) -4-MΞTHYL-BENZOYL] -ISOPROPYL- AMINO} -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 506 3- [ (l-CARBAMIMIDOYL-PIPERIDIN-4-YL) - (2 , 4-DICHLORO-BENZOYL) ■ AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 507 4- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -AZΞPANE-1-CARBOXYLIC ACID TERT -BUTYL ESTER
Compound 508 4-{ [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -METHYL} -PIPΞRIDINE-1-CARBOXYLIC ACID BENZYL ESTER Compound 509 3- [AZEPAN-4-YL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL-
THIOPHENΞ-2-CARBOXYLIC ACID Compound 510 3- [ (4-METHYL-CYCLOHEXANECARBONYL) -PIPERIDIN-4-YL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID LITHIUM SALT
Compound 511 3- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -PI ERIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER
Compound 512 3- [ (4-BΞNZYLOXYCARBONYLAMINO-CYCLOHEXYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 513 3- [ISOPROPYL- (4-METHYL-2-OXO-CYCLOHEXANECARBONYL) -AMINO] -5-
PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 514 3-[ (2, 4-DICHLORO-BENZOYL) -PIPERIDIN-3-YL-AMINO] -5-PHENYL-
THIOPHENΞ~2-CARBOXYLIC ACID; COMPOUND WITH GENERIC INORGANIC NEUTRAL COMPONENT
Compound 515 3- [ (4-BENZYLOXYCARBONYLAMINO-CYCLOHEXYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 5-16 3- [ (2-BENZYLOXY-l-METHYL-ΞTHYL) - (2 , 4-DICHLORO-BBNZOYL) -AMINO] •
5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 517 3- [ (2 , 2-DIMETHYL- [1, 3] DIOXAN-5-YL) - (4-MΞTHYL-
CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 518 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-HYDROXY-l-HYDROXYMETHYL-ETHYL) - AMINO] -5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 519 3- [ (2 , 4-DICHLORO-BENZOYL) -PIPERIDIN-4-YLMETHYL-AMINO] -5-
PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID
Compound 520 3- [ (2-CHLORO-BENZOYL) -PIPERIDIN-4-YLMETHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 521 3- [ (4, 6-DICHLORO-1H-INDOLΞ-2-CARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 522 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-HYDROXY-l-METHYL-ΞTHYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 523 4-{l- [ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -ETHYL}-PIPERIDINE-l-CARBOXYLIC ACID BENZYL ESTER
Compound 524 4-{5-CARBOXY-4- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -
AMINO] -THIOPHEN-2-YL}-3,6-DIHYDRO-2 H -PYRIDINE-1-CARBOXYLIC ACID BENZYL ESTER Compound 525 3- [ (4-METHYL-CYCLOHEXANECARBONYL) -PYRIDIN-4-YL-AMINO] -5-
PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 526 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PIPERIDIN-4-YL- THIOPHENΞ-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUORO-ACETIC ACID
Compound 527 3- [ISOPROPYL- (4-PROPYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 528 4- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) -
AMINO] -CYCLOHEXYL-AMMONIUM; TRIFLUORO-ACETATE Compound 529 3- [ (2 , 4-DICHLORO-BENZOYL) - (l-PIPERIDIN-4-YL-ETHYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUOROACETIC ACID
Compound 530 3- [ (CYCLOHEX-3-ENECARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 531 3- [ (4-ETHYL-CYCLOHEXANΞCARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 532 3- [ (4-CHLORO-CYCLOHΞXANECARBONYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 533 4- [ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -3-METHYL-PIPERIDINE-l-CARBOXYLIC ACID BENZYL 'ESTER
Compound 534 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-METHOXY-CYCLOHEXYL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 535 3- [ (2 , 4-DICHLORO-BΞNZOYL) - (2 , 2-DIMΞTHYL- [1, 3] DIOXAN-5-YL) -
AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 536 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- (1- METHYL-PIPERIDIN-4-YL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 537 3- [ (2, 4-DICHLORO-BENZOYL) - (3-METHYL-PIPERIDIN-4-YL) -AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUOROACETIC ACID Compound 538 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-HYDROXY-CYCLOHΞXYL) -AMINO] -5-
PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 539 4-{ [ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL) - (4-METHYLCYCLOHΞXANE CARBONYL) -AMINO] -METHYL} -PIPERIDINΞ-1-CARBOXYLIC ACID BENZYL ESTER
Compound 540 3- [ ( (1R, 2S, 4R) -2-HYDROXY-4-METHYL-CYCLOHEXANECARBONYL) - ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 541 3-{ISOPROPYL- [1- (4-METHOXY-2 , 3 , 6-TRIMETHYL-BENZENESULFONYL) -5-
METHYL-1 , 2,3, 6-TETRAHYDRO-PYRIDINE-2-CARBONYL] -AMINO} -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 542 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -4-FLUORO-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 543 3- [ (2 , 4-DICHLORO-BENZOYL) - (l-METHYL-PIPERIDIN-4-YL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 544 4-{ [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (4-METHYLCYCLOHEXANΞ
CARBONYL) -AMINO] -METHYL} -PIPERIDINIUM; TRIFLUORO-ACETATE
Compound 545 3- [ (2-TΞRT-BUTOXYCARBONYLAMINO-l-METHYL-ETHYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 546 2- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO-BENZOYL) ■ AMINO] -PROPYL-AMINE TRIFLUOROACETIC ACID SALT
Compound 547 3- [ (3-CARBOXY-CYCLOPENTYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 548 3- [ (3-CARBOXY-CYCLOPENTYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 549 2- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - ( 2 , 4-DICHLORO-BENZOYL) AMINO] -CYCLOHEXYL-AMMONIUM CHLORIDE
Compound 550 3- (BENZOYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 551 { [5-PHENYL-3- (TOLUENE-4-SULFONYLAMINO) -THIOPHΞNE-2-CARBONYL] - AMINO} -ACETIC ACID
Compound 552 5-BROMO-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 553 3- [CYCLOHEXYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 554 3- [ [l,3]DIOXAN-5-YL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID
Compound 555 3- [ [2- (TERT-BUTYL-DIMETHYL-SILANYLOXY) -1-METHYL-2-PHΞNYL- ETHYL] - (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 556 3- [ [2- (TERT-BUTYL-DIMETHYL-SILANYLOXY) -l-METHYL-2-PHENYL- ETHYL] - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 557 3- [ (2, 4-DICHLORO-BENZOYL) - (2-DIETHYLAMINO-THIAZOL-5-YLMETHYL) - AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 558 (5-{ [ (2-CARBOXY-5-PHΞNYL-THIOPHEN-3-YL)- (2, 4-DICHLORO- BENZOYL) -AMINO] -METHYL}-THIAZOL-2-YL) -DIETHYL-AMMONIUM; CHLORIDE
Compound 559 5- (4-FLUORO-PHENYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANECARBONYL) -AMINO] -THIOPHENE-2-rCARBOXYLIC ACID
Compound 560 3- [ ( (IS, 2R, 4S) -2-HYDROXY-4-METHYL-CYCLOHEXANECARBONYL) - ISOPROPYL-AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 561 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-METHOXY-1-METHYL-ETHYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 562 3- [ (4S) -ISOPROPYL- (4-METHYL-CYCLOHEX-l-ENΞCARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 566 3-MΞTHYL- (4-METHYLBENZOYL) -AMINO) 5-PHENYL THIOPHENΞ-2- CARBOXYLIC ACID (2-HYDROXY-ETHYL) AMIDE
Compound 567 5-PHENYL-3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID CYCLOBUTYLAMIDE
Compound 568 3- (2, 4-DIMETHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID AMIDE Compound 569 5-BROMO-3- [ (2 , 4-DICHLORO-BΞNZOYL) -ISOPROPYL-AMINO] -THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 570 5- (4-CHLORO-PHENYL) -3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 571 5- (4 ' -CHLORO-BIPHENYL-4-YL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANECARBONYL) -AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 572 3- [ (4-METHYL-CYCLOHEXANECARBONYL) - (TETRAHYDRO-PYRAN-4-YL) - AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 573 3- [ (4-METHYL-CYCLOHEXANECARBONYL) - (l-METHYL-PIPERIDIN-4-YL) - AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 574 3- [ (4-METHYL-CYCLOHEXANECARBONYL) -PIPERIDIN-4-YL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 575 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANΞCARBONYL) -AMINO] -5- (4- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 576 5- (4-CYANO-PHENYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANΞCARBONYL) -AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 577 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- (4- MΞTHOXY-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 578 3- [ (2-METHOXY-l-METHYL-ETHYL) - (4-METHYL-CYCLOHEXANECARBONYL) - AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 579 3- [CYCLOHEXYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 581 5- (4-ISOBUTYL-PHΞNYL) -3- [5- (5-TRIFLUOROMETHYL-ISOXAZOL-3-YL) - THIOPHENE-2-SULFONYLAMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 582 5- (4-ISOBUTYL-PHENYL) -3- (2 , 3 , 4-TRIFLUORO- BΞNZENESULFONYLAMINO) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 583 3- [ (2 , 4-DICHLORO-PHENYL) -ISOPROPYL-CARBAMOYL] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 584 3- (MΞTHYL-P-TOLYL-CARBAMOYL) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 585 3- [ (2 , 4-DICHLORO-PHENYL) -METHYL-CARBAMOYL] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
or pharmaceutically acceptable salts thereof.
Preferably, the compounds of the present invention are provided in the form of a single enantiomer at least 95%, more preferrably at least 97% and most preferably at least 99% free of the corresponding enantiomer .
More preferably the compound of the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer . More preferably the compound of the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.
More preferably the compound of the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.
In a more preferred embodiment, the compound of the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.
Most preferably the compound of the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.
More preferably the compound of the present invention are in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.
There is also provided a pharmaceutically acceptable salts of the present invention. By the term pharmaceutically acceptable salts of compounds of general formula (I) or (la) are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases . Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric,, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic,' citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts .
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR4+ (where R is C]__4 alkyl) salts. References hereinafter to a compound according to the invention . includes compounds of the general formula (I) or (la) and their pharmaceutically acceptable salts .
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
As used in this application, the term "alkyl" represents a straight chain, branched chain or cyclic hydrocarbon moiety which mayoptionallybesubstitutedby one or more of: halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido;
wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle;
or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle. Useful examples of alkyls include isopropyl, ethyl, fluorohexyl or cyclopropyl. The term alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an oxygen, (e.g. a benzoyl) or an halogen, more preferably, the halogen is fluoro (e.g. CF3- or CF3CH2-) .
The terms "alkenyl" and "alkynyl" represent an alkyl containing at least one unsaturated group (e.g. allyl, acetylene, •ethylene) . The term "aryl" represents a carbocyclic moiety containing at least one benzenoid-type ring which may optionally be substituted by one or more of halogen, nitro, nitroso, S03R12, P03RcRd, C0NR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido;
wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle. Examples of aryl include phenyl and naphthyl .
The term "aralkyl" represents an aryl group attached to the adjacent atom by a Cl-6alkyl, Cl-6alkenyl, or Cl-6alkynyl (e.g. , benzyl) .
The term "heterocycle" represents a saturated or unsaturated, cyclic moiety wherein said cyclic moeity is interrupted by at least one heteroatom, (e.g. oxygen, sulfur or nitrogen) which may optionally be substituted halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 12 aralkyl, C6-12 aryl, Cl-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(0)Cl-6 alkyl, C(0)C2-6 alkenyl, C(0)C2-6 alkynyl, C(0)C6-12 aryl, C(0)C6-12 aralkyl, C3-10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, Cl-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-14 aryl, C3-12 heterocycle, C3-18 heteroaralkyl, C6-18 aralkyl; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle. It is understood that the term heterocyclic ring represents a mono or polycyclic (e.g., bicyclic) ring. Examples of heterocyclic rings include but are not limited to epoxide; furan; benzofuran; isobenzofuran; oxathiolane; dithiolane; dioxolane; pyrrole; pyrrolidine; imidazole; pyridine; pyrimidine; indole; piperidine; morpholine; thiophene and thio orpholine.
The term "heteroaralkyl" represents an heterocycle group attached to the adjacent atom by a Ch lky!, C^ alkenyl, or C _6 alkynyl.
When there is a sulfur atom present, the sulfur atom can be at different oxidation levels, ie. S, SO, or S02. All such oxidation levels are within the scope of the present invention.
The term "independently" means that a substituent can be the same or different definition for each item.
As used in this application, the term " hydride donating agent " means a suitable ionic or covalent inorganic compound of hydrogen with another element (e.g. boron, sodium, lithium or aluminum) allowing the process to occur under the reaction conditions without causing adverse effect on the reagents or product. Useful examples of hydride donating agent include but are not limited to sodium borohydride (NaBH4) , sodium cyanoborohydride (NaCNBH3) , sodium triacetoxyborohydride (Na(OAc)3BH) and borane-pyridine complexe (BH3-Py) . Alternatively, resin or polymer supported hydride donating agent on a may be used.
The term "organic carboxylic acid" include but is not limited to aliphatic acid (e.g. acetic, formic, trifluoroacetic), aromatic acid (e.g. benzoic and salicylic) , dicarboxylic acid (e.g. oxalic and phthalic) . It will be apparent to one of ordinary skill that resin supported organic carboxylic acid may also be used. The term ,enol ether" as used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . Enol ethers may be obtained commercially or prepared by well-known methods . Non-limiting examples of preparation include alkylation or silylation of enolates obtained from carbonyl compounds such as aldehydes, ketones, esters .
It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75μM, preferably about 2 to 50 μM, most preferably about' 3 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising compounds of formula (I) or (la) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers' therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. '
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual) , transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulation suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents . The tablets may be coated according to methods well known in the art. Oral liquid. preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non- aqueous vehicles (which may include edible oils) , or preservatives .
The compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing an/or dispersing agents . Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments , creams or lotions, or as a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents . Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents , or colouring agents .
Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier (s) followed by chilling and shaping in moulds .
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops . Drops may be formulated with an aqueous or non- aqueous base also comprising one more dispersing agents, solubilising agents or suspending agents . Liquid sprays are conveniently delivered from pressurized packs.
For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
When desired the above described formulations adapted to give sustained release of the active ingredient may be employed. The compounds of the invention may also be used in combination with other antiviral agents or in combination with any additional agents useful in therapy and may be administered sequentially or simultaneously.
In one aspect of the invention, the compounds of the invention may be employed together with at least one other antiviral agent chosen from protease inhibitors, polymerase inhibitors, and helicase inhibitors .
In another aspect of the invention, the compounds of the invention may be employed together with at least one other antiviral agent chosen from Interferon- and Ribavirin.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations .
When. the compounds of formula (I) or (la) or a pharmaceutically acceptable salts thereof is used in combination with a second therapeutic agent active against the same virus the dose of each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
The following general schemes and examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope.
Example 1
Preparation of 3- (2-Chloro-benzenesulfonylamino) -5-phenyl- thiophene-2-carboxylic acid, compound #29
Figure imgf000073_0001
STEP I
3-Amino-5-phenyl-thiophene-2-carboxylic acid.
To a suspension of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (5 g, 21.459 mmol) in a mixture of THF:MeOH:H20 (3:2:1, 75 mL) , IN aqueous solution of LiOH.H20 (64 mL, 64.378 mmol) was added. The reaction mixture was stirred at 85°C (external temperature) for 4h. Solvents were removed under reduced pressure and the residue was partitioned between water ' and ethyl acetate. The water layer was separated and acidified with IN HCI solution and then ethyl acetate was added to it. The organic phase was separated, dried (Na2S04) and concentrated to obtain 3-Amino-5-phenyl-thiophene-2-carboxylic acid (4.15 g, 88%) as a yellowish solid. XH NMR (DMS0-D6, 400 MHz): 7.59 (d, 2H) , 7.40 (m, 3H) , 6.92 (s, 1H) .
STEP II
3- (2-Chloro-benzenesulfonylamino) -5-phenyl-thiophene-2- carboxylic acid
3-Amino-5-phenyl-thiophene-2-carboxylic acid (lOOmg, 0.457 mmol) was taken in a mixture of dioxane and water (1:1, 25 mL) and then added sodium carbonate (242 mg, 2.285 mmol) and 1- chlorobenzenesulfonyl chloride (289 mg, 1.369 mmol). The reaction mixture was stirred at room temperature for 12 h. Half of the solvent was removed under reduced pressure and then diluted with water and ether in a separatory funnel . The ether layer was separated and the aqueous layer was acidified with 10% KHS04 solution. Ethyl acetate was added to the aqueous phase to dissolve the white precipitate. The ethyl acetate layer was separated, dried (Na2S04) and concentrated to 5 mL. The white solid was filtered and then washed with cold ethyl acetate to obtain 3- (2-Chloro-benzenesulfonylamino) -5-phenyl-thiophene-2- carboxylic acid (125 mg, 69%). XH NMR (DMS0-D6, 400 MHz): 10.51 (bs, 1H) , 8.30 (d, 1H) , 7.72-7.60 ( , 4H) , 7.57 (m, 1H) , 7.44 (m, 4H) .
The following compounds were prepared in a similar manner as described in general scheme 1 : Compound #3, Compound #5, Compound #7, Compound #13, Compound #15, Compound #16, Compound #17, Compound .#18, Compound #21, Compound #22, Compound #23, Compound #29, Compound #30, Compound #34, Compound #37, Compound #38, Compound #39, Compound #40, Compound #41, Compound #42, Compound #44, Compound #45, Compound #46, Compound #49, Compound #50, Compound #52, Compound #53, Compound #54, Compound #55, Compound #76, Compound #94
Example 2
3- (Toluene-2-sulfonylamino) -5-p-tolyl-thiophene-2-carboxylic acid , compound #62
Figure imgf000075_0001
Figure imgf000075_0002
STEP I
3- (bis- (Toluene-2-sulfonyl) -amino) -thiophene-2-carboxylic acid methyl ester
To a cold (0°C) stirred sodium hypochlorite (NaOCl, 10.8% commercial bleach, 124 mL, 180.00 mmol) solution was added o- thiocresol (2.23 g, 2.12 mL, 18.0 mmol). To this vigorous stirred solution was added cone. Sulfuric acid (caution! extremely exothermic, 92 g, 50 L, 938 mmol) dropwise. The resultant yellow reaction mixture was stirred for 2 h at the same temperature, diluted with water (50 mL) and dichloromethane 50 mL. The organic solution was separated, aqueous solution was extracted with CH2C12 ( 2 50 mL) . The combined organic extracts were washed with water, brine and dried. Evaporation of the solvent under reduced pressure furnished the 2-methylsulfonyl chloride (3.13 g, 91.5% yield), which was used in the next step without purification. XH NMR (CDC13,300 MHz) 8.07 (td, J = 7.3, 1.5 Hz, 1H) , 7.61 (tt, J = 7.5, 1.1 Hz, 1H) , 7.44-7.40 (m, 2H) , 2.80 (s, 3H) .
To a stirred solution of the methyl 3-amino-thiophene-2- carboxylic acid (1.0 g, 6.36 mmol) and DMAP (776 mg, 6.36 mmol) in CH2C12 was sequentially added triethyl amine (1.61 g, 15.9 mmol, 2.5 eq) and o-toluenesulfonyl chloride (3.02 g, 15.9 mmol, 2.5 eq) , stirred for 24 h. The reaction mixture was diluted with EtOAc (100 mL) , washed with 1.2 N HCI (2 x 50 mL) , 6 N HCI (40 mL) , saturated NaHC03 solution, brine and dried. Evaporation of the solvent under reduced pressure yielded 3- (bis- (Toluene-2- sulfonyl) -amino) -thiophene-2-carboxylic acid methyl ester (2.78 g, 93.3%) as a solid. The crude product was used in the next step without purification. XH NMR (CDC13,300 MHz) 8.198 (dd, J = 8.0, 1.2 Hz, 2H) , 7.52 (d, J = 5.3 Hz, 1H) , 7.5 (dt, J = 7.5 Hz, 1.1 Hz, 2H) , -7.36 (t, J = 7.5 Hz, 3H) , 7.28 (d, J = 7.6 Hz, 2H) , 7.16 (d, J = 5.3 Hz, 1H) , 3.44 (s, 3H) , 2.43 (s, 3H) .
STEP II
3- (Toluene-2-sulfonylamino) -thiophene-2-carboxylic acid
To a stirred mixture of 3- (bis- (Toluene-2-sulfonyl) -amino) - thiophene-2-carboxylic acid methyl ester (2.5 g, 5.35 mmol) in 1, 4-dioxane/MeOH/water (3:1:1; 62.5 mL) was added aq. 1 N NaOH solution (16.05 L, 16.05 mmol, 3.0 eq) and heated at 85°C for 3.. 5 h and it was then cooled to rt. To the reaction mixture was added 1.2 N HCI (16.0 mL) , extracted with CHC13 (3 x 30 L) , washed with brine and dried. Evaporation of the solvent gave 3- (Toluene-2-sulfonylamino) -thiophene-2-carboxylic acid (1.5 g, 99%) as a white solid. E NMR (DMSO-d6,300 MHz) 7.94 (dd, .7= 7.9 Hz, 1.3 Hz, 1H) , 7.76 (d, J = 5.5 Hz, 1H) , 7.55 (dt, J = 7.5 Hz, 1.3 Hz, 1H) , 7.42-7.37 (m, 2H) , 7.1 (d, J = 5.5 Hz, 1H) , 2.57 (s, 3H) .
STEP III
3- (Toluene-2-sulfonylamino) -thiophene-2-carboxylic acid tert- butyl ester To a cold (-40°C) mixture of 3- (Toluene-2-sulfonylamino) - thiophene-2-carboxylic acid (1.5 g, 5.05 mmol) in 1,4- dioxane/CHCl3 (1:2, 12 mL) was bubbled 2-methyl-2-propene gas (15 mL) in a sealed tube. To this was added Cone. H2S04 (0.070 L, 1.3 mmol) and slowly warmed up to room temperature. The resultant reaction mixture was heated at 70°C for 2.5 days in a sealed tube, cooled to -40°C, stopper was removed. The reaction mixture was slowly brought up to room temperature and stirred until the excess gas is released. The mixture was extracted with EtOAc, washed with aq. NaHC03 solution, brine and dried. Evaporation of the solvent and purification of the residue on silica gel using EtOAc/hexane (1:10 ) as an eluent furnished 3- (Toluene-2-sulfonylamino) -thiophene-2-carboxylic acid tert-butyl ester (1.31 g, 73.5% based on 90% conversion). XH NMR (CDC13 ,300 MHz) 9.89 (s, 1H) , 8.01 (d, J = 7.9 Hz, 1H) , 7.43 (dt, J = 7.5 Hz, 1.5 Hz, 1H) , 7.3-7.25 (m, 3H) , 7.2 (d, J = 5.4 Hz, 1H) , 2.69 (s, 3H) , 1.56 (s, 9H) .
STEP IV
5-Bromo-3- (toluene-2-sulfonylamino) -thiophene-2-carboxylic acid tert-butyl ester
To a cold (-30°C) stirred solution of diisopropylamine (1.345 g, 1.86 mL, 13.3 mmol, 3.6 eq) in THF (74.0 mL) was added n-BuLi (1.6 M in hexane, 7.63 mL, 12.21 mmol, 3.3 eq) dropwise and stirred for 20 min. To the cold (-78°C) LDA solution was added a solution of 3- (Toluene-2-sulfonylamino) -thiophene-2-carboxylic acid tert-butyl ester (1.31 g, 3.7 mmol, 1.0 eq) in THF (20 mL) dropwise and the solution was stirred for 2h at the same temperature. The resultant red colored solution was then quenched with 1, 2-dibromotetrafluoroethane (5.77 g, 2.65 mL, 22.2 mmol, 6.0 eq, passed through K2C03 prior to use) in one portion, stirred for 1 h.before being added sat. NH4Cl solution (15.0 L) . The reaction mixture was warmed up to rt, extracted with EtOAc, washed with brine and dried. Evaporation of the solvent and purification of the residue over silica gel column furnished 5-Bromo-3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid tert-butyl ester (1.2 g, 75% yield). *Η NMR
(CDC13, 300 MHz) 9.72 (s, 1H) , 8.0 (dd, J = 7.8, 1.3 Hz, 1H) , 7.47 (dt, J = 7.5, 1.2 Hz, 1H) , 7.35-7.30 (m, 2H) , 7.24 (s, 1H) , 2.68 (s, 3H) , 1.53 (s, 9H) .
STEP V
3- (Toluene-2-sulfonylamino) -5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester
To the mixture of 4-methylbenzeneboronic acid (38.0 mg, 0.279 mmol) and 5-Bromo-3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid tert-butyl ester (40 mg, 0.0925 mmol) in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol%) in toluene (1.0 mL) followed by aqueous 2M Na2C03 solution (0.1 mL, 0.2 mmol) . The resultant reaction mixture was heated at 70°C for 16 h, cooled to room temperature, filtered off through MgS04 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60A°) using ethyl acetate/hexane (1:10) as an eluent furnished 3- (Toluene-2- sulfonylamino) -5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 81% yield). XH NMR (CDC13, 300 MHz) 9.94 (s, 1H) , 8.05 (d, J = 8.0 Hz, 1H) , 7.44-7.25 (m, 6H) , 7.18 (d, J = 8.1 Hz, 2H) , 2.71 (s, 3H) , 2.36 (s, 3H) , 1.56 (s, 9H) .
STEP VI
3- (Toluene-2-sulfonylamino) -5-p-tolyl-thiophene-2-carboxylic acid
To a stirred solution of 3- (Toluene-2-sulfonylamino) -5-p-tolyl- thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 0.081 mmol) in CH2C12 (1.0 mL) was added TFA (0.5 mL) , stirred for 1 h at room temperature and diluted with hexane. Evaporation of the solvent under reduced pressure gave essentially the pure product as a solid. The product was purified by triturating with hexane/ CH2C12 furnished 3- (Toluene-2-sulfonylamino) -5-p-tolyl-thiophene- 2-carboxylic acid (28.0 mg, 89% yield). αH NMR (DMSO-d6, 300 MHz) 10.21 (br s, 1H) , 8.06 (d, J = 7.9 Hz, 1H) , 7.56-7.36 (m, " 6H) , 7.24 (d, J = 7.9 Hz, 2H) , 2.59 (s, 3H) , 2.48 (s, 3H) . The following compounds were prepared in a similar manner as described in general scheme 2 :
Compound #6, Compound #8, Compound #11, Compound #14, Compound #24, Compound #56, Compound #57, Compound #58, Compound #59, Compound #60, Compound #62, Compound #63, Compound #64, Compound #65, Compound #66, Compound #67, Compound #68, Compound #69, Compound #70, Compound #71, Compound #552, Compound #79, Compound #80, Compound #81, Compound #83, Compound #84, Compound #85, Compound #86, Compound #87, Compound #88, Compound #89, Compound #90, Compound #91
Example 3 3- (4-Choro-benzoylamino) -5-phenyl-thiophene-2-carboxylic acid compound #72
Figure imgf000079_0001
STEP I
3- (4-Chloro-benzoylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester
To mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate
(100 mg, 0.428 mmol) in anhydrous pyridine (4.3 ml) was added p- chlorobenzoyl chloride (71 μl, 0.556 mmol) . The mixture was stirred for 3 hours at room temperature and concentrated. , Purification chromatography (silica gel, hexane to hexane: ethyl acetate; 95:5) gave 145 mg (91% yield) of 3- (4-Chloro- benzoylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester. *H NMR (CDC13, 400 MHz) 8.54(s, 1H) , 7.99-7.96 (m, 2H) , 7.73- 7.71 (m, 2H) , 7.52-7.50 (m, 2H) , 7.46-7.39 (m, 3H) , 3.95 (s, 3H) .
STEP II
3- (4-Chlorobenzoylamino) -5-phenyl-thiophene-2-carboxylic acid
To a mixture of 3- (4-Chloro-benzoylamino) -5-phenyl-thiophene-2- carboxylic acid methyl ester (30 mg, 0.081 mmol) in 1 ml of a 3:2:1 solution made with tetrahydrofuran, methanol and water respectively was added lithium hydroxide monohydrated (20 mg, 0.484 mmol) . The mixture was stirred 30 minutes at 60°C, cooled to room temperature, diluted with water and washed with ether (2x) . The collected aqueous layer was then acidified with KHS04 20% to pH 3 and extracted with ethyl acetate (3x) . The combined ethyl acetate layers were washed with brine, dried (Na2S04) and concentrated. The resulting crude was taken in ethyl acetate and reexctracted with NaOH 0.5 N (2x) . The combined aqueous layers were then back-washed with ethyl acetate and acidified to pH3 with KHS04 20% and back-extracted with ethyl acetate (2x) . The combined organic layers were washed with brine and dried (Na2S04) . Η NMR (DMSO-d6, 400 MHz) 8.35 (s, 1H) , 8.02-7.99 (m, 2H) , 7.71-7.68 ( , 2H) , 7.56-7.53 (m, 2H) , 7.43-7.39 (m, 2H) , 7.35-7.31 (m, 1H) .
The following compounds were prepared in a similar manner as described in example 3 : Compound #74, Compound #77, Compound #92, Compound #96 ;
Example 4
3- (Benzoyl-methyl-amino) -5-phenyl-thiophene-2-carboxylic acid; compound #550
Figure imgf000081_0001
STEP I
3-Methylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester To a mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (200 mg, 0.855 mmol) in anhydrous N,N-dimethylformamide (4.6 ml) were added 4.2 ml (8.55 mmol) of 2M iodomethane solution in t- buthylmethylether . The mixture was stirred at 60°C for 18 hours, concentrated and purified using biotage technics (silica gel, hexane to hexane: ethyl acetate; 95: 5 containing few drops of triethylamine) to give 68 mg (32% yield) of 3-methylamino-5- phenyl-thiophene-2-carboxylic acid methyl ester. "Η NMR (CDC13, 400
MHz) 7.65-7.62 (m, 2H) , 7.42-7.36 (m, 3H) , 6.86 (broad s, 1H) , .
3.83 (s, 3H) , 3.04 (d, 3H)
STEP II
3- (Benzoyl-methyl-amino) -5-phenyl-thiophene-2-carboxylic acid methyl ester
This compound was prepared in a similar manner as for Example 3, Step I; 3- (Benzoyl-methyl-amino) -5-phenyl-thiophene-2-carboxylic acid methyl ester was obtained XH NMR (CDC13, 400 MHz) 7.60-7.49 (m, 2H) , 7.47-7.35 (m, 5H) , 7.28-7.20 (m, 3H) , 7.11 (broad s, 1H) , 3.83 (s, 3H) , 3.44 (s, 3H) STEP III
3- (Benzoyl-methyl-amino) -5-phenyl-thiophene-2-carboxylic acid
This compound was prepared in a similar manner as in Example 3, step II; 3- (Benzoyl-methyl-amino) -5-phenyl-thiophene-2- carboxylic acid was obtained; H NMR (CD3OD, 400 MHz) 7.64-7.62 (m, 2H) , 7.47 (s, 1H) , 7.44-7.36 ( , 5H) , 7.29-7.20 (m, 3H) , 3.42 (s, 3H)
The following compounds were prepared in a similar manner as described in example 4:
Compound #9 ; Compound #73 Compound #75 ; Compound #75 ; Compound #78 ; Compound #93 ; Compound #95v
Example 5
{ [5-Phenyl-3- (toluene-4-sulfonylamino) -thiophene-2-carbonyl] amino} -acetic acid , compound #551
Figure imgf000082_0001
STEP I
{ [5-Phenyl-3- (toluene-4-sulfonylamino) -thiophene-2-carbonyl] - amino} -acetic acid methyl ester
To a mixture of 5-phenyl-3- (toluene-4-sulfonylamino) -thiophene- 2-carboxylic acid (prepared according to example 2) (50 mg,
0.134 mmol) in anhydrous dimethylformamide (1.4 ml) were added HATU 152 mg, 0.402 mmol), glycine methyl ester hydrochloride (20 mg, 0.161 mmol) followed by collidine (124μl, 0.938 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and pre-absorbed on Si02 Purification chromatography (hexane to hexane: ethyl acetate; 6:4 to dichloromethane: methanol ; 95 : 5) gave 47 mg of a mixture of {[5- Phenyl-3- (toluene-4-sulfonylamino) -thiophene-2-carbonyl] -amino}- acetic acid methyl ester and collidine. XH NMR (CDCl3, 400 MHz) 7.76-7.73 (m, 2H) , 7.61 (s, 1H) , 7.57-7.54 (m, 2H) , 7.42-7.36
( , 3H) , 7.24-7.22 (m, 2H) , 6.19-6.17 ( , 1H) , 4.14-4.12 (m,
2H) , 3.79 (s, 3H) , 2.35 (s, 3H) .
STEP II
{ [5-Phenyl-3- (toluene-4-sulfonylamino) ■thiophene-2-carbonyl] amino} -acetic acid
Following the procedure described for example 3 (STEP II) , 28 mg (88% yield) of { [5-phenyl-3- (toluene-4-sulfonylamino) -thiophene- 2-carbonyl] -amino}-acetic acid were isolated from 33 mg (0.075 mmol) of the { [5-Phenyl-3- (toluene-4-sulfonylamino) -thiophene-2- carbonyl] -amino}-acetic acid methyl ester. XH NMR (CD3OD, 400 MHz): 7.73-7.71 (m, 2H) , 7.63-7.61 (m, 2H) , 7.54 (s, 1H) , 7.45- 7.39 (m, 3H) , 7.33-7.31 (m, 2H) , 4.88 (s, 2H) , 2.36 (s,3H).'
Example 6
3- (2 , 4-Dichloro-benzylamino) -5-phenyl-thiophene-2-carboxylic acid Compound #48
Figure imgf000083_0001
STEP I
3- (2, 4-Dichloro-benzylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester
Sodium hydride (60% dispersion in oil, 180 mg, 4,72 mmol) was added to an ice-cold solution of 3-Amino-5-phenyl-thiophene-2- carboxylic acid methyl ester (1000 mg, 4,29 mmol) in 25 ml of dimethylformamide in an atmosphere of N2. After 5 min, 2,4- dichloro-1-chloromethyl-benzene (755 mg, 3,86 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0°C and 30 min at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2X20 mL) and the combined ether layer was dried (MgS04) and concentrated. The residue obtained was then purified by precipitation. The crude product was taken in 25 ml of ethyl acetate, a yellow precipitate came out which was filtered to obtain 3- (2 , 4-Dichloro-benzylamino) -5-phenyl-thiophene-2- carboxylic acid methyl ester, 835 mg (55%) H-NMR (DMSO, 400 MHz): 7,67 ppm (m, 2H, Haro) ; 7,44-7,35 ppm (m, 6H, Haro) ; 7,26 ppm (s, 1H, Haro) ; 4,63 ppm (d, 2H, N-CH2) ; 3,75 ppm (s, 3H, 0-CH3)
STEP II
3- (2 , 4-Dichloro-benzylamino) -5-phenyl-thiophene-2-carboxylic acid
3- (2 , 4-Dichloro-benzylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 0,18 mmol) was dissolved in a mixture of THF-MeOH-H20 (3:2:1) (20 mL) and then 1080 ul of LiOH IN was added to it. After 16 h of stirring at temperature of 100°C, solvents were removed and then partitioned between 10 ml of H20, 2 ml of KHS04 5% and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2 X 10 mL) . The combined ethyl acetate layer was dried (MgS04) and concentrated to obtain 43 mg (63%) of 3- (2, 4- Dichloro-benzylamino) -5-phenyl-thiophene-2-carboxylic acid ^- MR
(DMSO, 400 MHz) :δ 7,65 ppm (m, 3H, Haro) ; 7,43-7,32 ppm (m, 5H, Haro) ; 7,23 ppm (s, 1H, Haro) ; 4,61 ppm (d, 2H, N-CH .
Example 7
3-{ (2, 4-Dichloro-benzoyl) - [5- (3-trifluoromethyl-phenyl) -furan-2- ylmethyl] -amino}-5-phenyl-thiophene-2-carboxylic acid, Compound
Figure imgf000085_0001
STEP I
5-Phenyl-3-{ [5- (3-trifluoromethyl-phenyl) -furan-2-ylmethyl] amino}-thiophene-2-carboxylic acid methylester
To a stirred solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.416mmol) in dichloromethane (15 mL) were added 5- (trifluoromethyl-phenyl) -furan-2-carbaldehyde (100 mg, 0.429 mmol) and molecular sieves. The reaction mixture was stirred at room temperature overnight. The solution was filtered over celite and the filtrate was evaporated under reduced pressure. The residue was dissolved in anhydrous methanol (15 mL) . and cooled to 0SC in an ice bath. Sodium borohydride (18 mg, 1.1 eq.) was added. The reaction mixture was stirred at this temperature for 2 h. Saturated ammonium chloride (10 mL) was added and stirring was continued for an additional 15 min. at room temperature . Methanol was removed and the resulted mixture was extracted with dichloromethane (3 x 30 mL) . The organic solution was washed with water, brine and was dried over sodium sulfate. Solvent was evaporated and the crude product was purified on silica gel using hexane : ethylacetate 9:1 as eluent to provide the desired product in 34% yield (65 mg) .
1HNMR(CDC13, 400MHz) : 7.80 (s, 1H) , 7.73 (m, 1H) , 7.55 (m, 2H) , 7.41 (m, 2H) , 7.33 (m, 3H) , 6.93 (s, 1H) , 6.48 (d, 1H) , 6.24 (d, 1H) , 4.43 (s, 2H) , 3.76 (s, 3H) .
STEP II
3-{ (2, 4-Dichloro-benzoyl) - [5- (3-trifluoromethyl-phenyl) -furan-2- ylmethyl] -amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester
To a stirred solution of 5-Phenyl-3-{ [5- (3-trifluoromethyl- phenyl) -furan-2-ylmethyl] -amino}-thiophene-2-carboxylic acid methylester (65 mg 0.142 mmol) in dichloromethane (3 ml) and saturated NaHC03 solution (3 ml) was added a solution of 2,4- dichloro-benzoyl chloride (36 mg, 1.2 eq. ) in dichloromethane (0.9 ml) . The reaction mixture was stirred vigorously at room temperature for overnight. The organic phase was collected and the aqueous phase was extracted twice with methylene chloride (2 x 15 ml) . The organic layers were combined, washed with water, brine and dried over anhydrous Na2S04. Solvent was removed and residue was purified on silica gel using Hexane : EtOAc 9:1 as eluant to give the desired product in 78% yield (70 mg) . The proton NMR ■ indicated the presence of rotamers .
1HNMR(CDC13, 400MHz) : 7.80 (s, 1H) , 7.73 (m, 1H) , 7.55 (m, 2H) , 7.45 (m, 2H) , 7.33 (m, 3H) , 7.20 (m, 2H) , 7.12 (m, 1H) , 6.93 (s, 1H) , 6.62 (d, 1H) , 6.42 (d, ' 1H) , 5.60 (bd, 1H) , 4.70 (bd, 1H) , 3.76 (s, 3H) .
STEP III
3-{ (2 , 4-Dichloro-benzoyl) - [5- (3-trifluoromethyl-phenyl) -furan-
2-ylmethyl] -amino}-5~phenyl-thiophene-2-carboxylic acid
3-{ (2, 4-Dichloro-benzoyl) - [5- (3-trifluoromethyl-phenyl) -furan-2- ylmethyl] -amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester (62 mg, 0.098 mmol) was dissolved in THF (5 mL) and water (2 mL) . A solution of lithium hydroxide (13 mg, 3eq. in 2 mL of water) was added dropwise. After first few drop, a pink color appeared and disappeared. Mixture was stirred for 5 hrs and acidified with IN HCl-solution. The product was extracted into ethyl acetate, washed once with water, dried over magnesium sulfate. Solvent was evaporated and the residue was purified on silica gel (Bond-Elute 2 g) . The product was elute with a 20 mL gradient of Hexane:EtOAc 9:1. 4:1, 7:3, 3:2, 1:1, 2:3 and EtOAc to give the desired product in 76% yield (46 mg)
1HNMR(CD3OD, 400MHz) : 7.90 (s, 1H) , 7.83 (m, 1H) , 7.55 (m, 2H) , 7.40-7.20 (m, 8H) , 7.10 (s,' lH), 6.82 (d, 1H) , 6.42 (d, 1H) , 5.60 (bd, 1H) , 4.70 (bd, 1H) , 3.86 (s, 3H) .
Example 8
Preparation of 3- [ (4-Chloro-2, 5-dimethyl-benzenesulfonyl) - (3- iodo-benzyl) -amino] -5-phenyl-thiophene-2-carboxylic acid Compound #1 and 3- [ (3-Benzofuran-2-yl-benzyl) - (4-chloro-2 , 5- dimethyl-benzenesulfonyl) -amino] -5-phenyl-thiophene~2-carboxylic acid compound #2.
Figure imgf000087_0001
STEP I
To a solution of 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5- phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.229 mmol) in anhydrous DMF (6 mL) , 3-iodobenzyl bromide (82 mg, 0.276 mmol) and cesium carbonate (88 mg, 0.276 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction mixture was partitioned between water and ether. The ether layer was separated, dried (Na2S04) , concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3- [ (4-Chloro-2, 5-dimethyl-benzenesulfonyl) - (3-iodo-benzyl) - amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester (130 mg, 87%) as a syrup.
STEP II
3- [ (4-Chloro-2, 5-dimethyl-benzenesulfonyl) - (3-iodo-benzyl) -amino] -
5-phenyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.038 mmol) was taken in a mixture of THF:MeOH:H20 (3:2:1, 3 mL) and then added IN aqueous solution of LiOH.H20 (0.24 mL, 0.228 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10 % KHS04 solution. The organic ■ layer was separated, dried (Na2S04) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (9:1) to obtain 3- [ (4-Chloro-2, 5-dimethyl-benzene-sulfonyl) - (3-iodo-benzyl) - amino] -5-phenyl-thiophene-2-carboxylic acid (22 mg, 88%) as a white solid. *H NMR (CDC13, 400 MHz): 7.69 (m, 3H) , 7.57 (m, 3H) ,
7.42 (m, 3H) , 7.33 (d, 1H) , 7.16 (s, 1H) , 6.04 (dd, 1H) , 4.90 (bs, 2H) , 2.36 (s, 6H) .
Compound #5 was prepared in a similar manner;
3- [ (3-Benzofuran-2-yl-benzyl) - (4-chloro-2 , 5-dimethyl- benzenesulfonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid compound #2
STEP I
To a degassed solution of 3- [ (4-Chloro-2 , 5-dimethyl- benzenesulfonyl) - (3-iodo-benzyl) -amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester (110 mg, 0.169 mmol) and benzofuran-2-boronic acid (55 mg, 0.185 mmol) in a mixture of DME (8 mL) and 2M aqueous Na2C03 (4 mL) , Pd(PPh3)4 (9 mg) was added and the reaction mixture was stirred at reflux conditions for 2h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2S04) and concentrated. 3- [ (3-Benzofuran-2-yl-benzyl) - (4-chloro-2 , 5-dimethyl-benzenesulfonyl) -amino] -5-phenyl- thiophene-2-carboxylic acid methyl ester (107 mg, 100%) was isolated as a thick syrup and used for the next reaction without any further purification.
STEP II
3- [ (3-Benzofuran-2-yl-benzyl) - (4-chloro-2 , 5-dimethyl- benzenesulfonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester (20 mg, 0.031 mmol) was taken in a mixture of THF:MeOH:H20 (3:2:1, 3 mL) and then added IN aqueous solution of LiOH.H20 (0.20 mL, 0.186 mmol) . The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10 % KHS04 solution. The organic layer was separated, dried (Na2S04) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (9:1) to obtain 3- [ (3-Benzofuran-2- yl-benzyl) - (4-chloro-2, 5-dimethyl-benzene-sulfonyl) -amino] -5- phenyl-thiophene-2-carboxylic acid (14 mg, 70%) as a white solid. "Η NMR (DMSO, 400 MHz): δ7.93(s, IH) , 7.84 (s, IH) , 7.74 (bd, IH) , 7.65-7.22 (m, 14H) , 4.95 (s, 2H) , 2.33, 2.23 (2s, 6H) .
Example 9
3- [ (4-Chloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid compound #210 .
Figure imgf000090_0001
STEP I Method A
A DMF (15 mL) solution of 3-Amino-5-phenyl-thiophene-2- carboxylic acid methyl ester (500 mg, 21.5 mmol) was cooled to 0 °C and then isopropyl iodide (2.57 mL) and NaH (60%, 775 mg, 32.3 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for lh. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2S0 ) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (5:95) as eluent to obtain 3- isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (189 mg, 32%) as a solid. XH NMR (CDC13, 400 MHz): 7.62 (d, 2H) , 7.40 (m, 3H) , 6.91 (s, IH) , 3.84 (s, 3H) , 1.35 (d, 6H) .
Method B
Figure imgf000090_0002
To a stirred solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.82 g, 7.8 mmol) in 1, 2-dichloroethane (40 mL) was added sequentially 2-methoxypropene (3.0 L, 31.2 mmol), AcOH ('1.8 mL, 31.2 mmol) and NaBH(0Ac)3 (3.31 g, 15.6 mmol) and stirred for 2 hrs. It was then diluted with EtOAc and H20. The aqueous solution was adjusted to pH = 7 by adding NaHC03. The aqueous phase was extracted with EtOAc, the combined extract was washed with brine and dried on MgS04 and filtered. Purification on bond elute with hexane to 5% EtOAc-hexane furnished 3-Amino- 5-phenyl-thiophene-2-carboxylic acid methyl ester (2.07 g, 96% yield) .
The intermediate compounds 3-Cyclohexylamino-5-phenyl-thiophene- 2-carboxylic acid methyl ester, 3- (l-Methyl-piperidin-4- ylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester and 3- (l-Methyl-piperidin-4-ylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester were prepared in a similar manner as described and used as intermediates in the synthesis of compound #543, compound #553 and compound #573
STEP II
To a suspension of 3-isopropylamino-5-phenyl-thiophene-2- carboxylic acid methyl ester (1.2 g, 4.364 mmol) in a mixture of
H20 (22 mL) and dioxane (35 mL) , IN aqueous solution of NaOH (13 mL, 13.00 mmol) was added. The reaction mixture was stirred at 100 C for 3h. The reaction mixture was used for the next reaction without any further purification.
To this reaction mixture of 3-Amino-5-phenyl-thiophene-2- carboxylic acid sodium salt (23 mL, 1.41 mmol), 4-chlorobenzoyl chloride (0.269 mL, 2.11 mmol) was added at 0°C. The pH of the solution was maintained at 9 by adding IN NaOH solution and then stirred at room temperature for 5h. The reaction mixture was diluted with ethyl acetate and water. The water layer was acidified by adding IN HCl solution. The organic layer was separated, dried (Na2S0 ) and concentrated. The crude product was purified by recrystallization from ethyl acetate to obtain the pure 3- [ (4-Chloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene- 2-carboxylic acid (45 mg) as a white solid. XH NMR (DMSO-D6, 400 MHz): 7.58 (d, 2H) , 7.38-7.26 ( , 6H) , 7.13 (d, IH) , 4.77 (m, IH) , 1.25 (d, 3H) , 1.02 (d, .3H) . ESI" (M-H): 398.
Similarly, the following compounds were made: Compound #218 , Compound #219 , Compound #226 , Compound #234 , Compound #243 , Compound #246 , Compound #250 , Compound #262 , Compound #324 , Compound 326 , Compound #331 .
Example 10
3- [ (2 , 4-Dichloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid compound #149
Figure imgf000092_0001
Step I
3- (2 , 4-Dichloro-benzoylamino) -5-phenyl-thiophene-2-carboxylic acid methyl ester.
To a ice-cold solution of 3-Amino-5-phenyl-thiophene-2- carboxylic acid methyl ester 1 (5 g, 21.5 mmol) and triethylamine (4.56 g, 45.0 mmol) in dichloromethane (100 ml) was added 2 , 4-dichlorobenzoyl chloride (3.90 g, 19.4 mmol). The reaction mixture was stirred for 30 min a 0°C and 16 h at room temperature. Then, the reaction mixture was partitioned between 25 ml of H20, 50 ml sat. NaHC03 and 50 ml of CH2C12. The organic layer was separated and the aqueous phase was washed twice with CH2C12 (2 X 50 mL) . The combined dichloromethane layer was dried (MgS04) , concentrated and the residue was purified by recrystallization in CH2C12 to obtain 5.832 g (74%) as a white solid of 3- (2, 4-Dichloro-benzoylamino) -5-phenyl-thiophene-2- carboxylic acid methyl ester. NMR 1H (CDC13, 400 MHz): 8,30 ppm (s, IH, Haro) ; 7,74-7,66 ppm (m , 3H, Haro) ; 7,51 ppm (d, IH, Haro); 7,46-7,34 ppm (m, 4H, Haro) ; 3,91 ppm (s, 3H) .
Step II 3- [ (2 , 4-Dichloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester.
Sodium Hydride (60% dispersion in oil, 190 mg, 5,2 mmol) was added to an ice-cold solution of 3- (2, 4-Dichloro-benzoylamino) - 5-phenyl-thiophene-2-carboxylic acid methyl ester (2) (1.5 g, 3,69 mmol) in 350 ml of N N-dimethylformamide in an atmosphere of Ν2. After 5 min, 2-Iodo-propane (941 mg, 5.54 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0°C and 64 h at room temperature. The mixture was partitioned between ether (200 mL) and water (350 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2 X 70 mL) and the combined ether layer was dried (MgS04) , concentrated and the residue was purified by flash chromatography (10% EtOAc/Hexane) to obtain 908 mg (55%) of 3- [ (2, 4-Dichloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester. NMR ^Η (CDC13, 400 MHz): Rotamere 95/05 : 7,54 ppm (dd, 2H, Haro) ; 7,49-7.35 ppm (m, 3H, Haro) ; 7,29-7,25 ppm (m, 2H, Haro) ; 7,15 ppm (d, IH, Haro) ; 7,05 ppm (d, IH, Haro) 5,09 ppm (hex, IH, N-CH(CH3) , major rotamere); 3,99 ppm (hex, N-CH(CH3) , minor rotamere); 3,89 ppm (s, 3H) ; 1,40 ppm (d, 3H, N-CH(CH3), major rotamere); 1,28 ppm (d, N-CH(CH3), minor rotamere); 1,09 ppm (d, 3H, N-CH(CH3), major rotamere); 1,01 ppm (d, N-CH(CH3), minor rotamere).
Step III
3- [ (2 , 4-Dichloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid.
3- [ (2 , 4-Dichloro-benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester (3) (345 mg, 0.77 mmol) was dissolved in a mixture of THF-MeOH-H20 (3:2:1) (30 mL) and then 4,6 ml of LiOH IN was added to it. After 120 min of stirring at room temperature, solvant was removed and then partitioned between 25 ml of H20, 4 ml of KHS04 5% and 25 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2 X 10 mL) . The combined ethyl acetate ■ layer was dried (MgS0 ) , concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 175 mg (53%) as a white solid of 3- [ (2, 4-Dichloro- benzoyl) -isopropyl-amino] -5-phenyl-thiophene-2-carboxylic acid. NMR U (DMSO, 400 MHz): Rotamer 95/05 : 7,82 ppm (m, Haro, minor rotamer) ; 7,69 ppm (d, 2H, Haro) ; 7,61 ppm (d, IH, Haro) ; 7,51- 7,37 ppm (m, 4H, Haro) ; 7,35-7,28 ppm (m, 2H, Haro) ; 4,89 ppm (hex, IH, N-CH(CH3), major rotamer); 3,84 ppm (hex, N-CH(CH3) , minor rotamer); 1,36 ppm (d, 3H, N-CH(CH3), major rotamer); 1,25 ppm (d, N-CH(CH3) , minor rotamer); 1,03 ppm (d, 3H, N-CH(CH3), major rotamer); 0,93 ppm (d, N-CH(CH3), minor rotamere).
The following compounds were prepared in a similar manner: Compound #201 , Compound #204 , Compound #233 , Compound #244 , Compound #261 , Compound #264 , Compound #299 . .
Example 11
3- [ (2 , 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl-thiophene-2- carboxylic acid. Compound #208.
Figure imgf000095_0001
Step I
5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester.
To a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1 g, 4.29 mmol) in dichloromethane (50 ml) was added phenyl boronic acid (1.05 g, 8.6 mmol), pyridine (680 mg, 8.6 mmol) and copper(II) acetate (1.18 g, 6.5 mmol). The reaction mixture was stirred for 16 h at room temperature. Then, the reaction mixture was filtered through celite, concentrated and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 435 mg ( 33%) of 5-Phenyl-3-phenylamino- thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7,38 ppm (dd, 2H, Haro) ; 7,35-7,26 ppm (m , 5H, Haro) ; 7,19 ppm (s, IH, Haro) ; 7,15 ppm (dd, 2H, Haro) ; 7,02 ppm (ddt, IH, Haro); 3,82 ppm (s, 3H) .
Step II
3- [ (2 , 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl-thiophene-2• carboxylic acid methyl ester. Sodium Hydride (60% dispersion in oil, 80 mg, 1,5 mmol) was added to an ice-cold solution 5-Phenyl-3-phenylamino-thiophene- 2-carboxylic acid methyl ester (2) (230 mg, 0,74 mmol) in 20 ml of N,N-dimethylformamide in an atmosphere of Ν2. After 5 min, 2 , 4-Dichloro-benzoyl chloride (310 mg, 1.48 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0°C and 16 h at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2 X 10 mL) and the combined ether layer was dried
(MgS0 ) , concentrated and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 58 mg (16%) of 3- [ (2 , 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester. NMR XH (CDC13, 400 MHz): 7,65-7,10 ppm (m, 14H, Haro) ; 3,77 ppm (s, 3H) .
Step III
3- [ (2 , 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl-thiophene-2- carboxylic acid.
3- [ (2, 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester (55 mg, 0.11 mmol) was dissolved in a mixture of THF-MeOH-H20 (3:2:1) (15 mL) and then 0.66 ml of LiOH IN was added to it. After 60 min of stirring at room temperature, solvents were removed and then partitioned between 15 ml of H20, 4 ml of KHS04 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2 X 10 mL) . The combined ethyl acetate layer was dried (MgS04) , concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 32 mg (60%) of 3- [ (2 , 4-Dichloro-benzoyl) -phenyl-amino] -5-phenyl- thiophene-2-carboxylic acid. NMR ^Η (DMSO, 400 MHz) : Rotamer : 7,75 ppm (d, IH, Haro) ; 7,68 ppm (2H, Haro) ; 7,53 ppm (d, Haro, minor rotamer); 7,51-7.23 ppm (m, 11H, Haro, minor rotamer); 7,17 ppm (Haro/ minor rotamer) . Compound #525 was prepared in a similar manner.
Example 12 3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene- 2-carboxylic acid compound #327
Figure imgf000097_0001
Step I 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Concentrated sulfuric acid ( 10 drop) was added to a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 2,15 mmol) in 20 ml of dioxane/ chloroforme (2 :3) in a sealed tube. After cooling the solution at -78 °C, put 20 ml of isobutene gaz . The sealed tube was closed and then the reaction mixture was stirred for 6 days at 60 °C. The solvant was removed and then partitioned between 15 ml of sat. Na2C03 solution and 15 ml of EtOAc. The organic layer was separated, the aqueous phase was washed twice with ethyl acetate and the combined ethyl acetate layer was dried (MgS04) , concentrated and the residue was purified by flash chromatography (5% EtOAc/Hexane) to obtain 385 mg (62%) of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDC13, 400 MHz): 7,65 ppm (d, 2H,
Haro); 7,44-7,38 ppm (m , 3H, Haro) ; 7,07 ppm (s, IH, Haro) ; 3,86 ppm (s, 3H) ; 1,48 ppm (s, 9H) .
Step II
3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester.
To a solution of 3-tert-Butylamino-5-phenyl-thiophene-2- carboxylic acid methyl ester (100 mg, 0.35 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4- dichloro-benzoyl chloride (79 mg, 0.38 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 112 mg ( 69%) of 3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR ^Η (CDC13, 400 MHz): 7,50 ppm (m, 2H, Haro); 7,44-7,34 ppm (m, 3H, Haro) ; 7,27 ppm (s, IH, Haro) ; 7,18 ppm (dl, IH, Haro); 7,14 ppm (d, IH, Haro) ; 7,00 ppm (dd, IH, Haro); 3,93 ppm (s, 3H) ; 1,56 ppm (s, 9H) .
Step III
3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-
2-carboxylic acid.
3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene- 2-carboxylic acid methyl ester (112 mg, 0.24 mmol) was dissolved in a mixture of THF-MeOH-H20 (3:2:1) (15 mL) and then 1.5 ml of LiOH IN was added to it. After 3 h of stirring at room temperature, solvant was removed and then partitioned between 15 ml of H20, 4 ml of KHS04 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2 X 10 L) . The combined ethyl acetate layer was dried (MgS04) , concentrated and the residue was purified by preparative chromatography (10% Me0H/CH2Cl2) to obtain 32 mg (29 %) of 3- [tert-Butyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2- carboxylic acid. NMR XH (DMSO, 400 MHz): 7,62 ppm (d, 2H, Haro) ; 7,44-7,34 ppm (m , 4H, Haro) ; 7,32-7,12 ppm (m, 3H, Haro) ; 2,48 ppm (s, 9H) .
Example 13
3- [Cyclopropyl- (2 , 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-
2-carboxylic acid. Compound #333
Figure imgf000099_0001
Step I
3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester.
To a solution of 3-Bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (250 mg, 0.89 mmol) in toluene (25 ml) was added cyclopropylamine (57 mg, 1.0 mmol), cesium carbonate (382 mg, 1.2 mmol), BINAP (50 mg, 0.08 mmol) and tris (dibenzyli- denacetone) dipaladium (0) (38 mg, 0.04 mmol). The reaction mixture was stirred for 16 h at 110 °C in a sealed tube. The mixture was partitioned between toluene (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with toluene (2 X 10 L) and the combined toluene layer was dried (MgS04) , concentrated and the residue was purified by preparative chromatography (10% EtOAc/Hexane) to obtain 52 mg (22 %) of 3-Cyclopropylamino-5-phenyl-thiophene-2- carboxylic acid methyl ester. NMR XH (CDC13, 400 MHz): 7,67-7,62 ppm (m, 2H, Haro) ; 7,43-7,32 ppm (m , 3H, Haro) ; 7,16 ppm (s, IH, Haro) ; 3,82 ppm (s, 3H) ; 2,65 ppm ( , IH) ; 0,62 ppm (m, 2H) ; 0,35 ppm (m, 2H)'.
Step II
3- [Cyclopropyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2- carboxylic acid methyl ester.
To a solution of 3-Cyclopropylamino-5-phenyl-thiophene-2- carboxylic acid methyl ester (52 mg, 0.19 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4- dichlorobenzoyl chloride (45 mg, 0.21 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvant was removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 85 mg ( 99%) of 3- [Cyclopropyl- (2 , 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDC13, 400 MHz): 7,64 ppm (d, 2H, Haro); 7,47 ppm (m , 2H, Haro) ; 7,44-7,33 ppm (m, 3H, Haro) ; 7,21- 7,12 ppm (m, 2H, Haro) ; 3,89 ppm (s, 3H) ; 3,33 ppm (m,' minor rotamer); 3,13 >ppm ( , IH, major rotamer) 1,01-0,49 ppm (m, 4H) . Step III
3- [Cyclopropyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene- 2-carboxylic acid.
3- [Cyclopropyl- (2 , 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene- 2-carboxylic acid methyl ester (85mg, 0.19mmol) was dissolved in a mixture of THF-MeOH-H20 (3:2:1) (10 mL) and then 1.2 ml of LiOH IN was added to it. After 60 min of stirring at room temperature, solvant was removed and then partitioned between 15 ml of H20, 4 ml of KHS04 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2 X 10 mL) . The combined ethyl acetate layer was dried (MgS04) , concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 22 mg (27 %) of 3- [Cyclopropyl- (2, 4-dichloro-benzoyl) -amino] -5-phenyl-thiophene-2- carboxylic acid. NMR ^Η (DMSO, 400 MHz): rotamer : 7,75 ppm (m, 2H, Haro) ; 7,68 ppm (m , Harθ/ minor rotamer) ; 7,62-7,55 ppm (m, 2H, Haro); 7,52 ppm (m, Haro, minor rotamer) ; 7,48-7.27 ppm (m, 5H, Haro) ; 3,14 ppm (m, minor rotamer); 3,04 ppm (m, IH, major rotamer); 0,87-0,42 ppm (m, 4H, ) .
The following compounds were prepared in a similar manner:
Compound #403 , Compound #404
Example 14 3- [ (2, 4-dichloro-benzoyl) -piperidin-4-ylmethylamino] -5-phenyl- thiophene-2-carboxylic acid Compound #519 .
Figure imgf000101_0001
STEP I A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.70 g, 3 mmol) and 4-formyl N-Cbz-piperidine (0.74 g, 3 mmol) in THF (1.2 mL) was treated with dibutyltin dichloride (46 mg, 0.15 mol) followed by phenylsilane (0.41 mL, 3.3 mmol) . The mixture was stirred for 2 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes :EtOAc as eluent to provide 4- [ (2-Methoxycarbonyl-
5-phenyl-thiophen-3-ylamino) -methyl] -piperidine-1-carboxylic acid benzyl ester (0.6906 g, 50% yield).
STEP II
4- [ (2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino) -methyl] - piperidine-1-carboxylic acid benzyl ester (133 mg ,0.28 mmol) was dissolved in 1, 2-dichloroethane (2.8 mL) and was treated with 2,4- dichlorobenzoyl chloride (60 μL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes :EtOAc as eluent to provide 4-{[ (2, 4-Dichloro-benzoyl) - (2- methoxycarbonyl-5-phenyl-thiophen-3-yl) -amino] -methyl}-piperidine- 1-carboxylic acid benzyl ester (0.156 g, 85% yield). STEP III
4-{ [ (2 , 4-Dichloro-benzoyl) - (2-methoxycarbonyl-5-phenyl-thiophen-3- yl) -amino] -methyl}-piperidine-1-carboxylic acid benzyl ester (150 mg, 0.24 mmol) was dissolved in a mixture of THF:MeOH:H20 (3:2:1, 2.4 mL) and treated with LiOH.H20 (29.6 mg, 0.7 mmol). The solution was heated at 55 aC for 2 h. The solvents were removed and the residue was acidified using HCI. The product was extracted with EtOAc and the organic layers were washed with brine and dried. The residue was purified by silica gel column chromatography using EtOAc :MeOH:AcOH as eluent to provide 4-{[(2- Carboxy-5-phenyl-thiophen-3-yl) - (2 , 4-dichloro-benzoyl) -amino] - methyl}-piperidine-l-carboxylic acid benzyl ester (124 mg, 85% yield) .
STEP IV 4- { [ (2-Carboxy-5-phenyl-thiophen-3-yl) - (2 , 4-dichloro-benzoyl) - amino] -methyl}-piperidine-l-carboxylic acid benzyl ester (124 mg, 0.2 mmol) was dissolved in MeOH (2 L) and treated with 10% Pd/C (200 mg) under H2 balloon. The reaction was stirred at room temperature for 18 h and the mixture was filtered on celite. The solution was evaporated to a residue that was purified by reverse-phase HPLC to provide 3- [ (2, 4-Dichloro-benzoyl) - piperidin-4-ylmethyl-amino] -5-phenyl-thiophene-2-carboxylic acid (17.3 mg, 18% yield). XH NMR (CD3OD, 300 MHz): 7.55 (d, 1 H) , 7.50 (m, 2 H) , 7.27-7.39 (m, 4 H) , 7.25 (s, 1 H) , 7.18 (dd, 1 H) , 4.12 (m, 1 H) , 3.75 (m, 1 H) , 3.43 (m, 2 H) , 2.96 (q, 2 H) , 2.65 (d, 2 H) , 2.05 (m, 1 H) , 1.62 (m, 2 H) .
The following compounds were prepared in a similar manner: Compound #503 , Compound #509 , Compound #519 , Compound #529 , Compound #537 , Compound #538 , Compound #516 , Compound #522 , Compound #535 .
Example 15
3- [Isopropyl- (3-methyl-cyclopent-3-enecarbonyl) -amino] -5 phenyl- thiophene-2-carboxylic acid Compound #405
Figure imgf000103_0001
Step I :
To a cold (-78 °C) stirred solution of LDA (generated from DIPA (1.42 L, 10.14 mmol), BuLi (5.85 mL, 9.36 mmol) in THF at -78°C for 20 min) in THF (31 mL) was added a solution of Pent-4-enoic acid ethyl ester (1.0 g, 7.8 mmol, 1.2 eq. ) in THF (9.0 mL) . After stirred for 1 h, neat 3-Bromo-2-methyl-propene (2.03 g, 15.0 mmol, 1.51 mL) was added and slowly warmed up to room temperature for overnight . The reaction mixture was then quenched with saturated NHC1 solution, extracted with ether, washed with brine and dried. Evaporation of the solution furnished the 2-Allyl-4-methyl-pent-4-enoic acid ethyl ester (1.45 g, 100%) as an oil which was used in the next step without purification. XH NMR (400 MHz', CDC13) , 5.78-5.71 (m, IH) , 5.05 (d, J = 18.6 Hz, IH) , 5.02 (d, J= 9.4 Hz, IH) , 4.76 (brs, IH) , 4.70 (s', IH) , 4.11 (dq, J = 7.2, 1.0 Hz, 2H) , 2.66-2.13 (m, 5H) , 1.72 (s, 3H) , 1.23 (dt, J = 7.2, 1.3 Hz, 3H) .
Step II: •
To a refluxing stirred solution of the 2-Allyl-4-methyl-pent-4- enoic acid ethyl ester (364 mg, 2.0 mmol) in CH2C12 (100 mL, 0.02 M solution) was added drop wise a solution of the tricyclohexylphosphine (1, 3-Bis (2,4, 6-trimethylphenyl) -4, 5- dihydroimidazol-2-ylidene) (benzylidine) ruthenium (IV) dichloride (85 mg, 0.1 mmol) in CH2C12 (3.0 mL) . After 50 min, the reaction mixture was cooled to room temperature, concentrated and purified on silica gel bond elute using EtOAc/hexane (1:20) as an eluent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (286 mg, 93% yield) as an oil. 1H NMR (CDC13, 400 MHz), 5.25 (brs, IH) , 4.17 (q, J = 7.1 Hz, 2H) , 3.2-3.1 (m, IH) , 2.65-2.46 (m, 4H) , 1.74 (s, 3H) , 1.28 (t, J = 7.1 Hz, 3H) .
Step III:
A solution of the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (255 mg, 1.65 mmol) in MeOH (4.0 mL) and 10% aq. NaOH (3.3 mL, 8.25 mmol) was heated at 50°C for 16 h, reaction mixture was cooled to room temperature, solvent was evaporated, diluted with water. The aqueous solution was washed with ether, and acidified with aq. 1 N HCI, extracted with ether. The ethereal solution was washed with brine and dried. Evaporation of the solvent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid (200 mg, 97% yield). IH NMR (CDC13, 400 MHz) 5.27 (brs, IH) , 3.26-3.17 (m, IH), 2.7-2.55 (m, 4H) , 1.74 (s, 3H) .
Step IV:
The coupling of the 3-Isopropylamino-5-phenyl-thiophene-2- carboxylic acid methyl ester (82 mg, 0.3 mmol) and the 3-Methyl- cyclopent-3-enecarboxylic acid (45 mg, 0.357 mmol) using PPh3 (95.4 mg, 0.363 mmol) and NCS (48.5 mg, 0.363 mmol) furnished the 3- [Isopropyl- (3-methyl-cyclopent-3-enecarbonyl) -amino] -5- phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 61% -yield) ^Ή NMR (CDC13, 400 MHz 1:1 mixture of rotamers), 7.68-7.64 (m, 4H) , 7.5-7.4 (m, 6H) , 7.1 (s, IH) , 7.09 (s, IH) , 5.2 (s, IH) , 5.1 (s, IH) , 5.06-4.98 (m, 2H) , 3.88 (s, 3H) , 3.87 (s, 3H) , 3.08-3.0 (m, 2H) , 2.85-2.76 (m, 2H) , 2.5-2.42 (m, 2H) , 2.3-2.1 (m, 4H) , 1.69 (s, 3H) , 1.64 (s, 3H) , 1.24 (d, J = 6.7 Hz, 3H) , 1.23 (d, J = 6.7 Hz, 3H) , 1.01 (d, J = 6.9 Hz, 3H) , 1.007 (d, J = 6.8 Hz, 3H) .
Saponification of 3- [Isopropyl- (3-methyl-cyclopent-3- enecarbonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.13 mmol) using LiOH.H20 (22 mg) asι previously described furnished the 3- [Isopropyl- (3-methyl-cyclopent-3- enecarbonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid (30 mg, 62.5% yield) as a solid. XH NMR (CD3OD, 400 MHz 1:1 mixture of rotamers) 7.73-7.70 ( , 4H) , 7.47-7.35 (m, 6H) , 7.29 (s, IH) , 7.27 (s, IH) , 5.16 (s,
IH) , 5.08 (s, IH) , 4.9-4.8 (m, 2H) , 3.15-3.05 (m, 2H) , 2.76-2.65 (m, 2H) , 2.42-2.12 ( , 6H) , 1.65 (s, 3H) , 1.61 (s, 3H) , 1.25 (d, J = 6.6 Hz, 3H) , 1.24 (d, J = 6.6 Hz, 3H) , 1.03 (d, J = 6.9 Hz, 6H) .
Example 16
5-tert-Butyl-3- (2, 4-dimethyl-benzenesulfonylamino) -thiophene-2- carboxylic acid Compound #315 :
Figure imgf000105_0001
STEP I A mixture of 3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (106.5 mg, 0.5 mmol) and 2 , 4-dimethylsulfonyl chloride (156 mg, 0.75 mmol) in pyridine (1.5 mL) was heated at 72 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with aq. IN HCI, brine and dried. Evaporation of the solvent and purification of the residue on silica gel bond elute using EtOAc (1:20 to 1:10) as an eluent furnished the 5-tert- Butyl-3- (2 , 4-dimethyl-benzenesulfonylamino) -thiophene-2- carboxylic acid methyl ester (188' mg, 99% yield) . 1H NMR (CDC13, 400 MHz) 9.73 (s, IH) , 7.89 (d, J = 8.6 Hz, IH) , 7.04-7.08 (m, 2H) , 7.03 (s, IH) , 3.82 (s, 3H) , 2.62 (s, 3H) , 2.33 (s, 3H) , 1.28 (s, 9H) .
STEP II Hydrolysis of the 5-tert-Butyl-3- (2 , 4-dimethyl- benzenesulfonylamino) -thiophene-2-carboxylic acid methyl ester (55 mg, 0.14 mmol) using LiOH.H20 (22 mg) as previously described provided the 5-tert-Butyl-3- (2, 4-dimethyl-benzenesulfonylamino) - thiophene-2-carboxylic acid (36 mg, 70% yield) as a solid. 1H NMR (CD3OD, 400 MHz) 7.85 (d, J = 8.6 Hz, IH) , 7.14-7.10 (m, 2H) , 7.0 (s, IH) , 2.56 (s, 3H) , 2.31 (s, 3H) , 1.27 (s, 9H) .
Example 17
5-Benzo[b] thiophen-2-yl-3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid Compound #230
Figure imgf000106_0001
STEP I
Suzuki coupling of 5-Bromo-3- (toluene-2-sulfonylamino) - thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) and bezothiophene-2-boronic acid (53.4 mg, 0.3 mmol) was carried out using Pd(PPh3)4 and Na2C03 (as described in example 2) resulted in 5-Benzo [b] thiophen-2-yl-3- (toluene-2-sulfonylamino) - thiophene-2-carboxylic acid tert-butyl ester (27 mg, 55% yield) . XH NMR (CDC13, 400 MHz) 9.92 (s, IH) , 8.07 (d, J = 7.8 Hz, IH) , 7.79-7.71 (m, 2H) , 7.45-7.24 (m, 7H) , 2.7 (s, 3H) , 1.56 (s, 9H) .
STEP II
5-Benzo [b] thiophen-2-yl-3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid tert-butyl ester was hydrolyzed to the acid using TFA as described for example 2 providing 5-
Benzo [b] thiophen-2-yl-3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid (24 mg, 99% yield) . ^Η NMR (DMSO-D6, 400 MHz) 10.19 (s, IH) , 8.0 (d, J= 7.7 Hz, IH) , 7.79-7.74 (m, lH) , 7.86 (s, IH) , 7.84-7.81 (m, IH) , 7.54 (t, J = 7.7 Hz, IH) , 7.53-7.36 (m, 4H) , 7.32 (s, lH) , 2.58 (s, 3H) .
Example 18
5- (lH-Pyrazol-3-yl) -3- (toluene-2-sulfonylamino) -thiophene-2- carboxylic acid Compound #170
Figure imgf000107_0001
Figure imgf000107_0002
Step I
To a stirred solution of 5-Bromo-3- (toluene-2-sulfonylamino) - thiophene-2-carboxylic acid tert-butyl ester (43mg, O.lmmol) in toluene (3.0 mL) was sequentially added a solution of Pd(PPh3)4 (12 mg, 0.01 mmol) in toluene (1.0 mL) and 3-Trimethylstannanyl- pyrazole-1-sulfonic acid dimethylamide (prepared according to J. Med. Chem (1998), 41, p-2019) (75 mg, 0.2 mmol, 2.0 eq) , and heated the resulting overnight' at 80°C. It was then cooled to room temperature, the solvent was evaporated and the crude was purified on preparative TLC using EtOAc/hexane (1:5). 5-(l-
Dimethylsulfamoyl-lH-pyrazol-3-yl) -3- (toluene-2-sulfonylamino) - thiophene-2-carboxylic acid tert-butyl ester (35 mg, 66.5% yield) was isolated. XH NMR (CDC13, 400 MHz) 9.93 (s, lH) , 8.11 (d, J = 0.7 Hz, IH) , 8.02 (dd, J = 6.7, 1.32 Hz, IH) , 7.84 (d, J = 0.7 Hz, IH) , 7.45 (dt, J = 7.5, 1.3 Hz, IH) , 7.31 (t, J = 8.2 Hz, 2H) , 7.26 (d, J= 1.0 Hz, lH) , 2.98 (s, 6H) , 2.7 (s, 3H) , 1.55 (s, 9H) .
Step II A reaction mixture of 5- (1-Dimethylsulfamoyl-lH-pyrazol-3-yl) -3- (toluene-2-sulfonylamino) -thiophene-2-carboxylic acid tert-butyl ester. (10 mg,. 0.019 mmol) and 4N HCI (0.3 mL) solution in dioxane in MeOH (0.3 L) was stirred at room temperature 26 h. Reaction mixture was then diluted with water and extracted with EtOAc, concentrated and purified on preparative TLC using
MeOH/CH2Cl2/AcOH (5:95:1) furnished the 5- (lH-Pyrazol-3-yl) -3- ( toluene-2-sulfonylamino) -thiophene-2-carboxylic acid (4.5 mg, ■ 65.2% yield). XB. NMR (CD3OD, 400 MHz) 7.99 (d, J = 7.9 Hz, IH) , 7.81 (s, IH) , 7.43 (t, J = 7.5, 1.3 Hz, IH) , 7.42-7.26 (m, 2H) , 7.19 (s, IH) , 2.69 (s, 3H) .
Example 19
3-Isopropyl- [ (4-methyl-cyclohexanecarbonyl) -amino] -5-m-tolyl- thiophene-2-carboxylic acid Compound #448
Figure imgf000109_0001
STEP I
Trans-4-methyl-cyclohexanecarbonyl chloride was prepared by 5 heating to reflux trans-4-methyl-cyclohexanecarboxylic acid (5g, 0.035 mmol) in thionylchloride (5.0 ml) for 2h followed by purification of the corresponding acyl chloride under reduced pressure in a Kugel-Rhorr apparatus collecting the fraction distilling at 95 °C yielding 5.1 g of the desired material which
10 was used in the next step without further purification. This acyl chloride (1.5 ml, aprox. 10 mmol) was dissolved along with 5-Bromo-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (2 g, 7.12 mmol) in anhydrous dichloroethane (2 mL) and heated at 80 °C (closed vial) for 12h. The solvents were •15 evaporated, the resulting crude material was dissolved in methanol and left 30 min. at room temperature, concentrated and purified via flash chromatography on silica gel using a 5% EtOAc 95% hexanes mixture of eluents, in this manner 600 mg (21%) of 5-Bromo-3- [isopropyl- (4-methyl-cyclohexanecarbonyl) -
20 amino] -thiophene-2-carboxylic acid methyl ester the was isolated. 1H NMR(CDC13, 300 MHz) : 6.78 (s, IH) , 4.93 (m, lH) , 3.69 (S, 3H) , 2.00-1.20 (m, 8H) , 1.14 (d, 3H) , 0.93 (d, 3H) , 0.81 (d, 3H) , 0.72-0.70 (m, 2H) .
25
STEP II To a degassed solution of 5-Bromo-3- [isopropyl- (4-methyl- cyclohexanecarbonyl) -amino] -thiophene-2-carboxylic acid methyl ester (100 mg, 0.249 mmol) and 3-methyl boronic acid (38 mg, 0.279 mmol) in a mixture of DME (6 mL) and 2M aqueous Na2C03 (3 mL) , Pd(PPh3) (12 mg) was added and the reaction mixture was stirred at reflux conditions for 12h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2S0 ) , concentrated. The residue was purified by column chromatography using ethyl acetate and hexane (1:3) as eluent. 35 mg (34%) of 3-Isopropyl- [ (4-methyl-cyclohexanecarbonyl) -amino] -5-m-tolyl-thiophene-2- , carboxylic acid methyl ester was isolated. 1H NMR (CDC13, 400 MHz): 7.45 (bs, 2H) , 7.36 (t, lH) , 7.23 (m, IH) , 7.01 (s, IH) , 4.99 (m, IH) , 3.83 (s, 3H) , 2.41 (s, 3H) , 2.01-0.61 (m, 20H) .
Step III
3-Isopropyl- [ (4-methyl-cyclohexanecarbonyl) -amino] -5-m-tolyl- thiophene-2-carboxylic acid methyl ester (30 mg, 0.073 mmol) was taken in a mixture of THF:MeOH:H20 (3:2:1, 3 mL) and then added IN aqueous solution of LiOH.H20 (0.44 mL, 0.438 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10 % KHS04 solution. The organic layer was separated, dried (Na2S04) and concentrated. The residue was purified by preparative TLC using chloroform:methanol : acetic acid (9:1:0.1) to obtain 3-Isopropyl- [ (4-methyl-cyclohexanecarbonyl) -amino] -5- m-tolyl-thiophene-2-carboxylic acid (15 mg, 52%) as a white solid. XH NMR (CDC13, 400 MHz): (s, 2H) , 7.38 (t, IH) , 7.24 ( , IH) , 7.08 (s, lH) , 5.01 (s, IH) , 2.42 (s, 3H) , 2.10-0.62 (m, 20H) . ESI" (M-H) : 398.
Example 20 (1R,2S,4R) -3- [Isopropyl- (2-hydroxy-4-methy1- cyclohexanecarbonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid Compound #402
Figure imgf000111_0001
(1R, 2S, 4R) -2-Hydroxy-4-methyl-cyclohexanecarboxylic acid methyl ester was prepared as described in J. Org. Chem, (1993), 58, pp.6255-6265. NMR K (CDC13, 400 MHz): 4,26 ppm (s, IH) ; 4,19- 4,13 ppm (m , 2H) ; 3,16 ppm (s, lH) ; 2,35-2,29 ppm (m, IH) ; 1,92-1,74 ppm (m, 5H) ; 1,31-1,24 ppm (m, 3H) ; 1,08-1,01 ppm (m, IH) ; 0,96-0,92 ppm ( , IH) ; 0,88 ppm (d, 3H) .
STEP I
To a solution of (1R, 2S, 4R) -2-Hydroxy-4-methyl- cyclohexanecarboxylic acid methyl ester (450 mg, 2.42 mmol) in methanol (12 ml) was added a 2.5 M solution of sodium hydroxide (9.7 ml, 24.2 mmol) . The reaction mixture was stirred for 4 h at 50 °C. Then, the solvents were removed and the residue was partitioned between 20 ml of H20 acidified to pH 4 and 20 ml of EtOAc. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2 X 20 ml) . The combined ethyl acetate layers were dried (Na2S0 ) and concentrated to obtain 313 mg (82 %) of (1R, 2S, 4R) -2-Hydroxy-4-methyl-cyclohexanecarboxylic acid. NMR XH (CDCI3, 400 MHz): 4,34 ppm (s, IH) ; 2,43-2,39 ppm
(m, IH) ; 1,96-1,76 ppm (m, 5H) ; 1,14-1,08 ppm (m, lH) ; 1,02-0,93 ppm (m, IH) ; 0,90 ppm (d, 3H) .
Step II
To a solution of (1R, 2S, 4R) -2-Hydroxy-4-methyl- cyclohexanecarboxylic acid (162 mg, 1.02 mmol) in dichloromethane (5 ml) was added pyridine (495 ul, 6.12 mmol) followed by acetic anhydride (385 ul, 4.08 mmol). The reaction mixture was stirred for 20 h at room temperature. Then, the solvents were removed and 10 ml of 3N HCI solution was added. This mixture was stirred for 30 minutes and then a saturated solution of NaHC03 was slowly added until pH = 9-10. This solution was then extracted with ethyl acetate (2 X 5 ml) . The aqueous phase was then acidified with a 10% HCI solution and extracted with ethyl acetate (3X5 ml) . The following ethyl acetate layers were combined, dried (Na2S0 ) and concentrated to obtain 109 mg (53 %) of (1R, 2S, 4R) -2-Acetoxy-4-methyl- cyclohexanecarboxylic acid. NMR 1H (CDCI3, 400 MHz): 5,45 ppm (s, IH) ; 2,46-2,42 ppm (m, IH) ; 2,02 ppm (s, 3H) ; 2,02-1,96 ppm (m, IH) ; 1,91-1,76 ppm (m, 3H) ; 1,70-1,61 ppm (m, lH) ; 1,16-1,08 ppm ( , IH) ; 0,99-0,88 ppm (m, IH) ; 0,87 ppm (d, 3H) .
Step III To a solution of (1R, 2S, 4R) -2-Acetoxy-4-methyl- cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 μl, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R, 2S, 4R) -2- Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride.
Step IV
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (136 mg, 0.50 mmol) in 1, 2-dichloroethane (1.0 ml) was added (IR, 2S, 4R) -2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride (119 mg, 0.54 mmol) dissolved in 1, 2-dichloroethane (0.6 ml) followed by PPh3 (136 mg, 0.52 mmol) . The resulting solution was stirred for 20 h at 90 °C and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHC03 (10 ml) . The aqueous phase was separated and washed with ethyl acetate (2x10 ml) and the combined organic layers were dried (Na2S04) , filtered and concentrated. The residue was purified by flash chromatography (0% to 25% EtOAc/Hexane) to obtain 110 mg (45%) of (IR, 2S, 4R) -3- [Isopropyl- (2-Acetoxy-4-methyl-cyclohexanecarbonyl) -amino] -5-phenyl- thiophene-2-carboxylic acid methyl ester. NMR •'Ή (CDC13/ 400 MHz): 1.5:1.0 mixture of rotamers 7,73-7,70 ppm (m, 2H, Haro) ; 7,69-7,63 ppm (m, IH, Haro); 7,51-7,41 ppm "(m 4H, Haro) ; 7,13 ppm (s, 0.6H, Haro, major rotamer); 5,79 ppm (s, 0.4H, minor rotamer); 5,21 ppm (s, 0.6H, major rotamer); 4,95-4,88 ppm (m, IH) ; 3,88 ppm (s, 1.8H, major rotamer); 3,87 ppm (s, 1.2H, minor rotamer); 2,40- 2,36 ppm ( , 0.6H, major rotamer); 2.11 ppm (s, 3H) ; 1,78-0,77 ppm (m, 16H) .
Step V
(IR, 2S, 4R) -3- [Isopropyl- (2-Acetoxy-4-methyl- cyclohexanecarbonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid methyl ester (36 mg, 0.17 mmol) was dissolved in a mixture of dioxane:H20 (4:1) (700 μl) and then 470 μl of LiOH IN was added to it. After 3 h at 50 °C the reaction mixture was cooled to room temperature and the solvents were removed. The residue was then partitioned between 10 ml of H20 acidified to pH 4 and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2 X 10 ml) . The combined ethyl acetate layers were dried (Na2S04) , concentrated and the residue was purified by preparative chromatography to obtain 9 mg (29 %) of (1R,2S,4R) -3- [Isopropyl- (2-hydroxy-4-methyl- cyclohexanecarbonyl) -amino] -5-phenyl-thiophene-2-carboxylic acid. NMR 1H (CDC13, 400 MHz): 3:2 mixture of rotamers 7,76- 7,73 ppm (m, 2H, Haro) ; 7,50-7,38 ppm (m, 3H, Haro) ; 7,36 ppm (s,
IH, Haro); 4,93-4,87 ppm (m, IH) ; 4,25 ppm (s, 0.70H, major rotamer); 3,97 ppm (s, 0.3H, minor rotamer); 2,35-2,28 ppm (m, lH) ; 1,99-1,53 ppm (m, 5H) ; 1,28 ppm (d, 0,6H, minor rotamer); 1,25 ppm (d, 1,4H, major rotamer); 1,06-1,03 ppm (m, 3H) , 0,96- 0,72 ppm (m, IH) ; 0,79 ppm (d, 3H) ; 0,67-0,56 ppm (m, IH) .
Example 21
3- [ (2 , 4-Dichloro-benzoyl) -piperidin-4-yl-amino] -5-phenyl- thiophene-2-carboxylic acid hydrochloride salt compound #368
Figure imgf000114_0001
Figure imgf000114_0002
Step I A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (745 mg, 3.2 mmol) in dry THF (1.3 ml), at 21 °C, under nitrogen, was treated with tert-butyl 4-oxo-l-piperidine carboxylate (673 mg, 3.2 mmol), followed by dibutyltin dichloride (19 mg, 0.064 mmol, 0.02 eq. ) . After 5 min the reaction was treated with phenyl silane (435 μL, 380 mg, 3.52 mmol, 1.1 eq) . The mixture was left to stir for 74h when a clear solution resulted. The reaction was stripped off solvent to leave a thick bright yellow gum (1.59 g) . The crude material was • purified by column chromatography using (CH2Cl :Hexane : EtOAc) = 15 : 5 :1 as eluent to provide 4- (2-Methoxycarbonyl-5-phenyl- thiophen-3-ylamino) -piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (713 mg, 54%) . αH NMR (CDC13, 400 MHz) 7.63-7.60 (m, 2H) , 7.74-7.36 (m, 3H) , 6.90-6.84 (bs, IH) , 6.84 (s, IH) , 3.97- 4.01 (m, 2H) , 3.80 ( s, 3H) , 3.48 (bs, lH) , 3.06- 2.99 (m, 2H ), 2.03-1.99 (m, 2H ), 1.51-1.48 (m, 2H) , 1.47 (bs, 9H)
Step II
4- (2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino) -piperidine-1- carboxylic acid tert-butyl ester (200 mg, 0.48 mmol) was treated with 2,4 dichlorobenzoylchloride (202 μL, 302 mg, 1.44 mmol, 3 eq) under previously described conditions (e.g. Example 14) to provide,' after column chromatography using (CH2C1 : Hexane : EtOAc = 15 :5 :1) as eluent , 4- [ (2, 4-Dichloro-benzoyl) - (2- methoxycarbonyl-5-phenyl-thiophen-3-yl) -amino] -piperidine-1- carboxylic acid tert-butyl ester as a pale yellow foam (165 mg, 58%), XB NMR (CDC13, 400 MHz) 7.54-7.51 (m, 2H) , 7.45-7.39 (m, 3H) , 7.27-7.25 (m , 2H) , 7.17 (d, J = 1.96Hz, IH) , 7.06 (dd, J = 1.92Hz, J = 8.34Hz, lH) , 4.86-4.92 (m, IH) , 4.11-4.21 (m, 2H) , 3.89 (a, 3H) , 2.82-2.89 (m, 2H) , 2.17-2.20 (m, IH) , 1.89-1.92 (m, IH) , 1.49-1.61 (m, lH) , 1.40 (bs, 9H) , 1.19-1.25 (m, IH)
Step III
A suspension of 4- [ (2, 4-Dichloro-benzoyl) - (2-methoxycarbonyl-5- phenyl-thiophen-3-yl) -amino] -piperidine-l~carboxylic acid tert- butyl ester (160 mg, 0.27 mmol) above in dioxane: water (4 :1, 3 ml) was treated with lithium hydroxide (2M aqueous solution, 41 μL, 341 mg, 0.814 mmol, 3 eq) and the reaction allowed to stir overnight for 18h. The reaction was stripped-off solvent and the residue partitioned between EtOAc : water (4 : 1) . The aqueous phase was separated and extracted several times, with EtOAc , following acidification to pH 5.5 with 0.1N HCI. The combined organic extract was evaporated to a solid. The solid was taken into EtOAc and the above acid wash repeated to give, after drying and evaporation, 4- [ (2-Carboxy-5-phenyl-thiophen-3-yl) -(2,4- dichloro-benzoyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester as a colourless solid (128 mg, 91%) , 1H NMR (Acetone, 400 MHz) 7.75-7.70 ( , IH) , 7.64 (s, lH) , 7.52-7.40 ( , 3H) , 7.52 (d, J = 1.98 Hz, IH) , 7.21 (dd, J = 1.96 Hz, J = 8.19 Hz, IH) , 4.80- 4.71 (m, IH) , 4.26-4.01 (m, 2H) , 2.71- 2.30 (bs, 3H) , 2.25-2.17 (m, IH) , 1.82-1.69 (m, IH) , 1.40 (bs, 9H) , 1.33-1.24 ( , IH) .
Step IV
A solution of 4- [ (2-Carboxy-5-phenyl-thiophen-3-yl) - (2 , 4-dichloro- benzoyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.42 mmol) in dioxane (4 ml) at 21 °C under nitrogen was treated with anhydrous 4M HCI (3 ml, 12.6 mmol, 30 eq) . After 4h the reaction was stripped off solvent and the residue triturated with ether to give 3- [ (2, 4-Dichloro-benzoyl) -piperidin-4-yl- amino] -5-phenyl-thiophene-2-carboxylic acid as a pale yellow powder (214 mg, 100 %) XH NMR (Acetone, 400 MHz) 7.76-7.73 ( , '2H), 7.64 (s, IH) , 7.45-7,38 (m, 3H) , 7.30 (bs, IH) , 7.28-7.24 (m,
IH) , 4.93-4.84 (m, IH) , 3.56-3.49 (m, 2H) , 3.25-3.14 (m, 2H) ,
3.05-2.55 (bs, IH) , 2.50-2.37 ( , 2H) , 2.13-1.83 (m, IH) . Similarly prepared were Compound #366 , Compound #553 , Compound
#543
Example 22
3- (Benzyl-eyelopropanecarbonyl-amino) -5-phenyl-thiophene-2- carboxylic acid. Compound #454
Figure imgf000117_0001
Step I
A solvent mixture of THF/MeOH/H20 (3:2:1) was added to 3.04 g of methyl (3-amino-5-phenyl) thiophene-2-carboxylate (13 mmol) and 1.64 g of lithium hydroxide monohydrate (39 mmol) . The mixture was refluxed for 8 hours and concentrated in vacuo . The crude material was taken in 100 ml of water, washed with ethyl acetate (2 x 100 ml) and transferred into a multineck flask. A 20% phosgene solution in toluene (11 ml, 39 mmol) was added dropwise at 0°C. A precipitate was then collected by filtration and sequentially washed by trituration with a saturated solution of bicarbonate, water, acetone and diethyl ether. 2.52 g (79%) of 6-phenyl-lH-thieno [3 , 2-d] [1, 3] oxazine-2 , 4-dione were isolated as a white solid. NMR XH (DMSO D6, 400 MHz): .7.79-7.76 ppm ( , 2H, Haro) ; 7.52-7.47 ppm (m, 3H, Haro) ; 7.25 ppm (s, lH, Hazoie) ; 0.4 ppm (s, lH, NH) .
Step II
A solution of 6-phenyl-lH-thieno [3 , 2-d] [1, 3] oxazine-2 , 4-dione (1 g, 4.1 mmol) and anhydrous sodium carbonate (477 mg, 4.5 mmol) diluted in 15 ml of anhydrous dimethylacetamide was stirred for one hour under nitrogen before adding benzyl bromide (785 mg, 4.5 mmol) . The mixture was stirred overnight at room temperature. 912 mg (66.3%) of 1-benzyl-6-phenyl-lH-thieno [3 , 2- d] [1, 3] oxazine-2 , 4-dione were obtained as a pale yellow solid after filtration and washing the precipitate with acetone and pentane. NMR XH (DMSO D6, 400 MHz): 7-.8-7.76 ppm (m, 3H, Haro) ; 7.51-7.45 ppm (m, 3H, Haro) ; 7.43-7.41 ppm (m, 2H, Haro) ; 7.35-7.3 - ppm (m, 2H, Haro) ; 7.28-7.24 ppm (m, lH, Haro) ; 5.22 ppm (s, IH, NCH2) .
Step III
To a solution of 1-benzyl-6-phenyl-lH-thieno [3 , 2-d] [1, 3 ] oxazine- 2,4-dione (880 mg, 2.62 mmol) were successively added 32 ml of dioxane and 7.87 ml of NaOH IN aqueous solution. The mixture was vigourously stirred for 2 h and then the solvents were concentrated in vacuo . Dichloromethane was added to the crude material and sodium 3-benzylamino-5-phenyl-thiophene-2- carboxylate (1.07 g, 100%) precipitated as a pale yellow solid. NMR Η. (DMSO D6, 400 MHz): 7.76 ppm (t, IH, J = 6.4 Hz, NH) ; 7.53-7.51 ppm (m, 2H, Haro) ; 7.33-7.26 ppm (m, 6H, Haro) ; 7.23- 7.16 ppm (m, 2H, Haro) ; 7.07 ppm (s, IH, Hazole) ; 4.36 ppm (d, , 2H, J = 6.4 Hz, NHCH2) .
Step IV
To a solution of sodium 3-benzylamino-5-phenyl-thiophene-2- carboxylate (41.1 mg, 0.1 mmol) was added 32 mg (0.3 mmol) of cyclopropanecarbonyl chloride, 1.5 ml of dioxane and 0.5 ml of water. The mixture was stirred overnight at room temperature and concentrated in vacuo . A 4N hydrogen chloride solution in dioxane (1 ml) was added and the mixture was stirred for one hour at room temperature. The mixture was again concentrated and the crude material was purified by reverse phase HPLC giving access to 11.9 mg (31.5%) of 3- (benzyl-cyclopropanecarbonyl- a ino) -5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR ^Η (DMSO D6, 400 MHz): 7.56-7.54 ppm (m, 2H, Haro) ; 7.39-7.13 ppm (m, 10H, Haro, Hazoιe and COOH); 5.27 ppm (d, IH, J = 15.2 Hz); 4.48 ppm (d, IH, J = 15.2 Hz); 1.49 ppm (m, IH) ; 0.77 ppm (m, 2H) ; 0.61 ppm (m, 2H) . The following repared in a similar manner: '
Compound #172 Compound #173 , Compound #175 , Compound #186 ,
Compound #187 Compound #188 , Compound #241 , Compound #247 , Compound #251 Compound #252 , Compound #253 , Compound #254 ,
Compound #255 Compound #256 , Compound #257 , Compound #276 ,
Compound #277 Compound #278 , Compound #279 , Compound #280 ,
Compound #281 Compound #330 , Compound #334 , Compound #335 ,
Compound #336 Compound #339 , Compound #340 , Compound #341 , Compound #342 Compound #343 , Compound #344 , Compound #345 ,
Compound #347 Compound #349 , Compound #350 , Compound #351 ,
Compound #352 Compound #353 BCH-23932, Compound #354 ,
Compound #384 Compound #385 , Compound #386 , Compound #388 ,
Compound #389 Compound #390 , Compound #391 , Compound #392 , Compound #393 Compound #394 , Compound #397 , Compound #398 ,
Compound #399 Compound #400 , Compound #401 .
Example 23
3 - [ ( 2 , 4-Dichloro-phenyl ) -isopropyl-carbamoyl ] -5-phenyl - thiophene-2 -carboxylic acid
Figure imgf000120_0001
Figure imgf000120_0003
Figure imgf000120_0002
Figure imgf000120_0004
Step I 3-Iodo-5-phenyl-thiophene-2-carboxylic acid methyl ester
A suspension of 3-Amino-5-pbenyl-thiophene-2-carboxylic acid methyl ester (10 g, 43 mmol) in anhydrous benzene (200 ml) , at 21 °C, under N2, was treated with t-butyl nitrite (21.8 g, 86 mmol) and the dark mixture cooled to 0 °C and treated dropwise, over 15 min, with iodine (21.8 ml, 184 mmol) . After 30 min at 0 °C, the solution was allowed to warm-up to ambient temperature and stirred for 2h. The reaction mixture was then poured into water (300 ml) and stirred vigorously for 15 min. The organic phase was separated and washed several times with 20% sodium thiosulfate (4x100 ml) . The resulting emulsion was filtered through celite. The celite pad was washed with EtOAc and the combined filtrate and washings were washed with more sodium thiosulfate (100 ml) to give an orange solution which was washed wth brine and dried. Evaporation of the solvent afforded an oil (7.4 g) . The crude oil was purified by biotage flash chromatography using Hexane/CH2Cl2/EtOAc (20/2/1) as eluent to give 4.42g (29%) of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid methyl ester as a pale yellow oil. NMR XH (CDC13, 400 MHz,) : 7.62-7.57 (m, 2H) ; 7.58 (s, IH) ; 7.50-7.36 (m, 3H) ; 3.91 (s, 3H)
Step II 3-Iodo-5-phenyl-thiophene-2-carboxylic acid
A solution of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid methyl ester (4.4 g, 12.78 mmol) in dioxane/water 4/1 (50 ml), at 21 °C, under N2, was treated with lithium hydroxyde (2N, 19.3 ml, 38 mmol) and the solution left to stir for 21.5 h. The reaction mixture was evaporated to dryness and the residue partitioned between EtOAc (75 ml) and water (25 ml) and acidified with 2N HCI to pH 5.5. The aqueous phase was separated and extracted with EtOAc (3x50 ml) . The combined organic extract were washed with brine, dried and evaporated to give 4.12 g (97%) of 3-Iodo- 5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR XH (CD3OD, 400 MHz) : 7.69-7.67 (m, 2H) ; 7.55 (s, IH) ; 7.46- 7.39 ( , 3H) .
Step III
3-Iodo-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester
A suspension of magnesium sulfate (4.61 g, 38.32 mmol) in dichloromethane (37 ml) at 21 °C, under N2, was treated with cone H2S0 (510 μl, 9.58 mmol). After 15 min solid 3-Iodo-5-phenyl- thiophene-2-carboxylic acid (3.7 g, 9.58 mmol) was added followed by t-butanol (4.55 ml, 47.9 mmol) and the flask was stoppered and left over-night for 19.5 h. The reaction mixture was treated with saturated bicarbonate aqueous solution, and filtered. The solid was washed with CH2C1 and the filtrate dried and concentrated to an oil. The crude material was purified by flash chromatography using Hexane/CH2C1 (3:1) as eluent to give 1,63 g (44%) of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester as a colorless solid. NMR 1H (CDC13, 400 MHz) 7.61-7.59 (m, 2H) ; 7.43-7.35 (m, 3H) , 7.25 (s, IH) , 1.60 (bs, 9H) .
Step IV
3~Formyl-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester
A solution of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid tert- butyl ester (1.41 g, 3.65 mmol) in dry THF (37 ml) at -78° C, under nitrogen, was treated dropwise, over 5 min with n-butyl lithium (4.8 ml, 7.66 mmol). The reaction gradually darkened to a red-brown color. After 15 min at -78 °C dimethylformamide (1.7 ml, 21.9 mmol) was added dropwise over 7 min. The dark solution was allowed to stirr for 2 h then quenched with saturated NHC1 solution (10 ml) and allowed to reach 21°C. The aqueous phase was separated and extracted with EtOAc (3x50 ml) . The combined organic extracts were evaporated and the residue taken into EtOAc and washed with water, brine, dried and concentrated to give 1.14 g of a brownn oil. The crude material was purified by flash chromatography using Hexane/CH2C12 (1/1) as eluent to provide 303 mg (28%) of 3-Formyl-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester as a colorless solid. NMR 1H : (CDC13, 400 MHz) : 10.62 (s, IH) ; 7.78 (s, IH) ; 7.64-7.62 (m, 2H) ; 7.48-7.38 (m, 3H) ; 1.62 (bs, 9H) .
Step V 5-Phenyl-thiophene-2 , 3-dicarboxylic acid 2-tert-butyl ester
A solution of 3-Formyl-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester (300 mg, 1.04 mmol) in dry THF (20 ml), at 0 °C, under nitrogen, was treated with methyl sulfide (10% w/w in THF, 3.8 ml, 5.2 mmol) followed by sodium dihydrogenphosphate (30% aqueous solution , 9.56 ml, 2.05 mmol). After 0.5 h, the solution was treated with sodium chlorite (30% w/w aqueous solution, 1.9 ml, 2.08 mmol) added over 1 min via a syringe. The pale yellow solution was stirred.for 1.5 h at 0 °C, then diluted with water (20 ml) and extracted with EtOAc (4x 40 ml) . The aqueous phase was separated, extracted with more EtOAc (40 ml) and the combined extracts were washed with brine dried and concentrated to give 316 mg (100 %) of 5-Phenyl-thiophene-2 , 3- dicarboxylic acid 2-tert-butyl ester as a pale brown solid. NMR XH (CD3CO; 400 MHz): 7.87 (s, IH) ; 7.83-7.81 (m, 2H) ; 7.17-7.53 (m, 3H) ; 1.65 (bs, 9H) .
Step VI
3- [ (2, 4-Dichloro-phenyl) -isopropyl-carbamoyl] -5-phenyl- thiophene-2-carboxylic acid tert-butyl ester
A solution of 5-Phenyl-thiophene-2 , 3-dicarboxylic acid 2-tert- butyl ester (40 mg, 0.13 mmol) in CH2C12 (1.3 ml), under nitrogen, at 0°C, was treated with diisopropylethylamine (27 DL, 0.16 mmol) followed by dimethylformamide (10 DL, 0.13 mmol) and oxalyl chloride (170 L, 0.34 mmol). Slight effervescence was observed. The reaction was kept at 0 °C for 30 min before being treated with (2 , 4-Dichloro-phenyl) -isopropyl-amine (described previously) (79 mg, 0.39 mmol) . The reaction was allowed to reach 21 °C and then placed in a bath at 90 °C for 15 h. Solvent was removed to leave a pale brown gum (144 mg) . The crude material was purified on bond-elute using Hexane/CH2Cl2/EtOAc (12.5/2/1) as eluent to give 39 mg, (62%) of 3- [ (2, 4-Dichloro- phenyl) -isopropyl-carbamoyl] -5-phenyl-thiophene-2-carboxylic acid tert-butyl ester as a pale brown solid. NMR XH (CDC13; 400 MHz) 7.50-7.48 (m, 2H) ; 7.38-7.25 (m, 6H) ; 7.10-7.03 (m, IH) ; 5.05 (quint, J = 6.88 Hz, lH) ; ' 1.57 (bs, 9H) ; 1.40 (d, J = 6.88 Hz, 3H) ; 1.12 (d, J = 6.88 Hz, 3H)
Step VII 3- [ (2, 4-Dichloro-phenyl) -isopropyl-carbamoyl] -5-phenyl- thiophene-2-carboxylic acid
A solution of 3- [ (2, 4-Dichloro-phenyl) -isopropyl-carbamoyl] -5- phenyl-thiophene-2-carboxylic acid tert-butyl ester (37 mg, 0.08 mmol) in CH2C12 (0.2 ml) at room temperature, under nitrogen was treated with trifluoroacetic acid (0.8 ml) . After 1 h the reaction was concentrated the residue was taken into EtOAc and washed sequentially with 2N HCI (2x15 ml) , water, brine dried and evaporated to a foam (33 mg) . The foam was redissolved in EtOAc and above acidic wash was repeated to yield 27 mg (84 %) of 3- [ (2, 4-Dichloro-phenyl) -isopropyl-carbamoyl] -5-phenyl- thiophene-2-carboxylic acid compound as pale brown foam. NMR 1H : (CD3OD; 400 MHz) 7.57-7.55 (m, 2H) ; 7.49-7.36 (m, 6H) , 7.30- 7.27 ( , lH) ; 4.89 (quint, J = 6.73 Hz, IH) ; 1.42 (d, J = 6.73 Hz, 3H) ; 1.12 (d, J = 6.73 Hz, 3H) .
Example 24 The following compound was obtained from Discovery Technology: 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5-phenyl- thiophene-2-carboxylic acid amide Compound #580
Example 25 The following compounds were obtained from Maybridge:
5- (4-Chloro-phenyl) -3- (toluene-4-sulfonylamino) -thiophene-2- carboxylic acid amide, Compound #563
5- (4-Fluoro-phenyl) -3- (toluene-4-sulfonylamino) -thiophene-2- carboxylic acid amide, Compound #564, GK 01137
5- (4-Methoxy-phenyl) -3- (toluene-4-sulfonylamino) -thiophene-2- carboxylic acid amide, Compound #565, GK 01175
Example 26 Evaluation of compounds in The HCV RNA-Dependent RNA
Polymerase Assay
The following references are all incorporated by reference: 1. Behrens, S., Tomei, L., De Francesco, R. (1996) EMBO 15, 12- 22 2. Harlow, E, and Lane, D. (1988) Antibodies : A Laboratory Manual . Cold Spring Harbord Laboratory. Cold Spring Harbord. NY.
3. Lohmann, V., Kδrner, F., Herian, U., and Bartenschlager, R. (1997) J. Virol . 71, 8416-8428
4. Tomei, L., Failla, C, Santolini, E., De Francesco, R. , and La Monica, N. (1993) J Virol 67, 4017-4026
Compounds were evaluated using an in vi tro polymerase assay containing purified recombinant HCV RNA-dependent RNA polymerase (NS5B protein) . HCV NS5B was expressed in insect cells using a recombinant baculovirus as vector. The experimental procedures used for the cloning, expression and purification of the HCV NS5B protein are described below. Follows, are details of the RNA-dependent RNA polymerase assays used to test the compounds.
Expression of the HCV NS5B protein in insect cells :
The cDNA encoding the entire NS5B protein of HCV-Bk strain, genotype lb, was amplified by PCR using the primers NS5Nhe5' (5 ' -GCTAGCGCTAGCTCAATGTCCTACACATGG-3 ' ) and XhoNS53 ' (5 ' -
CTCGAGCTCGAGCGTCCATCGGTTGGGGAG-3 ' ) and the plasmid pCD 3.8-9.4 as template (Tomei et al, 1993). NS5Nhe5' and XhoNS53 ' contain two Nhel and Xhol sites (underlined sequences) , respectively, at their 5' end. The amplified DNA fragment was cloned in the bacterial expression plasmid pET-21b (Novagen) between the restriction sites Nhel and Xhol , to generate the plasmid pET/NS5B. This plasmid was later used as template to PCR- amplify the NS5B coding region, using the'primers NS5B-H9 (5'- ATACATATGGCTAGCATGTCAATGTCCTACACATGG-3' ) and NS5B-R4 (5'- GGATCCGGATCCCGTTCATCGGTTGGGGAG-3 ' ) . NS5B-H9 spans a region of 15 nucleotides in the plasmid pET-21b followed by the translation initiation codon (ATG) and 8 nucleotides corresponding to the 5' end of the NS5B coding region (nt. 7590- 7607 in the HCV sequence with the accession number M58335) . NS5B-R4 contains two BairiKI sites (underlined) followed by 18 nucleotides corresponding to the region around the stop codon in the HCV genome (nt. 9365-9347). The amplified sequence, of 1.8 kb, was digested with Nhel and BaπE.1 and ligated to a predigested pBlueBacII plasmid (Invitrogen) . The resulting recombinant plasmid was designated pBac/NS5B. Sf9 cells were co-transfected with 3 μg of pBac/NS5B, together with 1 μg of linearized baculovirus DNA (Invitrogen) , as described in the manufacturer's protocol. Following two rounds of plaque purification, an NS5B-recombinant baculovirus, BacNS5B, was isolated. The presence of the recombinant NS5B protein was determined by western blot analysis (Harlow and Lane, 1988) of BacNS5B-infected Sf9 cells, using a rabbit polyclonal antiserum (anti-NS5B) raised against a His-tagged version of the NS5B protein expressed in E. coli . Infections of Sf9 cells with this plaque purified virus were performed in one-liter spinner flasks at a cell density of 1.2 x 106 cells/ml and a multiplicity of infection of 5.
Preparation of a soluble recombinant NS5B protein Sf9 cells were infected as described above. Sixty hours post- infection, cells were harvested then washed twice with phosphate buffer saline (PBS) . Total proteins were solubilized as described in Lohmann et al . (1997) with some modifications. In brief, proteins were extracted in three steps, SI, S2, S3, using lysis buffers (LB) I, LB II and LB III (Lohmann et al, 1997) . The composition of LBII was modified to contain 0.1 % triton X- 100 and 150 mM NaCl to reduce the amount of solubilized NS5B protein at this step. In addition, sonication of cell extracts was avoided throughout the protocol to preserve the integrity of the protein structure.
Purification of recombinant NS5B using fast protein liquid chromatography (FPLC) :
Soluble NS5B protein in the S3 fraction was diluted to lower the NaCl concentration to 300 mM, then it incubated batchwise with
DEAE sepharose beads (Amersham-Pharmacia) for 2 hrs at 4°C, as described by Behrens et al . (1996) . Unbound material was cleared by centrifugation for 15 min at 4°C, at 25 000 rpm using a SW41 rotor (Beckman) . The supernatant was further diluted to lower the NaCl concentration to 200 mM and subsequently loaded, with a flow rate of 1 ml/min, on a 5 ml HiTrap® heparin column (Amersham-Pharmacia) connected to an FPLC® system (Amersham- Pharmacia) . Bound proteins were eluted in 1 ml fractions, using a continuous NaCl gradient of 0.2 to 1 M, over a 25 ml volume. NS5B-containing fractions were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) , followed by western blotting using the anti-NS5B antiserum at a dilution of 1:2000. Positive fractions were pooled and the elution buffer was exchanged against a 50 mM NaP04 pH 7.0, 20 % glycerol, 0.5 % triton X-100 and 10 mM DTT, using a PD-10 column (Amersham-Pharmacia) . The sample was then loaded onto a 1 ml HiTrap® SP column (Amersham-Pharmacia) , with a flow rate of 0.1 ml/min. Bound proteins were eluted using a continuous 0 to 1 M NaCl gradient over a 15 ml volume. Eluted fractions were analyzed by SDS-PAGE and western blotting. Alternatively, proteins were visualized, following SDS-PAGE, by silver staining using the Silver Stain Plus kit (BioRad) as described by the manufacturer. Positive fractions were tested for RdRp activity (see below) and the most active ones were pooled, and stored as a 40 % glycerol solution at -70°C.
In vitro HCV RdRp Flashplate scintillation proximity assay (STREP-FLASH ASSAY) used to evaluate analogues:
This assay consists on measuring the incorporation of [3H] radiolabelled UTP in a polyrA/ biotinylated-oligo dT template- primer, captured on the surface of streptavidin-coated scintillant-embeded microtiter Flashplates™ (NEN Life Science Products inc, MA, USA, SMP 103A) . In brief, a 400 ng/μl polyrA solution (Amersham Pharmacia Biotech) was mixed volume-to-volume with 5' biotin-oligo dT15 at 20 pmol/μl. The template and primers were denatured at 95 C for 5 minutes then incubated at 37 C for 10 minutes. Annealed template-primers were subsequently diluted in a Tris-HCl containing buffer and allowed to bind to streptavidin-coated flashplates overnight. Unbound material was discarded, compounds were added in a 10 μl solution followed by a 10 μl of a solution containing 50 mM MgCl2, 100 mM Tris-HCl pH 7.5, 250 mM NaCl and 5 mM DTT. The enzymatic reaction was initiated upon addition of a 30 μl solution containing the enzyme and substrate to obtain the following concentrations: 25 μM UTP, 1 μCi [3H] UTP and 100 nM recombinant HCV NS5B. RdRp reactions were allowed to proceed for 2 hrs at room temperature after which wells were washed three times with a 250μL of 0.15 M NaCl solution, air dried at 37 C, and counted using a liquid scintillation counter (Wallac Microbeta Trilex, Perkin-Elmer, MA, -USA). Results are shown in Table 1.
In vitro HCV RdRp filtration assay used to evaluate analogues RdRp assays were conducted using the homopolymeric template/primer polyA/oligo dT. All RdRp reactions were performed in a total volume of 50 μl, and in a basic buffer- consisting of 20 mM Tris-HCl pH 7.5, ImM DTT, 50 mM NaCl, 5 mM
MgCl2, 0.5 μCi [γ32?] -UTP (3000 Ci/mmol) , 15 μM cold UTP and 20 U RNasin (Promega) . Standard HCV RdRp reactions contained 200 ng of purified NS5B protein. PolyA RNAs (Amersham-Pharmacia) was resuspended at 400 ng/μl . The primer oligodT15 (Canadian life technologies) was diluted to a concentration of 20 pmol/μl (7.6 ng/ml) . Templates and primers were mixed volume to volume, denatured at 95°C for 5 min and annealed at 37°C for 10 min.
Following a two hour incubation at 22°C, reactions were stopped by the addition of 100 μg of sonicated salmon sperm DNA (Life Technologies) and 1 ml of 10 % trichloroacetic acid-0.5 % tetrasodium pyrophosphate (TCA-PPi) . Nucleic acids were precipitated at 4°C for 30 min after which samples were filtered on GF/C glass microfiber filters (Millipore) . Membranes were subsequently washed with 25 ml of a 1% TCA-0.1 % PPi solution, then air dried. Incorporated radioactivity was quantified using a liquid scintillation counter (1450-Microbeta, Wallac) . Results are shown in Table 1.
Example 27 Evaluation of Analogues for measurement of ATPase activity of HCV NS3. helicase
Malachite Green Assay:
The measurement of ATPase activity was performed by measuring the amount of free inorganic phosphate released during the conversion of ATP to ADP by the HCV NS3 ATPase activity. The assay is as follows: In a 96-well microtiter-plate, compounds were dissolved at various concentrations in a final volume of 25 μL of ATPase buffer containing 400 μM ATP. The enzymatic reaction was initiated by the addition of 25 μl of ATPase buffer containing 6 nM of HCV NS3 enzyme without ATP to the wells followed by an incubation of 30 min. at 37 C. Essentially, the final concentration of the ATPase buffer components are as follows: 44 mM MOPS pH 7.0, 8.8 mM NaCl, 2.2 mM MgCl2, 125 μg/ml poly A, 1% DMSO, 200 μM ATP, and 3 nM HCV NS3 enzyme. The reaction was stopped by the addition of 100 μl of Biomol Green™ reagent (BIOMOL® Research Laboratories Inc., Plymouth Meeting, PA) . In order to allow the development of the green color, the plate was incubated for 15 min. at room temperature. Then the plate was read on a micro-plate reader at 620 nm. The 50% inhibitory concentration (IC50) for anti-ATPase activity was defined as the concentration of compound that resulted in a 50 % reduction of the signal compared to the signal observed in control sample without compound. The signal recorded was also corrected from the background signal obtained with control samples with compound only. The IC50 was determined from dose- response curves using six to eight concentrations per compound. Curves were fitted to data points using a non-linear regression analysis, and IC50s were interpolated from the resulting curves using GraphPad Prism software, version 2.0 (GraphPad Software Inc, San Diego, CA) .
HPLC Assay:
The measurement of HCV NS3 ATPase activity was performed by measuring the amount of ADP produced during the conversion of ATP to ADP by the HCV NS3 enzyme using paired-ion HPLC on a reverse phase column. The assay is as follows: The same protocol as mentioned above was used except that the final concentration of HCV NS3 enzyme was reduced to 1 nM in a 50 μl reaction mixture and that the ATPase reaction was stopped by the addition of 12.5 μl of 0.5 M EDTA. A modular liquid chromatography system (TSP Spectrasystern®, ThermoQuest Corporation, San Diego, USA) using a ChromQuest™ software (ThermoQuest Corporation, San Diego, USA) controlled the autosampling of 25 μl from each reaction. The mobile phase was an isocratic solution of 0.15 M triethylamine, 6% methanol, and phosphoric acid to pH 5.5. ADP and ATP peaks were resolved using the Aqua 5 μ, C18, 125 A, (150 X 4.6 mm) reverse phase column. The extent of ATP conversion to ADP was evaluated by measuring the area under the ADP peak produced which was detected at 259 nm. The amount of ADP was corrected for the presence of ADP contaminant in the original ATP solution. The 50% inhibitory concentration (ICS0) for anti-ATPase activity was defined as the concentration of compound that resulted in a 50 % reduction of the ADP peak area compared to the ADP peak area observed in control sample without compound. The IC50 was determined from dose-response curves using six to eight concentrations per compound. Curves were fitted to data points using a non-linear regression analysis, and IC50s were interpolated from the resulting curves using GraphPad Prism software, version 2.0 (GraphPad Software Inc, San Diego, CA) .
EXAMPLE 27 List of compounds and related polymerase activity *
MOLSTRUCTURE COMPOUND NAME IC50
3-[(4-CHLORO-2,5-DIMETHYL- BENZENESULFONYL)-(3-IODO-BENZYL)- AMINO]-5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID ++
3-[(3-BENZOFURAN-2-YL-BENZYL)-(4- . CHLORO-2.5-DIMETHYL-
Figure imgf000131_0001
BENZENESULFONYL)-AMINO]-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID ++
3-(4-CHLORO-2,5-DIMETHYL-
Figure imgf000131_0002
BENZENESULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID ++
3-{(2,4-DICHLORO-BENZOYL)-[5-(3- TRIFLUOROMETHYL-PHENYL)-FURAN-2-
Figure imgf000131_0003
YLMETHYL]-AMINO}-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-(4-METH0XY-2,3,6-TRIMETHYL-
Figure imgf000135_0001
BENZENESULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
5-PHENYL-3-(THIOPHENE-2-
Figure imgf000135_0002
SULFONYLAMINO)-THIOPHENE-2- CARBOXYLIC ACID +++
4-(4-CHLORO-2,5-DIMETHYL-
Figure imgf000135_0003
BENZENESULFONYLAMINO)- r2,3']BITHI0PHENYL-5-CARBQXYLIC ACID +++
5-(3,5-BIS-TRIFLUOROMETHYL-PHENYL)- 3-(4-CHLORO-2,5-DIMETHYL-
Figure imgf000135_0004
BENZENESULFONYLAMINO)- THIOPHENE-2-CARBOXYLIC ACID
8-CHLORO-3-(4-CHLORO-2,5-DIMETHYL- BENZENESULFONYLAMINO)-4#H!-1 ,5- DITHIA-
Figure imgf000135_0005
CYCLOPENTA[#A!]NAPHTHALENE-2- CARBOXYLIC ACID ++
3-(2,4-DIFLUORO-
Figure imgf000135_0006
BENZENESULFONYLAMlNO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000136_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-(3,4-DICHL0R0-
Figure imgf000137_0001
BENZENESULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID ++
5-PH ENYL-3-(2-TRI FLUOROM ETHYL-
Figure imgf000137_0002
BENZENESULFONYLAMINO)- THIOPHENE-2-CARBOXYLIC ACID
3-(5-BROMO-6-CHLORO-PYR]DINE-3-
Figure imgf000137_0003
SULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
3-(5-CHLORO-THIOPHENE-2-
Figure imgf000137_0004
SULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
3-(5-CHLORO-3-METHYL- BENZO[#B!]THIOPHENE-2-
Figure imgf000137_0005
SULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000138_0001
Figure imgf000139_0001
MOLSTRUCTURE COMPOUND NAME IC50
5-PHENYL-3-(3-TRIFLUOROMETHYL-
Figure imgf000140_0001
BENZENESULFONYLAMINO)- THIOPHENE-2-CARBOXYLIC ACID ++
3-(2-CARBOXY-BENZOYLAMINO)-5-
Figure imgf000140_0002
PHENYL-THIOPHENE-2-CARBOXYLIC ACID METHYL ESTER ++
5-PHENYL-3-(4-TRIFLUOROMETHYL-
Figure imgf000140_0003
BENZENESULFONYLAMINO)- THIOPHENE-2-CARBOXYLIC ACID +++
3-(2,5-DIFLUORO-
Figure imgf000140_0004
BENZENESULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
3-(2-CYANO-
Figure imgf000140_0005
BENZENESULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID +++
3-(2,5-DICHLORO-THIOPHENE-3-
Figure imgf000140_0006
SULFONYLAMINO)-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID ++
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
MOLSTRUCTURE COMPOUND NAME IC50
5~(4-CHLORO-PHENYL)-3-(PYRIDINE-2-
Figure imgf000151_0001
SULFONYLAMINO)-THIOPHENE-2-
116 CARBOXYLIC ACID ++
5-(3-CYANO-PH ENYL)-3-(TOLU EN E-2- SULFONYLAMINO)-THIOPHENE-2-
117 CARBOXYLIC ACID +++
3-(2,5-DIMETHYL-
BENZENESULFONYLAMINO)-5-P-TOLYL-
118 THIOPHENE-2-CARBOXYLIC ACID +++
3-(2,4-DIFLUORO-
Figure imgf000151_0002
BENZENESULFONYLAMINO)-5-P-TOLYL-
119 THIOPHENE-2-CARBOXYLIC ACID +++
5-PHENETHYL-3-(TOLUENE-2-
Figure imgf000151_0003
SULFONYLAMINO)-THIOPHENE-2-
120 CARBOXYLIC ACID ++
5-(3-ETHOXYCARBONYL-PHENYL)-3-
Figure imgf000151_0004
(TOLUENE-2-SULFONYLAMINO)-
121 THIOPHENE-2-CARBOXYLIC ACID ++
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-(4-ACETYL-
Figure imgf000155_0001
BENZENESULFONYLAMINO)-5-PHENYL-
140 THIOPHENE-2-CARBOXYLIC ACID ++
3-(4-FLUORO-2-TRIFLUOROMETHYL-
Figure imgf000155_0002
BENZENESULFONYLAMINO)-5-PHENYL-
141 THIOPHENE-2-CARBOXYLIC ACID ++
3-(2-METHOXY-4-METHYL-
Figure imgf000155_0003
BENZENESULFONYLAMINO)-5-PHENYL-
142 THIOPHENE-2-CARBOXYLIC ACID ++
3-(3,4-DIFLUORO-
Figure imgf000155_0004
BENZENESULFONYLAMINO)-5-PHENYL-
143 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000156_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[(2,4-DICHLORO-BENZOYL)-
Figure imgf000157_0001
ISOPROPYL-AMINO]-5-PHENYL-
149 THIOPHENE-2-CARBOXYLIC ACID +++
5-(3-CYANO-BENZYL)-3-(TOLUENE-2-
Figure imgf000157_0002
SULFONYLAMINO)-THIOPHENE-2-
150 CARBOXYLIC ACID
Figure imgf000157_0003
5-PHENYL-3-(2,4,6-TRIFLUORO- BENZENESULFONYLAMINO)-
151 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000157_0004
3-(4-METHOXY-2-NITRO- BENZENESULFONYLAMINO)-5-PHENYL-
152 THIOPHENE-2-CARBOXYLIC ACID ++ MOLSTRUCTURE COMPOUND NAME IC50
5-PHENYL-3-(2,3,4-TRICHL0R0-
Figure imgf000158_0001
BENZENESULFONYLAMINO)-
153 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000158_0002
5-(2-CARB0XY-5-PHENYL-THI0PHEN-3- YLSULFAM0YL)-2-M ETHYL-FU RAN-3-
154 CARBOXYLIC ACID METHYL ESTER +++
4-(2-CARB0XY-5-PHENYL-THI0PHEN-3- YLSULFAM0YL)-2-METHYL-1 ,5-
Figure imgf000158_0003
DIPHENYL-1 H-PYRROLE-3-CARBOXYLIC
155 ACID ETHYL ESTER +++
5-PH EN YL-3-{[4-(3-TRI FLUOROM ETHYL-
Figure imgf000158_0004
PHENYL)-PIPERAZINE-1 -CARBONYL]-
156 AMIN}-THIOPHENE-2-CARBOXYLIC ACID ++
Figure imgf000159_0001
Figure imgf000160_0001
MOLSTRUCTURE COMPOUND NAME IC50
4-(2-CARBOXY-5-PHENYL-THIOPHEN-3- YLSULFAMOYL)-2,5-DIMETHYL-1 H-
Figure imgf000161_0001
PYRROLE-3-CARBOXYLIC ACID ETHYL
167 ESTER ++
4-(2-CARBOXY-5-PHENYL-THIOPHEN-3- YLSULFAMOYL)-5-(4-CHLORO-PHENYL)-
Figure imgf000161_0002
3-METHYL-1-PHENYL-1 H-PYRROLE-2-
168 CARBOXYLIC ACID ETHYL ESTER ++
3-(3,5~DICHLORO-4-HYDROXY-
Figure imgf000161_0003
BENZENESULFONYLAMINO)-5-PHENYL-
169 THIOPHENE-2-CARBOXYLIC ACID ++
5-(1#H!-PYRAZOL-4-YL)-3-(TOLUENE-2-
Figure imgf000161_0004
SULFONYLAMINO)-THIOPHENE-2-
170 CARBOXYLIC ACID +++
5-(3-HYDROXY-PH ENYL)-3-(TOLU EN E-2-
Figure imgf000161_0005
SULFONYLAMINO)-THIOPHENE-2-
171 CARBOXYLIC ACID +++
3-[M ETHYL-(3-M ETHYL-BUTYRYL)- AMINO]-5-PHENYL-THIOPHENE-2-
172
Figure imgf000161_0006
CARBOXYLIC ACID +++
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
MOLSTRUCTURE COMPOUND NAME IC50
5-(3-CYANO-PHENYL)-3-[METHYL-(4-
Figure imgf000168_0001
METHYL-BENZOYL)-AMINO]-THIOPHENE-
206 2-CARBOXYLIC ACID +++
5-(2-CHLORO-PHENYL)-3~[METHYL-(4-
Figure imgf000168_0002
M ETH YL-BENZOYL)-AM I NO]-TH IOPH ENE-
207 2-CARBOXYLIC ACID ++
Figure imgf000168_0003
3-[(2,4-DICHLORO-BENZOYL)-PHENYL- AMINO]-5-PHENYL-THIOPHENE-2-
208 CARBOXYLIC ACID +++
Figure imgf000168_0004
3-[4-(TRIFLUOROMETHYL- BENZOYL)METHYLAMINE]-5-PHENYL-
209 THIOPHENE-2-CARBOXYLIC ACID ++
3-[(4-CHLORO-BENZOYL)-ISOPROPYL-
Figure imgf000168_0005
AMINO]-5-PHENYL-THIOPHENE-2-
210 CARBOXYLIC ACID +++
3-[ISOPROPYL-(4-METHYL-BENZOYL)-
Figure imgf000168_0006
AMINO]-5-PHENYL-THIOPHENE-2-
211 CARBOXYLIC ACID +++ MOLSTRUCTURE COMPOUND NAME IC50
5-(3,5-DIFLUORO-PHENYL)-3-[METHYL-(4-
Figure imgf000169_0001
METHYL-BENZOYL)-AMINO]-THIOPHENE-
212 2-CARBOXYLIC ACID +++
5-(3-FLUORO-PHENYL)-3-[METHYL-(4-
Figure imgf000169_0002
M ETH YL-BENZOYL)-AM I NO]-TH IOPH ENE-
213 2-CARBOXYLIC ACID +++
5-(2,4-DIFLUORO-PHENYL)-3-[METHYL-(4- METHYL-BENZOYL)-AMINO]-THIOPHENE
214 2-CARBOXYLIC ACID ++
5-(4-HYDROXY-PHENYL)-3-[METHYL-(4- METHYL-BENZOYL)-AMINO]-THIOPHENE-
215 2-CARBOXYLIC ACID +++
3-[METHYL-(4-METHYL-BENZOYL)- AMINO]-5-(4-TRIFLUOROMETHOXY-
Figure imgf000169_0003
PHENYL)-THIOPHENE-2-
216 CARBOXYLIC ACID ++
5-(2-HYDROXY-PHENYL)-3-(TOLUENE-2-
Figure imgf000169_0004
SULFONYLAMINO)-THIOPHENE-2-
217 CARBOXYLIC ACID ++
3-[(2-CHLORO-BENZOYL)-ISOPROPYL-
Figure imgf000169_0005
AMINO]-5-PHENYL-THIOPHENE-2-
218 CARBOXYLIC ACID ++ MOLSTRUCTURE COMPOUND NAME IC50
3-[(3,5-DICHL0R0-BENZ0YL)-
Figure imgf000170_0001
ISOPROPYL-AMINO]-5-PHENYL-
219 THIOPHENE-2-CARBOXYLIC ACID ++
3-(4-BROMO-2-METHYL-
Figure imgf000170_0002
BENZENESULFONYLAMINO)-5-PHENYL-
220 THIOPHENE-2-CARBOXYLIC ACID +++
3-(5-CARBOXY-4-CHLORO-2-FLUORO-
Figure imgf000170_0003
BENZENESULFONYLAMINO)-5-PHENYL-
221 THIOPHENE-2-CARBOXYLIC ACID
5-PHENYL-3-(2,3,4-TRIFLUORO-
Figure imgf000170_0004
BENZENESULFONYLAMINO)-
222 THIOPHENE-2-CARBOXYLIC ACID ++
3-(4-BROMO-2-FLUORO- BENZENESULFONYLAMINO)-5-(4-
Figure imgf000170_0005
ISOBUTYL-PHENYL)-THIOPHENE-2-
223 CARBOXYLIC ACID ++
Figure imgf000171_0001
MOLSTRUCTURE COMPOUND NAME IC50
5'-ACETYL-4-(TOLUENE-2-
Figure imgf000172_0001
SULFONYLAMINOH2,2']BITHIOPHENYL-5-
229 CARBOXYLIC ACID +++
5-BENZO[B]THIOPHEN-2-YL-3-(TOLUENE-
Figure imgf000172_0002
2-SULFONYLAMINO)-THIOPHENE-2-
230 CARBOXYLIC ACID +++
5-(4-BUTYL-PHENYL)-3-(TOLUENE-2-
Figure imgf000172_0003
SULFONYLAMINO)-THIOPHENE-2-
231 CARBOXYLIC ACID +++
5-(4-ETHYL-PHENYL)-3-(TOLUENE-2-
Figure imgf000172_0004
SULFONYLAMINO)-THIOPHENE-2-
232 CARBOXYLIC ACID +++
3-[BENZYL-(2,4-DICHLORO-BENZOYL)-
Figure imgf000172_0005
AMINO]-5-PHENYL-THIOPHENE-2-
233 CARBOXYLIC ACID +++
3-[(4-CHLORO-2-METHYL-BENZOYL)-
Figure imgf000172_0006
ISOPROPYL-AMINO]-5-PHENYL-
234 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
MOLSTRUCTURE COMPOUND NAME IC50
5-(1 H-IND0L-5-YL)-3-(T0LUENE-2-
Figure imgf000177_0001
SULFONYLAMINO)-THIOPHENE-2-
260 CARBOXYLIC ACID ++
3-[#SEC!-BUTYL-(2,4-DICHLORO-
Figure imgf000177_0002
BENZOYL)-AMINO]-5-PHENYL-
261 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(2,4-DIMETHYL-BENZOYL)-
Figure imgf000177_0003
ISOPROPYL-AMINO]-5-PHENYL-
262 THIOPHENE-2-CARBOXYLIC ACID +++
5-(4-AZIDO-PHENYL)-3-(TOLUENE-2-
Figure imgf000177_0004
SULFONYLAMINO)-THIOPHENE-2-
263 CARBOXYLIC ACID +++
3-[(2,4-DICHLORO-BENZOYL)-(1-PHENYL- ETHYL)-AMINO]-5-PHENYL-THIOPHENE-
264 2-CARBOXYLIC ACID +++
5-(4-CARBAMOYL-PHENYL)-3-(4-
Figure imgf000177_0005
CHLORO-BENZENESULFONYLAMINO)-
265 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
MOLSTRUCTURE COMPOUND NAME IC50
5'-CYANO-4-(TOLUENE-2-
Figure imgf000183_0001
SULFONYLAMINO)-[2,2']BITHIOPHENYL-5-
295 CARBOXYLIC ACID +++
3-[METHYL-(4-METHYL-BENZOYL)-
Figure imgf000183_0002
AMINO]-5-PYRIDIN-2-YL-THIOPHENE-2-
296 CARBOXYLIC ACID ++
Figure imgf000183_0003
3~[(2,4-DICHLORO-THIOBENZOYL)- ISOPROPYL-AMINOJ-5-PHENYL-
297 THIOPHENE-2-CARBOXYLIC ACID +++
5-PHENYL-3-(2,4,6-TRIMETHYL-
Figure imgf000183_0004
BENZENESULFONYLAMINO)-
298 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000183_0005
3-[(1-CARBOXY-ETHYL)-(2,4-DICHLORO- BENZOYL)-AMINO]-5-PHENYL-
299 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000183_0006
3-[(4-METHYL-BENZOYL)-(3-METHYL- BUT-2-ENYL)-AMINO]-5-PHENYL-
300 THIOPHENE-2-CARBOXYLIC ACID ++
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[(4-M ETHYL-BENZOYL)-(4-N ITRO-
Figure imgf000191_0001
BENZYL)-AMINO]-5-PHENYL~THIOPHENE-
342 2-CARBOXYLIC ACID +++
3-[(4-METHYL-BENZOYL)-(2-METHYL- BENZYL)-AMINO]-5-PHENYL-THIOPHENE-
343 2-CARBOXYLIC ACID +++
Figure imgf000191_0002
3-[(3-METHOXY-BENZYL)-(4-METHYL- BENZOYL)-AMINO]-5-PHENYL-
344 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(2-CHLORO-BENZYL)-(4-METHYL-
Figure imgf000191_0003
BENZOYL)-AMINO]-5-PHENYL-
345 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(2,4-DICHLORO-BENZOYL)- ISOPROPYL-AMINO]-5-ISOBUTYL-
Figure imgf000191_0004
THIOPHENE-2-CARB
346 OXYLIC ACID +++ MOLSTRUCTURE COMPOUND NAME IC50
3-[ALLYL-(2-NAPHTHALEN-2-YL-ACETYL)-
Figure imgf000192_0001
AMINO]-5-PHENYL-THIOPHENE-2-
347 CARBOXYLIC ACID
3-{ALLYL-[2-(2,4-DICHLORO-PHENYL)-
Figure imgf000192_0002
ACETYL]-AMINO}-5-PHENYL-THIOPHENE-
348 2-CARBOXYLIC ACID ++
Figure imgf000192_0003
3-{ALLYL-[2-(2-CHLORO-4-FLUORO- PH EN YL)-ACETYL]-AM I NOJ-5-PHENYL-
349 THIOPHENE-2-CARBOXYLIC ACID ++
Figure imgf000192_0004
3-{ALLYL-[2-(3,4-DICHLORO-PHENYL)- ACETYL]-AMINO}-5-PHENYL-THIOPHENE-
350 2-CARBOXYLIC ACID ++
3-{ALLYL-[2-(2,4-DIFLUORO-PHENYL)- ACETYL]-AMINO}-5-PHENYL-THIOPHENE-
351
Figure imgf000192_0005
2-CARBOXYLIC ACID ++
Figure imgf000193_0001
Figure imgf000194_0001
MOLSTRUCTURE COMPOUND NAME IC50
Figure imgf000195_0001
3-(CYCLOHEXANECARBONYL- ISOPROPYL-AMINO)-5-PHENYL-
362 THIOPHENE-2-CARBOXYLIC ACID ++
3-{(2,4-DICHLORO-BENZOYL)-[1-(2,4- DICHLORO-BENZOYL)-PIPERIDIN-4-YL]-
Figure imgf000195_0002
AMINO}-5-PHENYL-THIOPHENE-2-
363 CARBOXYLIC ACID +++
4-[(2-CARBOXY-5-PHENYL-THIOPHEN-3-
Figure imgf000195_0003
YL)-(4-M ETH YL-BENZOYL)-AM I NO]- PIPERIDINE-1 -CARBOXYLIC ACID
364 #TERT!-BUTYL ESTER +++
4-[(2-CARBOXY-5-PHENYL-THlOPHEN-3- YL)-(2,4-DICHLORO-BENZOYL)-AMINO]-
Figure imgf000195_0004
PIPERIDINE-1 -CARBOXYLIC ACID
365 #TERTJ-BUTYL ESTER +++ MOLSTRUCTURE COMPOUND NAME IC50
Cl
Figure imgf000196_0001
3-[(4-METHYL-BENZOYL)-PIPERIDIN-4-YL- AMINO]-5-PHENYL-THIOPHENE-2-
366 CARBOXYLIC ACID +++
5'-ACETYL-4-(2,4-DIMETHYL-
Figure imgf000196_0002
BENZENESULFONYLAMINO)-
367 [2,3'1BITHIOPHENYL-5-CARBOXYLIC ACID +++
cm
3-[(2,4-DICHLORO-BENZOYL)-PIPERIDIN-
Figure imgf000196_0003
4-YL-AMINO]-5-PHENYL-THIOPHENE-2-
368 CARBOXYLIC ACID +++
5-(4-METHANESULFONYLAMINO- PHENYL)-3
(TOLUENE-2-SULFONYLAMINO)-
Figure imgf000196_0004
THIOPHEN
369 E-2-CARBOXYLIC ACID ++
3-(4-FLUORO-2-METHYL-
Figure imgf000196_0005
BENZENESULFONYLAMINO)-5-PHENYL-
370 THIOPHENE-2-CARBOXYLIC ACID ++
3-[(3-METHYL-
CYCLOHEXANECARBONYL)-ISOPROPYL- AMINO]-5-PHENYL-THIOPHENE-2-
371
Figure imgf000196_0006
CARBOXYLIC ACID
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[(2,4-DICHLORO-BENZOYL)-(1-PHENYL-
Figure imgf000203_0001
ETHYL)-AMINO]-5-PHENYL-THIOPHENE- tf-03 2-CARBOXYLIC ACID +++
3-[(2,4-DICHLORO-BENZOYL)-(1-PHENYL-
Figure imgf000203_0002
ETHYL)-AMINO]-5-PHENYL-THIOPHENE-
W04 2-CARBOXYLIC ACID +++
3-[ISOPROPYL-(3-METHYL-CYCLOPENT-
Figure imgf000203_0003
3-ENECARBONYL)-AM I NO]-5-PH EN YL- μo5 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(2-BENZYLOXY-4-METHYL-BENZOYL)- ISOPROPYL-AMINO]-5-(3-
Figure imgf000203_0004
TRIFLUOROMETHYL-PHENYL)-
W06 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(2,4-DIMETHYL-
CYCLOHEXANECARBONYL)-ISOPROPYL-
Figure imgf000203_0005
AMINO]-5-PHENYL-THIOPHENE-2-
W07 CARBOXYLIC ACID +++
Figure imgf000204_0001
Figure imgf000205_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[(4-TERT-BUTYL-BENZYL)-PROPIONYL-
Figure imgf000206_0001
AMINO]-5-PHENYL-THIOPHENE-2-
W17 CARBOXYLIC ACID ++
3-[(4-NITRO-BENZYL)-PROPIONYL-
Figure imgf000206_0002
AMINO]-5-PHENYL-THIOPHENE-2-
W18 CARBOXYLIC ACID ++
3-[(3-METHYL-BUTYRYL)-(4-NITRO-
Figure imgf000206_0003
BENZYL)-AMINO]-5-PHENYL-THIOPHENE-
W19 2-CARBOXYLIC ACID +++
3-[CYCLOPROPANECARBONYL-(4-
Figure imgf000206_0004
N ITRO-BENZYL)-AM I NO]-5-PH ENYL-
W20 THIOPHENE-2-CARBOXYLIC ACID ++
3-[(2-CHLORO-BENZYL)-ISOBUTYRYL-
Figure imgf000206_0005
AMINO]-5-PHENYL-THIOPHENE-2-
W21 CARBOXYLIC ACID ++
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[(4-METHYL-BENZYL)-PROPIONYL-
Figure imgf000216_0001
AMINO]-5-PHENYL-THIOPHENE-2-
467 CARBOXYLIC ACID ++
3-[ISOBUTYRYL-(4-METHYL-BENZYL)-
Figure imgf000216_0002
AMINO]-5-PHENYL-THIOPHENE-2-
468 CARBOXYLIC ACID ++
3-[CYCLOPROPANECARBONYL-(4-
Figure imgf000216_0003
METHYL-BENZYL)-AMINO]-5-PHENYL-
469 THIOPHENE-2-CARBOXYLIC ACID ++
3-[BUTYRYL-(4-METHYL-BENZYL)-
Figure imgf000216_0004
AMINO]-5-PHENYL-THIOPHENE-2-
470 CARBOXYLIC ACID ++
3-[(3-METHOXY-BENZYL)-PROPIONYL-
Figure imgf000216_0005
AMINO]-5-PHENYL-THIOPHENE-2-
471 CARBOXYLIC ACID
Figure imgf000217_0001
Figure imgf000218_0001
MOLSTRUCTURE COMPOUND NAME IC50
3-[BUTYRYL-(3-CHLORO-BENZYL)-
Figure imgf000219_0001
AMINO]-5-PHENYL-THIOPHENE-2-
482 CARBOXYLIC ACID +++
3-[ACETYL-(2,4-DIFLUORO-BENZYL)-
Figure imgf000219_0002
AMINO]-5-PHENYL-THIOPHENE-2-
483 CARBOXYLIC ACID ++
3-[(2,4-DIFLUORO-BENZYL)-(2-METHOXY-
Figure imgf000219_0003
ACETYL)-AMINO]-5-PHENYL-THIOPHENE-
484 2-CARBOXYLIC ACID ++
3~[(2,4-DIFLUORO-BENZYL)-
Figure imgf000219_0004
ISOBUTYRYL-AMINO]-5-PHENYL-
485 THIOPHENE-2-CARBOXYLIC ACID ++
3-[(2,4-DIFLUORO-BENZYL)-(3-METHYL-
Figure imgf000219_0005
BUTYRYL)-AMINO]-5-PHENYL-
486 THIOPHENE-2-CARBOXYLIC ACID ++ MOLSTRUCTURE COMPOUND NAME IC50
3-[BENZYL-(2-CYCLOPENTYL-ACETYL)-
Figure imgf000220_0001
AMINO]-5-PHENYL-THIOPHENE-2-
487 CARBOXYLIC ACID +++
3-[(2,4-DICHLORO-BENZOYL)-
Figure imgf000220_0002
ISOPROPYL-AMINO]-5-(1 H-INDOL-5-YL)-
488 THIOPHENE-2-CARBOXYLIC ACID +++
3-(BENZYL-CYCLOBUTANECARBONYL-
Figure imgf000220_0003
AMINO)-5-PHENYL-THIOPHENE-2-
489 CARBOXYLIC ACID +++
3-[CYCLOHEXANECARBONYL-(2,4-
Figure imgf000220_0004
DIFLUORO-BENZYL)-AMINO]-5-PHENYL-
490 THIOPHENE-2-CARBOXYLIC ACID +++
3-{ALLYL-[2-(4-METHOXY-PHENYL)-
Figure imgf000220_0005
ACETYL]-AMINO}-5-PHENYL-THIOPHENE-
491 2-CARBOXYLIC ACID MOLSTRUCTURE COMPOUND NAME IC50
Figure imgf000221_0001
3-(ETHYL-HEXANOYL-AMINO)-5-PHENYL-
492 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000221_0002
3-(BUTYRYL-ETHYL-AMINO)-5-PHENYL-
493 THIOPHENE-2-CARBOXYLIC ACID ++
3-[ETHYL-(4-METHYL-PENTANOYL)-
Figure imgf000221_0003
AMINO]-5-PHENYL-THIOPHENE-2-
494 CARBOXYLIC ACID +++
3-[CYCLOBUTANECARBONYL-(2,4-
Figure imgf000221_0004
DIFLUORO-BENZYL)-AMINO]-5-PHENYL-
495 THIOPHENE-2-CARBOXYLIC ACID I+++
3-[BUTYRYL-(2,4-DIFLUORO-BENZYL)-
Figure imgf000221_0005
AMINO]-5-PHENYL-THIOPHENE-2-
496 CARBOXYLIC ACID +++ MOLSTRUCTURE COMPOUND NAME IC50
3-(CYCLOPENTANECARBONYL-METHYL-
Figure imgf000222_0001
AMINO)-5-PHENYL-THIOPHENE-2-
497 CARBOXYLIC ACID +++
3-(CYCLOHEXANECARBONYL-METHYL-
Figure imgf000222_0002
AMlNO)-5-PHENYL-THIOPHENE-2-
498 CARBOXYLIC ACID +++
3-[(2-CARBOXY-5-PHENYL-THIOPHEN-3- YL)-(2,4-DICHLORO-BENZOYL)-AMINO]-
Figure imgf000222_0003
PYRROLIDINE-1 -CARBOXYLIC ACID
499 #TERT!-BUTYL ESTER +++
3-[(1 ,4-DIMETHYL-
CYCLOHEXANECARBONYL)-ISOPROPYL-
Figure imgf000222_0004
AMINO]-5-PHENYL-THIOPHENE-2-
500 CARBOXYLIC ACID +++
5-(4-ETHYL-PHENYL)-3-[(2-HYDROXY-4-
Figure imgf000222_0005
METHYL-BENZOYL)-ISOPROPYL-AMINO]-
501 THIOPHENE-2-CARBOXYLIC ACID +++
Figure imgf000223_0001
MOLSTRUCTURE COMPOUND NAME IC50
4-[(2-CARBOXY-5-PHENYL-THIOPHEN-3- YL)-(2,4-DICHLORO-BENZOYL)-AMINO]-
Figure imgf000224_0001
AZEPANE-1 -CARBOXYLIC ACID TERT!-
507 BUTYL ESTER +++
4-{[(2-CARBOXY-5-PHENYL-THIOPHEN-3- YL)-(2,4-DICHLORO-BENZOYL)-AMINO]-
Figure imgf000224_0002
METHYL}-PIPERIDINE-1 -CARBOXYLIC
508 ACID BENZYL ESTER +++
CIH
3-[AZEPAN-4-YL-(2,4-DICHLORO-
Figure imgf000224_0003
BENZOYL)-AMINO]-5-PHENYL-
509 THIOPHENE-2-CARBOXYLIC ACID +++
3-[(4-METHYL-
CYCLOHEXANECARBONYL)-PIPERIDIN-
Figure imgf000224_0004
4-YL-AMINO]-5-PHENYL-THIOPHENE-2-
510 CARBOXYLIC ACID LITHIUM SALT ++
3-[(2-CARBOXY-5-PHENYL-THIOPHEN-3- YL)-(2,4-DICHLORO-BENZOYL)-AMINO]-
Figure imgf000224_0005
PIPERIDINE-1-CARBOXYLIC ACID
51 1 #TERT!-BUTYL ESTER !+++
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
+++ ιc5o <5μM ++ IC50 5μ -20μM + IC5o >20μ EXAMPLE 28 List of compounds having anti-helicase activity *
Figure imgf000237_0001
+++ ICso <5μM ++ IC50 5μM-20μM + IC50 >20μM

Claims

We claim:
1. A compound having the formula I :
Figure imgf000239_0001
(I) or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
N R. or ,N s "R,
wherein,
M is chosen from:
Figure imgf000239_0002
Figure imgf000239_0003
wherein,
R4 is C 1_6 alkyl;
R8 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and
RI5 is chosen from H or C 1-s alkyl; J is chosen from:
Figure imgf000240_0001
wherein, W is chosen from 0, S or NR,, wherein R7 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_ 12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1_12 alkyl, C 6_14 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, Cλ_6 alkyl, C 2_s alkenyl or C 2_s alkynyl ;
Y is chosen from COOR15, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)2OR5ι tetrazole, CO (R9) CH (R5) C00R5 , CONR10RU., C0N(R9) -S02-R5 , CONR9OH or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 3_12 heterocycle, C3_18 heteroaralkyl, Cs_18 aralkyl; or R10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle; .
Ra and R^ are each independently chosen from H, C x_12 alkyl, C 2_
12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.1B heteroaralkyl and C6.18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C
6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl and C6_18 aralkyl; provided that R16 is other than methyl or ethyl;
Rx is chosen from C 2_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl or C 6_18 aralkyl;
R2 is chosen from C 2_12 alkyl, C2.12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl, or C 6_18 aralkyl; R3 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl or C 6_18 aralkyl;
Z is chosen from H, halogen, C _6 alkyl;
with the proviso that :
i) when X is 4-Chloro-2 , 6-dimethyl-benzenesulfonamide and, R1 is phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #580
ii) when X is Toluene-4-sulfonamide and R1 is 4-chloro- phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #563
iii) when X is Toluene-4-sulfonamide and Rx is 4-fluorophenyl, and R3 is H, and Y1 is a bond, then Y is other than ■ CONH2; compound #564
iv) when X is Toluene-4-sulfonamide and Rx is 4-methoxy- phenyl, and R3 is H, and Y1 is a bond, then . Y is other than CONH2; compound #565 v) when X is Benzamide and Ri is phenyl Y1 is a bond and Y is COOH then R3 is other than hydrogen.
A compound having the formula la:
Figure imgf000241_0001
(la)
pharmaceutically acceptable salts thereof; wherein-,
X is chosen from:
Figure imgf000242_0001
wherein,
M is chosen from:
Figure imgf000242_0002
Figure imgf000242_0003
wherein,
R4 is C 1.6 alkyl;
R8 is chosen from H, C 1.12 alkyl, C 2.12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6.16 aralkyl; and
R15 is chosen from H or C x_6 alkyl;
J is chosen from:
Figure imgf000242_0004
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_ 16 aralkyl; and R6 is chosen from H, C 1_12 alkyl, C 6_14 aryl or C 6_16 aralkyl ; Y1 is chosen from a bond, C _6 alkyl, C 2_s alkenyl or C 2.6 alkynyl ;
Y 'is chosen from COORls, COCOOR5, P(0)ORaORb, S(0)OR5, S(0)2OR5/ tetrazole, CON(R9) CH(R5) COOR5 , CO R^R^, CON(R9) -S02~Rs , CONR9OH or halogen, wherein R9, R5, R10 and R1X are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 3_12 heterocycle, C3_I8 heteroaralkyl, Cε_18 aralkyl; or R10 and Ru are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rj, are each independently chosen from H, C 1_12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and Cs_18 aralkyl; or Ra and Rj, are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; provided that R1S is other than methyl or ethyl;
Rx is chosen from C 2_12 alkyl, C 2.12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl or C 6_18 aralkyl;
R2 is chosen from C 2_12 alkyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, or C 6_18 aralkyl;
R3 is chosen from H, C 1-12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3„12 heterocycle, C3.18 heteroaralkyl or C 6_18 aralkyl;
Z is chosen from H, halogen, C1.6 alkyl;
with the proviso that :
i) when X is 4-Chloro-2 , 6-dimethyl-benzenesulfonamide and, R1 is phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #580 ii) when X is Toluene-4-sulfonamide and R1 is 4-chloro- phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #563
iii) when X is Toluene-4-sulfonamide and R2 is 4-fluorophenyl, and R3 is H, and Y1 is a bond, then Y is other than C0NH2; compound #564 iv) when X is Toluene-4-sulfonamide and Ri is 4-methoxy- phenyl, and R3 is H, and Y1 is a bond, then Y is other than CONH2; compound #565 v) when X is Benzamide and Rl is phenyl Yl is a bond and Y is COOH then R3 is other than hydrogen.
3. A compound as defined in claims 1 or 2 , wherein X is:
y R2
R3
4. A compound as defined in claims 1 or 2, wherein
X is:
■ ■?■
5. The compound as defined in claims 1 or 2, wherein Z is H.
6. The compound as defined in claims 1 or 2, wherein Y1 is a bond.
7. The compound as defined in anyone of claims 1 or 2 , wherein R1 .is chosen from C2_ι2 alkyl, C2_ι2 alkenyl, C2_ι2 alkynyl, Cε- aryl, C3_ι2 heterocycle, C3_18 heteroaralkyl or C6_18 aralkyl .
8. The compound as defined in anyone of claims 1 or 2 , wherein Rx is chosen from a C2-12 alkyl, Cs-n aryl or C3_ι2 heterocycle.
9. The- compound as defined in anyone of claims 1 or 2 , wherein R± is a C2-12 alkyl .
10. The compound as defined in anyone of claims 1 or 2 , wherein R-_ is a C6-14 aryl .
11. The compound as defined in anyone of claims 1 or 2 , wherein R1 is a C3-12 heterocycle.
12. The compound as defined in anyone of claims 1 or 2 , wherein R1 is chosen from t-butyl, isobutyl, allyl, ethynyl, 2- phenylethenyl, isobutenyl, benzyl, phenyl, phenethyl, benzodioxolyl, thienyl, thiophenyl, pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl, or benzothiophenyl any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, COOH, Cι_6 alkyl, C2-e alkenyl, C2_6 alkynyl, C6-ι2 aralkyl, C6-ι2 aryl, Cι_6 alkyloxy, C2_6 alkenyloxy, C_6 alkynyloxy, C6-12 aryloxy, C (0) C±-β alkyl, C(0)C2_ 6 alkenyl, C (0) C-6 alkynyl, C (0) C6-ι2 aryl, C (0)C6-ι2 aralkyl, C3_ 10 heterocycle, hydroxyl, NRι3Rι4, C(0)0Rι2, cyano, azido, amidino or guanido; wherein R12/ Rc, Rd, Ri3 and Ri4 are each independently chosen from H, Cι-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-ι aryl, C3-12 heterocycle, C3-18 heteroaralkyl, Cε-iβ aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and Rι4 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
13. The compound as defined in claim 12 , wherein R1 is chosen from thienyl, t-butyl, phenyl or pyridinyl .
14. The compound as defined in claim 12, wherein Rx is phenyl.
15. The compound as defined in anyone of claims 1 or 2 , wherein R1 is phenyl substituted by at least one fluoride.
16. The compound as defined in anyone of claims 1 or 2, wherein R1 phenyl substituted by at least one chloride.
17. The compound as defined in anyone of claims 1 or 2 , wherein R1 is phenyl substituted by at least one nitro.
18. The compound as defined in anyone of claims 1 or 2, wherein Rx is phenyl substituted by at least one methyl.
19. The compound as defined in anyone of claims 1 or 2, wherein R1 phenyl substituted by at least one methoxy.
20. The compound as defined in anyone of claims 1 or 2 , wherein Rx is thienyl .
21. The compound as defined in anyone of claims 1 or 2 , wherein R__ is thienyl substituted by at least one halogen.
22. The compound as defined in anyone of claims 1 or 2 , wherein R__ is thienyl substituted by at least one chloride.
23. The compound as defined in anyone of claims 1 or 2 , wherein R1 is thienyl substituted by at least one methyl .
24. The compound as defined in anyone of claims 1 or 2 , wherein Rx is thienyl substituted by at least one methyl and one chloride.
25. The compound as defined in anyone of claims 1 or 2 , wherein Rx is isoxazolyl substituted by at least one methyl.
26. The compound as defined in anyone of claims 1 or 2 , wherein Rx is pyridinyl .
27. The compound as defined in anyone of claims 1 or 2 , wherein M is chosen from:
Figure imgf000247_0001
28. The compound as defined in anyone of claims 1 or 2 , wherein M is :
Figure imgf000247_0002
29. The compound as defined anyone of claims 1 or 2 , wherein M is
O
30. The compound as defined in anyone of claims 1 or 2 , wherein J is chosen from:
Figure imgf000247_0003
wherein W is as defined in claim 1.
31. The compound as defined in anyone of claims 1 or 2 , wherein J is :
O
32. The compound as defined in anyone of claims 1 or 2 , wherein J is :
O o
33. The compound as defined in anyone of claims 1 or 2, wherein Y is chosen from C00R16, C0C00R5, P(0)ORaORb, S(0)20RSι tetrazole, C0N(R,9)'CH(R C00R, , C0NR..R., ,
Figure imgf000248_0001
34. The compound as defined in claim 33, wherein any of R5, Ra, Rb, R9, R10, R and R16 are each independently chosen from H or C^g alkyl; provided that R16 is other than methyl or ethyl.
35. The compound as defined in anyone of claims 1 or 2 , wherein Y is chosen from C00R16, CONR10R1:L or C0N(R9) CH(R5) -COOR5.
36. The compound as defined in claim 33, wherein any of R5, R9, R10, R11 and R16 are each independently chosen from H or C^ alkyl; provided that R16 is other than methyl or ethyl .
37. The compound as defined in anyone of claims 1 or 2 , wherein Y is COOH. The compound as defined in anyone of claims 1 or 2 , wherein Y
1S C0NHCH2C00H.
39. The compound as defined in anyone of claims 1 or 2 , wherein Y is C00CH3.
40. The compound as defined in anyone of claims 1 or 2, wherein Y is C00NH2.
41. The compound as defined in anyone of claims 1 or 2, wherein R3 is chosen from H, Cj__12 alkyl, C6.18 aralkyl , C3_12 heterocycle or C3_ 18 heteroaralkyl .
42. The compound as defined in anyone of claims 1 or 2 , wherein R3 is chosen from H, C1_12 alkyl, C6.18 aralkyl or C3_12 heterocycle.
43. The compound as defined in anyone of claims 1 or 2 , wherein R3 is Cx_u alkyl .
44. The compound as defined in anyone of claims 1 or 2 , wherein R3 is C6.18 aralkyl .
45. The compound as defined in anyone of claims 1 or 2 , wherein R3 ' is C3_12 heterocycle.
46. The compound as defined in anyone of claims 1 or 2 , wherein R3 is chosen from H, methyl, ethyl, i-propyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl; any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, SOjR^, P03RcRd, C0NR13R14, C _6 alkyl, C2_s alkenyl , • C2_6 alkynyl, C6_12 aralkyl, C6.12 aryl, Cλ_s alkyloxy, C2_s alkenyloxy, C2_6 alkynyloxy, C6.12 aryloxy, C (0) C1_6 alkyl , C (0) C2_6 alkenyl ,
C (0) C2_6 alkynyl, C (0) C6.12 aryl, C (0) C6_12 aralkyl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C1.12 alkyl, C2.12 alkenyl, C2_12 alkynyl , C6_14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
47. The compound as defined in claim 43 , wherein R3 is chosen from H or Methyl, isopropyl, piperidinyl, piperidinylmethyl or ι cyclohexyl .
48. The compound as defined in anyone of claims 1 or 2 , wherein R3 is H.
49. The compound as defined in anyone of claims 1 or 2, wherein R3 is Methyl .
50. The compound as defined in anyone of claims 1 or 2 , wherein R2 is C2_12 alkyl, Cs_14 aryl or C3_12 heterocycle.
51. The compound as defined in anyone of claims 1 or 2, wherein R2 is C3.6 heterocycle.
52. The compound as defined in anyone of claims 1 or 2, wherein R2 is chosen from thienyl, furanyl, pyridinyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl, piperazinyl, pyrrolidinyl or quinolinyl any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, C0NR13R14, C^ alkyl, C2_6 alkenyl, C2_6 alkynyl, C6.12 aralkyl, Cs_12 aryl, C1.6 alkyloxy, C2_6 alkenyloxy, C2.6 alkynyloxy,
Cg_12 aryloxy, C (0) C^. alkyl, C (0) C2.6 alkenyl, C(0)C2.6 alkynyl,
C (0) Cg_12 aryl , C (O) Cs_12 aralkyl, C3.10 heterocycle, hydroxyl,
NR13R14, C(0)OR12, cyano, azido, amidino or guanido; wherein RL2, Rc, Rd, R13 and R14 are each independently chosen from H, Cx_12 alkyl, C2_12 alkenyl , C2_12 alkynyl , C6.14aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
53. The compound as defined in claim 49, wherein R2 is a heterocycle chosen from thienyl, furanyl, pyridinyl, pyrrolyl, indolyl, piperazinyl or benzothienyl.
54. The compound as defined in anyone of claims 1 or 2 , wherein R2 is C2.12 alkyl .
55. The compound as defined in anyone of claims 2 to 4, wherein R2 is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl cyclohexyl, cycloheptyl, 2- (cyclopentyl) -ethyl, methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl any of which can be optionally substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, C^g alkyl , C2_6 alkenyl , C2.6 alkynyl , C6.12 aralkyl , C6_12 aryl , Cλ_6 alkyloxy, C2.6 alkenyloxy, C2.6 alkynyloxy, C6_12 aryloxy, 0(0)0^ alkyl, C (0) C2.s alkenyl, C (0) C2_6 alkynyl, C (0) C6.12 aryl, C(0)C6.12 aralkyl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C1.12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6.14aryl, C3.12 heterocycle, C3_18 heteroaralkyl , C6_18 aralkyl ; or Rc and Rd are taken together with .the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
56. The compound as defined in anyone of claims 1 or 2 , wherein R2 is C6.12 aryl .
57. The compound as defined in anyone of claims 1 or 2 , wherein R2 is an aryl chosen from indenyl, naphthyl or biphenyl.
58. The compound as defined in anyone of claims 2 to 4, wherein R2 is phenyl substituted by one or more substituent chosen from halogen, nitro, nitroso, S03R12, P03RcRd, C0NR13R14, Cx_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Cs_12 aralkyl, C6_12 aryl, C^ alkyloxy, C2_6 alkenyloxy, C2.6 alkynyloxy, C6_12 aryloxy, C (0) C^ alkyl, C(0)C2_6 alkenyl, C (0) C2.6 alkynyl, C (0) C6.12 aryl, C (0) Cs_12 aralkyl, C3.10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C1_12 alkyl , C2_12 alkenyl , C2_12 alkynyl, C6_14aryl, C3_12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
59. The compound as defined in anyone of claims 1 or 2, wherein R2 is phenyl substituted by one or two substituents chosen from halogen, nitro, nitroso, S03R12, P03RcRd, CONR13R14, Cx.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6_12 aralkyl, Cs_12 aryl, C^ alkyloxy, C2.6 alkenyloxy, C2_6 alkynyloxy, Cs_12 aryloxy, C (0) C _s alkyl, C(0)C2_s alkenyl , C (0) C2_6 alkynyl , C (0) C6.12 aryl , C (0) C6_12 aralkyl , C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, amidino or guanido; wherein R12, Rc, Rd, R13 and R14 are each independently chosen from H, C^^ alkyl, C2_12 alkenyl, C2.12 alkynyl , C6_14aryl, C3_12 heterocycle, C3.18 heteroaralkyl , Cs_18 aralkyl ; or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
60. The compound as defined in anyone of claims 1 or 2 , wherein R2 is phenyl substituted by one or more substituent chosen from halogen, nitro, CONR13R14, C1- alkyl, C2_6 alkenyl, Cx_6 alkyloxy,
C (0)0^ alkyl, C6.12 aryl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)OR12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, C1_12 alkyl, C2_12 alkenyl , C2.12 alkynyl, C6_14aryl, C3_12 heterocycle, C3.18 heteroaralkyl , Cs_18 aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
61. The compound as defined in anyone of claims 1 or 2 , wherein R2 is phenyl substituted by one or two substituents chosen from halogen, nitro, CONR13R14, _6 alkyl, C2_6 alkenyl, C16 alkyloxy, 0(0)0^ alkyl, C6_12 aryl, C3_10 heterocycle, hydroxyl, NR13R14, C(0)0R12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, C^^ alkyl, C2.12 alkenyl, C2.12 alkynyl, C6_14aryl, C3_12 heterocycle, C3_18 heteroaralkyl , C6_18 "aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
62. The compound as defined in anyone of claims 1 or 2 , wherein R2 is phenyl substituted by one or two substituents chosen from halogen, Cx_6 alkyl, NR13R14, nitro, C0NR13R14, C (0) OC^ alkyl, COOH or Cx_6 alkyloxy C(0)0R12, cyano, azido, wherein R12, R13 and R14 are each independently chosen from H, C1.12 alkyl, C2_12 alkenyl, C2.12 alkynyl , Cs_14aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl ; or R13 and R14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
63. The compound as defined in anyone of claims 1 or 2 , wherein R2 is methylphenyl .
64. The compound as defined in anyone of claims 1 or 2 , wherein R2 is dichlorophenyl .
65. The compound -as defined in anyone of claims 1 or 2 , wherein R2 is chlorophenyl .
66. A compound chosen from:
Compound 1 3- [ (4-CHL0R0-2, 5-DIMETHYL-BENZENESULFONYL) - (3-IODO-BENZYL) -
AMINO] - 5 -PHENYL-THIOPHENE- 2 -CARBOXYLIC ACID
Compound 2 3- [ (3-BΞNZ0FURAN-2-YL-BENZYL) - (4-CHL0R0-2 , 5-DIMETHYL-
BΞNZENESULFONYL) -AMINO] -5-PHΞNYL-THI0PHENE-2-CARB0XYLIC ACID
Compound 3 3- (4-CHL0R0-2 , 5-DIMETHYL-BENZΞNESULFONYLAMINO) -5-PHENYL-
THI0PHENE-2 -CARBOXYLIC ACID
Compound 4 3-{ (2, 4-DICHLORO-BENZOYL) - [5- ( 3 -TRIFLUOROMETHYL- PHENYL) -
FURAN- 2 -YLMETHYL] -AMINO} -5-PHENYL-THI0PHENE-2-CARB0XYLIC ACID Compound 5 3- [ (4-CHL0R0-2 , 5-DIMETHYL-BENZENESULFONYL) -METHYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 6 5- (4-FLUORO-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 7 3- (2, 4-DICHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 8 3- (4-CHLORO-2 , 5-D METHYL-BENZENESULFONYLAMINO) -5- (4-FLUORO- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 9 3- [ (2 , 4-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 10 5- TERT -BUTYL-3- (4-CHLORO-BENZENESULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 11 4- (TOLUENE-4-SULFONYLAMINO) -[2,3'] BITHIOPHΞNYL-5-CARBOXYLIC ACID
Compound 12 3-[ (5-BENZOFURAN-2-YL-THIOPHEN-2-YLMETHYL) - (2, 4-DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 13 5-PHENYL-3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 14 3- (4-CHLORO-2 , 5-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-CHLORO- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 15 5-PHENYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 16 5-PHENYL-3- (TOLUENE-3-SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 17 3-BENZENESULFONYLAMINO-5-PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 18 3- (4-CHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 19 3- (4-CHLORO-2, 5-DIMETHYL-BENZENESULFONYLAMINO) -5- (4- ISOBUTYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 20 5-TERT-BUTYL-3- (4-CHLORO-2 , 5-DIMETHYL-
BENZENESULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID
Compound 21 3- (2, 5-DIMETHYL-BΞNZΞNESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 22 3- (4-METHOXY-2 , 3 , 6-TRIMΞTHYL-BENZENΞSULFONYLAMINO) -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 23 5-PHENYL-3- (THIOPHENΞ-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 24 4- (4-CHLORO-2 , 5-DIMETHYL-BΞNZENΞSULFONYLAMINO) - [2,3'] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 25 5- (3 , 5-BIS-TRIFLUOROMΞTHYL-PHENYL) -3- (4-CHL0R0-2 , 5- DIMETHYL-BENZENESULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 26 8-CHLORO-3- (4-CHLORO-2, 5-DIMETHYL-BΞNZENESULFONYLAMINO) -4H- l,5-DITHIA-CYCLOPENTA[ A ] NAPHTHALENE-2-CARBOXYLIC ACID Compound 27 3- (2 , 4-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 28 3- [3- (2 , 6-DICHLORO-PYRIDIN-4-YL) -UREIDO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 29 3- (2-CHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 30 3- (2-FLUORO-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 31 5-PHΞNYL-3- (2-TRIFLUOROMETHOXY-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 32 3- (4- TERT -BUTYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 33 3- (4-CHLORO-PHENOXYCARBONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 34 3- (3 , 4-DICHLORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 35 5-PHENYL-3- (2-TRIFLUOROMETHYL-BENZENESULFONYLAMINO) - THIOPHΞNE-2-CARBOXYLIC ACID Compound 36 3- (5-BROMO-6-CHLORO-PYRIDINΞ-3-SULFONYLAMINO) -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 37 3- (5-CHLORO-THIOPHENE-2-SULFONYLAMINO) -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 38 3- ( 5-CHLORO-3-METHYL-BENZO [ B ] THIOPHENE-2-SULFONYLAMINO) - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 39 3- (4-BROMO-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 40 3- (3-CHLORO-BENZENESULFONYLAMINO) -5-PHΞNYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 41 3- (5-CHLORO-l, 3-DIMETHYL-1H-PYRAZOLE-4-SULFONYLAMINO) -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 42 3- (3-BROMO-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 43 3- (4-ISOPROPYL-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 44 3- (2, 6-DICHLORO-BENZΞNΞSULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXY IC ACID Compound 45 3- (2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 46 5-PHENYL-3- ( 5- [1 , 2 , 3 ] THIADIAZOL-4-YL-THIOPHENE-2- SULFONYLAMINO)-THIOPHENE-2-CARBOXYLIC ACID Compound 47 5-PHENYL-3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID Compound 48 3- (2, -DICHLORO-BENZYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 49 3- (3-FLUORO-BENZΞNESULFONYLAMINO) -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID Compound 50 5-PHENYL-3- (3-TRIFLUOROMETHYL-BENZENΞSULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID Compound 51 3- (2-CARBOXY-BΞNZOYLAMINO) -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID METHYL ESTER Compound 52 5-PHENYL-3- (4-TRIFLUOROMETHYL-BΞNZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 53 3- (2, 5-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 54 3- (2-CYANO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 55 3- (2, 5-DICHLORO-THIOPHENE-3-SULFONYLAMINO) -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 56 4- (TOLUENΞ-2-SULFONYLAMINO) -[2,2' ] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 57 5'-CHLORO-4-(TOLUENE-2-SULFONYLAMINO)- [2,2 ' ] BITHIOPHENYL-5- CARBOXYLIC ACID ( Compound 58 5- (2, 4-DICHLORO-PHENYL) -3- (TOLUΞNE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 59 5- (4-NITRO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 60 3- (TOLUENΞ-2-SULFONYLAMINO) -5- (4-TRIFLUOROMETHOXY-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 61 5-QUINOLIN-8-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 62 5-PHENYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 63 5- (3-NITRO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID Compound 64 3- (TOLUENE-2-SULFONYLAMINO) -5-M-TOLYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 65 5- (3-CHLORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 66 5- (4-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE- 2-CARBOXYLIC ACID
Compound 67 5- (3-FLUORO-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 68 5- ( 4-CHLORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 69 5- (3 , 5-DIFLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID
Compound 70 5- (3 , 4-DIFLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHΞNE-2-CARBOXYLIC ACID
Compound 71 3- (TOLUENE-2-SULFONYLAMINO) -5-VINYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 72 3- (4-CHLORO-BΞNZOYLAMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 73 3-[ (4-CHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 74 5-PHΞNYL-3- [ (THIOPHENE-2-CARBONYL) -AMINO] -THIOPHENΞ-2- CARBOXYLIC ACID
Compound 75 3- [METHYL- (THIOPHENE-2-CARBONYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 76 3- (2-BROMO-BΞNZΞNESULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 77 3- (2, 4-DIFLUORO-BENZOYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 78 3- [ (2 , 4-DIFLUORO-BENZOYL) -METHYL-AMINO] -5-PHΞNYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 79 3- (TOLUENE-2-SULFONYLAMINO) -5-TRIMΞTHYLSILANYLETHYNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 80 5-ETHYNYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID
Compound 81 3- (TOLUENE-2-SULFONYLAMINO) -5- (3-TRIFLUOROMETHOXY-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 82 5-BENZOYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 83 5- (4-CYANO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 84 5- (3-CHLORO-4-FLUORO-PHENYL) -3- (TOLUΞNE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 85 5- (3, 4-DICHLORO-PHΞNYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 86 5-PYRIDIN-4-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID
Compound 87 5-PYRIDIN-3-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID
Compound 88 3- (TOLUENE-2-SULFONYLAMINO) -5- (4-TRIFLUOROMETHYL-PHΞNYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 89 5- (4-METHANESULFONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHΞNE-2-CARBOXYLIC ACID
Compound 90 5- (3-ACETYLAMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID
Compound 91 5- (3-CHLORO-4-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHΞNE-2-CARBOXYLIC ACID
Compound 92 3- (4-MΞTHYL-BENZOYLAMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 93 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 94 3- (3 , 5-DIMETHYL-ISOXAZOLE-4-SULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 95 ' 3- [ (2-CHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID
Compound 96 3- (2-METHYL-BΞNZOYLAMINO) • 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 97 3- [METHYL- (2-MΞTHYL-BENZOYL) -AMINO] -5-PHΞNYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 98 5-PHΞNYL-3- (5-TRIFLUOROMETHYL-PYRIDINE-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID Compound 99 5-PHENYLETHYNYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 100 3-(2,5-DIMETHYL-BENZENESULFONYLAMINO)-5- (4-NITRO-PHENYL) - THIOPHΞNE-2-CARBOXYLIC ACID Compound 101 5- (2-FLUORO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 102 5- (2-CYANO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID Compound 103 5- (2-ETHOXYCARBONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID
Compound 104 5- (2-METHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 105 3 ' -METHYL-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5- CARBOXYLIC ACID
Compound 106 3- (TOLUENE-2-SULFONYLAMINO) -5- (2-TRIFLUOROMETHYL-PHENYL) - THIOPHΞNE-2-CARBOXYLIC ACID
Compound 107 3- (2, 5-DIMETHYL-BENZΞNESULFONYLAMINO) -5- (4-FLUORO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID
Compound 108 5-STYRYL-3- (TOLUENE-2- SULFONYLAMINO)- ■THIOPHENE-2-CARBOXYLIC ACID
Compound 109 3- (2, 4-DIFLUORO-BENZΞNESULFONYLAMINO) -5- (4-NITRO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 110 3- (2 , 4-DIFLUORO-BΞNZENESULFONYLAMINO) -5- (4-FLUORO-PHΞNYL) - THIOPHΞNE-2-CARBOXYLIC ACID Compound 111 3- [ [5- (3-CHLORO-4-FLUORO-PHENYL) -THIOPHEN-2-YLMΞTHYL] -(2,4- DICHLORO-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 112 3- [ (4-OXO-l-PHΞNYL-l , 3 , 8-TRIAZA-SPIRO [4.5 ] DECANΞ-8- CARBONYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 113 3-{ [4- (2-0X0-2, 3-DIHYDRO-BΞNZOIMIDAZOL-l-YD-PIPΞRIDINE-l- CARBONYL] -AMINO}-5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 114 3-{ [4- (4-NITRO-PHENYL) -PIPERAZINΞ-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 115 5- (2-CARBOXY-PHENYL) -3- (TOLUΞNE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 116 5- (4-CHLORO-PHENYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 117 5- (3-CYANO-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 118 3- (2, 5-DIMETHYL-BΞNZENESULFONYLAMINO) -5-P-TOLYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 119 3- (2, 4-DIFLUORO-BENZΞNESULFONYLAMINO) -5-P-TOLYL-THIOPHENΞ- 2-CARBOXYLIC ACID Compound 120 5-PHENETHYL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID Compound 121 5- (3-ETHOXYCARBONYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHΞNE-2-CARBOXYLIC ACID Compound 122 5- (4-METHOXY-PHENYL) -3- (T0LUENE-2-SULF0NYLAMIN0) -THIOPHENE- 2-CARBOXYLIC ACID Compound 123 5- (3-METHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 124 5- (4 ' -BROMO-BIPHENYL-4-YL) -3- (TOLUENΞ-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 125 5- ( 4-HYDROXYMETHYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 126 5 FURAN~3-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 127 5-BΞNZOFURAN-2-YL-3- (TOLUΞNE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 128 5-PYRIDIN-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID Compound 129 5- (4-NITRO-PHENYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 130 3- [ (BENZOFURAN-2-CARBONYL) -METHYL-AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 131 3- [ (2, 4-DIMETHYL-BΞNZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 132 3- [ [5- (2-CYANO-PHENYL) -THIOPHEN-2-YLMETHYL] - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 133 5- (4-FLUORO-PHΞNYL) -3- (PYRIDINE-2-SULFONYLAMINO) -THIOPHΞNE- 2-CARBOXYLIC ACID Compound 134 5- [2- (4-CHLORO-PHENYL) -VINYL] -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 135 3-BENZENESULFONYLAMINO-5- (4-FLUORO-PHENYL) -THIOPHΞNE-2- CARBOXY IC ACID Compound 136 3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 137 5-PHENYL-3- (2-VINYL-BΞNZΞNΞSULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 138 3- (4-BROMO-2 , 5-DIFLUORO-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 139 3- (2-ACΞTYLAMINO-4-METHYL-THIAZOLE-5-SULFONYLAMINO) -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 140 3- (4-ACETYL-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID. Compound 141 3- (4-FLUORO-2-TRIFLUOROMETHYL-BENZENESULFONYLAMINO) -5- PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 142 3- (2-METHOXY-4-METHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 143 3- (3, 4-DIFLUORO-BΞNZENΞSULFONYLAMINO) -5-PHENYL-THI0PHENE-2- CARBOXYLIC ACID Compound 144 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -5- (4-CHLORO- PHΞNYL)-2-METHYL-FURAN-3-CARBOXYLIC ACID ETHYL ESTER Compound 145 3- (4-FLUORO-3-TRIFLUOROMETHYL-BENZENESULFONYLAMINO) -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 146 3- (2-AMINO-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 147 3- (3-NITRO-BENZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 148 3- (4-NITRO-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 149 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMLNO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 150 5- (3-CYANO-BENZYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 151 5-PHENYL-3- (2, , 6-TRIFLUORO-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 152 3- (4-MΞTHOXY-2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 153 5-PHENYL-3- (2,3, 4-TRICHLORO-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 154 5- (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YLSULFAMOYL) -2-METHYL- FURAN-3-CARBOXYLIC ACID METHYL ESTER Compound 155 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -2-METHYL-l , 5- DIPHENYL-1H-PYRROLΞ-3-CARBOXYLIC ACID ETHYL ESTER Compound 156 5-PHΞNYL-3-{ [4- (3-TRIFLUOROMETHYL-PHENYL) -PIPERAZINE-1- CARBONYL] -AMIN}-THIOPHENE-2-CARBOXYLIC ACID Compound 157 3-{ [4- (4-FLUORO-PHENYL) -PIPΞRAZINE-1-CARBONYL] -AMINO} -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 158 3-{ [4-(2,6-DIMETHYL-PHENYL)-PIPΞRAZINE-l-CARBONYL]-AMINO}~ 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 159 3-{ [4-(2-CHLORO-PHENYL)-PIPERAZINE-l-CARBONYL]-AMINO}-5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 160 3-{ [4- (3-CHLORO-PHENYL) -PIPERAZINE-1-CARBONYL] -AMINO} -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 161 4,4' -BIS- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5 , 5 ' - DICARBOXYLIC ACID Compound 162 3- [ALLYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 163 5- (1-DIMΞTHYLSULFAMOYL-1H-PYRAZOL-4-YL) -3- (TOLUENE-2- SULFONYLAMINO) -THIOPHΞNE-2-CARBOXYLIC ACID Compound 164 5- (3-AMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 165 5- (4-AMINO-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID Compound 166 5- (4- CETYL-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 167 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -2 , 5-DIMETHYL- 1H-PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER Compound 168 4- (2-CARBOXY-5-PHENYL-THIOPHEN-3-YLSULFAMOYL) -5- (4-CHLORO- PHENYL) -3-METHYL-1-PHENYL-1H-PYRROLE-2-CARBOXYLIC ACID ETHYL ESTER
Compound 169 3- (3, 5-DICHLORO-4-HYDROXY-BΞNZENESULFONYLAMINO) -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 170 5- (1H-PYRAZOL-4-YL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 171 5- (3-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 172 3- [METHYL- (3-MΞTHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 173 3-{ [2- (4-FLUORO-PHENYL) -ACETYL] -METHYL-AMINO} -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 174 3- (4-PENTYL-BENZΞNΞSULFONYLAMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 175 3- (METHYL-PHENYLACETYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 176 3- [2 , 5-BIS- (2 , 2 , 2-TRIFLUORO-ETHOXY) -BENZENESULFONYLAMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 177 3- (4-METHYL-2-NITRO-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 178 5-THIAZOL-2-YL-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 179 5-PHENYL-3- [3- (3-PHΞNYL-PROPYL) -UREIDO] -THIOPHΞNE-2- CARBOXYLIC ACID Compound 180 3-[ (3,4-DIHYDRO-lH-ISOQUINOLINE-2-CARBONYL)-AMINO]-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 181 3-{ [4- (4-METHOXY-PHENYL) -PIPERAZINE-1-CARBONYL] -AMINO}-5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 182 3-{ [4-(6-MΞTHYL-PYRIDIN-2-YL)-PIPERAZINE-l-CARBONYL]- AMINO}-5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID HYDROCHLORIDE Compound 183 3-{ [4- (4-CHLORO-BENZYL) -PIPERAZINE-1-CARBONYL] -AMINO} -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID HYDROCHLORIDE Compound 184 5- (5-MΞTHYL-PYRIDIN-2-YL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 185 3- [ETHYL- (4-METHYL-BENZOYL) -AMINO] -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID Compound 186 3- [ ( 3-CHLORO-THIOPHENΞ-2-CARBONYL) -METHYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 187 3- [ (2-BROMO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 188 3- [ (4-BUTYL-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 189 3- (2-CHLOROMΞTHYL-BΞNZENESULFONYLAMINO) -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID Compound 190 5- (4-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 191 5- (5-CHLORO-PYRIDIN-2-YL) -3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 192 5- (4-CHLORO-PHENYL) -3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 193 5- (4-CYANO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 194 3- [METHYL- (4-METHYL-BΞNZOYL) -AMINO] -5- (4-NITRO-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 195 5- (4-HYDROXYMETHYL-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) - AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 196 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (3-NITRO-PHΞNYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 197 5- (4-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 198 5- (4-MΞTHOXY-PHENYL) -3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 199 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-P-TOLYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 200 5- (4-AMINO-PHΞNYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 201 3- [CYCLOPENTYL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 202 5-BENZO[l,3]DIOXOL-5-YL-3-(TOLUENE-2-SULFONYLAMINO)- THIOPHENΞ-2-CARBOXYLIC ACID Compound 203 3- [ (2-HYDROXY-ETHYL) - (4-MΞTHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 204 3- [ (2, 4-DICHLORO-BENZOYL) -ISOBUTYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 205 3- [ (2-METHOXY-4-METHYL-BΞNZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 206 5- (3-CYANO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 207 5- (2-CHLORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 208 3- [ (2, 4-DICHLORO-BENZOYL) -PHENYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 209 3- [4- (TRIFLUOROMETHYL-BENZOYL)METHYLAMINE] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 210 3- [ (4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 211 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 212 5- (3, 5-DIFLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) - AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 213 5- (3-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 214 5- (2, 4-DIFLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) - AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 215 5- (4-HYDROXY-PHΞNYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 216 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (4-TRIFLUOROMΞTHOXY- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 217 5- (2-HYDROXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID Compound 218 3- [ (2-CHLORO-BΞNZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 219 3- [ (3, 5-DICHL0R0-BENZ0YL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 220 3- (4-BROMO-2-METHYL-BENZENESULFONYLAMINO) -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 221 3- (5-CARBOXY-4-CHLORO-2-FLUORO-BENZΞNESULFONYLAMINO) -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 222 5-PHENYL-3- (2 , 3 , 4-TRIFLUORO-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 223 3- (4-BROMO-2-FLUORO-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL- PHΞNYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 224 3- (4-BROMO-2-METHYL-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 225 5- (4-ISOBUTYL-PHENYL) -3- (3-MΞTHOXY-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 226 3- [ (4-FLUORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 227 3- [2, 5-BIS- (2, 2, 2-TRIFLUORO-ΞTHOXY) -BENZENESULFONYLAMINO] - 5- (4-ISOBUTYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 228 3- (2-CHLORO-4-CYANO-BENZENESULFONYLAMINO) -5- (4-ISOBUTYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 229 5 ' -ACETYL-4- (TOLUENE-2-SULFONYLAMINO) -[2,2'] BITHIOPHENYL-5- CARBOXYLIC ACID Compound 230 5-BENZO [B]THIOPHEN-2-YL-3- (TOLUENE-2-SULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 231 5- (4-BUTYL-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENΞ-2- CARBOXYLIC ACID Compound 232 5- (4-ETHYL-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 233 3- [BENZYL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHΞNYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 234 3- [ (4-CHLORO-2-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 235 3- [ (2 , 4-DIMETHYL-BENZENESULFONYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 236 5- (4-ACETYL-PHENYL) -3- (2 , 4-DIMETHYL-BENZΞNESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 237 5- (4-ACETYL-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENΞ- 2-CARBOXYLIC ACID Compound 238 5- (4-ACETYL-PHENYL) -3- (4-CHLORO-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 239 5- (4-CARBOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHΞNE- 2-CARBOXYLIC ACID TERT-BUTYL ESTER
Compound 240 3- [ (2 , 4-DIMETHYL-BENZENΞSULFONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 241 3- [ACETYL- (4-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 242 3-ΞTHANESULFONYLAMINO-5-PHENYL-THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 243 3- [ISOPROPYL- (4-TRIFLUOROMETHYL-BENZOYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 244 3- [ (2 , 4-DICHLORO-BΞNZOYL) - (3-METHYL-BUT-2-ENYL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 245 3-[ (2, 6-DICHLORO-PYRIDINE-3-CARBONYL) -METHYL-AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 246 3- [ (6-CHLORO-PYRIDINE-3-CARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID
Compound 247 3- [ (4-TERT-BUTYL-BΞNZOYL) -METHYL-AMINO] -5-PHΞNYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 248 5- (4-CARBOXY-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) -THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 249 5- (4-ETHOXY-PHENYL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE- 2-CARBOXYLIC ACID
Compound 250 3-[ (2, 6-DICHLORO-PYRIDINE-3-CARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 251 3- [ (BENZO [B] THIOPHENE-2-CARBONYL) -METHYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 252 3- [METHYL- (NAPHTHALENE-2-CARBONYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 253 3- [ (3 , 4-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 254 3- [ (3 , 5-DICHLORO-BENZOYL) -METHYL-AMINO] -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID
Compound 255 3- [ (4-BROMO-3-METHYL-BENZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 256 3- [ (3-CHLORO-BΞNZO[B]THIOPHENE-2-CARBONYL) -METHYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 257 3- [METHYL- (4-METHYL-3-NITRO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 258 5- (4-CARBAMOYL-PHENYL) -3- (2 , 4-DIMETHYL- BENZENESULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 259 5- (4-CARBAMOYL-PHENYL) -3- (T0LUENE-4-SULF0NYLAMIN0) - THIOPHENE-2-CARBOXYLIC ACID Compound 260 5- (1H-INDOL-5-YL) -3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 261 3-[ SEC -BUTYL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CAR.BOXYLIC ACID Compound 262 3- [ (2, 4-DIMETHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 263 5- (4-AZIDO-PHENYL) -3- (TOLUΞNE-2-SULPONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 264 3- [ (2, 4-DICHLORO-BENZOYL) - (l-PHENYL-ETHYL)'-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 265 5- (4-CARBAMOYL-PHENYL) -3- (4-CHLORO-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 266 5- (2-FLUORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 267 3- [METHYL- (4-MΞTHYL-BENZOYL) -AMINO] -5- O -TOLYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 268 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-M-TOLYL-THIOPHENE-2- CARBOXYLIC ACID Compound 269 5- (3-CHLORO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 270 5- (3, 4-DIFLUORO-PHENYL) -3- [METHYL- (4-METHYL-BΞNZOYL) - AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 271 5- (3-AMINO-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 272 5- (3-ACETYL-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 273 5- (3-HYDROXY-PHENYL) -3- [METHYL- (4-METHYL-BENZOYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 274 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (3-TRIFLUOROMETHYL- PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 275 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5- (4-TRIFLUOROMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 276 3- [ (3 , 4-DIMΞTHOXY-BΞNZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 277 3- [METHYL- (2,4, 6-TRIFLUORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 278 3- [ (2 , 3-DIFLUORO-4-TRIFLUOROMΞTHYL-BENZOYL) -METHYL-AMINO] - 5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 279 3- [ (3-FLUORO-4-TRIFLUOROMETHYL-BENZOYL) -METHYL-AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 280 3- [ (2, 3-DIFLUORO-4-METHYL-BENZOYL) -METHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 281 3- [ (2-FLUORO-4-TRIFLUOROMETHYL-BENZOYL) -METHYL-AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 282 5- (4-CARBAMOYL-PHENYL) -3- (TOLUENΞ-2-SULFONYLAMINO) - THIOPHENΞ-2-CARBOXYLIC ACID Compound 283 5- (4-FLUORO-PHENYL) -3- [ISOPROPYL- (4-MΞTHYL-BENZOYL) -AMINO] - THIOPHENΞ-2-CARBOXYLIC ACID Compound 284 3- [ (2-BROMO-4-CHLORO-BΞNZOYL) -METHYL-AMINO] -5-PHΞNYL- THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 285 3- (2, 6-DIMΞTHYL-BENZENΞSULFONYLAMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 286 3- [METHYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 287 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID METHYL ESTER Compound 288 5- (4-CYANO-PHENYL) -3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 289 3- (4-CHLORO-BENZENESULFONYLAMINO) -5- (4-CYANO-PHΞNYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 290 5- (4-CYANO-PHENYL) -3- (TOLUENE-4-SULFONYLAMINO) -THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 291 5 ' -ACETYL-4- (2, 4-DIMETHYL-BENZΞNESULFONYLAMINO) - [2,2' ]BITHIOPHΞNYL-5-CARBOXYLIC ACID Compound 292 5 ' -ACETYL-4- (2, 6-DIMETHYL-BENZΞNΞSULFONYLAMINO) - [2,2 ' ]BITHIOPHENYL-5-CARBOXYLIC ACID Compound 293 3- [METHYL- (4-METHYL-THIOPHENE-2-CARBONYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 294 5- (3-CHLORO-PHENYL) -3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 295 5'-CYANO-4- (TOLUENE-2-SULFONYLAMINO)-[2,2 ' ] BITHIOPHENYL-5- CARBOXYLIC ACID Compound 296 3- [METHYL- (4-METHYL-BENZOYL) -AMINO] -5-PYRIDIN-2-YL- THIOPHENE-2-CARBOXYLIC ACID Compound 297 3- [ (2, 4-DICHLORO-THIOBENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- - THIOPHENE-2-CARBOXYLIC ACID Compound 298 5-PHΞNYL-3- (2,4, 6-TRIMETHYL-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 299 3- [ (1-CARBOXY-ETHYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- ,PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 300 3- [ (4-METHYL-BENZOYL) - (3-METHYL-BUT-2-ΞNYL) -AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 301 3- [ (2-HYDROXY-4-METHYL-BΞNZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 302 3- [METHYL- (4-METHYL-BΞNZOYL) -AMINO] -5-PYRIDIN-3-YL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 303 5 ' -ACΞTYL-4- [METHYL- (4-METHYL-BENZOYL) -AMINO] - [2., 2 ' ] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 304 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5- (3- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 305 3- [ISOPROPYL- (4-METHYL-BENZOYL) -AMINO] -5-M-TOLYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 306 3- [ (-2-BROMO-4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 307 3- [ (4-CHLORO-2-FLUORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 308 3- (2 , 4-DIMETHYL-BENZENESULFONYLAMINO) -4-METHYL-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 309 3- [ (2-BROMO-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 310 3- [ (4-CHLORO-2-IODO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 311 3- [ (4-CYANO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 312 3- [ALLYL- (4-METHYL-BENZOYL) -AMINO] -5- [4- (2-CARBOXY-VINYL) - PHENYL] -THIOPHENE-2-CARBOXYLIC ACID Compound 313 3- [ (4-CHLORO-2-HYDROXY-BΞNZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 314 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -4-METHYL-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 315 5- TERT -BUTYL-3-(2,4-DI-METHYL-BENZENESULFONYLAMINO)- THIOPHΞNE-2-CARBOXYLIC ACID Compound 316 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 317 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 318 5- [4- (2-CARBOXY-ETHYL) -PHENYL] -3- [ (4-METHYL-BΞNZOYL) - PROPYL-AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 319 5-BΞNZOFURAN-2-YL-3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 320 3- (2, 4-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-HYDROXYMETHYL- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 321 3- (2 , 4-DIMΞTHYL-BENZENESULFONYLAMINO) -5- (4-METHANESULFONYL- PHΞNYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 322 5- [4- (2-CARBOXY-VINYL) -PHENYL] -3- (2 , 4-DIMETHYL- BENZENESULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 323 3- [ALLYL- (4-METHYL-BENZOYL) -AMINO] -5- [3- (2-CARBOXY-VINYL) - PHENYL] -THIOPHENΞ-2-CARBOXYLIC ACID Compound 324 3- [ISOPROPYL- (2,4, 6-TRIMETHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 325 5- [3- (2-CARBOXY-ETHYL) -PHENYL] -3- [ (4-METHYL-BENZOYL) - PROPYL-AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 326 3- [ (2-FLUORO-4-TRIFLUOROMETHYL-BΞNZOYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 327 3-[ TERT -BUTYL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 328 3- [ (2-AMINO-4-CHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 329 3- [ (4-CHLORO-2-NITRO-BENZOYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 330 3- [ (4-METHYL-BENZOYL) - (3-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 331 3- [ (3-FLUORO-4-MΞTHYL-BENZOYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 332 5- (4-CARBOXY-PHENYL) -3- (2 , 4-DIMΞTHYL-BΞNZENESULFONYLAMINO) - THIOPHENE-2-CARBOXYLIC ACID Compound 333 3- [CYCLOPROPYL- (2, 4-DICHLORO-BΞNZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 334 3- [ (3-TERT-BUTYL-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 335 3- [ (3-CHLORO-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 336 3- [ (2 , 4-DIFLUORO-BENZYL) - (4-MΞTHYL-BENZOYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 337 3- [ (4-CHLORO-2, 5-DIFLUORO-BENZOYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 338 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (2-METHYL- ALLYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 339 3-{ALLYL- [2- (4-CHLORO-PHΞNYL) -ACETYL] -AMINO} -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 340 3- [BENZYL- (4-METHYL-BΞNZOYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 341 3- [ (4-CHLORO-BΞNZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 342 3- [ (4-MΞTHYL-BENZOYL) - (4-NITRO-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 343 3- [ (4-METHYL-BENZOYL) - (2-METHYL-BENZYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 344 3- [ (3-METHOXY-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 345 3- [ (2-CHLORO-BENZYL) - (4-METHYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 346 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-ISOBUTYL- THIOPHENE-2-CARBOXYLIC ACID Compound 347 3- [ALLYL- (2-NAPHTHALEN-2-YL-ACETYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 348 3- {ALLYL- [2- (2, 4-DICHLORO-PHENYL) -ACETYL] -AMINO} -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 349 3- {ALLYL- [2- (2-CHLORO-4-FLUORO-PHENYL) -ACETYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 350 3- {ALLYL- [2- (3, -DICHLORO-PHENYL) -ACETYL] -AMINO} -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 351 3- {ALLYL- [2- (2, 4-DIFLUORO-PHENYL) -ACETYL] -AMINO} -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 352 3-{ALLYL- [2- (4-TRIFLUOROMETHYL-PHENYL) -ACETYL] -AMINO}-5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 353 3-{ALLYL- [2- (2, 6-DICHLORO-PHΞNYL) -ACETYL] -AMINO}-5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID' Compound 354 3- [ALLYL- (2-M-TOLYL-ACETYL) -AMINO] -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID Compound 355 5- (4-ACETYL-PHENYL) -3- [ (2 , 4-DICHLORO-BΞNZOYL) -ISOPROPYL- AMINO] -THIOPHENE-2-CARBOXYLIC ACID Compound 356 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4-FLU0R0- PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 357 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-M-TOLYL- THIOPHENE-2-CARBOXYLIC ACID Compound 358 5 '-ACETYL-4- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] - [2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 359 3-[ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (3- TRIFLUOROMETHYL-PHENYL) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 360 4- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5 ' -METHYL- [2,2'] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 361 3- (2, 4-DIMETHYL-BENZENESULFONYLAMINO) -5- (4-METHOXY-PHENYL) - THIOPHENE-2-CARBOXYLIC ACID Compound 362 3- (CYCLOHEXANECARBONYL-ISOPROPYL-AMINO) -5-PHENYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 363 3-{ (2, 4-DICHLORO-BΞNZOYL) - [1- (2 , 4-DICHLORO-BENZOYL) - PIPERIDIN-4-YL] -AMINO} -5-PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 364 4- [ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL) - (4-METHYL-BENZOYL) - AMINO] -PIPERIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER Compound 365 4- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -PIPERIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER
Compound 366 3- [ (4-METHYL-BENZOYL) -PIPERIDIN-4-YL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 367 5 ' -ACETYL-4- (2, 4-DIMETHYL-BENZΞNESULFONYLAMINO) - [2,3'] BITHIOPHENYL-5-CARBOXYLIC ACID Compound 368 3- [ (2, -DICHLORO-BENZOYL) -PIPERIDIN-4-YL-AMINO] -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 369 5- (4-METHANΞSULFONYLAMINO-PHENYL) -3- (TOLUENE-2- SULFONYLAMINO) -THIOPHENE-2-CARBOXYLIC ACID Compound 370 3- (4-FLUORO-2-METHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 371 3- [ (3-METHYL-CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 372 3- (4-CHLORO-2-MΞTHYL-BENZENESULFONYLAMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 373 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4- MΞTHANΞSULFONYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 374 3-[ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- (4- METHANESULFINYL-PHΞNYL) -THIOPHENΞ-2-CARBOXYLIC ACID Compound 375 5- (4-CARBOXY-PHENYL) -3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 376 5-BENZOFURAN-2-YL-3-[ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL- AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID
Compound 377 3- [ (2-ACET0XY-4-METHYL-BENZ0YL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 378 3- [ISOPROPYL- (2-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 379 3- [ISOPROPYL- (2-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- PHENYL-THIOPHΞNΞ-2-CARBOXYLIC ACID
Compound 380 3- (CYCLOHΞPTANECARBONYL-ISOPROPYL-AMINO) -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 381 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- (3- TRIFLUOROMΞTHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID
Compound 382 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-METHYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 383 3- [ISOPROPYL- (4-MΞTHYL-CYCLOHEXANECARBONYL) -AMINO] -5- (3- NITRO-PHΞNYL) -THIOPHΞNE-2-CARBOXYLIC ACID
Compound 384 3- [ (3-CYCLOPENTYL-PROPIONYL) -METHYL-AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 385 3- (BUTYRYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC
ACID Compound 386 3- (MΞTHYL-PENT-4-ENOYL-AMINO) -5-PHENYL-THIOPHENE-2-
CARBOXYLIC ACID
Compound 387 3- [ISOPROPYL- (5-MΞTHYL-3-OXO-3H-ISOINDOL-1-YL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 388 3- [METHYL- (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 389 3- (METHYL-PENTANOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 390 3- [METHYL- (4-METHYL-PENTANOYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 391 3- (CYCLOPENTANECARBONYL-ETHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 392 3- [ (3-CYCLOPENTYL-PROPIONYL) -ETHYL-AMINO] -5-PHENYL-' THIOPHENE-2-CARBOXYLIC ACID
Compound 393 3- (CYCLOBUTANECARBONYL-ETHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 394 3- (BUT-2-ΞNOYL-ETHYL-AMINO) -5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 395 3- [ISOPROPYL- (4-METHYL-2-VINYL-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 396 3- [ISOPROPYL- (4-METHYL-CYCLOHEX-l-ENECARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 397 3- (ALLYL-HEXANOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 398 3- (ALLYL-CYCLOBUTANΞCARBONYL-AMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 399 3- (ALLYL-PENTANOYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 400 3- [ALLYL- (4-METHYL-PΞNTANOYL) -AMINO] -5-PHΞNYL-THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 401 3- [ALLYL- (2-CYCLOPENTYL-ACΞTYL) -AMINO] -5-PHENYL-THIOPHENΞ- 2-CARBOXYLIC ACID Compound 402 3- [ (2-HYDROXY-4-METHYL-CYCLOHEXANECARBONYL) -ISOPROPYL- AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 403 3- [ (2, 4-DICHLORO-BENZOYL) - (1-PHENYL-ETHYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 404 3- [ (2, 4-DICHLORO-BENZOYL)- (1-PHENYL-ETHYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 405 3- [ISOPROPYL- (3-METHYL-CYCLOPENT-3-ENECARBONYL) -AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 406 3- [ (2-BENZYLOXY-4-METHYL-BENZOYL) -ISOPROPYL-AMINO] -5- (3- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 407 3- [ (2 , 4-DIMETHYL-CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 408 3- [ISOPROPYL- (3-METHYL-CYCLOPENTANECARBONYL) -AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 409 3- [ (2-HYDROXY-4-MΞTHYL-CYCLOHΞXANΞCARBONYL) -ISOPROPYL- AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 410 5-PHENYL-3- [PROPIONYL- (4-TRIFLUOROMΞTHYL-BENZYL) -AMINO] - THIOPHENE-2-CARBOXYLIC ACID Compound 411 3- [ISOBUTYRYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 412 3- [ (3-METHYL-BUTYRYL) - (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 413 3- [CYCLOPROPANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 414 3- [CYCLOBUTANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHΞNYL-THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 415 3- [BUTYRYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 416 3- [ (2-CYCLOPENTYL-ACETYL) - (4-TRIFLUOROMETHYL-BENZYL) - AMINO] -5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 417 3- [ (4-TERT-BUTYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 418 3- [ (4-NITRO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 419 3- [ (3-METHYL-BUTYRYL) - (4-NITRO-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 420 3- [CYCLOPROPANECARBONYL- (4-NITRO-BΞNZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 421 3- [ (2-CHLORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 422 3- [ (2-CHLORO-BENZYL) - (3-MΞTHYL-BUTYRYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 423 3- [ (2-CHLORO-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 424 3- [ (ADAMANTANE-1-CARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 425 3- [ (2-CHLORO-BENZYL) -CYCLOBUTANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 426 3- [ACETYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 427 3- [ (2-METHYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 428 3- [ (2-HYDROXY-4-MΞTHYL-BΞNZOYL) -ISOPROPYL-AMINO] -5- (3- TRIFLUOROMΞTHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 429 3- [ (l-ACETYL-PIPERIDIN-4-YL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 430 3- [ (2, 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5- [4- (1 H - TΞTRAZOL-5-YL) -PHENYL] -THIOPHENE-2-CARBOXYLIC ACID Compound 431 3- [ (2-CYAN0-4-METHYL-BENZ0YL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 432 ■ 3- [CYCLOBUTANECARBONYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 433 3- [BUTYRYL- (2-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 434 3- [ACETYL- (3-METHYL-BENZYL) -AMINO] -5-PHΞNYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 435 3- [CYCLOBUTANECARBONYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 436 3- [CYCLOHEXANECARBONYL- (4-TRIFLUOROMETHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 437 3- [ (4-TERT-BUTYL-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 438 3- [ (4-TERT-BUTYL-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 439 3- [ (4-TERT-BUTYL-BΞNZYL) -CYCLOBUTANECARBONYL-AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 440 3- [ (4-TERT-BUTYL-BENZYL) -BUTYRYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 441 3- [ (4-TERT-BUTYL-BENZYL) -CYCLOHEXANECARBONYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 442 3- [ (4-TERT-BUTYL-BΞNZYL) - (2-CYCLOPΞNTYL-ACETYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 443 3- [ (2-CYCLOPΞNTYL-ACETYL) - (4-NITRO-BENZYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 444 3- [ (2-CHLORO-BENZYL) -CYCLOHEXANECARBONYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 445 3- [ (2-CYCLOPENTYL-ACETYL) - (3-METHYL-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 446 3- [BUTYRYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 447 3- [BUTYRYL- (2-CHLORO-BΞNZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 448 3- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] -5- M - TOLYL-THIOPHENE-2-CARBOXYLIC ACID Compound 449 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-THIAZOL-2-YL- THIOPHENE-2-CARBOXYLIC ACID Compound 450 3- (ACΞTYL-BENZYL-AMINO) -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 451 3- (BENZYL-PROPIONYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 452 3- [BENZYL- (2-METHOXY-ACETYL) -AMINO] -5-PHΞNYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 453 3- [BENZYL- (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 454 3- (BENZYL-CYCLOPROPANECARBONYL-AMINO) -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID
Compound 455 3- [ACETYL- (4-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 456 3-[ (4-CHLORO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 457 3-[ (4-CHLORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 458 3- [ (4-CHLORO-BΞNZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 459 3-[ (4-CHLORO-BENZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 460 5- (4-ACETYL-PHENYL) -3- [ISOPROPYL- (4-METHYL-
CYCLOHEXANΞCARBONYL) -AMINO] -THIOPHENE-2-CARBOXYLIC ACID
Compound 461 3- [ (4-CHLORO-BENZYL) -CYCLOBUTANECARBONYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 462 3- [BUTYRYL- (4-CHLORO-BENZYL) -AMINO] -5-PHΞNYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 463 3- [ (4-CHLORO-BENZYL) - (2-CYCLOPENTYL-ACETYL) -AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 464 3- [ACETYL- (4-TRIFLUOROMETHYL-BΞNZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 465 3- [ISOBUTYRYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHΞNΞ- 2-CARBOXYLIC ACID
Compound 466 3- [CYCLOPROPANECARBONYL- (3-METHYL-BENZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 467 3-[ (4-METHYL-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 468 3- [ISOBUTYRYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 469 3- [CYCLOPROPANECARBONYL- (4-METHYL-BΞNZYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 470 3- [BUTYRYL- (4-METHYL-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 471 3- [ (3-MΞTHOXY-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID
Compound 472 3- [ (3-METHOXY-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 473 3- [CYCLOBUTANECARBONYL- (3-MΞTHOXY-BENZYL) -AMINO] -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID Compound 474 3- [ (2-CARBAMOYL-4-METHYL-BΞNZOYL) -ISOPROPYL-AMINO] -5- PHENYL-THI0PHΞNE-2-CARBOXYLIC ACID Compound 475 3- [BUTYRYL- (3-METHOXY-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 476 3- [ACETYL- (3-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 477 3- [ (3-CHLORO-BENZYL) -PROPIONYL-AMINO] -5-PHENYL-THIOPHΞNE-2- CARBOXYLIC ACID Compound 478 3- [ (3-CHLORO-BENZYL) - (2^METHOXY-ACETYL) -AMINO] -5-PHΞNYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 479 3- [ (3-CHLORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 480 3- [ (3-CHLORO-BΞNZYL) -CYCLOPROPANECARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 481 3- [ (3-CHLORO-BENZYL) -CYCLOBUTANΞCARBONYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 482 3- [BUTYRYL- (3-CHLORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 483 3- [ACETYL- (2, 4-DIFLUORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 484 3- [ (2 , 4-DIFLUORO-BENZYL) - (2-METHOXY-ACETYL) -AMINO] -5- PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 485 3- [ (2, 4-DIFLUORO-BENZYL) -ISOBUTYRYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID Compound 486 3- [ (2 , 4-DIFLUORO-BENZYL) - (3-METHYL-BUTYRYL) -AMINO] -5- PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 487 3- [BENZYL- (2-CYCLOPENTYL-ACETYL) -AMINO] -5-PHENYL-THIOPHΞNE- 2-CARBOXYLIC ACID Compound 488 3- [ (2 , 4-DICHLORO-BΞNZOYL) -ISOPROPYL-AMINO] -5- (1H-INDOL-5- YL) -THIOPHENE-2-CARBOXYLIC ACID Compound 489 3- (BΞNZYL-CYCLOBUTANΞCARBONYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 490 3- [CYCLOHEXANECARBONYL- (2, 4-DIFLUORO-BENZYL) -AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 491 3-{ALLYL- [2- (4-METHOXY-PHENYL) -ACETYL] -AMINO} -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 492 3- (ETHYL-HEXANOYL-AMINO) -5-PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 493 3- (BUTYRYL-ETHYL-AMINO) -5-PHΞNYL-THI0PHENE-2-CARB0XYLIC ACID Compound 494 3- [ETHYL- (4-METHYL-PΞNTANOYL) -AMINO] -5-PHENYL-THIOPHENΞ-2- CARBOXYLIC ACID Compound 495 3- [CYCLOBUTANECARBONYL- (2 , 4-DIFLUORO-BENZYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 496 3- [BUTYRYL- (2, 4-DIFLUORO-BENZYL) -AMINO] -5-PHENYL-THIOPHENE- 2-CARBOXYLIC ACID Compound 497 3- (CYCLOPΞNTANECARBONYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID Compound 498 3- (CYCLOHEXANECARBONYL-METHYL-AMINO) -5-PHENYL-THIOPHΞNΞ-2- CARBOXYLIC ACID Compound 499 3-[ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL)- (2, 4-DICHLORO- BENZOYL) -AMINO] -PYRROLIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER
Compound 500 3- [ (1, 4-DIMETHYL-CYCLOHΞXANECARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 501 5- (4-ETHYL-PHENYL) -3- [ (2-HYDROXY-4-METHYL-BENZOYL) - ISOPROPYL-AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID Compound 502 3- [ (2-HYDROXY-4-MΞTHYL-BENZOYL) -ISOPROPYL-AMINO] -5- M - TOLYL-THIOPHENE-2-CARBOXYLIC ACID Compound 503 3- [ (2 , 4-DICHLORO-BENZOYL) -PYRROLIDIN-3-YL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 504 4-{5-CARBOXY-4- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] - THIOPHEN-2-YL}-3, 6-DIHYDRO-2H-PYRIDINE-1-CARBOXYLIC ACID BENZYL ESTER
Compound 505 3-{ [2- (HYDROXYIMINO-METHYL) -4-METHYL-BENZOYL] -ISOPROPYL- AMINO} -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 506 3- [ (l-CARBAMIMIDOYL-PIPERIDIN-4-YL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 507 4-[ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL)- (2, 4-DICHLORO- BENZOYL) -AMINO] -AZEPANE-1-CARBOXYLIC ACID TERT -BUTYL ESTER Compound 508 4-{ [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL)- (2 , 4-DICHLORO- BENZOYL) -AMINO] -METHYL} -PIPERIDINE-1-CARBOXYLIC ACID BENZYL ESTER
Compound 509 3- [AZEPAN-4-YL- (2, 4-DICHLORO-BENZOYL) -AMINO] -5-PHΞNYL- THIOPHENE-2-CARBOXYLIC ACID Compound 510 3- [ (4-METHYL-CYCLOHΞXANECARBONYL) -PIPΞRIDIN-4-YL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID LITHIUM SALT Compound 511 3- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL)- (2, 4-DICHL0R0- BENZOYL) -AMINO] -PIPERIDINE-1-CARBOXYLIC ACID TERT -BUTYL ESTER
Compound 512 3- [ (4-BENZYLOXYCARBONYLAMINO-CYCLOHΞXYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 513 3- [ISOPROPYL- (4-MΞTHYL-2-OXO-CYCLOHEXANECARBONYL) -AMINO] -5- PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 514 3- [ (2 , 4-DICHLORO-BENZOYL) -PIPERIDIN-3-YL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID; COMPOUND WITH GENERIC INORGANIC NEUTRAL COMPONENT
Compound 515 3- [ (4-BΞNZYLOXYCARBONYLAMINO-CYCLOHΞXYL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 516 3- [ (2-BENZYLOXY-l-METHYL-ETHYL) - (2 , 4-DICHLORO-BENZOYL) - AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound* 517 3-[ (2,2-DIMETHYL-[l,3]DIOXAN-5-YL)-(4-METHYL-
CYCLOHEXANECARBONYL) -AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID
Compound 518 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-HYDROXY-1-HYDR0XYMΞTHYL- ΞTHYL) -AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 519 3- [ (2, 4-DICHLORO-BΞNZOYL)-PIPERIDIN-4-YLMΞTHYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 520 3- [ (2-CHLORO-BΞNZOYL) -PIPERIDIN-4-YLMETHYL-AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID Compound 521 3-[ (4, 6-DICHLORO-1H-INDOLE-2-CARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 522 3- [ (2, 4-DICHLORO-BΞNZOYL) - (2-HYDROXY-l-METHYL-ETHYL) - AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 523 4-{l- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2, 4-DICHLORO- BΞNZOYL) -AMINO] -ETHYL}-PIPΞRIDINE-l-CARBOXYLIC ACID BENZYL ESTER
Compound 524 4-{5-CARBOXY-4- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) - AMINO] -THIOPHEN-2-YL}-3,6-DIHYDRO-2 H -PYRIDINE-1- CARBOXYLIC ACID BENZYL ESTER
Compound 525 3- [ (4-METHYL-CYCLOHEXANECARBONYL) -PYRIDIN-4-YL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 526 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -5-PIPERIDIN-4- YL-THIOPHENE-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUOROACETIC ACID
Compound 527 3- [ISOPROPYL- (4-PROPYL-CYCLOHEXANΞCARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 528 4- [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) - (2 , 4-DICHLORO- BENZOYL) -AMINO] -CYCLOHΞXYL-AMMONIUM; TRIFLUORO-ACΞTATΞ Compound 529 3- [ (2 , 4-DICHLORO-BENZOYL) - (l-PIPERIDIN-4-YL-ETHYL) -AMINO] - 5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUORO-ACETIC ACID
Compound 530 3- [ (CYCLOHEX-3-ΞNΞCARBONYL) -ISOPROPYL-AMINO] -5-PHENYL- THIOPHENΞ-2-CARBOXYLIC ACID
Compound 531 3- [ (4-ETHYL-CYCLOHΞXANECARBONYL) -ISOPROPYL-AMINO] -5-PHΞNYL- THIOPHΞNE-2-CARBOXYLIC ACID
Compound 532 3- [ (4-CHLORO-CYCLOHΞXANECARBONYL) -ISOPROPYL-AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 533 4- [(2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL)- (2, 4-DICHLORO- BENZOYL) -AMINO] -3-METHYL-PIPERIDINE-l-CARBOXYLIC ACID BENZYL ESTER
Compound 534 3- [ (2 , 4-DICHLORO-BENZOYL) - (2-MΞTHOXY-CYCLOHEXYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 535 3- [ (2 , 4-DICHLORO-BENZOYL) - ( 2 , 2-DIMΞTHYL- [1,3] DIOXAN-5-YL) - AMINO] -5-PHENYL-THIOPHΞNΞ-2-CARBOXYLIC ACID Compound 536 3- [ISOPROPYL- (4-METHYL-CYCLOHΞXANECARBONYL) -AMINO] -5- (1- METHYL-PIPERIDIN-4-YL) -THIOPHENE-2-CARBOXYLIC ACID Compound 537 3- [ (2 , 4-DICHLORO-BΞNZOYL) - (3-METHYL-PIPERIDIN-4-YL) -AMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID; COMPOUND WITH TRIFLUORO-ACETIC ACID
Compound 538 3- [ (2 , 4-DICHLORO-BΞNZOYL) - (2-HYDROXY-CYCLOHEXYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 539 "•4-{ [ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL) - (4-METHYLCYCLOHEXANE CARBONYL) -AMINO] -METHYL} -PIPERIDINE-1-CARBOXYLIC ACID BENZYL ESTER
Compound 540 3- [ ( (IR, 2S, 4R) -2-HYDROXY-4-METHYL CYCLOHEXANECARBONYL) - ISOPROPYL-AMINO] -5-PHΞNYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 541 3- {ISOPROPYL- [1- (4-METHOXY-2 , 3 , 6-TRIMETHYL- BENZENESULFONYL) -5-METHYL-1,2,3, 6-TETRAHYDRO-PYRIDINE-2- CARBONYL] -AMINO}-5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 542 3- [ (2 , 4-DICHLORO-BENZOYL) -ISOPROPYL-AMINO] -4-FLUORO-5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 543 3- [ (2 , 4-DICHLORO-BENZOYL) - (l-METHYL-PIPΞRIDIN-4-YL) -AMINO] - 5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 544 4-{ [ (2-CARBOXY-5-PHΞNYL-THIOPHEN-3-YL) - (4-METHYLCYCLOHEXANE CARBONYL) -AMINO] -METHYL} -PIPERIDINIUM; TRIFLUORO-ACETATE Compound 545 3- [ (2-TERT-BUTOXYCARBONYLAMINO-l-METHYL-ETHYL) -(2,4- DICHLORO-BΞNZOYL) -AMINO] -5-PHΞNYL-THIOPHENE-2-CARBOXYLIC ACID Compound 546 2-[ (2-CARBOXY-5-PHENYL-THIOPHΞN-3-YL)-(2,4-DICHLORO- BΞNZOYL) -AMINO] -PROPYL-AMINE TRIFLUOROACETIC ACID SALT Compound 547 3- [ (3-CARBOXY-CYCLOPΞNTYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 548 3- [ (3-CARBOXY-CYCLOPENTYL) - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 549 2- [ (2-CARBOXY-5-PHΞNYL-THIOPHEN-3-YL) - (2, 4-DICHLORO- BENZOYL) -AMINO] -CYCLOHEXYL-AMMONIUM CHLORIDE
Compound 550 3- (BENZOYL-METHYL-AMINO) -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 551 { [5-PHΞNYL-3- (TOLUENE-4-SULFONYLAMINO) -THIOPHENE-2- CARBONYL] -AMINO} -ACETIC ACID Compound 552 5-BROMO-3- (TOLUENE-2-SULFONYLAMINO) -THIOPHENE-2- CARBOXYLIC ACID Compound 553 3- [CYCLOHEXYL- (2 , 4-DICHLORO-BENZOYL) -AMINO] -5- PHENYL-THIOPHΞNE-2-CARBOXYLIC ACID Compound 554 3- [ [1, 33DIOXAN-5-YL- (4-METHYL-CYCLOHEXANΞCARBONYL) - AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 555 3- [ [2- (TERT-BUTYL-DIMETHYL-SILANYLOXY) -1-METHYL-2-PHENYL- ETHYL] - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL-TH10PHENΞ-2- CARBOXYLIC ACID
Compound 556 3- [ [2- (TERT-BUTYL-DIMETHYL-SILANYLOXY) -l-METHYL-2- PHENYL-ETHYL] - (2 , 4-DICHLORO-BENZOYL) -AMINO] -5-PHENYL- THIOPHENE-2-CARBOXYLIC ACID
Compound 557 3- [ (2, 4-DICHLORO-BENZOYL) - (2-DIΞTHYLAMINO-THIAZOL- 5-YLMETHYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 558 (5-{ [ (2-CARBOXY-5-PHENYL-THIOPHEN-3-YL) -(2,4- DICHLORO-BENZOYL) -AMINO] -METHYL} -THIAZOL-2-YL) -DIETHYL- AMMONIUM; CHLORIDE
Compound 559 5- (4-FLUORO-PHENYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHΞXANECARBONYL) -AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID Compound 560 3-[ ( (lS,2R,4S)-2-HYDROXY-4-METHYL-
CYCLOHEXANECARBONYL) -ISOPROPYL-AMINO] -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 561 3- [ (2, 4-DICHLORO-BENZOYL) - (2-METHOXY-l-MΞTHYL-ETHYL) - AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 562 3- [ (4S) -ISOPROPYL- (4-MΞTHYL-CYCLOHEX-l- ENECARBONYL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 566 3-METHYL- (4-METHYLBENZOYL) -AMINO) 5-PHENYL THIOPHENE-2-CARBOXYLIC ACID (2-HYDROXY-ΞTHYL) AMIDE Compound 567 5-PHENYL-3- (TOLUENE- -SULFONYLAMINO) -THIOPHΞNE-2- CARBOXYLIC ACID CYCLOBUTYLAMIDE Compound 568 3- (2 , 4-DIMETHYL-BΞNZENESULFONYLAMIN0) -5-PHENYL- THIOPHΞNE-2-CARBOXYLIC ACID AMIDE Compound 569 5-BROMO-3- [ (2 , 4-DICHLORO-BΞNZOYL) -ISOPROPYL-AMINO] - THIOPHΞNE-2-CARBOXYLIC ACID Compound 570 5- (4-CHLORO-PHΞNYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANE-CARBONYL) -AMINO] -THIOPHΞNE-2-CARBOXYLIC ACID Compound 571 5- (4 ' -CHLORO-BIPHENYL-4-YL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANΞCARBONYL) -AMINO] -THIOPHΞNE-2-CARBOXYLIC ACID Compound 572 3- [ (4-METHYL-CYCLOHEXANΞCARBONYL) - (TETRAHYDRO- PYRAN-4-YL) -AMINO] -5-PHENYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 5733- [ (4-METHYL-CYCLOHEXANECARBONYL) - (l-METHYL-PIPERIDIN-4- YL) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 5743- [ (4-METHYL-CYCLOHEXANECARBONYL) -PIPERIDIN-4-YL-AMINO] - 5-PHΞNYL-THIOPHENΞ-2-CARBOXYLIC ACID Compound 5753- [ISOPROPYL- (4-METHYL-CYCLOHEXANECARBONYL) -AMINO] ■ 5- (4- TRIFLUOROMETHYL-PHENYL) -THIOPHENE-2-CARBOXYLIC ACID Compound 5765- (4-CYANO-PHENYL) -3- [ISOPROPYL- (4-METHYL- CYCLOHEXANECARBONYL) -AMINO] -THIOPHENΞ-2-CARBOXYLIC ACID Compound 5773- [ISOPROPYL- (4-METHYL-CYCLOHΞXANECARBONYL) -AMINO] -5- (4- METHOXY- PHENYL) -THIOPHENE-2 -CARBOXYLIC ACID Compound 5783- [ (2-METHOXY-l-MΞTHYL-ETHYL) - (4-MΞTHYL- CYCLOHEXANECARBONYL ) -AMINO] -5-PHENYL-THIOPHENE-2-CARBOXYLIC ACID
Compound 5793- [CYCLOHEXYL- (4-MΞTHYL-CYCLOHEXANΞCARBONYL) -AMINO] -5- PHENYL-THIOPHENE-2-CARBOXYLIC ACID Compound 5815- (4-ISOBUTYL-PHΞNYL) -3- [5- ( 5-TRIFLUOROMETHYL-ISOXAZOL- 3-YL) -THIOPHENE-2-SULFONYLAMINO] -THIOPHΞNE-2-CARBOXYLIC ACID
Compound 5825- (4-ISOBUTYL-PHENYL) -3- (2 , 3 , 4 -TRI FLUORO - BENZENESULFONYLAMINO) -THIOPHENE-2 -CARBOXYLIC ACID
Compound 5833- [ (2, 4-DICHLORO-PHENYL) -ISOPROPYL-CARBAMOYL] -5-PHENYL- THIOPHENE-2 -CARBOXYLIC ACID
Compound 5843- (METHYL-P-TOLYL-CARBAMOYL) -5-PHENYL-THIOPHENE-2- CARBOXYLIC ACID
Compound 5853- [ (2 , 4-DICHLORO-PHENYL) -METHYL-CARBAMOYL] -5-PHENYL- THIOPHENE- 2 -CARBOXYLIC ACID or pharmaceutically acceptable salts thereof
7. A method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound having the formula III:
Figure imgf000285_0001
(III)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
Figure imgf000285_0002
wherein,
M is chosen from:
Figure imgf000285_0003
Figure imgf000285_0004
wherein, .
R4 is chosen from H or C 1-6 alkyl;
R8 is chosen from H, C 1„12 alkyl, C 2.12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_1S aralkyl; and
R15 is chosen from H or C _6 alkyl; J is chosen from:
Figure imgf000286_0001
wherein,
W is chosen from 0, S or NR7, wherein R, is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_12 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_ 16 aralkyl; and Rs is chosen from H, C 1_12 alkyl, C 6_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, Cx_e alkyl, C 2.6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, COCOOR5, . P (0) 0Ra0Rb, S(0)0R5, S(0)20R5/ tetrazole, C0N(R9) CH(R5) C00R5 , CONR^R^, C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C H! alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl; or R10 and RX1 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rb are each independently chosen from H, C λ_12 alkyl, C 2.
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl;
Rx is chosen from C1_12 alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3.18 heteroaralkyl, C6_18 aralkyl, or halogen; R2 is chosen from Cx_12 alkyl, C2_12 alkenyl, C2.12 alkynyl, C6_14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, C _12 alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl or C6.18 aralkyl;
•Z is chosen from H, halogen, C _s alkyl .
68. The method of claim 65, further comprising at least one antiviral agent .
69. The method according to claim 66, wherein the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
70. The method according to claim 66, wherein the antiviral agent is chosen from interferon α and ribavirin.
71. The method according to anyone of claims 66 to 68, wherein said compound and said antiviral agent are administered sequentially.
72. The method according to anyone of claims 66 to 68, wherein said compound and said antiviral agent are administered simultaneously.
73. The method of claim 65, further comprising at least one additional agent chosen from immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
74. The method of claim 71, wherein said additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
75. The method according to anyone of claims 71 or 72, wherein said compound and said additionnal agent are administered sequentially.
76. A method according to anyone of claims 71 or 72, wherein said compound and said additionnal agent are administered simultaneously.
77. The method as defined in anyone of claims 65 to 74, wherein said Flaviviridea viral infection is hepatitis C viral infection (HCV) .
78. A pharmaceutical composition comprising at least one compound having the formula III:
Figure imgf000288_0001
(Ill)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
JVL 2
R3 J K3 wherein,
M is chosen from:
Figure imgf000289_0001
Figure imgf000289_0002
wherein,
R4 is chosen from H or C 1_6 alkyl;
R8 is chosen from H, C W! alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and
R15 is chosen from H or C x_6 alkyl;
J is chosen from:
S
II
W RE O O °
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_ 12 alkynyl, C 6_12 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1_12 alkyl, C 6_12 aryl or C s_16 aralkyl ;
Y1 is chosen from a bond, Cλ_6 alkyl, C 2_6 alkenyl or C 2.6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)20R5ι tetrazole, C0N(R9) CH(R5) C00R5 , CO R^R^, C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and Ru are each independently . chosen from H, C H2 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl; or R10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Ri, are each independently chosen from H, C 1.12 alkyl, C 2.
12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl ; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2.12 alkenyl, C2.12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl;
Rx is chosen from Cλ_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, Cs_14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl or halogen;
R2 is chosen from C1.12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, C _12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl or Cs_18 aralkyl;
Z is chosen from H, halogen, Cα_6 alkyl; and
at least one pharmaceutically acceptable carrier or excipient.
79. A pharmaceutical composition as defined in claim 76, further comprising one or more additional agent is chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
80. The pharmaceutical composition as defined in claim 77, wherein the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
81. The pharmaceutical composition as defined in claim 77, wherein the antiviral agent is chosen from interferon α and ribavirin.
82. The pharmaceutical composition as defined in claim 77, wherein said additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
83. The composition as defined in anyone of claims 76-80 wherein said Flaviviridae viral infection is hepatitis C viral infection (HCV) .
84. The use of a compound having the formula III:
Figure imgf000291_0001
(III)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
JVL R5
*R, or
I R k,3 wherein,
M is chosen from:
Figure imgf000292_0001
Figure imgf000292_0002
wherein,
R4 is chosen from H or C x_6 alkyl ;
R8 is chosen from H, C 1_12 alkyl , C 2_12 alkenyl , C2_12 alkynyl , C 6_14 aryl , C 3_12 heterocycle , C3.12 heteroaralkyl , C 6.16 aralkyl ; and
R15 is chosen from H or C 1-6 alkyl ;
J is chosen from:
Figure imgf000292_0003
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C λ_12 alkyl, C 2_12 alkenyl, C2 12 alkynyl, C s_12 aryl, C 3_12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1.12 alkyl, C s_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, C^ alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R1S, C0C00R5, P(0)ORaORb, S(0)0R5, S(0)20R5/ tetrazole, CON(R9) CH(R5) C00R5 , CONR10RX1, CON (R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl; or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and R^ are each independently chosen from H, C 1_12 alkyl, C 2.
12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl; or Ra and ^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl;
Rx is chosen from Cl.12 alkyl, C2_12 alkenyl, C2_12 alkynyl, Cs_14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl, Cs_18 aralkyl or halogen;
R2 is chosen from C^^ alkyl, C2_12 alkenyl, C2_12 alkynyl, Cs_14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, or C6.18 aralkyl;
R3 is chosen from H, C^^ alkyl, C2_12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl or C6_18 aralkyl;
Z is chosen from H, halogen, Cx_6 alkyl;
for the manufacture of a medicament for treating or preventing a viral Flaviridea infection in a host.
15. The use as defined in claim 84, wherein said Flaviviridae viral infection is hepatitis C viral infection (HCV) .
16. The use of a compound having the formula III:
Figure imgf000294_0001
(Ill)
or pharmaceutically acceptable salts thereof in therapy;
wherein,
X is chosen from:
JVL R;
ΪST *R_ I or
I
Rs wherein,
M is chosen from:
Figure imgf000294_0002
Figure imgf000294_0003
wherein,
R4 is chosen from H or C 1.6 alkyl;
R8 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and
R15 is chosen from H or C _s alkyl;
J is chosen from:
Figure imgf000295_0001
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_ 12 alkynyl, C 6_12 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C s_16 aralkyl; and R6 is chosen from H, C 1-12 alkyl, C 6_12 aryl or C 6.16 aralkyl ;
Y1 is chosen from a bond, C^ alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(O)0R5, S(0)20R5ι tetrazole, CON (R9) CH (R5 ) C00R5 , CO R^R,, , C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and R11 are each independently chosen from H, C _12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3_18 heteroaralkyl, Cs_18 aralkyl; or R10 and RX1 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and ^ are each independently chosen from H, C 1.12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6_18 aralkyl ; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and Cs_18 aralkyl;
R1 is chosen from C^^ alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3.12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl or halogen;
R2 is chosen from C^ alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, or Cs_18 aralkyl; R3 is chosen from H, C1.12 alkyl , C2_12 alkenyl ., C2_12 alkynyl , C6_14 aryl , C3.12 heterocycle , C3_18 heteroaralkyl or C6.18 aralkyl ;
Z is chosen from H, halogen, Ct_s alkyl .
. The use of a compound having the formula III:
Figure imgf000296_0001
(III) or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
R2
N R2 or I
ΛSL
R, "R,
wherein,
M is chosen from:
Figure imgf000296_0002
Figure imgf000296_0003
wherein,
R4 is chosen from H or C ^ alkyl;
R8 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and RL5 is chosen from H or C x_6 alkyl;
J is chosen from:
Figure imgf000297_0001
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2. 12 alkynyl, C 6.12 aryl, C 3_12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1_12 alkyl, C s_12 aryl or C s_16 aralkyl ;
Y1 is chosen from a bond, Cj_6 alkyl, C 2.6 alkenyl or C 2.6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)20R5ι tetrazole, C0N(R9) CH(R5) C00R5 , CONR10RU, C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and R11 are each independently chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl; or R10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and R,, are each independently chosen from H, C 1_12 alkyl, C 2.
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6.18 aralkyl;
Rx is chosen from C1-12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl, or halogen; Rj is chosen from C^ alkyl, C2_12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, C1_12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3,12 heterocycle, C3.18 heteroaralkyl or Cε_18 aralkyl;
Z is chosen from H, halogen, x_6 alkyl;
for treating or preventing Flaviviridae viral infection in a host.
88. The use of a compound as defined in claim 85, further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
89. The use as defined in claim 86, wherein said antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
90. The use as defined in claim 86, wherein said antiviral agent is chosen from interferon and ribavirin.
91. The use of as defined in claim 86 wherein said additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
92. The use as defined in anyone of claims 86 to 89, wherein said compound and said additionnal agent are administered sequentially.
93. The use as defined in anyone of claims 86 to 89, wherein said compound and said additionnal agent are administered simultaneously.
94. The use as defined in anyone of claims 85 to 91, wherein said Flaviviridea viral infection is hepatitis C viral infection (HCV) .
95. A method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound having the formula III:
Figure imgf000299_0001
(III)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
N R2 or ϊ-
R, \ R,
wherein,
M is chosen from:
Figure imgf000300_0001
Figure imgf000300_0002
wherein,
R4 is chosen from H or C x_6 alkyl;
R8 is chosen from H, C H2 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C s.14 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C s_16 aralkyl; and
R^ is chosen from H or C x_6 alkyl;
J is chosen from:
Figure imgf000300_0003
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2 12 alkynyl, C 6_12 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C 1_12 alkyl, C 6_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, Cx_e alkyl, C 2.6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R1S, C0C00R5, P(0)ORaORb, S(0)0R5, S(0)20R5ι tetrazole, CON(R9) CH(R5) C00R5 , CO R^R,,, CON(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and RX1 are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6.14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl, C6.l8 aralkyl; or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rb are each independently chosen from H, C 1_12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl and C6_18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and Cs_18 aralkyl;
R1 is chosen from C^^ alkyl, C2_12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl, or halogen;
R2 is chosen from C^^ alkyl, C2_12 alkenyl, C2.12 alkynyl, Cs_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, or C6.18 aralkyl;
R3 is chosen from H, C1-12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl or C6_18 aralkyl;
Z is chosen from H, halogen, C1_6 alkyl .
96. The method as defined in claim 93, further comprising one or more viral polymerase inhibitor.
97. The method as defined in anyone of claims 93 or 94, wherein said viral polymerase is a Flaviviridae viral polymerase.
98. The method as defined in anyone of claims 93 or 94, wherein said viral polymerase is a RNA-dependant RNA-polymerase .
99. The method as defined in. anyone of claims 93 or 94, wherein said viral polymerase is HCV polymerase.
0. A method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula III:
Figure imgf000302_0001
(ill) or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
M. R,
N R
I or ,N. R3 'R:
wherein,
M is chosen from:
Figure imgf000302_0002
Figure imgf000302_0003
wherein,
R4 is chosen from H or C 1-s 'alkyl;
R8 is chosen from H, C _12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C 6_1S aralkyl; and
R15 is chosen from H or C _6 alkyl; J is chosen from:
Figure imgf000303_0001
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2. 12 alkynyl, C 6_12 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and R6 is chosen from H, C x_12 alkyl, C e_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, Cx_s alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)OR5, S(0)2OR5ι tetrazole, C0N(R9) CH(R5) C00R5 , CONR10R , CON (R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and R11 are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, CG_18 aralkyl; or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rh are each independently chosen from H, C x_12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl ; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl;
Rx is chosen from C1.12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, Cs_18 aralkyl or halogen;
R2 is chosen from C _12 alkyl, C2_12 alkenyl, C2.12 alkynyl', C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, or C6.18 aralkyl; ' R3 is chosen from H, C^ alkyl, C2.12 alkenyl, C2_12 alkynyl, C6.3 aryl, C3_12 heterocycle, C3.18 heteroaralkyl or C6_18 aralkyl;
Z is chosen from H, halogen, C^ alkyl .
101. The method as defined in claim 98, wherein said compound is chosen from:
Compound #14 3- (4-Chloro-2, 5-dimethyl-benzenesulfonylamino) -5- (4-chloro-phenyl) -thiophene-2-carboxylic acid
Compound #19 3- (4-Chloro-2 , 5-dimethyl-benzenesulfonylamino) -5- (4-isobutyl-phenyl) -thiophene-2-carboxylic acid
Compound #223 3- (4-Bromo-2-fluorobenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #224 3- (4-Bromo-2-methylbenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #225 5- (4-Isobutylphenyl 3- (3-methoxy-benzenesulfonylamino) -thiophene-2-carboxylic acid
Compound #581 5- (4-Isobutyl-phenyl) -3- [5- (5-trifluorome hyl- isoxazol-3-yl) -thiophene-2-sulfonylamino] - thiophene-2-carboxylic acid
Compound #227 3-[2 , 5-Bis- (2 , 2 , 2-trifluoroethoxy) - benzenesulfonylamino]-5- (4-isobutyl-phenyl) - thiophene-2-carboxylic acid
Compound #228 3- (2-Chloro-4-cyanobenzenesulfonylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #582 5- (4-Isobutyl-phenyl) -3- (2 , 3 , 4-trifluoro- benzenesulfonylamino) -thiophene-2-carboxylic acid or pharmaceutically acceptable salts thereof.
102. The method as defined in anyone of claims 98 or 99, wherein said viral helicase is a flaviviridea helicase
103. The method as defined in anyone of claims 98 or 99, wherein said viral helicase is HCV helicase. The use of a compound having the formula III:
Figure imgf000305_0001
(Hi) or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
N R, or N.
R, s' SR3
wherein,
M is chosen from:
Figure imgf000305_0002
Figure imgf000305_0003
wherein,
R4 is chosen from H or C x_6 alkyl;
R8 is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C aryl, C 3_12 heterocycle, C3.12 heteroaralkyl, C 6.16 aralkyl; and
R15 is chosen from H or C 1-s alkyl;
J is chosen from:
-w S' II O O o
W Ra wherein W is chosen from 0, S or NR7, wherein R, is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C s_12 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C 6.ιe aralkyl ; and R6 is chosen from H, C 1-12 alkyl, C s_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, C1_s alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)20R5/ tetrazole, CON (Rg) CH (R5) C00R5 , CO R^R^ , C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R3 , R5, RL0 and Ru are each independently chosen from H, C x„12 alkyl, C 2_12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl; or R10 and R are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and R^ are each independently chosen from H, C x_12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl; or Ra and Rb are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C λ_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and Cs_18 aralkyl;
R1 is chosen from Cx_12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl, Cε_18 aralkyl or halogen;
R2 is chosen from C1.12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, C1.12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl or Cs_18 aralkyl;
Z is chosen from H, halogen, C1.β alkyl; for inhibiting or reducing the activity of viral polymerase in a host.
105. The use as defined in claim 102 further comprising one or more viral polymerase inhibitor.
106. The use as defined in anyone of claims 102 or 103, wherein said viral polymerase is Flaviviridae viral polymerase.
107. The use as defined in anyone of claims 102 or 103 wherein said viral polymerase is RNA-dependant RNA-polymerase.
108. The use as defined in anyone of claims 102 or 103, wherein said viral polymerase is HCV polymerase.
109. The use of a compound having the formula III:
Figure imgf000307_0001
(Ill)
or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
Figure imgf000307_0002
wherein,
M is chosen from:
Figure imgf000308_0001
Figure imgf000308_0002
wherein,
R4 is chosen from H or C x_6 alkyl;
R8 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C 6_16 aralkyl; and
R15 is chosen from H or C x_6 alkyl;
J is chosen from:
Figure imgf000308_0003
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C W! alkyl, C' 2_12 alkenyl, C2_12 alkynyl, C 6_12 aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl ; and R6 is chosen from H, C 1_12 alkyl, C 6_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, C1.6 alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)20R5ι tetrazole, CO (R9) CH (R5) C00R5 , CONR10R , C0N(R9) -S02-R5 , C0NR90H or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C _12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl; or R10 and R11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rb are each independently chosen from H, C 1_12 alkyl, C 2_
12 alkenyl, C2_12 alkynyl, C s_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl; or Ra and Rb are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R16 is chosen from H, C _12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6.18 aralkyl;
R1 is chosen from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl, C6.18 aralkyl or halogen;
R2 is chosen from C^^ alkyl, C2.12 alkenyl, C2.12 alkynyl, C6.14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, C^^ alkyl, C2.12 alkenyl, C2_12 alkynyl, C6.14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl or C6.18 aralkyl;
Z is chosen from H, halogen, C1.s alkyl;
for inhibiting or reducing the activity of viral helicase in a host.
110. The use as defined in claim 109, wherein said compound is chosen from:
Compound #14 3- (4-Chloro-2, 5-dimethyl-benzenesulfonylamino) -5- (4- chloro-phenyl) -thiophene-2-carboxylic acid
Compound #19 3- (4-Chloro-2, 5-dimethyl-benzenesulfonylamino) -5- (4- isobutyl-phenyl) -thiophene-2-carboxylic acid
Compound #223 3- (4-Bromo-2-fluorobenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #224 3- (4-Bromo-2-methylbenzenesulfo-nylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid
Compound #225 5- (4-Isobutylphenyl 3- (3-methoxy-benzenesulfonyl- amino) -thiophene-2-carboxylic acid
Compound #581 5- (4-Isobutyl-phenyl) -3- [5- (5-trifluoromethyl- isoxazol-3-yl) -thiophene-2-sulfonylamino] - thiophene-2-carboxylic acid
Compound #227 3-[2 , 5-Bis- (2 , 2, 2-trifluoroethoxy) - benzenesulfonylamino]-5- (4-isobutyl-phenyl) - thiophene-2-carboxylic acid Compound #228 3- (2-Chloro-4-cyanobenzenesulfonylamino) -5- (4- isobutylphenyl) -thiophene-2-carboxylic acid Compound #582 5- (4-Isobutyl-phenyl) -3- (2 , 3 , 4-trifluoro- benzenesulfonylamino) -thiophene-2-carboxylic acid or pharmaceutically acceptable salts thereof.
111. The use as defined in anyone of claims 109 and 110 further comprising one or more viral helicase inhibitor.
112. The use as defined in anyone of claims 109 or 111, wherein said viral helicase is Flaviviridae viral helicase.
113. The use as defined in anyone of claims 109 or 111, wherein said viral helicase is HCV helicase.
114. A combination comprising a compound having the formula III:
Figure imgf000310_0001
(III) or pharmaceutically acceptable salts thereof;
wherein,
X is chosen from:
Figure imgf000310_0002
wherein,
M is chosen from:
Figure imgf000311_0001
Figure imgf000311_0002
wherein,
R4 is chosen from H or C 1-6 alkyl;
R8 is chosen from H, C 1.12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_: aryl, C 3_12 heterocycle, C3_12 heteroaralkyl, C 6_16 aralkyl; and •
R15 is chosen from H or C 1-6 alkyl;
J is chosen from:
' ^ ■' Y ■ X
W ^6 o o' o
wherein W is chosen from 0, S or NR7, wherein R7 is chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C s_12 aryl, C 3.12 heterocycle, C3.12 heteroaralkyl, C s_16 aralkyl ; and Rs is chosen from H, C 1_12 alkyl, C 6_12 aryl or C 6_16 aralkyl ;
Y1 is chosen from a bond, Cx_e alkyl, C 2_6 alkenyl or C 2_6 alkynyl ;
Y is chosen from C00R16, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)20R5 tetrazole, C0N(R9) CH(R5) C00R5 , CONR10RX1, CON(R9) -S02-R5 , CONR9OH or halogen, wherein R9, R5, R10 and R are each independently chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl; or R10 and Ru are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and Rj, are each independently chosen from H, C 1_X2 alkyl, C 2_
12 alkenyl, C2.12 alkynyl, C 6_14 aryl, C 3.12 heterocycle, C3.18 heteroaralkyl and C6.18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R1S is chosen from H, C λ_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6_14 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6.18 aralkyl;
Rx is chosen from C _12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3.18 heteroaralkyl, C6.18 aralkyl, or halogen;
R2 is chosen from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, Cs_14 aryl, C3.12 heterocycle, C3_18 heteroaralkyl, or C6_18 aralkyl;
R3 is chosen from H, Cλ_12 alkyl, C2.12 alkenyl, C2_12 alkynyl, C6_14 aryl, C3_12 heterocycle, C3_18 heteroaralkyl or C6_18 aralkyl;
Z is chosen from H, halogen, C.^ alkyl;
and one or- more additionnal agent chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.
115. The combination as defined in claim 114, wherein said additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine, cyclosporin, interferon and ribavirin.
116. The combination as defined in anyone of claims 114 or 115, wherein said compound and said additionnal agent are administered sequentially.
117. The combination as defined in anyone of claims 114 or 115, wherein said compound and said additionnal agent are administered simultaneously.
118. A process for preparing a compound of formula A:
Figure imgf000313_0001
said process comprising the steps of adding:
• an enol ether;
• an hydride donating agent; and
• an organic carboxylic .acid;
to a compound of formula B:
Figure imgf000313_0002
wherein,
Y1 is chosen from a bond, C1_6 alkyl, C 2_s alkenyl or C 2_β alkynyl ;
Y is chosen from COOR16, COCOOR5, P(0)ORaORb, S(0)0R5, S(0)2OR5 tetrazole, CON(R9)CH(R5)COOR5 , CO R^R^, CON(R9) -S02-R5 , CONR9OH or halogen, wherein R9, R5, R10 and Ru are each independently chosen from H, C x_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl, C6_18 aralkyl; or R10 and Rn are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
Ra and R^ are each independently chosen from H, C 1_12 alkyl, C 2_
12 alkenyl, C2.l2 alkynyl, C 6_14 aryl, C 3_12 heterocycle, C3_18 heteroaralkyl and C6_18 aralkyl; or Ra and R^ are taken together with the oxygens to form a 5 to
10 membered heterocycle;
R1S is chosen from H, C 1_12 alkyl, C 2_12 alkenyl, C2_12 alkynyl, C
6-i4 aryl, C 3_12 heterocycle, C3.18 heteroaralkyl and C6_18 aralkyl;
Rx is chosen from Cx_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C6.14 'aryl, C3_12 heterocycle, C3.18 heteroaralkyl, Cs_18 aralkyl or halogen;
R2 is chosen from C^^ alkyl , C2_12 alkenyl , C2_12 alkynyl , C3_12 heterocycle, C3_18 heteroaralkyl , or C6_18 aralkyl ;
R3 is chosen from H, Cx_12 alkyl , C2.12 alkenyl , C2_12 alkynyl , C6_14 aryl , C3.12 heterocycle, C3_18 heteroaralkyl or Cs_18 aralkyl ;
Z is chosen from H, halogen, C1-6 alkyl
PCT/CA2002/000876 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection WO2002100851A2 (en)

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CA2450007A CA2450007C (en) 2001-06-11 2002-06-11 Compounds and methods for the treatment or prevention of flavivirus infections
EA200400022A EA007484B1 (en) 2001-06-11 2002-06-11 Compounds and methods for the treatment or prevention of flavivirus infections
SI200230851T SI1401825T1 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
JP2003503618A JP4544857B2 (en) 2001-06-11 2002-06-11 Compounds and methods for the treatment or prevention of FLAVIRIRUS infection
APAP/P/2003/002932A AP1753A (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavvivirus infection
SK1520-2003A SK288015B6 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
KR1020037016240A KR100900304B1 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
AT02742563T ATE438637T1 (en) 2001-06-11 2002-06-11 THIOPHEN DERIVATIVES AS ANTIVIRAL AGENTS AGAINST FLAVIVIRUS INFECTION
BR0210357-5A BR0210357A (en) 2001-06-11 2002-06-11 Compound and methods for the treatment or prevention of flavivirus infections
MXPA03011452A MXPA03011452A (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection.
DK02742563T DK1401825T3 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
DE60233227T DE60233227D1 (en) 2001-06-11 2002-06-11 THIOPHEN DERIVATIVES AS ANTIVIRAL AGENTS AGAINST FLAVIVIRUS INFECTION
AU2002344854A AU2002344854B2 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
EP02742563A EP1401825B1 (en) 2001-06-11 2002-06-11 Thiophene derivatives as antiviral agents for flavivirus infection
NO20035485A NO331721B1 (en) 2001-06-11 2003-12-10 Thiophene derivatives as antiviral agents for flavivirus infection, pharmaceutical preparation, use of thiophene derivatives for the preparation of medicament and methods for the preparation of compounds.

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Cited By (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052879A1 (en) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Thiophenederivatives for the treatment of flavivirus infections
WO2004052885A1 (en) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
WO2004056797A1 (en) * 2002-12-23 2004-07-08 4Sc Ag Aromatic compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2005034850A2 (en) 2003-09-11 2005-04-21 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis c virus
WO2005037214A2 (en) 2003-10-14 2005-04-28 Intermune, Inc. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication
WO2005042020A2 (en) * 2003-10-27 2005-05-12 Vertex Pharmaceuticals Incorporated Combinations for hcv treatment
WO2005063734A2 (en) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Substituted thiophenes
WO2005080388A1 (en) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7071355B2 (en) 2002-12-23 2006-07-04 4 Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2006072348A2 (en) * 2004-12-22 2006-07-13 Aicuris Gmbh & Co. Kg Alkinyl-substituted thiophenes
WO2006072347A2 (en) * 2004-12-22 2006-07-13 Aicuris Gmbh & Co. Kg Alkinyl-substituted thiophenes
WO2006117306A1 (en) 2005-05-04 2006-11-09 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
WO2006119646A1 (en) 2005-05-13 2006-11-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2007070600A2 (en) * 2005-12-12 2007-06-21 Genelabs Technologies, Inc. N-(5-membered heteroaromatic ring)-amido anti-viral compounds
WO2007071434A1 (en) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Antiviral 2-carboxy-thiophene compounds
US7247736B2 (en) 2002-12-23 2007-07-24 4Sc Ag Method of identifying inhibitors of DHODH
WO2008008907A2 (en) * 2006-07-14 2008-01-17 Genelabs Technologies, Inc. Antiviral agents
WO2008017688A1 (en) * 2006-08-11 2008-02-14 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti-viral agents
WO2008043704A1 (en) 2006-10-10 2008-04-17 Medivir Ab Hcv nucleoside inhibitor
WO2008043791A2 (en) * 2006-10-13 2008-04-17 Smithkline Beecham Corporation Thiophene derivatives for treating hepatitis c
US7365094B2 (en) 2002-12-23 2008-04-29 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2008059042A1 (en) * 2006-11-17 2008-05-22 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti viral agents
US7393868B2 (en) 2005-06-06 2008-07-01 Eli Lilly And Company AMPA receptor potentiators
EP1944042A1 (en) * 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinations for HCV treatment
WO2008125599A1 (en) * 2007-04-12 2008-10-23 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti-viral agents
WO2009000818A1 (en) * 2007-06-26 2008-12-31 Smithkline Beecham Corporation 3-carbonylaminothiophene-2-carboxylic acids as hepatitis c virus inhibitors
EP2033654A1 (en) 2003-04-16 2009-03-11 Bristol-Myers Squibb Company Macrocyclic isoquinoline peptide inhibitors of hepatitis c virus
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2065369A1 (en) * 2006-08-23 2009-06-03 Astellas Pharma Inc. Urea compound or salt thereof
EP2093235A1 (en) 2006-02-08 2009-08-26 Alios Biopharma Inc. Hyperglycosylated variants of interferon alfacon-1
EP2104674A1 (en) * 2006-11-15 2009-09-30 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of flavivirus infections
WO2010031832A2 (en) * 2008-09-18 2010-03-25 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Synergistic combinations of a macrocyclic inhibitor of hcv and a thiophene-2-carboxylic acid derivative
US7759390B2 (en) 2005-12-22 2010-07-20 Novartis Ag Inhibitors of CCR9 activity
WO2010107739A2 (en) 2009-03-18 2010-09-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions of treating a flaviviridae family viral infection
WO2011011303A1 (en) 2009-07-21 2011-01-27 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011031669A1 (en) 2009-09-09 2011-03-17 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011058084A1 (en) 2009-11-14 2011-05-19 F. Hoffmann-La Roche Ag Biomarkers for predicting rapid response to hcv treatment
WO2011067195A1 (en) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarkers for predicting sustained response to hcv treatment
WO2011068715A1 (en) 2009-11-25 2011-06-09 Vertex Pharmaceuticals Incorporated 5-alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections
WO2011079327A1 (en) 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011088345A1 (en) 2010-01-15 2011-07-21 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011088303A1 (en) 2010-01-15 2011-07-21 Gilead Sciences , Inc. Inhibitors of flaviviridae viruses
EP2351560A1 (en) 2005-01-04 2011-08-03 Novartis AG Treatment Of HCV infections with FTY720
WO2011094489A1 (en) 2010-01-29 2011-08-04 Vertex Pharmaceuticals Incorporated Therapies for treating hepatitis c virus infection
WO2011119853A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119870A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119858A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119860A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011159826A2 (en) 2010-06-15 2011-12-22 Vertex Pharmaceuticals Incorporated Hcv ns5b protease mutants
WO2012006055A2 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006070A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006060A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012010663A1 (en) * 2010-07-22 2012-01-26 Novartis Ag 2,3,5-trisubstituted thiophene compounds and uses thereof
WO2012020036A1 (en) 2010-08-13 2012-02-16 F. Hoffmann-La Roche Ag Hepatitis c virus inhibitors
WO2012024363A2 (en) 2010-08-17 2012-02-23 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
WO2012058125A1 (en) 2010-10-26 2012-05-03 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis c virus
US8178699B2 (en) * 2008-07-30 2012-05-15 Pfizer Inc. Modulators of CCR9 receptor and methods of use thereof
EP2494991A1 (en) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Combination therapy for the treatment of HCV infection
WO2012123298A1 (en) 2011-03-11 2012-09-20 F. Hoffmann-La Roche Ag Antiviral compounds
WO2012175581A1 (en) 2011-06-24 2012-12-27 F. Hoffmann-La Roche Ag Antiviral compounds
WO2013010112A1 (en) 2011-07-13 2013-01-17 Gilead Sciences, Inc. Thiophen-2-carboxylic acid derivatives useful as inhibitors of flaviviridae viruses
WO2013016492A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016499A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Methods for preparation of thiophene compounds
WO2013053657A1 (en) 2011-10-10 2013-04-18 F. Hoffmann-La Roche Ag Antiviral compounds
AU2011205048B2 (en) * 2005-05-13 2013-05-02 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
WO2013087743A1 (en) 2011-12-16 2013-06-20 F. Hoffmann-La Roche Ag Inhibitors of hcv ns5a
WO2013092447A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
WO2013092481A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
US8618151B2 (en) 2008-12-03 2013-12-31 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2014006066A1 (en) 2012-07-06 2014-01-09 F. Hoffmann-La Roche Ag Triazole compounds as antivirals
US8759544B2 (en) 2012-08-17 2014-06-24 Gilead Sciences, Inc. Synthesis of an antiviral compound
US8771665B2 (en) 2010-12-17 2014-07-08 Cocrystal Discovery, Inc. Inhibitors of hepatitis C virus polymerase
WO2014114573A1 (en) 2013-01-23 2014-07-31 F. Hoffmann-La Roche Ag Antiviral triazole derivatives
WO2014134251A1 (en) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
EP2774927A1 (en) 2008-12-03 2014-09-10 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2014135422A1 (en) 2013-03-05 2014-09-12 F. Hoffmann-La Roche Ag Antiviral compounds
US8841340B2 (en) 2012-08-17 2014-09-23 Gilead Sciences, Inc. Solid forms of an antiviral compound
WO2014148949A1 (en) 2013-03-22 2014-09-25 Асави, Ллс Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof
US8877707B2 (en) 2010-05-24 2014-11-04 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2014186637A1 (en) 2013-05-16 2014-11-20 Riboscience Llc 4'-fluor0-2'-methyl substituted nucleoside derivatives
US8927741B2 (en) 2012-08-17 2015-01-06 Gilead Sciences, Inc. Synthesis of an antiviral compound
US9150554B2 (en) 2009-03-27 2015-10-06 Presidio Pharmaceuticals, Inc. Fused ring inhibitors of hepatitis C
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
EP3025727A1 (en) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Methods of treating liver disease
WO2016090313A1 (en) * 2014-12-05 2016-06-09 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use
US9364484B2 (en) 2011-12-06 2016-06-14 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
WO2016154241A1 (en) 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibitors of hepatitis c virus polymerase
US9511070B2 (en) 2012-08-31 2016-12-06 Novadrug, Llc Heterocyclyl carboxamides for treating viral diseases
US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
EP3166637A4 (en) * 2014-07-10 2018-03-14 The J. David Gladstone Institutes Compositions and methods for treating dengue virus infection
WO2019217643A1 (en) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Combination therapy for treatment of hcv
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI1401825T1 (en) * 2001-06-11 2010-01-29 Virochem Pharma Inc Thiophene derivatives as antiviral agents for flavivirus infection
US8329924B2 (en) * 2001-06-11 2012-12-11 Vertex Pharmaceuticals (Canada) Incorporated Compounds and methods for the treatment or prevention of Flavivirus infections
SE0102616D0 (en) * 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
ES2315430T3 (en) * 2001-10-04 2009-04-01 Smithkline Beecham Corporation NF-KB INHIBITORS.
WO2003104218A1 (en) * 2002-06-06 2003-12-18 Smithkline Beecham Corporation Nf-:b inhibitors
US7179836B2 (en) * 2002-09-20 2007-02-20 Smithkline Beecham Corporation Chemical compounds
TW200418863A (en) * 2002-10-17 2004-10-01 Upjohn Co Novel anthelmintic and insecticidal compositions
PT1569929E (en) * 2002-12-10 2010-06-18 Virochem Pharma Inc Compounds and methods for the treatment or prevention of flavivirus infections
SE0300092D0 (en) * 2003-01-15 2003-01-15 Astrazeneca Ab Novel compounds
SE0300091D0 (en) * 2003-01-15 2003-01-15 Astrazeneca Ab Novel compounds
EP1836179B1 (en) 2004-12-30 2015-05-06 Janssen Pharmaceutica NV Piperidine- and piperazine-1-carboxylic acid amide derivatives and related compounds as modulators of fatty acid amide hydrolase (faah) for the treatment of anxiety, pain and other conditions
EP2164493A2 (en) * 2007-05-25 2010-03-24 Janssen Pharmaceutica, N.V. Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
CA2734500A1 (en) * 2008-08-27 2010-03-11 Calcimedica Inc. Compounds that modulate intracellular calcium
WO2010068453A1 (en) 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010068452A1 (en) * 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
CN102245604A (en) 2008-12-23 2011-11-16 雅培制药有限公司 Anti-viral compounds
JP2012513409A (en) * 2008-12-23 2012-06-14 アボット・ラボラトリーズ Antiviral compounds
JP5690286B2 (en) * 2009-03-04 2015-03-25 イデニク プハルマセウティカルス，インコーポレイテッド Phosphothiophene and phosphothiazole HCV polymerase inhibitors
CA2758484A1 (en) * 2009-04-15 2010-10-21 David A. Degoey Anti-viral compounds
US8901111B2 (en) 2009-06-05 2014-12-02 Janssen Pharmaceutica Nv Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase
US20120083476A1 (en) 2009-06-05 2012-04-05 Janssen Pharmaceutica Nv Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase
DK2455376T3 (en) 2009-06-11 2015-03-02 Abbvie Bahamas Ltd Heterocyclic compounds as inhibitors of hepatitis C virus (HCV)
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
UA108233C2 (en) 2010-05-03 2015-04-10 Fatty acid amide hydrolysis activity modulators
NZ605440A (en) 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
CN103619836A (en) * 2011-03-03 2014-03-05 德诺瓦姆德有限公司 Antimicrobial/adjuvant compounds and methods
US20140057953A1 (en) * 2011-03-03 2014-02-27 Rolf Hartmann Biaryl derivatives as selective 17beta-hydroxysteroid dehydrogenase type 2 inhibitors
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
CN103059042B (en) * 2011-10-18 2015-10-07 银杏树药业(苏州)有限公司 Thiophene derivants and the purposes in pharmacy thereof
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
WO2013142157A1 (en) 2012-03-22 2013-09-26 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
WO2015103490A1 (en) 2014-01-03 2015-07-09 Abbvie, Inc. Solid antiviral dosage forms
US9833463B2 (en) 2014-04-17 2017-12-05 Merck Sharp & Dohme Corp. Sitagliptin tannate complex
EP3759091A1 (en) * 2018-03-01 2021-01-06 Thomas Helledays stiftelse för medicinsk forskning Substituted benzodiazoles and use thereof in therapy
CN108558822B (en) * 2018-06-01 2020-12-18 盐城锦明药业有限公司 Synthesis method of N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19903398A1 (en) * 1999-01-29 2000-08-10 Hassan Jomaa Use of thiadiazole derivatives for the prophylactic and therapeutic treatment of infections
DE19920247A1 (en) * 1999-05-03 2000-11-16 Hassan Jomaa Drugs containing compounds containing a nitrogen-oxygen heterocycle as an active ingredient and their use

Family Cites Families (110)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3076817A (en) 1963-02-05 New j-amino-thiophene-z
DE1055077B (en) 1956-02-08 1959-04-16 Bayerische Schrauben Und Feder Telephone cable connectors
DE1055007B (en) 1957-08-29 1959-04-16 Dr Hans Fiesselmann Process for the preparation of 3-aminothiophene-2-carboxylic acid esters and the corresponding free carboxylic acids
US3470151A (en) * 1966-05-17 1969-09-30 Beecham Group Ltd Furyl- and thienyl-penicillins and salts thereof
JPS4810463B1 (en) 1967-07-07 1973-04-03
US3823161A (en) 1970-05-07 1974-07-09 Exxon Research Engineering Co Aminothiophene derivatives
US3852293A (en) 1972-06-21 1974-12-03 Uniroyal Inc 4-phenyl-2-(3-pyridyl)-thiazole carboxamides
AU518216B2 (en) * 1977-09-06 1981-09-17 Hafslund Nycomed Pharma Aktiengesellschaft Thienothiazine derivatives
DD146952A1 (en) 1979-11-09 1981-03-11 Karl Gewald PROCESS FOR THE PREPARATION OF SUBSTITUTED 3-AMINO-4-CYAN-5-PHENYLTHIOPHENESE
JPS57116077A (en) 1981-01-12 1982-07-19 Kanebo Ltd Thieno(3,2-b)pyridinecarboxylic acid derivative
US4666502A (en) 1982-02-09 1987-05-19 Sandoz Ltd. Herbicidal N-thienyl-chloroacetamides
ATE26720T1 (en) 1982-09-09 1987-05-15 Hoffmann La Roche THIENO(2,3-E)-1,2-THIAZINE DERIVATIVES.
GB8515207D0 (en) 1985-06-15 1985-07-17 Boots Co Plc Therapeutic agents
JPS63126884A (en) 1986-11-17 1988-05-30 Sankyo Co Ltd Oxazolothienopyrimidine derivative
GB8627698D0 (en) * 1986-11-20 1986-12-17 Boots Co Plc Therapeutic agents
DD263055A1 (en) 1987-07-28 1988-12-21 Univ Dresden Tech PROCESS FOR PRODUCING SUBSTITUTED 3-AMINO-5-PHENYL-THIOPHENE
DE3932052A1 (en) 1989-09-26 1991-04-04 Basf Ag OXAZOL- BZW. thiazolecarboxamides
ATE127122T1 (en) 1990-06-23 1995-09-15 Basf Ag DICARBONIC ACID IMIDES AS HERBICIDES.
DE4023048A1 (en) 1990-07-20 1992-01-23 Basf Ag Dicarboxylic acid imides, process for their preparation and their use as herbicides
JP2574085B2 (en) 1991-10-28 1997-01-22 株式会社トクヤマ Method for producing 3-amino-2-thiophenecarboxylic acid derivative
FR2689129B1 (en) 1992-03-27 1995-05-12 Atochem Elf Sa New derivatives of 3-mercapto-2-thenoic acid and their preparation processes.
JPH0625221A (en) 1992-07-10 1994-02-01 Tokuyama Soda Co Ltd Production of 3-amino-2-thiophenecarboxylic acid derivative
DE4244069A1 (en) 1992-12-24 1994-06-30 Hoechst Ag Cephalosporin salts and process for their preparation
JPH0748360A (en) 1993-05-31 1995-02-21 Yoshitomi Pharmaceut Ind Ltd Biphenyl tetrazole derivative
JPH0718360A (en) 1993-07-07 1995-01-20 Sumitomo Light Metal Ind Ltd Ti-al intermetallic compound member excellent in wear resistance and its production
EP0658559A1 (en) 1993-12-14 1995-06-21 Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. Thienothiazin derivatives, process for their preparation and their use as 5-dipoxygenase and cyclooxygenase inhibitors
MX9702380A (en) 1995-08-02 1998-02-28 Uriach & Cia Sa J New carboxamides with antifungal activity.
AU6870396A (en) 1995-08-02 1997-02-26 J. Uriach & Cia S.A. New pyrimidone derivatives with antifungal activity
WO1998008839A1 (en) 1996-08-26 1998-03-05 Eli Lilly And Company Combinatorial process for preparing substituted thiophene libraries
JP4000608B2 (en) 1996-11-07 2007-10-31 トヨタ自動車株式会社 Hydrogen production filling device and electric vehicle
TW523506B (en) * 1996-12-18 2003-03-11 Ono Pharmaceutical Co Sulfonamide or carbamide derivatives and drugs containing the same as active ingredients
WO1998046588A2 (en) * 1997-04-11 1998-10-22 Neorx Corporation Compounds and therapies for the prevention of vascular and non-vascular pathologies
ES2241133T3 (en) 1997-04-28 2005-10-16 Encysive Pharmaceuticals Inc. SULFAMIDS FOR THE TREATMENT OF DISORDERS INDUCED BY ENDOTHELINE.
US5783705A (en) 1997-04-28 1998-07-21 Texas Biotechnology Corporation Process of preparing alkali metal salys of hydrophobic sulfonamides
AU7585598A (en) * 1997-05-23 1998-12-11 Bayer Corporation Raf kinase inhibitors
US6187799B1 (en) * 1997-05-23 2001-02-13 Onyx Pharmaceuticals Inhibition of raf kinase activity using aryl ureas
US6344476B1 (en) 1997-05-23 2002-02-05 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas
ES2151467T3 (en) 1997-05-23 2005-03-01 Bayer Corporation ARILURES FOR THE TREATMENT OF INFLAMMATORY OR IMMUNOMODULATING DISEASES.
JP3156933B2 (en) 1997-09-02 2001-04-16 ウェルファイド株式会社 Fused thiophene compounds and their pharmaceutical uses
US6140351A (en) 1997-12-19 2000-10-31 Berlex Laboratories, Inc. Ortho-anthranilamide derivatives as anti-coagulants
US20070244120A1 (en) 2000-08-18 2007-10-18 Jacques Dumas Inhibition of raf kinase using substituted heterocyclic ureas
AU2003204708B2 (en) 1997-12-22 2006-05-25 Bayer Healthcare Llc Inhibition of Raf Kinase using Substituted Heterocyclic Ureas
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
US6262044B1 (en) 1998-03-12 2001-07-17 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPASES)
US20050119332A1 (en) 1998-03-12 2005-06-02 Lone Jeppesen Substituted thiophene compounds as modulators of protein tyrosine phosphatases (PTPases)
US6214879B1 (en) 1998-03-24 2001-04-10 Virginia Commonwealth University Allosteric inhibitors of pyruvate kinase
US6147085A (en) * 1999-04-01 2000-11-14 Neurogen Corporation Aminoalkyl substituted 9H-pyridino[2,3-b] indole and 9H-pyrimidino[4,5-b] indole derivatives
US6689754B1 (en) 1998-04-10 2004-02-10 G. D. Searle & Co. Heterocyclic glycyl β-alanine derivatives
ATE228119T1 (en) 1998-04-15 2002-12-15 Pfizer Prod Inc HETEROCYCLIC CARBOXAMIDES
EP0960882A1 (en) * 1998-05-19 1999-12-01 Hoechst Marion Roussel Deutschland GmbH Thienyl substituted acylguanidines as inhibitors of bone resorption and vitronectin receptor antagonists
US6858223B2 (en) * 1998-06-23 2005-02-22 Altana Pharma Ag Compositions comprising phenylaminothiophenacetic acid derivatives for the treatment of acute or adult respiratory distress syndrome (ARDS) and infant respiratory distress syndrome (IRDS)
EP1091952B1 (en) * 1998-06-29 2003-10-29 Biochem Pharma Inc Thiophene and furan 2,5-dicarboxamides useful in the treatment of cancer
US7101878B1 (en) 1998-08-20 2006-09-05 Agouron Pharmaceuticals, Inc. Non-peptide GNRH agents, methods and intermediates for their preparation
ID29244A (en) * 1998-08-20 2001-08-16 Agouron Pharma NON-PEPTID GnRH SUBSTANCE, METHODS AND SUBSTANCE BETWEEN THEIR PRODUCTION
EP1152759A2 (en) 1999-02-09 2001-11-14 3-Dimensional Pharmaceuticals, Inc. METHODS OF TREATING C1s-MEDIATED DISEASES AND CONDITIONS, AND COMPOUNDS AND COMPOSITIONS THEREFOR
MXPA01009077A (en) 1999-03-12 2002-03-27 Boehringer Ingelheim Pharma Aromatic heterocyclic compounds as anti-inflammatory agents.
DE60014603T2 (en) * 1999-03-12 2006-02-16 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield Heterocyclic urea and related compounds as anti-inflammatory agents
JP2001010957A (en) 1999-04-28 2001-01-16 Sankyo Co Ltd Prophylactic or inhibitor for hepatopathy
HN2000000051A (en) * 1999-05-19 2001-02-02 Pfizer Prod Inc USEFUL HETEROCICLIC DERIVATIVES AS ANTI-TARGET AGENTS
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
GB9929552D0 (en) 1999-12-14 2000-02-09 Proteus Molecular Design Compounds
WO2001025190A1 (en) 1999-10-01 2001-04-12 Japan Energy Corporation Novel diarylamide derivatives and use thereof as medicines
MXPA02005338A (en) * 1999-11-29 2002-11-29 Novartis Ag Pesticidal n heteroaryl alpha alkoximino carboxamides.
DE10002424A1 (en) * 2000-01-20 2001-07-26 Siemens Ag New 3,4-substituted 2-N,N-di(het)arylamino-thiophene derivatives, used in organic light-emitting diodes and organic photovoltaic components
GB0003154D0 (en) 2000-02-12 2000-04-05 Astrazeneca Uk Ltd Novel compounds
MY138097A (en) 2000-03-22 2009-04-30 Du Pont Insecticidal anthranilamides
JP2001354658A (en) 2000-06-15 2001-12-25 Taisho Pharmaceut Co Ltd Hydroxyformamidine compound and its salt and medicine comprising the same
US6414013B1 (en) * 2000-06-19 2002-07-02 Pharmacia & Upjohn S.P.A. Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention
WO2002028353A2 (en) 2000-10-05 2002-04-11 Smithkline Beecham Corporation Phosphate transport inhibitors
JP4284064B2 (en) 2000-11-08 2009-06-24 シンジエンタ パーテイスィペイシヨンズ アクチエンゲゼルシヤフト Pyrrole carboxamide and pyrrole carbothioamide and their agricultural use
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US6892279B2 (en) * 2000-11-30 2005-05-10 Mosaid Technologies Incorporated Method and apparatus for accelerating retrieval of data from a memory system with cache by reducing latency
DE10061876A1 (en) 2000-12-12 2002-06-20 Aventis Pharma Gmbh Arylated furan and thiophene carboxamides, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them
WO2002064598A1 (en) 2001-02-14 2002-08-22 Warner-Lambert Company Llc Thieno'2,3-d pyrimidindione derivatives as matrix metalloproteinase inhibitors
JP4343534B2 (en) 2001-03-02 2009-10-14 ゲーペーツェー バイオテック アクチェンゲゼルシャフト Three hybrid assay system
US20040102324A1 (en) 2002-02-28 2004-05-27 Annis Gary David Heterocyclic diamide invertebrate pest control agents
EP1386166A2 (en) 2001-03-13 2004-02-04 Queen's University At Kingston Anti-epileptogenic agents
US6734207B2 (en) * 2001-04-20 2004-05-11 Parker Hughes Institute Cytotoxic compounds
US6713638B2 (en) * 2001-05-18 2004-03-30 Joel M. Linden 2-amino-3-aroyl-4,5 alkylthiophenes: agonist allosteric enhancers at human A1 adenosine receptors
SI1401825T1 (en) * 2001-06-11 2010-01-29 Virochem Pharma Inc Thiophene derivatives as antiviral agents for flavivirus infection
EP1395571A1 (en) 2001-06-11 2004-03-10 Shire Biochem Inc. Compounds and methods for the treatment or prevention of flavivirus infections
SE0102617D0 (en) * 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
SE0102616D0 (en) 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
JP2003073357A (en) 2001-09-03 2003-03-12 Mitsubishi Pharma Corp Rho KINASE INHIBITOR COMPRISING AMIDE COMPOUND
US6924276B2 (en) 2001-09-10 2005-08-02 Warner-Lambert Company Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors
ES2315430T3 (en) * 2001-10-04 2009-04-01 Smithkline Beecham Corporation NF-KB INHIBITORS.
US7220777B2 (en) 2001-10-15 2007-05-22 Smithkline Beecham P.L.C. Lactam derivatives as antagonists for human 11cby receptors
US7285557B2 (en) 2001-10-15 2007-10-23 Smithkline Beecham P.L.C. Pyrimidinones as melanin concentrating hormone receptor 1
TWI281916B (en) * 2001-10-25 2007-06-01 Lilly Co Eli Antitumor compounds and methods
WO2003055479A1 (en) * 2001-12-21 2003-07-10 Consejo Superior De Investigaciones Cientificas Compounds and their therapeutic use related to the phosphorylating activity of the enzyme gsk-3
US6835745B2 (en) * 2002-01-15 2004-12-28 Wyeth Phenyl substituted thiophenes as estrogenic agents
AU2003210969A1 (en) 2002-02-11 2003-09-04 Bayer Corporation Aryl ureas with raf kinase and angiogenesis inhibiting activity
US20030220336A1 (en) 2002-04-05 2003-11-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method of treating mucus hypersecretion
US7109354B2 (en) * 2002-05-28 2006-09-19 3-Dimensional Pharmaceuticals, Inc. Thiophene amidines, compositions thereof, and methods of treating complement-mediated diseases and conditions
CN1155679C (en) 2002-09-20 2004-06-30 华南理工大学 Liquid crystal compound contg. oligothiophene skeleton, preparing process thereof
US7179836B2 (en) * 2002-09-20 2007-02-20 Smithkline Beecham Corporation Chemical compounds
BR0315580A (en) 2002-10-24 2005-08-30 Merck Patent Gmbh Methylene Urea Derivatives
US20050075331A1 (en) 2003-10-06 2005-04-07 Pratt John K. Anti-infective agents
US20040097492A1 (en) 2002-11-01 2004-05-20 Pratt John K Anti-infective agents
MXPA05004670A (en) 2002-11-01 2005-08-18 Abbott Lab Anti-infective agents.
US7902203B2 (en) 2002-11-01 2011-03-08 Abbott Laboratories, Inc. Anti-infective agents
US20040162285A1 (en) 2002-11-01 2004-08-19 Pratt John K. Anti-infective agents
PT1569929E (en) 2002-12-10 2010-06-18 Virochem Pharma Inc Compounds and methods for the treatment or prevention of flavivirus infections
US20040192707A1 (en) 2002-12-10 2004-09-30 Laval Chan Chun Kong Compounds and methods for the treatment or prevention of Flavivirus infections
TW200418825A (en) * 2002-12-16 2004-10-01 Hoffmann La Roche Novel (R)-and (S) enantiomers of thiophene hydroxamic acid derivatives
DE10359791A1 (en) 2003-12-19 2005-07-21 Bayer Healthcare Ag Substituted thiophenes
CA2561977A1 (en) 2004-03-30 2005-10-13 Chiron Corporation Substituted thiophene derivatives as anti-cancer agents
DE102005028077A1 (en) 2004-12-22 2006-07-13 Aicuris Gmbh & Co. Kg Alkynyl-substituted thiophenes
US7569600B2 (en) * 2005-05-13 2009-08-04 Virochem Pharma Inc. Compounds and methods for the treatment of prevention of Flavivirus infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19903398A1 (en) * 1999-01-29 2000-08-10 Hassan Jomaa Use of thiadiazole derivatives for the prophylactic and therapeutic treatment of infections
DE19920247A1 (en) * 1999-05-03 2000-11-16 Hassan Jomaa Drugs containing compounds containing a nitrogen-oxygen heterocycle as an active ingredient and their use

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
A. M. REDMAN ET AL.: "P38 Kinase Inhibitors for the Treatment of Arthritis and Osteoporosis: Thienyl, Furyl, and Pyrrolyl Ureas" BIOORG. MED. CHEM. LETT., vol. 11, 2000, pages 9-12, XP004225311 *
B. S. KIM ET AL.: "Reactions of Thioaroylketene S,N-Acetals with 1,3-Dicarbonyl Compounds in the Presence of Mercury(II) Acetate: A General Route to 2-Acyl- and 2-Aroyl-3-(alkylamino)-5-arylthiophenes and 2-(Ethoxycarbonyl)-3-(methylamino)-5-arylt hiophenes" J. ORG. CHEM., vol. 63, no. 18, 1998, pages 6086-6087, XP001118697 *
B. S. KIM, K. KIM: "A Facile and Convenient Synthesis of 3-Alkylamino-5-arylthiophenes with a Variety of Substituents at C-2 and Studies of Reaction Mechanisms" J. ORG. CHEM., vol. 65, no. 12, 2000, pages 3690-3699, XP001118698 *
D. M. MCKINNON ET AL.: "The conversion of isothiazolium salts into thiophenecarboxylic ester derivatives" CAN. J. CHEM., vol. 62, no. 8, 1984, pages 1580-1584, XP002220248 *
DATABASE CAPLUS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; D. J. LEE ET AL.: "Novel Synthesis of 5,6-Dihydro-4H-thieno[3,2-b]pyrrol-5-ones via the Rhodium(II)-Mediated Wolff Rearrangement of 3-(2-Thienyl)-3-oxo-2-diazopropanoates" Database accession no. 2002:151873 XP002220252 & ORGANIC LETTERS, vol. 4, no. 6, 2002, pages 873-876, *
E. MARCHAND, G. MOREL: ".alpha.-Thioxothioamides. Réactions de cycloaddition [4+2] avec l'acétylènedicarboxylate de diméthyle et le propiolate de méthyle" BULL. SOC. FR., vol. 133, no. 9, 1996, pages 903-912, XP002220251 *
J. C. LANCELOT ET AL.: "A Facile Synthesis of New .beta.-Lactams" J. HETEROCYCL. CHEM., vol. 33, no. 2, 1996, pages 427-430, XP002220247 *
J. R. DESAI ET AL.: "Thieno[3,2-d]pyrimidines - Part - II: Preparation and antimicrobial activity of 2-methyl-3-N-arylsulphonamido-6-phenylthie no[3,2-d]pyrimidin-4(3H)-ones" J. INST. CHEMISTS (INDIA), vol. 67, 1995, pages 136-137, XP002220249 *
J. R. DESAI ET AL.: "Thieno[3,2-d]pyrimidines. Part-I: Preparation and Antimicrobial Activity of 3-N-Substituted-thioureido-2-methyl-6-phen ylthieno[3,2-d]pyrimidin-4(3H)-ones" J. IND. CHEM. SOC., vol. 74, 1997, page 160 XP002220250 *
M. SUGIYAMA ET AL.: "Condensed Thienopyrimidines. I. Synthesis and Gastric Antisecretory Activity of 2,3-Dihydro-5H-oxazolothienopyrimidin-5-on e Derivatives" CHEM. PHARM. BULL., vol. 37, no. 8, 1989, pages 2091-2102, XP001118351 *
R. A. SMITH ET AL.: "Discovery of Heterocyclic Ureas as a New Class of Raf Kinase Inhibitors: Identification of a Second Generation Lead by a Combinatorial Chemistry Approach" BIOORG. MED. CHEM. LETT., vol. 11, no. 20, 2001, pages 2775-2778, XP001118699 *
S. VEGA ET AL.: "Thiophene isosteres: synthesis and pharmacological study of 3-(azol-1-yl)thieno isothiazole-1,1-dioxides" EUR. J. MED. CHEM., vol. 23, no. 4, 1988, pages 329-334, XP002220246 *
See also references of EP1401825A2 *
W. KANTLEHNER ET AL.: "Orthoamide. IL. Umsetzungen von Orthoamid-Derivaten mitSchwefel und Selen, Synthesen von 1,3-Thiazol- und 1,3-Selenazolderivaten" J. PRAKT. CHEM., vol. 338, 1996, pages 403-413, XP002220245 *

Cited By (162)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
WO2004052885A1 (en) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
JP4926403B2 (en) * 2002-12-10 2012-05-09 ヴァイロケム ファーマ インコーポレイテッド Compounds and methods for the treatment or prevention of flavivirus infections
JP2006510636A (en) * 2002-12-10 2006-03-30 ヴァイロケム ファーマ インコーポレイテッド Compounds and methods for the treatment or prevention of flavivirus infections
WO2004052879A1 (en) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Thiophenederivatives for the treatment of flavivirus infections
US7365094B2 (en) 2002-12-23 2008-04-29 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2004056797A1 (en) * 2002-12-23 2004-07-08 4Sc Ag Aromatic compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7247736B2 (en) 2002-12-23 2007-07-24 4Sc Ag Method of identifying inhibitors of DHODH
US7071355B2 (en) 2002-12-23 2006-07-04 4 Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7888363B2 (en) 2003-01-22 2011-02-15 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2033654A1 (en) 2003-04-16 2009-03-11 Bristol-Myers Squibb Company Macrocyclic isoquinoline peptide inhibitors of hepatitis c virus
US7112601B2 (en) 2003-09-11 2006-09-26 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis C virus
WO2005034850A2 (en) 2003-09-11 2005-04-21 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis c virus
EP2407470A2 (en) 2003-10-14 2012-01-18 F. Hoffmann-La Roche Ltd. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication
WO2005037214A2 (en) 2003-10-14 2005-04-28 Intermune, Inc. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication
WO2005042020A3 (en) * 2003-10-27 2005-06-23 Vertex Pharma Combinations for hcv treatment
EP1944042A1 (en) * 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinations for HCV treatment
WO2005042020A2 (en) * 2003-10-27 2005-05-12 Vertex Pharmaceuticals Incorporated Combinations for hcv treatment
WO2005063734A3 (en) * 2003-12-19 2007-08-30 Aicuris Gmbh & Co Kg Substituted thiophenes
WO2005063734A2 (en) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Substituted thiophenes
US8030309B2 (en) 2004-02-20 2011-10-04 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2626354A1 (en) 2004-02-20 2013-08-14 Boehringer Ingelheim International GmbH Viral polymerase inhibitors
US7879851B2 (en) 2004-02-20 2011-02-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2005080388A1 (en) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2006072348A3 (en) * 2004-12-22 2006-09-21 Aicuris Gmbh & Co Kg Alkinyl-substituted thiophenes
WO2006072348A2 (en) * 2004-12-22 2006-07-13 Aicuris Gmbh & Co. Kg Alkinyl-substituted thiophenes
WO2006072347A3 (en) * 2004-12-22 2006-12-07 Aicuris Gmbh & Co Kg Alkinyl-substituted thiophenes
WO2006072347A2 (en) * 2004-12-22 2006-07-13 Aicuris Gmbh & Co. Kg Alkinyl-substituted thiophenes
EP2351560A1 (en) 2005-01-04 2011-08-03 Novartis AG Treatment Of HCV infections with FTY720
WO2006117306A1 (en) 2005-05-04 2006-11-09 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
EP2546246A3 (en) * 2005-05-13 2013-04-24 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
WO2006119646A1 (en) 2005-05-13 2006-11-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
EP2543664A1 (en) 2005-05-13 2013-01-09 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
EP2546246A2 (en) 2005-05-13 2013-01-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
AU2006246227B2 (en) * 2005-05-13 2011-04-28 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
EP1879879A1 (en) * 2005-05-13 2008-01-23 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
AU2011205048B2 (en) * 2005-05-13 2013-05-02 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
CN101218224B (en) * 2005-05-13 2013-05-08 Viro化学制药公司 Compounds and methods for the treatment or prevention of flavivirus infections
EP1879879A4 (en) * 2005-05-13 2010-03-10 Virochem Pharma Inc Compounds and methods for the treatment or prevention of flavivirus infections
US7652064B2 (en) 2005-06-06 2010-01-26 Eli Lilly And Company AMPA receptor potentiators
US7393868B2 (en) 2005-06-06 2008-07-01 Eli Lilly And Company AMPA receptor potentiators
WO2007070600A3 (en) * 2005-12-12 2007-11-15 Genelabs Tech Inc N-(5-membered heteroaromatic ring)-amido anti-viral compounds
US7595398B2 (en) 2005-12-12 2009-09-29 Smithkline Beecham Corporation N-(5-membered aromatic ring)-amido anti-viral compounds
WO2007070600A2 (en) * 2005-12-12 2007-06-21 Genelabs Technologies, Inc. N-(5-membered heteroaromatic ring)-amido anti-viral compounds
WO2007071434A1 (en) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Antiviral 2-carboxy-thiophene compounds
US7759390B2 (en) 2005-12-22 2010-07-20 Novartis Ag Inhibitors of CCR9 activity
EP2093235A1 (en) 2006-02-08 2009-08-26 Alios Biopharma Inc. Hyperglycosylated variants of interferon alfacon-1
WO2008008912A1 (en) * 2006-07-14 2008-01-17 Genelabs Technologies, Inc. Antiviral agents
WO2008008907A3 (en) * 2006-07-14 2008-03-20 Genelabs Tech Inc Antiviral agents
WO2008008907A2 (en) * 2006-07-14 2008-01-17 Genelabs Technologies, Inc. Antiviral agents
WO2008017688A1 (en) * 2006-08-11 2008-02-14 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti-viral agents
EP2065369A4 (en) * 2006-08-23 2011-12-28 Astellas Pharma Inc Urea compound or salt thereof
EP2065369A1 (en) * 2006-08-23 2009-06-03 Astellas Pharma Inc. Urea compound or salt thereof
EP2361922A1 (en) 2006-10-10 2011-08-31 Medivir AB Intermediate to HCV-Nucleoside Inhibitors
WO2008043704A1 (en) 2006-10-10 2008-04-17 Medivir Ab Hcv nucleoside inhibitor
WO2008043791A3 (en) * 2006-10-13 2008-06-05 Smithkline Beecham Corp Thiophene derivatives for treating hepatitis c
WO2008043791A2 (en) * 2006-10-13 2008-04-17 Smithkline Beecham Corporation Thiophene derivatives for treating hepatitis c
EP2104674A1 (en) * 2006-11-15 2009-09-30 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of flavivirus infections
EP2559692A1 (en) 2006-11-15 2013-02-20 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of Flavivirus infections
EP2559691A1 (en) 2006-11-15 2013-02-20 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of Flavivirus infections
EP2104674A4 (en) * 2006-11-15 2010-03-17 Virochem Pharma Inc Thiophene analogues for the treatment or prevention of flavivirus infections
WO2008059042A1 (en) * 2006-11-17 2008-05-22 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti viral agents
WO2008125599A1 (en) * 2007-04-12 2008-10-23 Smithkline Beecham Corporation 2-carboxy thiophene derivatives as anti-viral agents
EP2494991A1 (en) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Combination therapy for the treatment of HCV infection
WO2009000818A1 (en) * 2007-06-26 2008-12-31 Smithkline Beecham Corporation 3-carbonylaminothiophene-2-carboxylic acids as hepatitis c virus inhibitors
US8178699B2 (en) * 2008-07-30 2012-05-15 Pfizer Inc. Modulators of CCR9 receptor and methods of use thereof
WO2010031832A2 (en) * 2008-09-18 2010-03-25 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Synergistic combinations of a macrocyclic inhibitor of hcv and a thiophene-2-carboxylic acid derivative
WO2010031832A3 (en) * 2008-09-18 2010-06-10 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Synergistic combinations of a macrocyclic inhibitor of hcv and a thiophene-2-carboxylic acid derivative
EP3025727A1 (en) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Methods of treating liver disease
US8618151B2 (en) 2008-12-03 2013-12-31 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
US8865756B2 (en) 2008-12-03 2014-10-21 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
EP2774927A1 (en) 2008-12-03 2014-09-10 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
EP2682393A1 (en) 2008-12-03 2014-01-08 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A comprising a bicyclic core.
WO2010107739A2 (en) 2009-03-18 2010-09-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions of treating a flaviviridae family viral infection
US9150554B2 (en) 2009-03-27 2015-10-06 Presidio Pharmaceuticals, Inc. Fused ring inhibitors of hepatitis C
US8569302B2 (en) 2009-07-21 2013-10-29 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011011303A1 (en) 2009-07-21 2011-01-27 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
US8765722B2 (en) 2009-09-09 2014-07-01 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011031669A1 (en) 2009-09-09 2011-03-17 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
US8501714B2 (en) 2009-09-09 2013-08-06 Gilead Sciences, Inc. Inhibitors of Flaviviridae viruses
WO2011058084A1 (en) 2009-11-14 2011-05-19 F. Hoffmann-La Roche Ag Biomarkers for predicting rapid response to hcv treatment
WO2011068715A1 (en) 2009-11-25 2011-06-09 Vertex Pharmaceuticals Incorporated 5-alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections
JP2013512247A (en) * 2009-11-25 2013-04-11 バーテックス ファーマシューティカルズ インコーポレイテッド 5-Alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections
WO2011067195A1 (en) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarkers for predicting sustained response to hcv treatment
WO2011079327A1 (en) 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
EP3219713A1 (en) 2010-01-15 2017-09-20 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
CN102712633A (en) * 2010-01-15 2012-10-03 吉里德科学公司 Inhibitors of flaviviridae viruses
CN102712632A (en) * 2010-01-15 2012-10-03 吉里德科学公司 Inhibitors of flaviviridae viruses
US8884030B2 (en) 2010-01-15 2014-11-11 Gilead Sciences, Inc. Inhibitors of Flaviviridae viruses
US9321753B2 (en) 2010-01-15 2016-04-26 Gilead Sciences, Inc. Inhibitors of Flaviviridae viruses
WO2011088303A1 (en) 2010-01-15 2011-07-21 Gilead Sciences , Inc. Inhibitors of flaviviridae viruses
WO2011088345A1 (en) 2010-01-15 2011-07-21 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
CN102712633B (en) * 2010-01-15 2015-07-29 吉里德科学公司 The inhibitor of flaviviridae
US8524764B2 (en) 2010-01-15 2013-09-03 Gilead Sciences, Inc. Inhibitors of Flaviviridae viruses
US8513298B2 (en) 2010-01-15 2013-08-20 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2011094489A1 (en) 2010-01-29 2011-08-04 Vertex Pharmaceuticals Incorporated Therapies for treating hepatitis c virus infection
WO2011119853A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119870A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119858A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119860A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
US8877707B2 (en) 2010-05-24 2014-11-04 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2011159826A2 (en) 2010-06-15 2011-12-22 Vertex Pharmaceuticals Incorporated Hcv ns5b protease mutants
WO2012006055A3 (en) * 2010-06-28 2012-03-01 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006070A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006060A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006055A2 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
AU2011281546B2 (en) * 2010-07-22 2014-07-10 Novartis Ag 2,3,5-trisubstituted thiophene compounds and uses thereof
WO2012010663A1 (en) * 2010-07-22 2012-01-26 Novartis Ag 2,3,5-trisubstituted thiophene compounds and uses thereof
US9040690B2 (en) 2010-07-22 2015-05-26 Novartis Ag 2,3,5-trisubstituted thiophene compounds and uses thereof
US9498483B2 (en) 2010-07-22 2016-11-22 Novartis Ag 2,3,5-trisubstituted thiophene compounds and uses thereof
WO2012020036A1 (en) 2010-08-13 2012-02-16 F. Hoffmann-La Roche Ag Hepatitis c virus inhibitors
WO2012024363A2 (en) 2010-08-17 2012-02-23 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
WO2012024363A3 (en) * 2010-08-17 2012-05-31 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
WO2012058125A1 (en) 2010-10-26 2012-05-03 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis c virus
US8771665B2 (en) 2010-12-17 2014-07-08 Cocrystal Discovery, Inc. Inhibitors of hepatitis C virus polymerase
WO2012123298A1 (en) 2011-03-11 2012-09-20 F. Hoffmann-La Roche Ag Antiviral compounds
WO2012175581A1 (en) 2011-06-24 2012-12-27 F. Hoffmann-La Roche Ag Antiviral compounds
US8741946B2 (en) 2011-07-13 2014-06-03 Gilead Sciences, Inc. Inhibitors of flaviviridae viruses
WO2013010112A1 (en) 2011-07-13 2013-01-17 Gilead Sciences, Inc. Thiophen-2-carboxylic acid derivatives useful as inhibitors of flaviviridae viruses
WO2013016501A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Formulations of thiophene compounds
WO2013016490A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016492A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016499A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Methods for preparation of thiophene compounds
WO2013016491A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013053657A1 (en) 2011-10-10 2013-04-18 F. Hoffmann-La Roche Ag Antiviral compounds
US9364484B2 (en) 2011-12-06 2016-06-14 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
US10869873B2 (en) 2011-12-06 2020-12-22 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
WO2013087743A1 (en) 2011-12-16 2013-06-20 F. Hoffmann-La Roche Ag Inhibitors of hcv ns5a
US9708357B2 (en) 2011-12-20 2017-07-18 Riboscience, LLC 4′-azido, 3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2013092481A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
US9108999B2 (en) 2011-12-20 2015-08-18 Riboscience Llc 2′, 4′-difluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2013092447A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
US10426762B2 (en) 2012-06-20 2019-10-01 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
WO2014006066A1 (en) 2012-07-06 2014-01-09 F. Hoffmann-La Roche Ag Triazole compounds as antivirals
US8927741B2 (en) 2012-08-17 2015-01-06 Gilead Sciences, Inc. Synthesis of an antiviral compound
US8841340B2 (en) 2012-08-17 2014-09-23 Gilead Sciences, Inc. Solid forms of an antiviral compound
US9045462B2 (en) 2012-08-17 2015-06-02 Gilead Sciences, Inc. Synthesis of an antiviral compound
US8759544B2 (en) 2012-08-17 2014-06-24 Gilead Sciences, Inc. Synthesis of an antiviral compound
US9409891B2 (en) 2012-08-17 2016-08-09 Gilead Pharmasset Llc Solid forms of an antiviral compound
US9511070B2 (en) 2012-08-31 2016-12-06 Novadrug, Llc Heterocyclyl carboxamides for treating viral diseases
WO2014114573A1 (en) 2013-01-23 2014-07-31 F. Hoffmann-La Roche Ag Antiviral triazole derivatives
WO2014134251A1 (en) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
WO2014135422A1 (en) 2013-03-05 2014-09-12 F. Hoffmann-La Roche Ag Antiviral compounds
WO2014148949A1 (en) 2013-03-22 2014-09-25 Асави, Ллс Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof
US9895442B2 (en) 2013-05-16 2018-02-20 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9694028B2 (en) 2013-05-16 2017-07-04 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2014186637A1 (en) 2013-05-16 2014-11-20 Riboscience Llc 4'-fluor0-2'-methyl substituted nucleoside derivatives
EP3166637A4 (en) * 2014-07-10 2018-03-14 The J. David Gladstone Institutes Compositions and methods for treating dengue virus infection
US10004751B2 (en) 2014-07-10 2018-06-26 The J. David Gladstone Institutes Compositions and methods for treating Dengue virus infection
WO2016090313A1 (en) * 2014-12-05 2016-06-09 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use
US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US10947210B2 (en) 2015-03-23 2021-03-16 Cocrystal Pharma, Inc. Inhibitors of Hepatitis C virus polymerase
WO2016154241A1 (en) 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibitors of hepatitis c virus polymerase
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US11351186B2 (en) 2017-09-21 2022-06-07 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2019217643A1 (en) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Combination therapy for treatment of hcv
US11752166B2 (en) 2018-05-09 2023-09-12 Cocrystal Pharma, Inc. Combination therapy for treatment of HCV

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