WO2006119646A1 - Compounds and methods for the treatment or prevention of flavivirus infections - Google Patents
Compounds and methods for the treatment or prevention of flavivirus infections Download PDFInfo
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- WO2006119646A1 WO2006119646A1 PCT/CA2006/000786 CA2006000786W WO2006119646A1 WO 2006119646 A1 WO2006119646 A1 WO 2006119646A1 CA 2006000786 W CA2006000786 W CA 2006000786W WO 2006119646 A1 WO2006119646 A1 WO 2006119646A1
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- 0 CC(CC1)CCC1C(N(C1CC[N+](C)(C)CC1)c1c2[s]c(C3=CCCCC3)c1)=*C2=O Chemical compound CC(CC1)CCC1C(N(C1CC[N+](C)(C)CC1)c1c2[s]c(C3=CCCCC3)c1)=*C2=O 0.000 description 2
- JEMOHNKXRFEUDT-UHFFFAOYSA-N CC(C)(C)OC(Nc1c(C(OC)=O)[s]cc1)=O Chemical compound CC(C)(C)OC(Nc1c(C(OC)=O)[s]cc1)=O JEMOHNKXRFEUDT-UHFFFAOYSA-N 0.000 description 1
- RMECAUXQAKJBPQ-BNFZFUHLSA-N CC(C)/C=C/C(C)C(N(C(C)/C=C/C(C)OC)c1c(C(OC)=O)[s]c(C(CC2)CCC2(F)F)c1)=O Chemical compound CC(C)/C=C/C(C)C(N(C(C)/C=C/C(C)OC)c1c(C(OC)=O)[s]c(C(CC2)CCC2(F)F)c1)=O RMECAUXQAKJBPQ-BNFZFUHLSA-N 0.000 description 1
- UODPHKFUTYRNDZ-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1=O)c1c(C(OC)=O)[s]c(C2C=CCCC2)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1=O)c1c(C(OC)=O)[s]c(C2C=CCCC2)c1)=O UODPHKFUTYRNDZ-UHFFFAOYSA-N 0.000 description 1
- MGIDOELNCIGRPO-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(O)=O)[s]c(C2=CCCCC2)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(O)=O)[s]c(C2=CCCCC2)c1)=O MGIDOELNCIGRPO-UHFFFAOYSA-N 0.000 description 1
- FPARYJXWWMDFFU-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(O)=O)[s]c(C2C=CCCC2)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(O)=O)[s]c(C2C=CCCC2)c1)=O FPARYJXWWMDFFU-UHFFFAOYSA-N 0.000 description 1
- YMZBNCXRVMHBHA-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(OC)=O)[s]c(C2C=CCCC2)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1O)c1c(C(OC)=O)[s]c(C2C=CCCC2)c1)=O YMZBNCXRVMHBHA-UHFFFAOYSA-N 0.000 description 1
- UFLNDZQEGXWPQV-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1OC)c1c(C(OC)=O)[s]c(C(CC2)CC=C2F)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1OC)c1c(C(OC)=O)[s]c(C(CC2)CC=C2F)c1)=O UFLNDZQEGXWPQV-UHFFFAOYSA-N 0.000 description 1
- FDVDLESUSZKVIW-UHFFFAOYSA-N CC(CC1)CCC1C(N(C(CC1)CCC1OC)c1c(C(OC)=O)[s]c(C(CC2)CCC2=O)c1)=O Chemical compound CC(CC1)CCC1C(N(C(CC1)CCC1OC)c1c(C(OC)=O)[s]c(C(CC2)CCC2=O)c1)=O FDVDLESUSZKVIW-UHFFFAOYSA-N 0.000 description 1
- JCSCIWGDMUXOSU-UHFFFAOYSA-N CC1CC(CC(N(C(CC2)CCC22OCCO2)c2c(C(OC)=O)[s]cc2)=O)CCC1 Chemical compound CC1CC(CC(N(C(CC2)CCC22OCCO2)c2c(C(OC)=O)[s]cc2)=O)CCC1 JCSCIWGDMUXOSU-UHFFFAOYSA-N 0.000 description 1
- XYRRRTDDQUCNQM-UHFFFAOYSA-N COC(c([s]c(C1=CCCCC1)c1)c1N)=O Chemical compound COC(c([s]c(C1=CCCCC1)c1)c1N)=O XYRRRTDDQUCNQM-UHFFFAOYSA-N 0.000 description 1
- TWEQNZZOOFKOER-UHFFFAOYSA-N COC(c([s]cc1)c1N)=O Chemical compound COC(c([s]cc1)c1N)=O TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/04—Ortho-condensed systems
-
- 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
-
- 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
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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 those, 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. 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!
- BVDV bovine viral diarrhea virus
- 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 in 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
- the present invention provides a compound having the formula I:
- Ri is chosen from optionally substituted C3-12 cycloalkyl, optionally substituted C 4 - 1 2 cycloalkenyl, optionally substituted -C(O)-C 3 -I 2 cycloalkyl, optionally substituted - C(O)-C 4 - I2 cycloalkenyl, optionally substituted 5 to 12 member spiroheterocycloalkyl and optionally substituted 8 to 12 member spiroheterocycloalkenyl;
- Z is chosen from H, halogen, optionally substituted d. 6 alkyl, optionally substituted C 2 - 6 alkenyl and optionally substituted C 2 . 6 alkynyl;
- N R 2 and X is chosen from: R, ⁇ T ⁇ R,
- M is chosen from:
- R 2 , R 3 and R 6 are each indendently chosen from H, optionally substituted C M2 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C 2 - I2 alkynyl, optionally substituted C 6 -i4 aryl, optionally substituted C7-1 6 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 merriber heterocycle-alkyl;
- R 4 and R 5 are ach independently chosen from H, optionally substituted Ci- 6 alkyl, optionally substituted C 2 . 6 alkenyl and optionally substituted C 2 - 6 alkynyl;
- J is chosen from: . ⁇ e / S , and ' S
- W is chosen from 0, S and NR 8 ;
- R 7 is chosen from H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl optionally substituted, optionally substituted C 2 - 12 alkynyl, optionally substituted C 6 - H aryl and optionally substituted C 7 -i 6 aralkyl;
- Rs is chosen from H, optionally substituted C1-12 alkyl, optionally substituted C 2 . 12 alkenyl, optionally substituted C2- 1 2 alkynyl, optionally substituted C 6 - H aryl, optionally substituted C 7- i 6 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl;
- Y 1 is chosen from a bond, optionally substituted Ci- 6 alkyl, optionally substituted C 2 - 6 alkenyl, and optionally substituted C 2 6 alkynyl;
- Y is chosen from COOR 9 , COCOOR 9 , P(O)OR a OR b , S(O)OR 9 , S(O) 2 OR 9 , tetrazole, CON(R 9 )CH(R 9 )COOR 9 , CONR10R11, CON(R 9 )-SO 2 -R 9 , CONR 9 OH and halogen;
- R 9 , R 1 O and R 11 are each independently chosen from H, optionally substituted CM 2 alkyl, optionally substituted C 2 12 alkenyl, optionally substituted C 2 . 12 alkynyl, optionally substituted C 6 - H aryl, optionally substituted C 7 . 16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 merpber heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl, or R 10 and R 11 are taken together with the nitrogen atom to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl; and
- R 3 and R b are each independently chosen from H, optionally substituted C 1 -12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2 . 12 alkynyl, optionally substituted C 6 -I 4 aryl, optionally substituted C 7 16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl, or R 3 and Rb are taken together with the oxygen atoms to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- a method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of a compound, composition or combination of the invention.
- composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient.
- a combination comprising a compound of the invention and one or more additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, and antisense agents.
- compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.
- each of X, Y 1 , Y and Ri are as defined above and wherein each of the above-mentioned alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heteroaryl, heteroaralkyl, heterocycle-alkyl, cycloalkyl and cycloalkenyl groups is optionally substituted.
- M is chosen from:
- M is: °
- M is:
- J is chosen f O O rom: wherein, W is as defined above.
- J is:
- J is:
- Y 1 is a bond.
- Y 1 -Y is COOH.
- each of X, Y 1 , Y and Ri are as defined above and wherein each of the above-mentioned alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heteroaryl, heteroaralkyl, heterocycle-alkyl, cycloalkyl and cycloalkenyl groups is optionally substituted.
- each of X, Y, Ri, R 2 and R 3 are as defined above and wherein each of the above-mentioned alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heter ⁇ aryl, heteroaralkyl, heterocycle-alkyl, cycloalkyl and cycloalkenyl groups is optionally substituted.
- Ri is CM 2 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl) unsubstituted or substituted one or more times by R 17 , C 4 - 12 cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl) unsubstituted or substituted one or more times by Ri 7 , -C(O)-C 3 - I2 cycloalkyl unsubstituted or substituted one or more times by R 17 , -C(O)-C 4 .
- cycloalkyl e.g., cyclopentyl, cyclohexyl, cycloheptyl
- Ri 7 e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl
- R 17 is halogen, oxo, -NH 2 , -NH(C M alkyl), -N(Ci- 4 alkyl) 2 , -CONH 2 , -CONH(C M alkyl), - CON(Ci- 4 alkyl) 2 , -NHCOH, -N(Ci- 4 alkyl)COH, -N(CM alkyOCOCw alkyl, -NHCOC M alkyl, -C(O)H, -C(O)C M alkyl, carboxy, -C(O)O CM alkyl, hydroxyl, C 1 ⁇ aIkOXy, nitro, nitroso, azido, cyano, -S(O) 0 - 2 H, -S(O) 0 - 2 Ci- 4 alkyl, -SO 2 NH 2 , -SO 2 NH(C M alkyl), -SO 2 N(C M alkyl)
- R 2 is H, C M2 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by R 17 , C 2 . 12 alkenyl (e.g., ethenyl or propenyl) unsubstituted or substituted one or more times by R 17 , C 2 .
- R18 is halogen, GXG 7 Cv 6 alkyl, -NH 2 , -NH(Cv 4 alkyl), -N(Cv 4 alkyl) 2 , -CONH 2 , - CONH(Ci- 4 alkyl), -CON(Cv 4 alkyl) 2 , -NHCOH, -N(C 1-4 alkyl)COH, -N(Cv 4 alkyl)CDCi. 4 alkyl, -NHCOC 1 -4 alkyl, -C(O)H, -C(O)Cv 4 alkyl, carboxy, -C(O)O C 1-4 alkyl, hydroxyl, C 1 .
- Ri9 is halogen, GX% CV 6 alkyl, -NH 2 , -NH(Cv 4 alkyl), -N(Cv 4 alkyl) 2 , -CONH 2 , - CONH(Cv 4 alkyl), -CON(Cv 4 alkyl) 2 , -NHCOH, -N(Cv 4 alkyl)COH, -N(Cv 4 alkyl)C0Cv 4 alkyl, -NHCOCv 4 alkyl, -C(O)H, -C(O)Cv 4 alkyl, carboxy, -C(O)O Cv 4 alkyl, hydroxyl, C 1 .
- R 20 IS halogen, oxo, Cv 6 alkyl, -NH 2 , -NH(Cv 4 alkyl), -N(Cv 4 alkyl) 2 , -CONH 2 , - CONH(Cv 4 alkyl), -CON(Cv 4 alkyl) 2 , -NHCOH, -N(Cv 4 alkyl)COH, -N(Cv 4 alkyl)C0d- 4 alkyl, -NHCOCv 4 alkyl, -C(O)H, -C(O)Cv 4 alkyl, carboxy, -C(O)O Cv 4 alkyl, hydroxyl, C 1 .
- R 21 is halogen, -NH 2 , -NH(Ci-4 alkyl), -N(C 1 .., alkyl) 2 , -CONH 2 , -CONH(CM alkyl), - CON(Ci- 4 alkyl) 2 , -NHCOH, -N(Ci- 4 alkyl)C0H, -N(Ci. 4 alkyl)COCi. 4 alkyl, -NHCOCM alkyl,
- R 3 is C M2 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by Ri 7 , C M2 alkenyl (e.g., ethenyl or propenyl) unsubstituted or substituted one or more times by Ri 7 , CM 2 alkynyl (e.g., ethynyl or propynyl) unsubstituted or substituted one or more times by Ri 7 , C 6 - H aryl (e.g., phenyl or naphthyl) which is unsubstituted or substituted one or more times by Ri 8 , or C 7- i ⁇ aralkyl (e.g., benzyl, phenethyl, phenpropyl) unsubstituted or substituted one or more times by Ri 8 , 5-12 member heteroaryl unsubstituted or substituted
- Z is H, halogen, is Ci- 6 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by Ri 7 , C 2-6 alkenyl
- Ri 7 e.g., ethenyl or propenyl
- C 2 - 6 alkynyl e.g., ethynyl or propynyl
- R 4 is H, Ci- 6 alkyl (e.g., methyl or ethyl) which is unsubstituted or substituted one or more times by Ri 7 , C 2 . 6 alkenyl (e.g., ethenyl or propenyl) which is unsubstituted or substituted one or more times by
- Ri 7 or C 2 - 6 alkynyl (e.g., ethynyl or propynyl) which is unsubstituted or substituted one or more times by R 17 .
- R 5 is H, C1.6 alkyl (e.g., methyl or ethyl) which is unsubstituted or substituted one or more times by R17, C 2 -6 alkenyl (e.g., ethenyl or propenyl) which is unsubstituted or substituted one or more times by R17, or
- C 2 - 6 alkynyl e.g., ethynyl or propynyl which is unsubstituted or substituted one or more
- R 6 is H, C 1-I2 alkyl (e.g., methyl or ethyl) which is unsubstituted or substituted one or more times by R17, C 2 . 12 alkenyl (e.g., ethenyl or propenyl) which is unsubstituted or substituted one or more times by
- C M2 alkynyl e.g., ethynyl or propynyl
- Ri 7 C 6 -i 4 aryl (e.g., phenyl or naphthyl) which is unsubstituted or substituted one or more times by R 18
- CM 6 aralkyl e.g., benzyl, phenethyl, phenpropyl
- R 18 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 1 ⁇ , 6-
- R 7 is H, C 1-12 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by Ri 7 , C 2- - I2 alkenyl ( ⁇ . ⁇ ., ethenyl or propenyl) unsubstituted or substituted one or more times by R 17 , C M2 alkynyl (e.g., ethynyl or propynyl) unsubstituted or substituted one or more times by R 17 , C 6 -H aryl (e.g., phenyl or naphthyl) which is unsubstituted or substituted one or
- Ri 8 25 more times by Ri 8 , or C 7 -i ⁇ aralkyl (e.g., benzyl, phenethyl, phenpropyl) unsubstituted or substituted one or more times by Ri 8 .
- C 7 -i ⁇ aralkyl e.g., benzyl, phenethyl, phenpropyl
- R 8 is H, Ci -12 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by R 17 , C 2 . 12 alkenyl (d.g., 30 ethenyl or propenyl) unsubstituted or substituted one or more times by Ri 7 , C M2 alkynyl (e.g., ethynyl or propynyl) unsubstituted or substituted one or more times by R 17 , C 6 - 14 aryl (e.g., phenyl or naphthyl) which is unsubstituted or substituted one or more times by Ri 8 , C 7 - 16 aralkyl (e.g., benzyl, phenethyl, phenpropyl) unsubstituted or substituted one or more times by R 18 , 5-12 member heteroaryl unsubstituted
- Y is chosen from COOR 9 , COCOOR 9 , CON(R 9 )SO 2 R 9 , P(O)OR a OR b , S(O) 2 OR 9 , tetrazole, CON(R 9 )CH(R 9 )COOR 9 , CONR 10 R 1 I, and CONR 9 OH.
- any of R 3 , R b , R9, R10, and R 11 are each independently chosen from H, optionally substituted C 1 ⁇ alkyl, optionally substituted C 2 . 6 alkenyl and optionally substituted C 2 . 6 alkynyl.
- R 9 , R 1O and R 11 are each independently H, C M2 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by R 17 , C 2-12 alkenyl (e.g., ethenyl or propenyl) unsubstituted or substituted one or more times by R 17 , C 2-12 alkynyl (e.g., ethynyl or propynyl) unsubstituted or substituted one or more times by R 17 , C 6 14 aryl (e.g., phenyl or naphthyl) which is unsubstituted or substituted one or more times by R 1 S, or C 7 .
- C M2 alkyl e.g., methyl or ethyl
- C 2-12 alkenyl e.g., ethenyl or propenyl
- C 2-12 alkynyl e.g.
- aralkyl e.g., benzyl, phenethyl, phenpropyl
- R 18 unsubstituted or substituted one or more times by R 18
- 6-18 member heteroaralkyl unsubstituted or substituted one or more times by R 19
- 4-18 member heterocycle-alkyl unsubstituted or substituted one or more times by R 19 ;
- R 1O and Rn are taken together with the nitrogen atom to form a 3 to 10 member heterocycle unsubstituted or substituted one or more times by R 19 or 5-12 member heteroaryl unsubstituted or substituted one or more times by R 19 .
- R 3 and R b are each independently C M2 alkyl (e.g., methyl or ethyl) unsubstituted or substituted one or more times by Ri7, C 2 - 12 alkenyl (e.g., ethenyl or propenyl) unsubstituted or substituted one or more times by R 17 , C 2 .
- R 3 , R b , R9, R1 0 , and Rn are each independently chosen from H and optionally substituted C1- 6 alkyl.
- R 3 , R b , R9, R1 0 , and Rn are each independently chosen from H and methyl.
- R a , R b , R9, R 10 , and Rn are each H.
- Y is chosen from COOR 9 , CONR 10 R 11 and CON(R 9 )CH(Rg)-COOR 9 .
- Y is chosen from COOR 9 , CONR1 0 R 11 and CON R 9 CH 2 COOR 9 .
- Y is COOH. In a further embodiment, Y is CONH 2 . In a further embodiment, Y is CONHCH 2 COOH. In a further embodiment, Y is COOCH 3 .
- Y 1 is a bond, Ci- 6 alkyl (e.g., methyl or ethyl) which is unsubstituted or substituted one or more times by Ri 7 , C 2 . 6 alkenyl (e.g., ethenyl or propenyl) which is unsubstituted or substituted one or more times by
- R 17 or C 2 -6 alkynyl (e.g., ethynyl or propynyl) which is unsubstituted or substituted one or more times by R 17 .
- C 2 -6 alkynyl e.g., ethynyl or propynyl
- R 3 is chosen from H, optionally substituted C M2 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2 . 12 alkynyl, optionally substituted C7- 16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 5-18 member heterocycle-alkyl;
- R 3 is Ci. 12 alkyl; R 3 is C 3 - I2 cycloalkyl; R 3 is C7-1 6 aralkyl;
- R 3 is 3-12 member heterocycle; R 3 is 5-12 member heteroaryl;
- R 3 is 5-7 member heterocycle, 5-7 member heteroaryl or C 5 .7cycloalkyl which are optionally substituted; or R 3 is 6-7 member heterocycle, 5-7 heteroaryl or C 6 - 7 cycloalkyl which are optionally substituted.
- R 3 is chosen from H, methyl, ethyl, i-propyl, cyclopropyl, cyclohexyl, piperidinyl, N(Ci-6 alkyl)-piperidinyl (e.g., N-methyl-piperidinyl), piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, piperidinylmethyl, dioxanyl, hexahydrothiopyrany, , methylazepanyl, N(Ci- 6 alkyl)-piperidinylmethyl dioxolanyl, tetrahydrothiopyranyl, dioxolanylmethyl, dioxanylmethyl, and azepanyl ; any of which can be optionally substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 Ri 2 , PO 3 R c Rd, CONRi 3 Ri
- R 3 is chosen from allyl, pyridinyl, pyridinylmethyl, phenyl and benzyl; any of which can be optionally substituted by one or more substituents chosen from halogen, nitro, nitroso, SO3R12, PO 3 R c Rd, CONR 13 RH, C 1 ⁇ alkyl, C 2 6 alkenyl, C 2 . 6 alkynyl, C7-12 aralkyl, C 6 -i2 aryl, C 1 ⁇ alkyloxy, C 2 -6 alkenyloxy, C 2 . 6 alkynyloxy, C 6 .
- R 12 , R c , R d , Ri 3 and RH are each independently chosen from H, CM 2 alkyl, C 2 -12 alkenyl, CM 2 alkynyl, C 6 - 14 aryl, 3-12 member heterocycle, 6-18 member heteroaralkyl, and C7-18 aralkyl, or R c and R d are taken together with the oxygens to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl, or R 13 and R H are taken together with the nitrogen to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- R 3 is cyclohexyl unsubstituted or substituted by one or more substituents independently chosen from halogen, SO 2 R f , CONRgR h , C 1-6 alkyl, C 7 . 12 aralkyl, C 6 . 12 aryl, C 1-6 alkyloxy, C 2 . 6 alkenyloxy, C 2 .
- R 3 is piperidinyl unsubstituted or substituted by one or more substituents independently chosen from halogen, SO 2 R f , CONRgR h , Ci- 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C7.12 aralkyl, C 6 -12 aryl, C1-6 alkyloxy, C 2 6 alkenyloxy, C 2 .
- R 3 is N(Ci- 6 alkyl)-piperidinyl unsubstituted or substituted by one or more substituents independently chosen from halogen, SO 2 Rf, CONRgRh, Ci- 6 alkyl, C 2 - ⁇ alkenyl, C 2 . 6 alkynyl, C 7 . 12 aralkyl, C6-12 aryl, C1- 6 alkyloxy, C 2 -6 alkenyloxy,
- R 3 is Ci- 12 alkyl (e.g., methyl, ethyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by R17, or C 6 - H aryl (e.g., phenyl or naphthyl, especially phenyl) which is unsubstituted or substituted one or more times by R 18 .
- Ci- 12 alkyl e.g., methyl, ethyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl
- R 3 is cyclohexyl, N-methyl-piperidinyl, N-ethyl-piperidinyl, N- propyl-piperidinyl, hexahydrothiopyranyl, azepanyl, methylazepanyl, tetrahydropyranyl, piperidinylmethyl, pyridinyl, pyridinylmethyl, tetrahydrothiopyranyl, dioxolanylmethyl, dioxanylmethyl.
- R 3 is chosen from H, methyl, isopropyl, piperidinyl, piperidinylmethyl, dioxolanyl and cyclohexyl;
- R 3 is cyclohexyl
- R 3 is N-methyl-4-piperidinyl
- R 3 is hydroxycyclohexyl; R 3 is 4-hydroxycyclohexyl;
- R 3 is methoxycyclohexyl
- R 3 is 4-methoxycyclohexyl
- R 3 is dioxolanyl
- R 3 is isopropyl; R 3 is cyclopentyl;
- R 3 is phenyl
- R 3 is H or methyl
- R 3 is H
- R 3 is methyl; or R 3 is benzyl, thiophenylmethyl, or furanylmethyl.
- R 2 is optionally substituted 3-6 member heterocycle or optionally substituted 5-7 member heteroaryl.
- R 2 is chosen from thienyl, furanyl, pyridinyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiaz ⁇ lyl, and quinolinyl, any of which can be optionally substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONRi 3 Ri 4 , Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
- Rc and Rd are taken together with the oxygens to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl
- Ru and R 14 are taken together with the nitrogen to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- R 2 is chosen from piperazinyl and pyrrolidinyl any of which can be optionally substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1 ⁇ alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 7 - I2 aralkyl, C 6 - 12 aryl, Ci-6 alkyloxy, C 2 .
- R c and R d are taken together with the oxygens to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl, or R 1J and R 14 are taken together with the nitrogen to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- R 2 is chosen from thienyl, furanyl, pyridinyl, pyrrolyl, indolyl, piperazinyl and benzothienyl.
- R 2 is Ci- 12 alkyl optionally substituted.
- R 2 is C 3 - 12 cycloalkyl optionally substituted.
- R 2 is C 5 - 12 cycloalkyl optionally substituted.
- R 2 is C 5 . 7 cycloalkyl optionally substituted.
- R 2 is optionally substituted C 6 . 7 cycloalkyl.
- R 2 is optionally substituted C 6 cycloalkyl.
- 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 substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONRi 3 R 14 , Ci -6 alkyl, C 2 .
- Rc and Rd are taken together with the oxygen atoms to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl, or R 13 and R 14 are taken together with the nitrogen atom to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- R 2 is cyclohexyl unsubstituted or substituted by one or more substituents independently chosen from halogen, nitro, nitroso, SO 3 R f , SO 2 R f , PO 3 R c Rd, CONRgRh, C 1-6 alkyl, C 7 12 aralkyl, C 6 - 12 aryl, Ci- 6 alkyloxyC 6 .
- R 2 is cyclohexyl unsubstituted or substituted by one or more substituents independently chosen from halogen, SO 2 Rf, CONR g R h , Ci- 6 alkyl, C 7 - I2 aralkyl, C 6 - 12 aryl, C1- 6 alkyloxy, C 2 . 6 alkenyloxy, C 2 .
- R 2 is cyclohexyl substituted by one or more substituents independently chosen from Ci- 6 alkyl, halogen, C 2-6 alkenyl, C 2 . 6 alkynyl or C 1-6 alkyloxy, C 2 -6 alkenyloxy, and C 2 . 6 alkynyloxy.
- R 2 is C 3 . 12 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by R 17 , or C 6 - 14 aryl (e.g., phenyl or naphthyl, especially phenyl) which is unsubstituted or substituted one or more times by Ri 8 .
- cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl
- R 17 or C 6 - 14 aryl (e.g., phenyl or naphthyl, especially phenyl) which is unsubstituted or substituted one or more times by Ri 8 .
- R 2 is cyclohexyl substituted by Ci- 6 alkyl
- R 2 is cyclohexyl substituted by Ci- 3 alkyl
- R 2 is 4-methyl-cyclohexyl or 2-hydroxy-4-methyl-cyclohexyl
- R 2 is 4-methylcyclohexyl.
- R 2 is chosen from optionally substituted C 6 - H aryl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl, and C 7 . 12 aralkyl.
- R 2 is chosen from a C 6 -i2 aryl, 3-10 member heterocycle and 5-10 member heteroaryl which in each case are optionally substituted.
- R 2 is a C 6 aryl, a 3-6 member heterocycle or 5-7 member heteroaryl which in each case is optionally substituted.
- R 2 is optionally substituted C 6 -i2 aryl.
- R 2 is an aryl chosen from indenyl, naphthyl and biphenyl which is in each case optionally substituted.
- R 2 is phenyl substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 Ri 2 , PO 3 R c R d , CONRi 3 Ri 4 , d- 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 7 -i 2 aralkyl, C 6 -i 2 aryl, C 1-6 alkyloxy, C 2 . 6 alkenyloxy, C 2 . 6 alkynyloxy, C 6 -i 2 aryloxy, C(O)Ci- 6 alkyl, C(O)C 2 . 6 alkenyl, C(O)C 2 .
- R 2 is phenyl substituted by one or more substituents chosen from halogen, nitro, CONRi 3 R 14 , Ci- 6 alkyl, C 2 6 alkenyl, C1-6 alkyloxy, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, C(O)Ci- 6 alkyl, C 6 -i2 aryl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, optionally substituted 4-18 member heterocycle-alkyl, hydroxyl, NR1 3 R14, C(O)OR 12 , cyano, and azido; wherein R 12 , R13 and Ru are each independently chosen from H, C M2 alkyl, C 2 - 12 alkenyl, C 2 .
- R 2 is phenyl substituted by one or two substituents chosen from halogen, C 1-6 alkyl, NRi 3 Ri 4 , nitro, CONR1 3 R14, C(O)OC I - 6 alkyl, COOH or C 1 -6 alkyloxy, C 2 . 6 alkenyloxy, C 2 . 6 alkynyloxy C(O)ORi 2 , cyano, and azido; wherein Ri 2 , R 13 and R 14 are each independently chosen from H, C M2 alkyl,
- R 2 is chosen from phenyl, pyridinyl, thiophenyl, benzofuran, thiazole, and pyrazole, which are unsubstituted or substituted with at least one substituent chosen from a halogen, C 1 -6 alkyl, C ⁇ alkyloxy, C 2 -6 alkenyloxy, C 2 . 6 alkynyloxy, CF 3 , COOH, COOC 1-6 alkyl, cyano, NH 2 , nitro, NH(Ci- 6 alkyl), N(Ci-6 alkyl) 2 and a C 3 -s heterocycle.
- R 2 is chosen from thienyl, furanyl, pyridyl, oxazolyl, thiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoxazolyl, benzothienyl, benzothiazolyl and quinolinyl, any of which can be substituted by at least one substituent chosen from Ci- 6 alkyl, amino, halogen, nitro, amido, CN, COOCi- 6 alkyl, C 1 ⁇ alkyloxy, C 2 6 alkenyloxy, and C 2 . 6 alkynyloxy.
- R 2 is methylphenyl
- R 2 is dichlorophenyl
- Ri is chosen from optionally substituted C 3-I2 cycloalkyl, optionally substituted C 4 -I 2 cycloalkenyl, optionally substituted -C(O)-C 3-12 cycloalkyl, optionally substituted -C(O)-C 4 .
- cycloalkenyl optionally substituted 5 to 12 member spiroheterocycloalkyl, and optionally substituted 8 to 12 member spiroheterocycloalkenyl; provided that the spiroheterocycloalkyl or spiroheterocycloalkenyl moiety comprises a cycloalkyl or cycloalkenyl moiety directly attached to position 5 of the compound of formula I.
- R 1 is chosen from optionally substituted C 3 . 12 cycloalkyl, optionally substituted C 4 12 cycloalkenyl, and optionally substituted 5 to 12 member spiroheterocycloalkyl provided that the spiroheterocycloalkyl moiety comprises a cycloalkyl moiety directly attached to position 5 of the compound of formula I.
- R 1 is chosen from optionally substituted C 3-I2 cycloalkyl, optionally substituted C 4 . 12 cycloalkenyl, and optionally substituted 9 to 12 member spiroheterocycloalkyl provided that the spiroheterocycloalkyl moiety comprises a cycloalkyl moiety directly attached to position 5 of the compound of formula I.
- R 1 is chosen from optionally substituted C 3 .12 cycloalkyl, optionally substituted C 4-12 cycloalkenyl, and optionally substituted 9 to 11 member spiroheterocycloalkyl provided that the spiroheterocycloalkyl moiety comprises a cycloalkyl moiety directly attached to position 5 of the compound of formula I.
- Ri is chosen from optionally substituted C3.12 cycloalkyl, and optionally substituted C 4 - 12 cycloalkenyl.
- Ri is C 3 -1 2 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by R 17 , or C4-12 cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, especially cyclohexenyl) which is unsubstituted or substituted one or more times by R17.
- cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl
- C4-12 cycloalkenyl e.g., cyclopentenyl, cyclohex
- Ri is chosen from optionally substituted C 3 - 10 cycloalkyl or optionally substituted C 4 . 10 cycloalkenyl.
- Ri is chosen from optionally substituted C 3 . 7 cycloalkyl or optionally substituted C4- 7 cycloalkenyl.
- Ri is C 5 -7 cycloalkyl or C 5 . 7 cycloalkenyl which are each unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 RcRd, CONR 13 R 14 , Ci -6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 7-12 aralkyl, C 6-12 aryl, Ci -6 alkyloxy, C 2 . 6 alkenyloxy, C 2 . 6 alkynyloxy, C 6 - 12 aryloxy, C(O)Ci_ 6 alkyl,
- R 12 , R c , R d , R 13 and R 14 are each independently chosen from H, C 1-12 alkyl, C 2 . 12 alkenyl, C 2 .
- R c and R d are taken together with the oxygens to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl
- Ri 3 and Ri 4 are taken together with the nitrogen to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- Ri is C 5 . 7 cycloalkyl or Cs- 7 cycloalkenyl which are each unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, CONR 13 R 14 , C 1 -6 alkyl, C 2 . 6 alkenyl, Ci- 6 alkyloxy, C 2 6 alkenyloxy, C(O)Ci . 6 alkyl,
- R 12 , R 13 and RH are each independently chosen from H, CM 2 alkyl, C 2 - 1 2 alkenyl, and C 2 -i 2 alkynyl.
- Ri is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl, cyclooctanyl, cyclocyclononanyl, cyclodecanyl, cycloundecanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclocyclononenyl, cyclodecenyl, cycloundecenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclodadienyl, cycloundecadienyl, bicyclohexyl, bicycloheptanyl, bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, bicyclounde
- R c and R d are taken together with the oxygens to form an optionally substituted 5 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl, or R 13 and R 14 are taken together with the nitrogen to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- R 1 is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl, cyclooctanyl, cyclocyclononanyl, cyclodecanyl, cycloundecanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclocyclononenyl cyclodecenyl, cycloundecenyl, Cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclodadienyl, cycloundecadienyl, bicyclohexyl, bicycloheptanyl, , bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, bicyclo
- Ri is chosen from cyclopentyl, cyclohexyl cycloheptyl, cyclooctanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, bicyclohexyl, bicycloheptanyl, bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, bicycloundecanyl, bicyclohexenyl, bicycloheptenyl, bicyclooctenyl, bicyclocyclononenyl, bicyclodecenyl, and bicycloundecenyl; each of which is unsubstituted or substituted by one or more substituent chosen from halogen, nitro,
- R 1 is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, bicyclohexyl, bicycloheptanyl, bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, bicycloundecanyl, bicyclohexenyl, bicycloheptenyl, bicyclooctenyl, bicyclocyclononenyl, bicyclodecenyl, and bicycloundecenyl; each optionally substituted.
- R 1 is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclohexyl, bicycloheptanyl, bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, and bicycloundecanyl; each of which is unsubstituted or substituted by one or more substituent chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONRi 3 Ru, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 6 alkynyl, C7.12 aralkyl, C 6 -u aryl, C 1-6 alkyloxy, C 2 -6 alkenyloxy, C 2 . 6 alkyny
- Ri is chosen from cyclopentyl, cyclohexyl cycloheptyl, cyclooctanyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclohexyl, bicycloheptanyl, bicyclootanyl, bicyclocyclononanyl, bicyclodecanyl, bicycloundecanyl; each optionally substituted.
- R 1 is chosen from optionally substituted cyclohexyl (e.g., substituted by Ri 7 ) and optionally substituted cyclohexenyl (e.g., substituted by Ri 7 ).
- the cycloalkenyl ring when Ri is cycloalkenyl, the cycloalkenyl ring preferably has one double bond. In addition, when Ri is cycloalkenyl, the cycloalkenyl ring preferably has one double bond which is between the carbons in positions 1 and 2 of the ring.
- R 3 is C1-12 alkyl (e.g., methyl, ethyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by R 17 , or C ⁇ -u aryl (e.g., phenyl or naphthyl, especially phenyl) which is unsubstituted or substituted one or more times by Ris;
- R 2 is C 3 - 12 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by Ri 7 , or C 6 - M aryl (e.g., phenyl or naphthyl, especially phenyl) which is unsubstituted or substituted one or more times by R 1S ; and
- Ri is C 3 - 12 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, especially cyclohexyl) unsubstituted or substituted one or more times by
- Ri 7 or C 4 - 12 cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, especially cyclohexenyl) which is unsubstituted or substituted one or more times by R 17 .
- cycloalkenyl e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, especially cyclohexenyl
- the compounds of the invention are selected from:
- a compound of formula (I) may be prepared by reacting a compound of formula (II):
- X is as defined above, for example, -NR 3 -CO-R 2 ,
- R 1 , R 2 and R 3 are as defined herein, Pg 1 is OH or a carboxyl protecting group, Hal is
- B 1 is a boronate such as .
- Pg 1 is methoxy.
- the Suzuki Coupling which is a palladium-catalyzed cross coupling between organoboronic acid and halides is well known in the art. Conditions for such coupling are described in the examples of the present application and in Suzuki et al. Chem. Rev. 1995, 95, 2457-2483.
- the term "carboxyl protecting group” is well known in the field of organic chemistry. Such protecting groups may be found in "Protective Groups in Organic Synthesis" second edition, Wiley-lnterscience publication, by T.W. Greene and P. G. M. Wuts.
- Example of carboxyl protecting groups include but are not limited to esters such as methyl ester, amides such as N,N-Dimethyl and hydrazides such as N- phenyl.
- a compound of formula (I) may be prepared by reacting a compound of formula:
- X is as defined above, for example, -NR 3 -CO-R 2 , R 1 , R 2 and R 3 are as defined herein, Pg 1 is OH or a carboxyl protecting group, n is an integer chosen between 0 and 2 and the compound of formula (Ilia) is optionally substituted by one or more R 17 .
- Pg 1 is methoxy, n is 1 and R 17 is H.
- the present invention provides a pharmaceutical composition comprising at least one compound according to the invention described herein and at least one pharmaceutically acceptable carrier or excipient.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound according to the invention described herein and at least one compound according to the invention described herein, and further comprising administering at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
- at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
- a combination comprising a least one compound according to the invention described herein and one or more additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
- additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
- the compound and additional agent are administered sequentially.
- the compound and additional agent are administered simultaneously.
- compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.
- the additional agents for the compositions and combinations include, for example, ribavirin, amantadine, merimepodib, Levovirin, Viramidine, and maxamine.
- Immunomodulatory agent as used herein means those agents that are effective to enhance or potentiate the immune system response in a mammal. Immunomodulatory agents include, for example, class I interferons (such as ⁇ -, ⁇ -, ⁇ - and ⁇ - interferons, ⁇ -interferons, consensus interferons and asialo-interferons), class Il interferons (such as ⁇ -interferons) and pegylated interferons.
- class I interferons such as ⁇ -, ⁇ -, ⁇ - and ⁇ - interferons, ⁇ -interferons, consensus interferons and asialo-interferons
- class Il interferons such as ⁇ -interferons
- pegylated interferons pegy
- class I interferon means an interferon selected from a group of interferons that all bind to receptor type 1. This includes both naturally and synthetically produced class I interferons. Examples of class I interferons include ⁇ -, ⁇ -, ⁇ - and ⁇ - interferons, ⁇ -interferons, consensus interferons and asialo-interferons.
- class Il interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type II. Examples of class Il interferons include ⁇ -interferons.
- viral serine protease inhibitor means an agent that is effective to inhibit the function of the viral serine protease including HCV serine protease in a mammal.
- Inhibitors of HCV serine protease include, for example, those compounds described in WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006039488 (Vertex), WO 2005077969 (Vertex), WO 2005035525 (Vertex), WO 2005028502 (vertex) WO 2005007681 (Vertex), WO 2004092162 (Vertex), WO 2004092161 (Vertex), WO 2003035060 (Vertex), of WO 03/087092 (
- inhibitors of HCV NS3 protease include BILN-2061 (Boehringer Ingelheim) SCH-6 and SCH-503034 (Schering-Plough), telaprevir( Vertex) and ITMN-B (InterMune) and GS9132 (Gilead).
- viral polymerase inhibitors as used herein means an agent that is effective to inhibit the function of a viral polymerase including an HCV polymerase in a mammal.
- Inhibitors of HCV polymerase include non-nucleosides, for example, those compounds described in:
- WO 03/010140 Boehringer Ingelheim
- WO 03/026587 Bristol Myers Squibb
- WO 02/100846 A1 WO 02/100851 A2
- WO 01 /85172 AI GSK
- WO 02/098424 A1 GSK
- WO 00/06529 Merck
- WO 02/06246 A1 Merck
- WO 01 /47883 Japan Tobacco
- WO 03/000254 Japan Tobacco
- EP 1 256 628 A2 Agouron
- inhibitors of HCV polymerase also include nucleoside analogs, for example, those compounds described in: WO 01 /90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), and WO 02/057287 A2 (Merck/ Isis) and WO 02/057425 A2 (Merck/lsis).
- inhibitors of an HCV polymerase include JTK-002/003 and JTK-109 (Japan Tobacco), HCV-796 (Viropharma) R1626/R1479 (Roche), R1656, (Roche-Pharmasset) and Valopicitabine (Idenix).
- ISIS-14803 ISIS Pharmaceuticals
- PTC therapeutics PTC therapeutics
- the additional agent is interferon ⁇ , ribavirin, silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
- the additional agent is interferon ⁇ 1A, interferon ⁇ 1 B, interferon ⁇ 2A, or interferon ⁇ 2B.
- viral serine protease inhibitor is a flaviviridae serine protease inhibitor.
- viral polymerase inhibitor is a flaviviridae polymerase inhibitor.
- viral helicase inhibitor is a flaviviridae helicase inhibitor.
- viral serine protease inhibitor is HCV serine protease inhibitor
- viral polymerase inhibitor is HCV polymerase inhibitor
- viral helicase inhibitor is HCV helicase inhibitor.
- the present invention provides 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 according to formula I.
- the viral infection is chosen from Flavivirus infections.
- the Flavivirus infection is Hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), hog cholera virus, dengue fever virus, Japanese encephalitis virus or yellow fever virus.
- HCV Hepatitis C virus
- BVDV bovine viral diarrhea virus
- hog cholera virus dengue fever virus
- Japanese encephalitis virus yellow fever virus.
- the Flaviviridea viral infection is hepatitis C viral infection (HCV).
- the present invention provides 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 according to the invention described herein, and further comprising administering at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
- IFS internal ribosome entry site
- a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound according to the invention described herein and further comprising administering one or more viral polymerase inhibitors.
- viral polymerase is a Raviviridae viral polymerase.
- viral polymerase is a RNA-dependant RNA-polymerase.
- viral polymerase is HCV polymerase.
- compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.
- the individual components for use in the method of the present invention or combinations of the present invention may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
- the present invention provides the use of a compound according to the invention described herein for treating or preventing Flaviviridae viral infection in a host.
- the present invention provides the use of a compound according to the invention described herein for the manufacture of a medicament for treating or preventing a viral Flaviridea infection in a host. In one embodiment, the present invention provides the use of a compound according to the invention described herein for inhibiting or reducing the activity of viral polymerase in a host.
- stereoisomers for example, optical (+ and -), geometrical (cis and trans) and conformational isomers (axial and equatorial). All such stereoisomers are included in the scope of the present invention.
- the compounds in accordance with the present invention can contain a chiral center.
- the compounds of formula may 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 the present invention are provided in the form of a single enantiomer at least 95%, at least 97% and 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.
- the compounds of the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer. In a further embodiment 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.
- pharmaceutically acceptable salts of the compounds 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 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 amino acids are also included (e.g. L-arginine, L-Lysine).
- Salts derived from appropriate bases include alkali metals (e.g. calcium, sodium, lithium, potassium), alkaline earth metals (e.g. magnesium), ammonium, NR4+
- alkali metals e.g. calcium, sodium, lithium, potassium
- alkaline earth metals e.g. magnesium
- ammonium NR4+
- a reference hereinafter to a compound according to the invention includes that compound and its pharmaceutically acceptable salts.
- the pharmaceutically acceptable salt is a sodium salt.
- the pharmaceutically acceptable salt is a lithium salt. In one embodiment of the invention, the pharmaceutically acceptable salt is a potassium salt.
- polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
- a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
- Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
- the compounds in accordance with the present invention can exist in different solvate forms, for example hydrates.
- Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
- alkyl represents a linear, branched or cyclic hydrocarbon moiety.
- alkenyl and alkynyl represent a linear, branched or cyclic hydrocarbon moiety which has one or more double bonds or triple bonds in the chain.
- alkyl, alkenyl, and alkynyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl
- alkyl alkenyl
- alkynyl can be optionally substituted such as in the case of haloalkyls in which one or more hydrogen atom is replaced by a halogen, e.g., an alkylhalide.
- haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl, chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl.
- cycloalkyl and “cycloalkenyl” represent a cyclic hydrocarbon alkyl or alkenyl, respectively, and are meant to include monocyclic (e.g., cyclohexyl), spiro (e.g., spiro [2.3]hexanyl), fused (e.g., bicyclo[4.4.0]decanyl), and bridged (e.g., bicyclo[2.2.1]heptanyl) hydrocarbon moieties.
- monocyclic e.g., cyclohexyl
- spiro e.g., spiro [2.3]hexanyl
- fused e.g., bicyclo[4.4.0]decanyl
- bridged e.g., bicyclo[2.2.1]heptanyl
- alkoxy represents an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to the adjacent atom through an oxygen atom.
- alkenyl and alkynyl groups where indicated the alkoxy, alkenyloxy and alkynyloxy groups can also be optionally substituted.
- Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy.
- aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic), and which where indicated may be optionally substituted with one or more substituents.
- Examples include but are not limited to phenyl, tolyl, dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl.
- the aryl groups can be optionally substituted by, for example, halogens, -NRdRe, - CONR d R e , -NR d CORe, carboxy, azido, cyano, hydroxyl, nitro, nitroso, -N(Rh)CONR 1 Rj, C 1 ⁇ alkyl, C 2 . 6 alkenyl, C 2 .
- R 3 -Rj are each independently H, C 1 ⁇ alkyl, C 2-4 alkenyl or C 2 . 4 alkynyl.
- aralkyl represents an aryl group attached to the adjacent atom by an alkyl, alkenyl or alkynyl. Like the aryl groups, where indicated the aralkyl groups can also be optionally substituted. Examples include but are not limited to benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, A- phenylbutyl and naphthylmethyl.
- heterocycle represents an optionally substituted, non aromatic, saturated or partially saturated wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). Heterocycles may be monocyclic or polycyclic rings.
- Examples include but are not limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidyl, piperidino, cyclopentapyrazolyl, cyclopentaoxazinyl, cyclopentafuranyl.
- heterocycle-alkyl represents an optionally substituted heterocycle group attached to the adjacent atom by an alkyl, alkenyl or alkynyl group. It is understood that in a 5-18 member heterocycle-alkyl moiety, the 5-18 member represent the atoms that are present in both the heterocycle moiety and the alkyl, alkenyl or alkynyl group. For example, the following groups are encompassed by a 7 member heterocycle-alkyl ( * represents the attachment point):
- heterocycle-alkyl groups can be optionally substituted by, for example, halogens, oxo, -NR d R e , -CONR d R e , -NR d COR e , carboxy, - hydroxyl, nitro, nitroso, - N(Rh)CONR 1 Rj, C1-6 alkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, Ci- 6 alkyloxy, C 2 .
- heteroaryl represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N). Heteroaryls may be monocyclic or polycyclic rings.
- Examples include but are not limited to azepinyl, aziridinyl, azetyl, diazepinyl, dithiadiazinyl, dioxazepinyl, dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, pyranyl, pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolyl, imidazothiazoly
- heteroaralkyl represents an optionally substituted heteroaryl group attached to the adjacent atom by an alkyl, alkenyl or alkynyl group.
- Halogen atom is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
- C 6 -I 2 aryl and C7-12 aralkyl, or R f and R g are taken together with the nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- the term "amido" represents -CONR d R e and -NR d COR e , wherein R d and R e are each independently selected from H, C M0 alkyl, C2- 10 alkenyl, C 2- io alkynyl, C 6 -i 2 aryl and C 7 . 12 aralkyl, or R d and R e are taken together with the nitrogen to which they are attached (or the nitrogen atom and CO group in the case of -NR d COR e ) to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- amino represents a derivative of ammonia obtained by substituting one or more hydrogen atom and includes -NR d R e , wherein R d and R e are each independently selected from H, C 1-I o alkyl, C 2- io alkenyl, C 2 -io alkynyl, C ⁇ -1 2 aryl and C 7 -I 2 aralkyl, or R d and R e are taken together with the nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- sulfonamido represents SO 2 NR d R e , and -NRdSO 2 R e , wherein R d and
- R e are each independently selected from H, C H0 alkyl, CM O alkenyl, C 2 . 10 alkynyl, C 6 -I 2 aryl and C7- 1 2 aralkyl, or R d and R e are taken together with the nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl.
- the sulfur atom can be at different oxidation levels, i.e., S, SO, or SO 2 . All such oxidation levels are within the scope of the present invention.
- a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, 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, about 2 to 50 ⁇ M, 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.
- 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.
- compositions comprising compounds of the present invention 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 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.
- 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.
- AU 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.
- compositions 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 and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization 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.
- 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.
- compositions 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 for example 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.
- compositions 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, solubilizing 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 5-bromo-3-[(1 ⁇ -dioxa-spiro ⁇ . ⁇ Jdec- ⁇ -yO ⁇ trans ⁇ -methylcyclohexane- carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (8.6g, 17 mmol) was dissolved in tetrahydrofuran (100 ml) and treated with 3N HCl solution (50 ml). The reaction was stirred at 4O 0 C for 3 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and wash with aq. sat. NaHCOj solution.
- reaction mixture was recuperated with water (25 ml) and extracted with EtOAC.
- organic phases were combined and dried over MgSO 4 and concentrated to dryness.
- the residue was purified by silica gel column chromatography using EtOAc:hexanes as eluent to obtain 5-Bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl- cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (4.5 g, 77% yield) as a solid.
- the white solid was filtered and washed with toluene.
- the filtrate was washed with 10 % citric acid, aq. NaHC ⁇ 3 , dried (Na 2 SO 4 ) and concentrated.
- the solid was purified by silica gel column chromatography using 20% EtOAc:hexane as eluent to obtain 3-[(1 ,4-dioxa-spiro[4.5]dec-8-yl)-(tr ⁇ ns-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.3 g, 68%).
- Step III Diisopropylamine (5.75 g, 56.8 mmol) and dry THF (58 ml.) were added to a dry 500 mL 3 neck round bottom flask under nitrogen. The solution was cooled to -40 0 C and nBuLi (39 mL, 47.4 mmol) was added slowly while keeping the internal temperature at -40 0 C.
- Step VII To a solution of 5-(4,4-dimethylcyclohex-1 -enyl)-3-[(trans-4-methoxy-cyclo-hexyl)- (4-trans-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (950 mg, 1.89 mmol) in methanol (25 mL) was added 10% palladium on charcoal (100 mg). The resulting reaction mixture was placed under H 2 atmosphere, stirred at room temperature for 20 h, and then filtered through a pad of celite.
- the reaction mixture was stirred at 70 0 C for 5h.
- the mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc.
- the EtOAc layer was dried over Na 2 SO 4 .
- Step I To a solution of 5-cyclohex-1 -enyl-3-[(trans-4-methylcyclohexanecarbonyl)- piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) in dichloromethane (3 ml_) was added triethylamine (3 mL) and isobutyryl chloride (28 ⁇ l_, 0.27 mmol). The reaction mixture was stirred at room temperature for 12h and then quenched with a saturated solution of NaHCCh. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated.
- trans-4-Methylcyclohexyl carboxylic acid chloride was added to a solution of 5- cyclohex-1 -enyl-3-[(3-oxo-octahydro-indolizin-7-yl)-amino]-thiophene-2-carboxylic acid methyl ester (698 mg, 1.86 mmol) and pyridine (166 ⁇ l_, 2.05 mmol) in dry toluene (8 ml_). The mixture was refluxed for 16 h, then it was brought to room temperature, additional amount of pyridine (0.2 ml_) and MeOH (1 mL) were added.
- step I Using essentially the same procedure described above the following compounds can be prepared utilizing other ketones in step I:
- the methyl ester from Step I (285 mg, 0.54 mmol) was dissolved in a 4:2:1 mixture of THF: H 2 O: methanol (7 mL), LiOH. H 2 O (225 mg, 5.36 mmol) was added to solution, and it was heated in a microwave oven at 12O 0 C for 5 min, then for an additional 5 min at 13O 0 C.
- the reaction mixture was diluted with CH 2 Cl 2 , acidified with 2N HCl, washed with brine, and organic fraction was dried over Na 2 SO 4 and evaporated to dryness.
- Step I To a solution of lithium 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4- methylcyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (498 mg, 1.10 mmol) and 1 ,4-dioxaspiro[4,5]dec-7-en-8-boronic acid (412 mg, 1.55 mmol) in DMF (6 ml_) was added 2M solution of Na 2 CO 3 (3 ml_), and the mixture was deoxygenated by bubbling nitrogen through solution for 10 min. Then Pd(PPh 3 ) 4 was added to the mixture, and it was refluxed under nitrogen for 2 h.
- Step III The product from Step Il (38 mg, 0.09 mmol) was hydrolysed with lithium hydroxide as previously described (example 3, step VIII) to give 32 mg (89%) of 5-cyclohex-1 - enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-phenyl-amino]-thiophene-2-carboxylic acid.
- step Il The product from step Il (922 mg, 1.77 mmol) was treated with methyl iodide (2.21 ml_, 35.48 mmol) and 60% oil suspension of sodium hydride (142 mg, 3.54 mmol) using procedure described in step I of example 4 to afford 1.143 g (100%) of crude 5-(1 ,4- dioxa-spiro[4.5]dec-8-yl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl- cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
- step III The product of step III was dissolved in THF (40 mL), 3N HCl (20 ml_) was added to this solution, and the mixture was heated for 3 h at 5O 0 C, then for an additional 3 h at 6O 0 C.
- the mixture was brought to room temperature, extracted with CH2CI2, washed with sodium bicarbonate and brine, organic fraction was separated, dried over Na 2 SO 4 , and concentrated under reduced pressure.
- step IV The product from step IV (61 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after column purification on silica gel (CH 2 Cl 2 -MeOH) 23 mg (39%) of 3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-5-(4-oxocyclohexyl)-thiophene-2-carboxylic acid.
- step I The product from step I (584 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after preparative HPLC separation 270 mg of 5-(4,4-difluoro-cyclohexyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4- methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid and 55 mg of RS-5- (4-fluoro-cyclohex-3-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
- step I The product from step I (30 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after column purification on silica gel (CH 2 Cl 2 -MeOH) 16 mg (57%) of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
- step III The product from step I (30 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after column purification on silica gel (CH 2 Cl 2 -MeOH) 16 mg (57%) of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
- Step I To a solution of 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (269 mg, 0.59 mmol) in dry DMF (2 mL) was added iodoethane (279 ⁇ l_, 2.95 mmol), the mixture was cooled to O 0 C, and NaH (60% suspension in oil, 47 mg, 1.17 mmol) was added in portions over 5 min. The mixture was stirred at O 0 C for 3h, and it was quenched by addition of water and acidified with 2N HCl.
- step I The product of step I (277 mg) was reacted with cyclohexene boronic acid (91 mg, 0.72 mmol) to give 173 mg (63%) of 5-bromo-3-[(trans-4-ethoxy-cyclohexyl)-(trans-4- methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid ethyl ester.
- Step I To a solution of 5-cyclohex-1 -enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1 - methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid (10 mg, 0.02 mmol) in 0.5 mL of dry dichloromethane at O 0 C (ice bath) under nitrogen was added methyl iodide (3.1 mg, 0.02 mmol). The mixture was stirred for 15 min at O 0 C and 150 min at room temperature.
- Step I To a solution of 5-cyclohex-1 -enyl-3-[(4-methyl-cyclohexanecarbonyl)-(1 -methyl- piperidin-4-yl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.27 mmol) in 5.0 mL of dry dimethylformamide under nitrogen was added cesium carbonate (351 mg, 1.08 mmol) and 2,2-dimethyl-propionic acid chloromethyl ester (45 mg, 0.297 mmol). The mixture was stirred for 120 min at 6O 0 C. The mixture was partitioned between ethyl acetate and water.
- Step I was followed from Example 3, step VIII.
- Step 1
- the resulting dirty green mixture was stirred at 21 0 C for 64h.
- the dirty green opaque reaction mixture was stripped off solvent and the residue taken into EtOAc and washed with water, brine dried (Na 2 SO 4 ) and evaporated to a gum (136 mg).
- Step I A suspension of S-amino-S-bromo-thiophene ⁇ -carboxylic acid methyl ester (0.5 g, 2.12 mmol) in dry THF (0.6 ml_) was treated with 2,2-dimethyl-[1 ,3]dioxan-5-one (253 ⁇ l, 2.12 mmol), followed by dibutyltin dichloride (32 mg, 0.11 mmol). After 5 min phenyl silane (280 ⁇ l, 2.27 mmol) was added and the reaction was stirred at room temperature for 3 days. It was dissolved in ethyl acetate (100 ml_), washed with NaHCCb solution and brine.
- Oxalyl chloride (2M in DCM, 2.7 ml.) was added dropwise to a suspension of the trans-4-methyl cyclohexyl carboxylic acid (365 mg, 2.57 mmol) in DCM and a drop of DMF. The mixture was stirred at room temperature for 3 h and evaporated. Hexane (4 mL) was added and the mixture was evaporated. This was repeated once more. The residue was diluted with dry toluene (2.3 mL) (total volume became 2.7 mL) and used for the next step.
- Step III A mixture of 5-bromo-3-[(2,2-dimethyl-[1 ,3]dioxan-5-yl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (35 mg) contaminated with a small impurity in THF (1.1 ml_) and 3N HCl (0.75 ml.) was stirred at room temperature for 16 h. It was neutralized with solid NaHCO 3 and evaporated down to dryness. The residue was triturated with ethyl acetate (3 x 8 mL).
- Step V Nitrogen was bubbled through a solution of 5-bromo-3-[[1 ,3]dioxan-5-yl-(trans-4- methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol) containing cyclohexen-1 -ylboronic acid (8 mg, 0.063 mmol) in 2M aqueous Na 2 CO 3 (0.9 mL) and DME (1.8 mL) for 10 min. Pd(PPh 3 )., (3mg) was added and the mixture was refluxed for 1 h 10 min.
- Step Vl Crude 5-cyclohex-1 -enyl-3-[[1 ,3]dioxan-5-yl-(trans-4-methyl-cyclohexane- carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) was dissolved in a mixture of THF, MeOH and H 2 O (3:2:1 ) (1.8 ml_) and 1 N LiOH (0.15 mL) was added. Rest of the procedure has been described earlier (example 3, step VIII).
- 5-Cyclohex-1 -enyl-3-[(4,4-difluoro-cyclohexyi)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (compound #91 ) can be prepared from 5-Bromo-3-[(trans-4-methyl-cydohexanecarbonyl)-(4-oxo-cyclohexyl)- amino] -thiophene-2-carboxylic acid methyl ester using synthetic steps described in example 39.
- Step III A solution of 5-(1 -hydroxy-cyclohex-2-enyl)-3- ⁇ (trans-4-methyl- cydohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino ⁇ - thiophene-2-carboxylic acid methyl ester (48mg, 0.086 mmol) in DCM (1 mL) was cooled to -5O 0 C. Triethylsilane (43 ⁇ l, 0.27 mmol) was added followed by gradual addition of trifluoroacetic acid (total 22 ⁇ l, 0.28 mmol) (4 ⁇ l to 6 ⁇ l every 30 min).
- step VIII pure 5-(3-Hydroxy-cyclohex-1- enyl)-3- ⁇ (trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)- cyclohexyl]-amino ⁇ -thiophene-2-carboxylic acid (10 mg, 46%) was obtained by chromatography over silica gel.
- 3-Bromo-5-(4,4-dimethyl-cyclohex-1 -enyl)-thiophene-2-carboxylic acid methyl ester was prepared from 3-bromo-thiophene-2-carboxylic acid methyl ester following a procedure described earlier (example 3, steps III and IV).
- Step II Nitrogen was bubbled through a mixture of 2-triisopropylsilanyloxy-1 - triisopropylsilanyloxymethyl-ethylamine (prepared from serinol using triisopropylsilyl chloride) (420 mg, 1.04 mmol) and 3-bromo-5-(4,4-dimethyl-cyclohex-1 -enyl)- thiophene-2-carboxylic acid methyl ester (350 mg, 1.06 mmol) in dioxane (3.5 mL) containing CS 2 CO 3 (1 g, 3.07 mmol) and Pd 2 (dba) 3 (96 mg, 0.1 mmol) for 6 min.
- 2-triisopropylsilanyloxy-1 - triisopropylsilanyloxymethyl-ethylamine prepared from serinol using triisopropylsilyl chloride
- Step IV To a solution of 5-Cyclohex-2-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl- cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (12mg, 0.026 mmol) in a mixture of THF:MeOH:H 2 O (3:2:1 )(1.6 mL) was added 1N LiOH (0.1 mL). The mixture was stirred at 5O 0 C for 4.5 h. The mixture was concentrated and dissolved in water. It was transferred to a separatory funnel. Ethyl acetate was added followed by addition of 0.1 N HCl (1 mL).
- the final compound was purified by HPLC preparative to afford 5-cyclohex-1 -enyl-3-[(trans-4-methyl- cyclohexanecarbonyl))-(cis-4-[1 ,2,4]triazol-1 -yl-cyclohexyl)-amino]-thiophene-2- carboxylic acid hydrochloride (92 mg, 18%) and 5-cyclohex-1 -enyl-3-[(trans-4-methyl- cyclohexanecarbonyl))-(trans-4-[1 ,2,4]triazol-1 -yl-cyclohexyl)-amino]-thiophene-2- carboxylic acid hydrochloride (141 mg, 26%) both as white solid.
- Step 1
- step Il The crude material obtained in step Il was diluted in 6 mL of a 3:2:1 solution of THF, methanol, water. It was treated by lithium hydroxide monohydrate (48 mg, 1.1 mmol). The resulting mixture was stirred 3h at 50 0 C. It was then acidified with 1 N HCl aqueous, concentrated and purified by HPLC preparative to afford 5-cyclohex-1 - enyl-3-[(trans-4-methyl-cyclohexanecarbonyl))-cis-(2-methyl-3-oxo-2-aza- spiro[4.5]dec-8-yl)-amino]-thiophene-2 ⁇ arboxylic (24 mg, 16%) as a white solid.
- Step 1
- Step I and step Il were performed as described before (example 1 , step I and using AM-Boc-aminocyclohexanone as intermediate
- step IV The crude material obtained in step IV was diluted in 4.3 mL of a 3:2:1 solution of THF, methanol, water. It was treated by lithium hydroxide monohydrate (37 mg, 0.87 mmol). The resulting mixture was stirred 24h at room temperature.
- Methanesulfonic acid 1 ,4-dioxa-spiro[4.5]dec-8-yl ester was prepared according to: Cheng, Chen Yu; Wu, Shou Chien; Hsin, Ling Wei; Tarn, S. William. Coll. Med., Natl. Taiwan Univ., Taipei, Taiwan. Journal of Medicinal Chemistry (1992), 35(12), 2243- 7.
- the solid was purified by silica gel column chromatography using a gradient from 100% EtOAc to 5% MeOH: EtOAc as eluent to furnished the final compound 1 -(1 ,4-dioxa-spiro[4.5]dec-8-yl)-1 H-[1 ,2,4]triazole as a white solid (247 mg, 49%).
- Step I A suspension of 1 ,4-dioxa-spiro[4.5]decan-8-one (10.0 g, 64.0 mmol) in 64 ml_ of methanol was treated with a solution of ammonium carbonate (18.4 g, 192 mmol) in 64 ml_ of water. Potassium cyanide (6.14 g, 96.0 mmol) was added and the mixture was stirred at 65 0 C for 18h. It was cooled to room temperature and a precipitate was formed. The precipitate was collected by filtration to give a white solid and the filtrate was extracted with ethyl acetate. The portion of ethyl acetate was concentrated to afford also a white solid. Both solids were combined to afford 9,12- dioxa-1 ,3-diaza-dispiro[4.2.4.2]tetradecane-2,4-dione (9.80 g g, 68%)
- io 1 ,4-Dioxa-spiro[4.5]decane-8-carbonitrile was prepared according to: Becker, Daniel P.; Flynn, Daniel L. Gastrointest. Dis. Res. Dep., Searle Res. Dev., Skokie, IL, USA. Synthesis (1992), (11), 1080-2.
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Also Published As
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CN101218224A (en) | 2008-07-09 |
HK1112910A1 (en) | 2008-09-19 |
US20060276533A1 (en) | 2006-12-07 |
CN102718744A (en) | 2012-10-10 |
CA2607359C (en) | 2011-08-09 |
EA200702493A1 (en) | 2008-04-28 |
AU2006246227B2 (en) | 2011-04-28 |
KR20080016597A (en) | 2008-02-21 |
EP2546246A2 (en) | 2013-01-16 |
SG161315A1 (en) | 2010-05-27 |
NZ563909A (en) | 2011-10-28 |
US20100093775A1 (en) | 2010-04-15 |
US8674118B2 (en) | 2014-03-18 |
EA016071B1 (en) | 2012-01-30 |
AU2006246227A1 (en) | 2006-11-16 |
JP2008540463A (en) | 2008-11-20 |
CA2607359A1 (en) | 2006-11-16 |
US7569600B2 (en) | 2009-08-04 |
ES2415742T3 (en) | 2013-07-26 |
EP1879879A4 (en) | 2010-03-10 |
EP2543664A1 (en) | 2013-01-09 |
EP2546246A3 (en) | 2013-04-24 |
MX2007014117A (en) | 2008-02-05 |
ZA200709727B (en) | 2008-11-26 |
JP5030947B2 (en) | 2012-09-19 |
US20120164103A1 (en) | 2012-06-28 |
AP2007004245A0 (en) | 2007-12-31 |
CN101218224B (en) | 2013-05-08 |
EP1879879B1 (en) | 2013-03-27 |
US8158675B2 (en) | 2012-04-17 |
BRPI0610283A2 (en) | 2010-10-19 |
EP1879879A1 (en) | 2008-01-23 |
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