Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero 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
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present disclosure is generally directed to antiviral compounds, and specifically directed to compounds which can inhibit the function of the NS5 A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein.
• HCV Hepatitis C virus
• HCV BACKGROUND OF THE DISCLOSURE HCV is a major human pathogen, infecting an estimated 170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.
• HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
• this polyprotein In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non- structural (NS) proteins.
• NS structural and non- structural
• HCV the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
• the first one is believed to be a metalloprotease and cleaves at the NS2- NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
• the NS4A protein appears to serve multiple functions by both acting as a cofactor for the NS3 protease and assisting in the membrane localization of NS3 and other viral replicase components.
• NS3-NS4A complex The formation of a NS3-NS4A complex is necessary for proper protease activity resulting in increased proteolytic efficiency of the cleavage events.
• the NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities.
• NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV with other HCV proteins, including NS5A, in a replicase complex.
• HCV NS5A protein is described, for example, in the following references: S. L. Tan, et al., Virology, 284: 1-12 (2001); K.-J. Park, et al, J. Biol. Chem., 30711-30718 (2003); T. L. Tellinghuisen, et al, Nature, 435, 374 (2005); R. A. Love, et al, J. Virol, 83, 4395 (2009); N. Appel, et al, J. Biol. Chem., 281, 9833 (2006); L. Huang, J. Biol. Chem., 280, 36417 (2005); C. Rice, et al, WO2006093867.
• X is hydrogen (H) or halogen and Z is hydrogen;
• X and Z together with the carbon atoms to which they are attached, form a five- to eight-membered aromatic or non-aromatic fused ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered ring is optionally substituted with one, two, or three substitutents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, carboxy, formyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR a R b , ( R a R b )alkyl, ( R a R b )carbonyl, oxo, and spirocycle;
• X' is hydrogen (H) or halogen and Z' is hydrogen;
• X' and Z' together with the carbon atoms to which they are attached, form a five- to eight-membered aromatic or non-aromatic fused ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered ring is optionally substituted with one, two, or three substitutents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, carboxy, formyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR a R b , ( R a R b )alkyl, ( R a R b )carbonyl, oxo, and spirocycle;
• Y and Y' are each independently -CH 2 -, -CH2CH2-, or -CH2O-, wherein the
• R p is hydrogen or Ci to C 4 alkyl
• R q is hydrogen, alkyl, or halo
• R p and R q together with the carbon atoms to which they are attached, form a cycloalkyl ring
• R v is selected from hydrogen, alkyl, halo, and hydroxy
• R v and R q together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring;
• R p ' is hydrogen or Ci to C 4 alkyl
• R q ' is hydrogen, alkyl, or halo
• R p ' and R q ' together with the carbon atoms to which they are attached, form a cycloalkyl ring
• R v are independently selected from hydrogen, alkyl, halo, and hydroxy; or R v and R q , together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring;
• R w and R w are independently selected from hydrogen and alkyl
• R 1 is hydrogen or -C(0)R x ;
• R 2 is hydrogen or -C(0)R y ;
• R x and R y are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy, and alkyl, said alkyl being substituted by one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, -OR 3 , -C(0)OR 4 , -NR a R b , and -C(0)NR c R d ,
• any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkenyl, alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, -C(0)OR 4 , -OR 5 , -NR a R b , ( R a R b )alkyl, and (MeO)(HO)P(0)0-, and
• any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, -NR a R b , oxo, and -C(0)OR 4 ;
• R 3 is hydrogen, alkyl, or arylalkyl
• R 4 is alkyl or arylalkyl
• R 5 is hydrogen, alkyl, or arylalkyl
• R a and R b are independently selected from hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, -C(0)R 6 , -C(0)OR 7 , -C(0)NR c R d , and (NR c R d )alkyl, or alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a five- or six-membered ring or bridged bicyclic ring structure, wherein said five- or six-membered ring or bridged bicyclic ring structure optionally may contain one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and may contain one, two, or three substituents independently selected from Ci to Ce alkyl, Ci to C 4 haloalkyl, aryl, hydroxyl, Ci to Ce alkoxy, Ci to C 4 haloalkoxy, and halogen;
• R 6 is alkyl
• R 7 is alkyl, arylalkyl, cycloalkyl, or haloalkyl
• R c and R d are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.
• X is hydrogen or chloro (CI) and Z is hydrogen;
• X' is hydrogen or chloro (CI) and Z' is hydrogen; or
• Y is -CH 2 -, -CH2CH2-, or -CH2O-, wherein the -CH 2 0- is drawn such that the oxygen atom is bound to the carbon atom substituted with R v and R q ;
• R p is hydrogen or Ci to C 4 alkyl
• R q is hydrogen, alkyl, or halo
• R v is selected from hydrogen, alkyl, halo, and hydroxy
• R v and R q together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring.
• the present disclosure provides a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein:
• R 1 is -C(0)R x ;
• R 2 is -C(0)R y ;
• R x and R y are independently alkyl substituted by at least one -NR a R b , characterized by Formula (A):
• n 0 or 1 ;
• R 8 is hydrogen or alkyl
• R 9 is selected from hydrogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, and alkyl optionally substituted with a substituent selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, heterobicyclyl, -OR 3 , -C(0)OR 4 , -NR a R b , and -C(0)NR c R d , wherein any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, -C(0)OR 4 , -OR 5 , -NR a R b , ( R a R b )alkyl, and (MeO)(HO)P(0)0-, and
• any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, -NR a R b , oxo, and -C(0)OR 4 ; and
• R 3 , R 4 , R 5 , R a , R b , R c , and R d are defined as in Formula (I).
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein m is 0;
• R 8 is hydrogen or Ci to C 4 alkyl
• R 9 is selected from hydrogen, Ci to Ce alkyl optionally substituted with - OR 12 , C 3 to C 6 cycloalkyl, allyl, -CH 2 C(0)NR c R d , ( R c R d )alkyl,
• j is 0 or 1 ;
• k is 1, 2, or 3;
• n is 0 or an integer selected from 1 through 4;
• each R 10 is independently hydrogen, Ci to C 4 alkyl, Ci to C 4 haloalkyl, halogen, nitro, -OBn, or (MeO)(OH)P(0)0-;
• R 11 is hydrogen, Ci to C 4 alkyl, or benzyl
• R 12 is hydrogen, Ci to C 4 alkyl, or benzyl
• R a is hydrogen or Ci to C 4 alkyl
• R b is Ci to C 4 alkyl, C3 to Ce cycloalkyl, benzyl, 3-pyridyl, pyrimidin-5-yl, acetyl, -C(0)OR 7 , or -C(0)NR c R d ;
• R 7 is Ci to C 4 alkyl or Ci to C 4 haloalkyl
• R c is hydrogen or Ci to C 4 alkyl
• R d is hydrogen, Ci to C 4 alkyl, or C3 to Ce cycloalkyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein m is 0; R 8 is hydrogen;
• R 9 is phenyl optionally substituted with one up to five substituents independently selected from Ci to Ce alkyl, Ci to C 4 haloalkyl, halogen, Ci to alkoxy, hydroxyl, cyano, and nitro; and
• NR a R b is a heterocyclyl or heterobicyclyl group selected from:
• n 0, 1
• each R 13 is independently selected from Ci to Ce alkyl, phenyl,
• R 14 is Ci to C 6 alkyl, phenyl, benzyl, or -C(0)OR 15 group, wherein R 15 is Ci to C 4 alkyl, phenyl, or benzyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein m is 1 ;
• R 8 is hydrogen
• R 9 is Ci to e alkyl, arylalkyl, or heteroarylalkyl
• R a is hydrogen
• R b is -C(0)OR 7 , wherein R 7 is Ci to C 6 alkyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(0)R x ;
• R 2 is -C(0)R y ;
• R x and R y are heteroaryl or heterocyclyl independently selected from:
• n is 0 or an integer selected from 1 through 4;
• each R 13 is independently selected from hydrogen, Ci to Ce alkyl, Ci to C 4 haloalkyl, phenyl, benzyl, Ci to Ce alkoxy, Ci to C 4 haloalkoxy, heterocyclyl, halogen, NR c R d , hydroxyl, cyano, and oxo, where R c and R d are independently hydrogen or Ci to C 4 alkyl; and
• R 14 is hydrogen (H), Ci to C 6 alkyl, benzyl, or -C(0)OR 4 , wherein R 4 is Ci to C 6 alkyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(0)R x ;
• R 2 is -C(0)R y ;
• R x and R y are cycloalkyl independently selected from: ( Rl3 )n _ NR a R b
• j 0, 1, 2, or 3;
• k 0, 1 , or 2;
• n is 0 or an integer selected from 1 through 4;
• each R 13 is independently selected from hydrogen, Ci to Ce alkyl, Ci to C 4 haloalkyl, Ci to Ce alkoxy, halogen, hydroxyl, cyano, and nitro;
• R a and R b are each independently hydrogen, Ci to Ce alkyl, or -C(0)OR , wherein R 7 is Ci to Ce alkyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(0)R x ;
• R 2 is -C(0)R y ;
• R x and R y are independently arylalkyl, wherein aryl part of said arylalkyl may optionally be substituted with (NR a R b )alkyl;
• R a and R b are independently hydrogen, Ci to Ce alkyl, or benzyl, or alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a five- or six-membered ring selected from
• R 15 is hydrogen, Ci to C(, alkyl, or benzyl.
• the present disclosure provides a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein 1 and R 2 are the same and are selected from the group consisting of:
• a squiggle bond ( ⁇ > ⁇ ) in the structure indicates that a stereogenic center to which the bond is attached can take either (R)- or (S)- configuration so long as chemical bonding principles are not violated.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(0)R x ;
• R 2 is -C(0)R y ;
• R x and R y are both t-butoxy.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
• R 1 and R 2 are both hydrogen.
• X and X' are independently hydrogen (H) or halogen
• R p is hydrogen or Ci to C 4 alkyl
• R q is hydrogen, or alternatively, R p and R q , together with the carbon atoms to which they are attached, form a cyclopropyl ring
• R p ' is hydrogen or Ci to C 4 alkyl
• R q ' is hydrogen, or alternatively, R p ' and R q ', together with the carbon atoms to which they are attached, form a cyclopropyl ring
• R 1 is hydrogen or -C(0)R x ;
• R 2 is hydrogen or -C(0)R y ;
• R x and R y are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy, and alkyl, said alkyl being substituted by one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, -OR 3 , -C(0)OR 4 , -NR a R b , and -C(0)NR c R d ,
• any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, -C(0)OR 4 , -OR 5 , -NR a R b , ( R a R b )alkyl, and (MeO)(HO)P(0)0-, and
• any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, -NR a R b , oxo, and
• R 3 is hydrogen, alkyl, or arylalkyl
• R 4 is alkyl or arylalkyl
• R 5 is hydrogen, alkyl, or arylalkyl
• R a and R b are independently selected from hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, -C(0)R 6 , -C(0)OR 7 , -C(0)NR c R d , and (NR c R d )alkyl, or alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a five- or six-membered ring or bridged bicyclic ring structure, wherein said five- or six-membered ring or bridged bicyclic ring structure optionally may contain one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and may contain one, two, or three substituents independently selected from Ci to Ce alkyl, Ci to C 4 haloalkyl, aryl, hydroxyl, Ci to Ce alkoxy, Ci to C 4 haloalkoxy, and halogen;
• R 6 is alkyl
• R 7 is alkyl, arylalkyl, or haloalkyl
• R c and R d are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.
• the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Formula (I) is defined according to any of the embodiments described above in the first aspect of the present disclosure.
• composition further comprises at least one additional compound having anti-HCV activity.
• At least one of the additional compounds is an interferon or a ribavirin.
• the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
• the present disclosure provides a composition
• a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one additional compound having anti-HCV activity, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
• the present disclosure provides a composition
• a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one additional compound having anti-HCV activity, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
• a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
• the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) is defined according to any of the embodiments described above in the first aspect of the present disclosure.
• At least one of the additional compounds is an interferon or a ribavirin.
• the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
• the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of
• the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
• a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
• compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (2) a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the "pyrrolidinyl-imidazole” moiety on the left side of the “linker” is independent from the “pyrrolidinyl-imidazole” moiety on the right side of the linker group in respect to, e.g., (1) tautomer form of imidazole ring, (2) absolute configuration of the stereogenic centers on the pyrrolidine ring, and (3) substituents on the pyrrolidine nitrogen, i.e., R 1 and R 2 are independent from each other, although in some circumstances they are preferably the same.
• the stereogenic carbon center to which the imidazole group is attached can take either (R)- or (S)- configuration as depicted below:
• this disclosure is intended to cover all possible stereoisomers even when a single stereoisomer, or no stereochemistry, is described in a structure.
• the linkage between a benzene ring of the linker group and an imidazole ring of a pyrrolidinyl-imidazole moiety can take place in either the C-4 or the C-5 position (see below) of the imidazole ring.
• a bonding of a benzene ring to the C-4 position may be equivalent to a bonding of the benzene ring to the C-5 osition as shown in the followin e uation:
• this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them.
• a floating bond e.g., ⁇ ⁇
• a floating substituent e.g.,
• any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
• substituent ( 10 ) n when n is 2, each of the two R 10 groups may be the same or different.
• aryl, cycloalkyl, heteroaryl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their respective definitions.
• aryl part of an arylalkyl group may be substituted as described in the definition of the term "aryl.”
• acetyl refers to -C(0)CH 3 .
• alkenyl refers to a monovalent, straight or branched hydrocarbon chain having one or more, preferably one to two, double bonds therein.
• the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
• Suitable alkenyl groups include, but are not limited to, C 2 to C 10 alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2- methyl-3-butene)-pentenyl.
• An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
• alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
• Representative examples of alkoxy group include, but are not limited to, methoxy (CH 3 O-), ethoxy (CH 3 CH 2 0-), and t-butoxy ((CH 3 ) 3 CO-).
• alkoxy alkyl refers to an alkyl group substituted with one, two, or three alkoxy groups.
• alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
• alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon by removal of a hydrogen from one of the saturated carbons.
• the alkyl group preferably contains from one to ten carbon atoms.
• alkyl group examples include, but are not limited to, methyl, ethyl, isopropyl, and tert-butyl.
• alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
• Representative examples of alkylcarbonyl group include, but are not limited to, acetyl (-C(0)CH 3 ), propanoyl (-C(0)CH 2 CH 3 ), n-butyryl (-C(0)CH 2 CH 2 CH 3 ), and 2,2-dimethylpropanoyl or pivaloyl (-C(0)C(CH 3 ) 3 ).
• alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
• aryl refers to a group derived from an aromatic carbocycle by removal of a hydrogen atom from an aromatic ring.
• the aryl group can be monocyclic, bicyclic or polycyclic, wherein in bicyclic or polycyclic aryl group, the aromatic carbocycle can be fused onto another four- to six-membered aromatic or non-aromatic carbocycle.
• Representative examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and 1,2,3,4- tetrahydronaphth-5 -yl.
• arylalkyl refers to an alkyl group substituted with one, two, or three aryl groups, wherein aryl part of the arylalkyl group may optionally be substituted by one to five substituents independently selected from Ci to Ce alkyl, Ci to C4 haloalkyl, Ci to Ce alkoxy, halogen, cyano, and nitro groups.
• substituents independently selected from Ci to Ce alkyl, Ci to C4 haloalkyl, Ci to Ce alkoxy, halogen, cyano, and nitro groups.
• Represented examples of arylalkyl include, but are not limited to, benzyl, 2 -phenyl- 1 -ethyl (PhCH 2 CH 2 -), (naphth- l-yl)methyl, and (naphth-2-yl)methyl.
• arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
• benzyl refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted by one to five substituents independently selected from methyl, trifluoromethyl (-CF 3 ), methoxy (-OCH 3 ), halogen, and nitro (-N0 2 ).
• benzyl group include, but are not limited to, PhCH 2 -, 4-MeO-C 6 H 4 CH 2 -, and 2,4,6-tri-methyl-C 6 H 4 CH 2 -.
• bridged bicyclic ring refers to a ring structure comprising a bridgehead between two of the ring members, wherein the ring and the bridgehead optionally may independently comprise one or more, preferably one to two, heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• bridged bicyclic ring structure examples include, but are not limited to:
• Cap refers to the group which is placed on the nitrogen atom of the pyrrolidine ring in the compounds of formula (I). It should be understood that “Cap” or “cap” can also refer to the reagent which is a precursor to the final “cap” in compounds of formula (I) and is used as one of the starting materials in the reaction to append a group on the pyrrolidine nitrogen that results in the final product, a compound which contains the functionalized pyrrolidine that will be present in the compound of formula (I).
• carbonyl refers to -C(O)-.
• cyano refers to -CN.
• cycloalkyl refers to a group derived from a saturated carbocycle, having preferably three to eight carbon atoms, by removal of a hydrogen atom from the saturated carbocycle, wherein the saturated carbocycle can optionally be fused onto one or two other aromatic or nonaromatic carbocycles.
• Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and 1,2,3,4-tetrahydronaphth-l-yl.
• halo and halogen, as used herein, refer to F, CI, Br, or I.
• haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
• haloalkyl refers to an alkyl group substituted by at least one halogen atom.
• the haloalkyl group can be an alkyl group of which all hydrogen atoms are substituted by halogens.
• Representative examples of haloalkyl include, but are not limited to, trifluoromethyl (CF 3 -), 1-chloroethyl (C1CH 2 CH 2 -), and 2,2,2-trifluoroethyl (CF 3 CH 2 -).
• heteroaryl refers to group derived from a monocyclic, bicyclic, or polycyclic compound comprising at least one aromatic ring comprising one or more, preferably one to three, heteroatoms independently selected from nitrogen, oxygen, and sulfur, by removal of a hydrogen atom from an aromatic ring thereof.
• heteroaryl rings have less aromatic character than their all-carbon counterparts.
• a heteroaryl group need only have some degree of aromatic character.
• heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, benzothiazolyl, benzothienyl, and pyrrolopyridinyl.
• heteroarylalkyl refers to an alkyl group substituted with one, two, or three heteroaryl groups.
• heterocyclyl refers to a ring structure comprising two fused or bridged rings that include carbon and one or more, preferably one to three, heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• the heterobicyclic ring structure is a subset of heterocyclic ring and can be saturated or unsaturated. Examples of heterobicyclic ring structures include, but are not limited to, tropane, quinuclidine, and 7-azabicyclo[2.2.1]heptane.
• heterocyclyl refers to a group derived from a monocyclic, bicyclic, or polycyclic compound comprising at least one nonaromatic ring comprising one or more, preferably one to three, heteroatoms independently selected from nitrogen, oxygen, and sulfur, by removal of a hydrogen atom from the nonaromatic ring.
• the heterocyclyl group encompasses the heterobicyclyl group.
• the heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
• heterocyclyl groups include, but are not limited to, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, thiomorpholinyl, and indolinyl.
• heterocyclylalkyl refers to an alkyl group substituted with one, two, or three heterocyclyl groups.
• hydroxy or "hydroxyl,” as used herein, refer to -OH.
• hydroxyalkyl refers to an alkyl group substituted with one, two, or three hydroxy groups.
• nitro refers to -N0 2 .
• -NR a R b refers to two groups, R a and R b , which are attached to the parent molecular moiety through a nitrogen atom, or alternatively R a and R b , together with the nitrogen atom to which they are attached, form a 5- or 6- membered ring or a fused- or bridged-bicyclic ring structure optionally containing one, two, or three additional heteroatom independently selected from nitrogen, oxygen, and sulfur.
• -NR c R d is defined similarly.
• (NR a R b )alkyl refers to an alkyl group substituted with one, two, or three -NR a R b groups.
• ( R c R d )alkyl is defined similarly.
• sulfonyl refers to -SO 2 -.
• trialkylsilyl refers to -S1R 3 , wherein each R is Ci to C 4 alkyl or phenyl.
• the three R groups may be the same or different.
• TMS trimethylsilyl
• TDPS tert-butyldiphenylsilyl
• TBDMS tert-butyldimethylsilyl
• TIPS triisopropylsilyl
• Certain compounds of the present disclosure may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
• the present disclosure includes each conformational isomer of these compounds and mixtures thereof.
• isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically- labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
• the compounds of the present disclosure can exist as pharmaceutically acceptable salts.
• pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds of the present disclosure which are water or oil-soluble or dispersible, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
• Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate; digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3- phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, gluta
• Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium,
• tetramethylammonium tetraethylammonium
• methylamine dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, ⁇ , ⁇ -dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ , ⁇ -dibenzylphenethylamine, and ⁇ , ⁇ '- dibenzylethylenediamine.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine,
• compositions which include therapeutically effective amounts of compounds of Formula (I) or pharmaceutically acceptable salts thereof, and one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or excipients.
• therapeutically effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone.
• the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
• the compounds of Formula (I) and pharmaceutically acceptable salts thereof are as described above.
• the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• a process for the preparation of a pharmaceutical formulation including admixing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or excipients.
• pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (“mg/kg”) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• mg/kg milligram per kilogram
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient.
• Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
• the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
• compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
• both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
• compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
• Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred.
• compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil emulsions.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
• Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
• Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
• a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
• suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
• a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
• the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
• the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
• the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
• the lubricated mixture is then compressed into tablets.
• the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
• a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
• Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
• Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
• Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and
• polyoxyethylene sorbitol ethers preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
• dosage unit formulations for oral administration can be microencapsulated.
• the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
• the compounds of Formula (I), and pharmaceutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
• the compounds of Formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
• the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharm. Res., 3(6):318 (1986).
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
• the formulations are preferably applied as a topical ointment or cream.
• the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
• the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in oil base.
• Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
• compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.
• Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
• compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
• Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
• compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and soutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
• formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• patient includes both human and other mammals.
• treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
• the compounds of the present disclosure can also be administered with a cyclosporin, for example, cyclosporin A.
• Cyclosporin A has been shown to be active against HCV in clinical trials (Hepatology, 38: 1282 (2003); Biochem. Biophys. Res. Commun., 313 :42 (2004); J. Gastroenterol, 38:567 (2003)).
• Table 1 lists some illustrative examples of compounds that can be administered with the compounds of this disclosure.
• the compounds of the disclosure can be administered with other anti-HCV activity compounds in combination therapy, either jointly or separately, or by combining the compounds into a composition.
• inhibitor Brand Name Physiological Class Type of Inhibitor or Source Company
• the compounds of the present disclosure may also be used as laboratory reagents.
• Compounds may be instrumental in providing research tools for designing of viral replication assays, validation of animal assay systems and structural biology studies to further enhance knowledge of the HCV disease mechanisms. Further, the compounds of the present disclosure are useful in establishing or determining the binding site of other antiviral compounds, for example, by competitive inhibition.
• the compounds of this disclosure may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials, e.g., blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection or transfusion apparatuses and materials.
• This disclosure is intended to encompass compounds having Formula (I) when prepared by synthetic processes or by metabolic processes including those occurring in the human or animal body (in vivo) or processes occurring in vitro.
• TFA trifluoroacetic acid
• MeCN or ACN for acetonitrile
• LDA lithium diisopropylamide
• DMSO dimethylsulfoxide
• h or hr or hrs for hours
• Boc or BOC for tert- butoxycarbonyl
• HATU for 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
• RT or Rt or rt for retention time or room temperature (context will dictate); Me for methyl; DMF for N,N-dimethylformamide; Pd(Ph 3 P) 4 for tetrakistriphenyl phosphine palladium; MeOH for methanol
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Solvent A 0.2 % H 3 P0 4 in 10% methanol/90% water
• Solvent B 0.2 % H 3 P0 4 in 90% methanol/10% water
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Solvent A 0.2 % H 3 P0 4 in 10% methanol/90% water
• Solvent B 0.2 % H 3 P0 4 in 90% methanol/10% water Condition 5
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water Condition 6
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Slovent A 0.1% TFA in 5% CH 3 CN/95%H 2 0
• Solvent B 0.1% TFA in 95% CH 3 CN/5% H 2 0
• Slovent A 0.1% TFA in 5% CH 3 CN/95%H 2 0
• Solvent B 0.1% TFA in 95% CH 3 CN/5% H 2 0 Condition 10
• Slovent A 0.1% TFA in 5% CH 3 CN/95%H 2 0
• Slovent A 0.1% TFA in 5% CH 3 CN/95%H 2 0
• Wavelength 1 220 nm
• Wavelength 2 254 nm
• Solvent A 0.1 % TFA in 5% MeCN/95% water
• Solvent B 0.1 % TFA in 95% MeCN/5% water
• Wavelength 1 220 nm
• Wavelength 2 254 nm
• Solvent A 0.1 % TFA in 5% MeCN/95% water
• Solvent B 0.1 % TFA in 95% MeCN/5% water
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Slovent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Wavelength 220 & 254 nm Condition 10e.2 (for a homogeneity index assessment on a Agilent 1200 series LC system)
• Slovent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Solvent A 10 mM NH 4 HCO 3 in H 2 0 (pH 9.5, adjusted with dilute ammonia)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Slovent A ACN (10%) 4 - 20 mM NH 4 OAc in H 2 0 (90%)
• Solvent B ACN (90%) ⁇ + ⁇ 20 mM NH 4 OAc in H 2 0 (10%)
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent A 0.1 % TFA in 10% methanol/90% water
• Solvent B 0.1 % TFA in 90% methanol/10% water
• Solvent A 5% methanol/95% water : 10 mM ammonium acetate
• Solvent B 95% methanol/5% water : 10 mM ammonium acetate
• Mobile phase B 0.05% TFA in acetonitrile Solvent system: Hold 10%B: 0-lmin; 10-98%B: l-32min; Hold 98%B: 32-35 min; 98-10%B: 35-35.3 min; hold 10%B: 35.3-40 min
• 4,4'-Oxybis-(benzoic acid) dimethyl ester (1.5 g, 5.24 mmol) was added to a solution of chloroiodomethane (3.05 mL, 41.92 mmol) in tetrahydrofuran (50 mL) and the resulting solution was cooled to -78 °C.
• a 1.8M solution of LDA (29 mL, 52 mmol) in tetrahydrofuran was added dropwise and the resulting brown suspension was stirred at -78 °C for 15 min.
• a solution of glacial acetic acid in tetrahydrofuran (10 mL in 50 mL) was then added slowly and the brown mixture was stirred at -78 °C for 10 min.
• N,N-Diisopropylethylamine (1.13 mL, 6.47 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (0.8 g, 3.73 mmol),
• HATU 52 mg, 0.137 mmol was added to a mixture of OL-le (35 mg, 0.06 mmol), diisopropylethylamine (58 ⁇ L, 0.33 mmol) and Cap-1 (22 mg, 0.12 mmol) in dimethylformamide (3 mL), and the resulting mixture was stirred at ambient for 3 h.
• Examples OL-2 and OL-3 were prepared as TFA salts by substituting the respective acids for Cap-1 using the same method described for Example OL-1.
• OL-4b was prepared from OL-4a, according to the same procedure used for the preparation of OL-la.
• OL-4c was prepared from Example OL-4b, according to the same procedure used for the preparation of Example OL- lb.
• LC Cond. 2): Anal. Calcd. for Ci 6 H 17 2 0 3 (M+H) + 285.12; found: 285.15.
• Example OL-4d Anal. Calcd. for Ci 6 H 17 2 0 3 (M+H) + 285.12; found: 285.15.
• Example OL-4d was prepared from Example OL-4c, according to the same procedure used for the preparation of Example OL- lc.
• Example OL-4e was prepared from Example OL-4d, according to the same procedure used for the preparation of Example OL-ld.
• LRMS Anal. Calcd. for C 36 H45 6 0 5 (M+H) + 641.3
• Example OL-4f was prepared from Example OL-4e, according to the same procedure used for the preparation of Example OL-le.
• X H NMR 500 MHz, DMSO- d 6 ) ⁇ ppm 1.94 - 2.06 (m, 2 H), 2.09 - 2.23 (m, 2 H), 2.28 - 2.38 (m, 1 H), 2.37 - 2.47 (m, 3 H), 3.27 - 3.50 (m, 4 H), 4.90 (br. s, 1 H), 4.99 (br.
• Example OL-4 was prepared from Example OL-4f according to the same procedure used for the preparation of Example OL-1.
• Examples OL-5 to OL-6 were prepared as TFA salts by substituting the respective acids for Cap-1 according to the same method described for Example OL-
• Example OL-7a (Diazomethyl)trimethylsilane (15 mL, 30 mmol, 2 M in hexanes) was added dropwise to a suspension of Example OL-7a (2.04 g, 7.5 mmol) in methanol (30 mL) at 5 °C (ice-water bath). When the addition was complete, the cooling bath was removed and the mixture was stirred at ambient overnight. The solvent was removed under reduced pressure and the remaining residue was taken up in ethyl acetate, washed with water, sodium bicarbonate and brine, dried (MgSC ⁇ ), filtered and concentrated in vacuo.
• Example OL-7b was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to provide Example OL-7b as white solid (1.5 g).
• LC (Cond. 1): RT 2.56 min; LRMS: Anal. Calcd. for Ci 7 Hi 6 0 5 (M+H) + 301.11 ; found: 301.22.
• Example OL-7c was prepared from Example OL-7b, according to the same procedure used for the preparation of Example OL-la.
• LC (Cond. 1): RT 2.36 min;
• LRMS Anal. Calcd. for Ci 7 H 15 Cl 2 0 3 (M+H) + 337.04 found: 337.09. Exam le OL-7d
• Example OL-7d was prepared from Example OL-7c, according to the same procedure used for the preparation of Example OL- lb.
• LRMS Anal. Calcd. for ⁇ 7 ⁇ 19 ⁇ 1 2 0 3 (M+H) + 299.14 found: 299.19.
• Example OL-7e was prepared from Example OL-7d, according to the same procedure used for the preparation of Example OL- lc.
• Example OL-7f was prepared from Example OL-7e, according to the same procedure used for the preparation of Example OL-ld.
• LC Cond. 1): RT
• Example OL-7g was prepared from Example OL-7fe, according to the same procedure used for the preparation of Example OL-le.
• Example OL-7 was prepared from Example OL-7g according to the same procedure used for the preparation of Example OL-1.
• Example OL-8 was prepared as TFA salt by substituting the respective acid for Cap-1 according to the same method described for Example OL-7.
• Example OL-9b was prepared from Example OL-9a, according to the same procedure used for the preparation of Example OL-la.
• Example OL-9c was prepared from Example OL-9b, according to the same procedure used for the preparation of Example OL-lb.
• LC (Cond. 3): RT 1.90 min; LRMS: Anal. Calcd. for
• Example OL-9d was prepared from Example OL-9c, according to the same procedure used for the preparation of Example OL- lc.
• X H NMR 500 MHz, CDC1 3 ) ⁇ ppm 1.38 - 1.56 (m, 18 H), 1.83 - 2.00 (m, 4 H), 2.08 - 2.38 (m, 4 H), 3.01 (s, 4 H), 3.32 - 3.65 (m, 4 H), 4.28 (br. s, 1 H), 4.39 (br.
• Example OL-9e was prepared from Example OL-9d, according to the same procedure used for the preparation of Example OL-ld.
• Example OL-9f was prepared from Example OL-9e, according to the same procedure used for the preparation of Example OL-le.
• Example OL-9 was prepared from Example OL-9f, according to the same procedure used for the preparation of Example OL-1.
• Examples OL-10 to OL-13 were prepared as TFA salts by substituting the respective acids for Cap-1 according to the same method described for Example OL- 9.
• Triethyl silane (5.84 mL, 36.55 mmol) was added dropwise to a solution of methyl 4-formylbenzoate (5 g, 30.46 mmol) and bismuth tribromide (0.273 g, 0.61 mmol) in acetonitrile (75 mL) and the opaque solution was stirred at ambient for 15 min. Volatiles were removed under reduced pressure and the remaining residue was taken up in ethyl acetate. The organic layer was then washed with water and brine, dried (MgSC ⁇ ), filtered and concentrated in vacuo.
• Example OL-14b was prepared from Example OL-14a, according to the same procedure used for the preparation of Example OL-la.
• LRMS Anal. Calcd. for CisHnC ⁇ Os (M+H) + 351.05, found: 351.06.
• Example OL-14c was prepared from Example OL-14b, according to the same procedure used for the preparation of Example OL-lb.
• Example OL-14d was prepared from Example OL-14c, according to the same procedure used for the preparation of Example OL- lc.
• Example OL-14e was prepared from Example OL-14d, according to the same procedure used for the preparation of Example OL-ld.
• Example OL-14f was prepared from Example OL-14e, according to the same procedure used for the preparation of Example OL-le.
• Example OL-14 was prepared from Example OL-14f, according to the same procedure used for the preparation of Example OL- 1.
• Examples OL-15 to OL-19 were prepared as TFA salts by substituting the respective acids for Cap-1 according to the same method described for Example OL- 14.
• Example OL-20a was submitted to flash chromatography (silica gel; 20 % ethyl acetate/hexanes) to provide Example OL-20a as a clear oil that solidified upon standing (2.49 g).
• LC (Cond. 1): RT 2.56 min;
• Example OL-20b was prepared from Example OL-20a, according to the same procedure used for the preparation of Example OL-la.
• LC (Cond. 1): RT 2.34 min;
• LRMS Anal. Calcd. for C18H17CI2O3 (M+H) + 351.05 found: 351.12.
• Example OL-20c was prepared from Example OL-20b, according to the same procedure used for the preparation of Example OL-lb.
• LC (Cond. 1): RT 1.32 min;
• LRMS Anal. Calcd. for Ci 8 H 21 N 2 03 (M+H) + 313.15 found: 313.24. Exam le OL-20d
• Example OL-20d was prepared from Example OL-20c, according to the same procedure used for the preparation of Example OL- lc.
• Example OL-20e was prepared from Example OL-20d, according to the same procedure used for the preparation of Example OL-ld.
• Example OL-20f was prepared from Example OL-20e, according to the same procedure used for the preparation of Example OL-le.
• Example OL-20 was prepared from Example OL-20f, according to the same procedure used for the preparation of Example OL- 1.
• Examples OL-21 to OL-25 were prepared as TFA salts by substituting the respective acids for Cap-1 according to the same method described for Example OL- 20.
• N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.14 g, 33.17 mmol), HATU (13.32 g, 35.04 mmol), the HCl salt of 2-amino-l-(4-bromophenyl)ethanone (8.13 g, 32.44 mmol), and DMF (105 mL), and stirred at ambient condition for 55 minutes. Most of the volatile component was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL).
• the resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of imidazole D-lb as a light-yellow, dense solid, weighing 5.85 g.
• the mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl
• Ci 8 H 23 Br 3 0 2 392.0974; found 392.0959.
• Relative retention time 2.83 minutes (R), 5.34 minutes (5).
• Pd(Ph 3 P) 4 (469 mg, 0.41 mmol) was added to a pressure tube containing a mixture of D-lb (4.01 g, 10.22 mmol), bis(pinacolato)diboron (5.42 g, 21.35 mmol), potassium acetate (2.57 g, 26.21 mmol) and 1,4-dioxane (80 mL).
• the pressure tube was purged with nitrogen, capped and heated in an oil bath at 80 °C for 16.5 hours.
• the reaction mixture was filtered and the filtrate was concentrated in vacuo.
• Example D-lc contaminated with pinacol, as an off- white dense solid; the relative mole ratio of Example D-lc to pinacol was about 10: 1 ( X H NMR).
• the sample weighed 3.925 g after -2.5 days exposure to high vacuum.
• 3 ⁇ 4 NMR 500 MHz, DMSO-d 6 ) ⁇ ppm 1.45-1.10 (m, 21H), 2.27-1.77 (m, 4H), 3.36 (m, 1H), 3.52 (app br s, 1H), 4.86-4.70 (m, 1H), 7.79-7.50/ 7.34-7.27 (m, 5H), 12.22/11.94/ 11.87 (m, 1H).
• LC (Cond. 7): RT 1.64 min;
• LRMS Anal. Calcd. for [M+H] + C24H 3 5BN 3 O4: 440.27; found 440.23.
• Tetrakistriphenylphosphine palladium (17.5 mg, 0.015 mmol) was added in one portion to a stirred suspension of D-lc (320 mg, 0.85 mmol), 1,4- diiodobenzene (100 mg, 0.30 mmol) and sodium bicarbonate (180 mg, 2.18 mmol) in
• D-le was prepared from D-ld, according to the same procedure used for the preparation of OL-le except that methanol (1 mL) was used instead of
• Example D-1 (TFA salt) was prepared from D-le, according to the same procedure used for the preparation of Example OL- 1. This gave Example D-1 as a tan solid (37.8 mg, 54 % yield).
• Example D-2 (TFA salt) was prepared from pyrrolidine D-le, according to the same procedure used for the preparation of Example OL- 1. This gave Example D-2 as a light yellow solid (15.4 mg, 38 % yield).
• X H NMR 500 MHz, DMSO-i3 ⁇ 4) ⁇ ppm 2.50-1.70 (m, 14 H), 2.98-2.62 (m, 6 H), 4.05-2.98 (m, 4 H), 5.79-5.12 (m, 4 H), 8.20-7.10 (m, 24 H), 10.25 (br s, 2 H). Note: The signal of the imidazole NH was too broad to assign a chemical shift.
• step a
• D-3bl and D-3b2 were prepared from D-3a and the appropriate Boc -protected prolines according to the same procedure used for the preparation of Example M3, step g.
• D-3cl and D-3c2 were prepared from D-3bl and D-3b2 respectively according to the same procedure used for the preparation of Example M3, step h.
• Ethynyltrimethylsilane (0.59 mL, 4.25 mmol) was added to a solution of D-lb (1.5 g, 3.82 mmol), triphenylphosphine (0.20 g, 0.77 mmol), diethylamine (4.25 mL, 40.70 mmol), copper (I) iodide (40 mg, 0.21 mmol) and /raws-dichloro(bis- triphenylphosphine)palladium (II) (149 mg, 0.21 mmol) in dry DMF (1.4 mL) at rt in a microwave vessel. The vessel was capped and irradiated for 25 min at 120 °C.
• D-3d2 to D-3d4 were prepared according to the procedures described for D-
• Tetrakis(triphenylphosphine)palladium (83 mg, 0.072 mmol) was added in one portion to a stirred, argon-degassed mixture of Example D-3cl (300 mg, 0.717 mmol), D-3el (315 mg, 0.932 mmol), triethylamine (0.40 mL, 2.87 mmol) and copper(I) iodide (13.7 mg, 0.072 mmol) in anhydrous DMF (6 mL) at rt in a thick- walled, screw-top vial.
• D-3f2 to D-3f4 were prepared according to the procedure described for D-3fl .
• Activated manganese dioxide (2.0 g, 23.12 mmol) was added in one portion to a stirred solution of D-3fl (260 mg, 0.39 mmol) in dry dichloromethane (5 mL). The suspension was stirred at rt for 6 h before additional activated manganese dioxide (1.0 g) was added. The suspension was stirred further for 14 h at rt before it suction-filtered through a pad of Celite with MeOH and the pad was washed with additional MeOH several times. The filtrate was then concentrated in vacuo to yield D-3gl (225.1 mg, 82% yield) as a yellow solid. A small amount (approx.
• D-3hl to D-3h6 were prepared from D-3fl, D-3gl, D-3f2, D-3G, D-3g2 and D-3f4, respectively, according to the same procedure used for the preparation of OL- le except that methanol (1 mL) was used instead of dichloromethane. This gave D- 3hl to D-3h6 as hydrochloride salts (or TFA salts when purified further with preparative HPLC) upon concentration of the solvent(s) in vacuo.
• Examples D-3 to D-11 were prepared from D-3hl to D-3h6 and the appropriate acids according to the same procedure used for the preparation of Example OL-1. This gave Examples D-3 to D-11 as TFA salts after HPLC purification.
• HATU (0.069 g, 0.181 mmol) was added to the DMF solution of pyrrolodine Mlb/4HC1 (70.5 mg, 0.103 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (36.3 mg, 0.207 mmol) and DIEA (0.1 mL, 0.573 mmol) and stirred at room temperature for 70 min.
• the volatile component was removed in vacuo and the residue was dissolved in MeOH and submitted to a reverse phase HPLC purification (MeOH/water/TFA) to afford the TFA salt of Example Ml as an off-white foam (68.9 mg).
• LC (Cond. 9 and 10): >95% homogeneity index.
• Example M2 to M2.1 were prepared as TFA salts from pyrrolidine Mlb and appropriate acids according to the procedure described for the preparation of Example Ml with a modified purification protocol noted in the table below.
• Chloroiodomethane (stabilized over copper; 3.0 mL, 41.2 mmol) was added dropwise over 10 min, and stirred while maintaining the bath temperature at -25 °C for 1 h and between -25 °C and -21 °C for 18.5 h.
• the reaction mixture was opened to the air and quenched by the slow addition of 50% saturated NaHCC solution (40 mL), and then removed from the cooling bath and stirred at ambient temperature for 20 min. It was filtered through a filter paper and the white cake was washed with 50 mL of toluene.
• the organic phase of the filtrate was separated and washed with water (40 mL, 2x), dried (MgS0 4 ) and concentrated in vacuo.
• the crude material was purified using a BIOTAGE® system (350 g silica gel; sample was loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) to afford a mixture of methanopyrrolidines M3d-1 and M3d-2 as a colorless viscous oil (3.69 g, 90.7%). [Note: the exact cis/trans-isomer ratio was not determined at this stage].
• TBAF (7.27 mL of 1.0 M in THF, 7.27 mmol) was added dropwise over 5 min to a THF (30 mL) solution of silyl ether M3d-l/-2 (3.13 g, 6.93 mmol) and the mixture stirred at ambient temperature for 4.75 h.
• saturated NH 4 CI solution 5 mL
• most of the volatile material was removed in vacuo and the residue partitioned between CH 2 CI 2 (70 mL) and 50% saturated NH 4 C1 solution (30 mL).
• the aqueous phase was extracted with CH 2 CI 2 (30 mL), and the combined organic phase was dried (MgS0 4 ), filtered, concentrated in vacuo and then exposed to high vacuum overnight.
• keto-ester M3g (3.07g, 7.24 mmol), ammonium acetate (5.48 g, 71.1 mmol) and Xylene (70 mL), capped and heated with an oil bath (140 °C) for 4.5 hr.
• the reaction mixture was allowed to cool to room temperature and the volatile component was removed in vacuo.
• CH 2 CI 2 100 mL
• 50% saturated aHC03 solution (30 mL) were added to the residue, vigorously stirred until gas evolution ceased, and the phases were separated.
• the organic layer was dried (MgSC ⁇ ), concentrated in vacuo, and purified with a BIOTAGE® (240 g silica gel; sample was loaded with (3 ⁇ 4(3 ⁇ 4; 40-80% EtOAc/hexanes) to afford imidazole M3h as a dark yellow foam (2.40 g).
• BIOTAGE® 240 g silica gel; sample was loaded with (3 ⁇ 4(3 ⁇ 4; 40-80% EtOAc/hexanes) to afford imidazole M3h as a dark yellow foam (2.40 g).
• Example M3 along with its analogs Examples M4-M7 highlighted in the table below, were prepared as TFA salts from pyrrolidine M3i (.4HC1) by employing the procedure described for the synthesis of Example Ml and appropriate acids.
• Example M7 an equimolar mixture of (S)-2-(methoxycarbonylamino)-3- methylbutanoic acid and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4- yl)acetic acid was employed for the coupling step and the resultant statistical mixture of products was separated by the HPLC technique described for Example Ml .
• Example M3 LC (Cond. 9 and 10): >95% homogeneity index.
• LC/MS (Cond. 3): R t 1.89 min.
• NCS (0.0195 g, 0.143 mmol) was added to a DMF (2 mL) solution of the free base form of Example M3 (obtained from the TFA salt via a standard MCX free- basing protocol; 0.109 g, 0.139 mmol), and stirred at room temperature for 16 hr and at 50°C for 25 hr. Most of the solvent was removed in vacuo, and the residue was dissolved in MeOH and submitted to a reverse phase HPLC purification
• Example M8 (MeOH/water/TFA) to afford the TFA salt of Example M8 (50 mg) and Example M9 (17.5 mg).
• Example R t (Cond. 3); % homogeneity index (Cond. 9a and 10a);
• NCS (0.021 g, 0.158 mmol) was added to a DMF (1.5 mL) solution of the free base form of Example M6 (obtained from the TFA salt via a standard MCX free- basing protocol; 0.1059 g, 0.122 mmol), and stirred at 50°C for 24 hr.
• the reaction mixture was diluted with MeOH (2.5 mL) and submitted to a reverse phase HPLC purification condition (XTERRA, 30X100 mm, S5; MeOH/water/TFA).
• Example M9.1 38.8 mg
• Example M9.2 32.6 mg

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Virology (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Oncology (AREA)
• Molecular Biology (AREA)
• Communicable Diseases (AREA)
• Gastroenterology & Hepatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (8)

Applications Claiming Priority (1)

Publications (1)

Family

ID=43037168

Family Applications (1)

Country Status (8)

Cited By (19)

Citations (9)

Family Cites Families (2)

• 2010
  • 2010-09-24 EP EP10761101.4A patent/EP2619195A1/en not_active Withdrawn
  • 2010-09-24 WO PCT/US2010/050138 patent/WO2012039717A1/en active Application Filing
  • 2010-09-24 CA CA2812699A patent/CA2812699A1/en not_active Abandoned
  • 2010-09-24 CN CN2010800703399A patent/CN103249730A/zh active Pending
  • 2010-09-24 EA EA201370078A patent/EA201370078A1/ru unknown
  • 2010-09-24 BR BR112013008148A patent/BR112013008148A2/pt not_active IP Right Cessation
  • 2010-09-24 MX MX2013002927A patent/MX2013002927A/es not_active Application Discontinuation
  • 2010-09-24 JP JP2013530121A patent/JP5619289B2/ja not_active Expired - Fee Related

Patent Citations (9)

Non-Patent Citations (15)

Also Published As

Similar Documents

Legal Events