Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • 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

Definitions

• the invention is directed to compounds useful as inhibitors of replication of the hepatitis C virus (HCV).
• HCV hepatitis C virus
• the invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat HCV infection, and processes and intermediates useful for preparing such compounds.
• HCV hepatitis C virus
• HCV Prior to mid-2011 , the accepted standard of care for HCV involved the use of a pegylated interferon which is believed to act by boosting the body's immune response, together with ribavirin.
• the course of treatment is lengthy, typically 48 weeks, often accompanied by serious adverse side effects, including depression, flu-like symptoms, fatigue, and hemolytic anemia, and ineffective in up to 50 % of patients.
• two HCV protease inhibitors were approved in the United States to be used in combination with interferon and ribavirin. Although better cure rates have been reported, the course of therapy is still lengthy and accompanied by undesirable side effects.
• the virus responsible for HCV infection has been identified as a positive-strand RNA virus belonging to the family Flaviviridae.
• the HCV genome encodes a polyprotein that during the viral lifecycle is cleaved into ten individual proteins, including both structural and non-structural proteins.
• the six non-structural proteins, denoted as NS2, NS3, NS4A, NS4B, NS5A, and NS5B have been shown to be required for RNA replication.
• the NS5A protein appears to play a significant role in viral replication, as well as in modulation of the physiology of the host cell. Effects of NS5A on interferon signaling, regulation of cell growth and apoptosis have also been identified. (Macdonald et al, Journal of General Virology (2004), 85, 2485-2502.) Compounds which inhibit the function of the NS5A protein are expected to provide a new approach to HCV therapy.
• the invention provides novel compounds which inhibit replication of the HCV virus.
• R 1 is selected from Ci- 6 alkyl, phenyl, C3- 6 cycloalkyl, heteroaryl, and heterocycle; wherein Ci_ 6 alkyl is optionally substituted with -OR q , wherein R q is hydrogen or Ci -3 alkyl;
• R 2 is selected from hydrogen and Ci- 6 alkyl
• R 3 is selected from hydrogen, C h alky!, -C(0)OCi_ 6 alkyl,
• R a and R b are independently hydrogen or Ci- 6 alkyl;
• R 4 is -C(0)R 5 or -S(0) 2 R 6 ;
• R 5 is selected from Ci_ 6 alkyl, C 3 - 6 cycloalkyl, Ci_ 6 alkoxy, -C(R k R d )NR e R f , -NR s R h , heteroaryl, heterocycle, -CH 2 -heteroaryl, and phenyl;
• Ci- 6 alkyl is optionally substituted with one or two substituents independently selected from -OR c , -S(0) 2 Ci_ 3 alkyl, -NHC(0)Ci_ 3 alkyl, and -NHC(0)OCi_ 3 alkyl;
• Ci_ 6 alkoxy is optionally substituted with -OR d ;
• C 3 - 6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from Ci_ 3 alkyl, NR j R m , -OR", and halo;
• any heterocycle is optionally substituted with one, two, or three substituents independently selected from Ci_ 3 alkyl, halo, -C(0)OCi- 3 alkyl , -C(0)Ci_ 6 alkyl, -C(0)C 3 _ 6 cycloalkyl, -C(0)NHCi_ 6 alkyl, -C(0)NHC 3 _ 6 cycloalkyl, and -S(0) 2 Ci_ 3 alkyl;
• any -C(0)Ci_ 6 alkyl is optionally substituted with
• any -C(0)C 3 _ 6 cycloalkyl is optionally substituted with one or two
• any -C(0)NHCi_ 6 alkyl is optionally substituted with -OR" or
• any heteroaryl is optionally substituted with Ci- 6 alkyl
• R c is independently selected from hydrogen, Ci_ 6 alkyl, and phenyl;
• R d is independently hydrogen or Ci- 6 alkyl
• R e is independently hydrogen or Ci- 6 alkyl
• R f is independently selected from hydrogen, Ci- 6 alkyl, -C(0)OCi_ 6 alkyl, and -C(0)Ci_ 6 alkyl;
• R n is independently hydrogen or Ci_ 3 alkyl
• R k is independently selected from hydrogen, Ci- 6 alkyl, C 3 _ 6 cycloalkyl, phenyl, and -CH 2 OR n ;
• R s is independently hydrogen or Ci_ 6 alkyl
• R h is independently selected from hydrogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, and -S(0) 2 Ci- 3 alkyl, wherein Ci_ 6 alkyl is optionally substituted with -OR d ;
• R J is independently hydrogen or Ci- 6 alkyl
• R m is independently selected from hydrogen, Ci- 6 alkyl, -C(0)OCi_ 6 alkyl, and -C(0)Ci_ 6 alkyl;
• R 6 is selected from Ci- 6 alkyl, C3_ 6 cycloalkyl, phenyl, and a heteroaryl ring;
• R 7 , R 8 , and R 11 are independently selected from halo, Ci_ 6 alkyl, Ci- 6 alkoxy, -C(0)OR n , -CH 2 NR a R b , and -CN, wherein Ci_ 6 alkyl and Ci_ 6 alkoxy are optionally substituted with one, two, three, four, or five halo, and wherein Ci- 6 alkoxy is optionally substituted with -OR d ;
• R 9 is independently selected from Ci_ 6 alkyl, -CH 2 OR n , -C(0)NR n R p , and C(0)OR n , wherein Ci- 6 alkyl is optionally substituted with -S(0)2Ci_ 3 alkyl or with -SCi_ 3 alkyl;
• R p is independently hydrogen or Ci_ 3 alkyl
• R 10 is selected from hydrogen, halo, Ci- 6 alkyl, -C(0)OR c , -C(0)NR a R b ,
• W, X', Y', and Z' are independently carbon or nitrogen wherein any carbon atom is bonded to hydrogen or to R 11 , provided that at least two of W, X', Y', and Z' are carbon;
• W, X, Y, and Z are independently carbon or nitrogen wherein any carbon atom is bonded to hydrogen or to R 7 , provided that at least two of W, X, Y, and Z are carbon;
• a m is -NHC(O)- or -C(0)NH-;
• Q, T, U, and V are independently carbon or nitrogen wherein any carbon atom is bonded to hydrogen or to R 8 , provided that at least two of Q, T, U, and V are carbon; and a, b, c, and d are independently 0, 1, or 2;
• compound of formula (I) means a compound of formula (I) or a pharmaceutically acceptable salt thereof; i.e., this phrase means a compound of formula (I) in free base form or in a pharmaceutically acceptable salt form unless otherwise indicated.
• the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
• the invention provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically-acceptable carrier and one or more other therapeutic agents useful for treating hepatitis C viral infections.
• the invention also provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound or of a pharmaceutical composition of the invention.
• the invention provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a compound or a pharmaceutical composition of the invention and one or more other therapeutic agents useful for treating hepatitis C viral infections.
• the invention provides a method of inhibiting replication of the hepatitis C virus in a mammal, the method comprising administering a compound or a pharmaceutical composition of the invention.
• the invention also provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
• the invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a hepatitis C viral infection in a mammal.
• the invention provides inhibitors of HCV replication of formula (I), pharmaceutically-acceptable salts thereof, and intermediates for the preparation thereof.
• substituents and values are intended to provide representative examples of various aspects of this invention. These representative values are intended to further define such aspects and are not intended to exclude other values or limit the scope of the invention.
• R 1 is selected from Ci- 6 alkyl, phenyl, C3_ 6 cycloalkyl, heteroaryl, and heterocycle; wherein Ci- 6 alkyl is optionally substituted with -OR q ;
• R q is hydrogen or Ci_ 3 alkyl.
• R 1 is selected from Ci_ 6 alkyl, phenyl, C3_ 6 cycloalkyl, heteroaryl, and heterocycle.
• R 1 is selected from Ci_ 6 alkyl, phenyl, and
• Ci- 6 alkyl is optionally substituted with -OR q ; wherein R q is hydrogen or C 1-3 alkyl.
• R 1 is selected from Ci_ 6 alkyl and phenyl.
• R 1 is C 1-3 alkyl.
• R 1 is isopropyl
• R 2 is hydrogen or Ci- 6 alkyl. In other specific aspects, R 2 is hydrogen or Ci_ 3 alkyl; or R 2 is hydrogen.
• R 3 is selected from hydrogen, Ci- 6 alkyl, -C(0)OCi_ 6 alkyl, -C(0)OC 3 - 6 cycloalkyl,-C(0)NR a R b , -C(0)C 1-6 alkyl, -C(0)C 3 - 6 cycloalkyl, and
• R 3 is selected from hydrogen, Ci- 6 alkyl,
• R 3 is selected from hydrogen, Ci- 6 alkyl, and
• R 3 is -C(0)OCi_ 3 alkyl.
• R 1 is Ci- 6 alkyl
• R 2 is hydrogen
• R 3 is -C(0)OCi_ 6 alkyl
• R 1 is isopropyl
• R 2 is hydrogen
• R 3 is -C(0)OCH 3 .
• R 1 is phenyl and R 2 and R 3 are each Ci- 3 alkyl, or R 1 is phenyl and R 2 and R 3 are each ethyl; or R 1 is phenyl, R 2 is hydrogen, and R 3 is -C(0)OCi_ 3 alkyl.
• R 4 is -C(0)R 5 wherein R 5 is defined as in formula (I).
• R 4 is -C(0)R 5 wherein R 5 is selected from Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 6 alkoxy, -C(R k R d )NR e R f , -NR s R h , heteroaryl, heterocycle,
• Ci_ 6 alkyl is optionally substituted with -OR c or -S(0) 2 Ci- 3 alkyl; C 3 _ 6 cycloalkyl is optionally substituted with one or two Ci_ 3 alkyl, or with NR J R m or -OR"; any heterocycle is optionally substituted with one or two substituents selected from Ci- 3 alkyl, halo, -C(0)OCi- 3 alkyl , -C(0)Ci- 6 alkyl optionally substituted with -NHC(0)OCi_ 3 alkyl, and-C(0)C 3 _ 6 cycloalkyl optionally substituted with one or two Ci- 3 alkyl; and any heteroaryl is optionally substituted with Ci_ 6 alkyl, wherein R h is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, and -S(0) 2 Ci_ 3 alkyl, and R c
• R 4 is -C(0)R 5 wherein R 5 is selected from Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 6 alkoxy, -C(R k R d )NR e R f , -NR s R h , heteroaryl, heterocycle, and -CH 2 -heteroaryl, wherein any heteroaryl or heterocycle has five or six ring atoms;
• C 3 _ 6 cycloalkyl is optionally substituted with one or two Ci_ 3 alkyl; any heterocycle is optionally substituted with one or two substituents selected from Ci_ 3 alkyl halo,
• R k , R d , R e , R s , and R h are each independently hydrogen or Ci_ 3 alkyl; and R f is selected from hydrogen and-C(0)Ci- 3 alkyl.
• R 4 is -C(0)R 5 wherein R 5 is selected from
• C3_ 4 cycloalkyl -CH 2 NR e R f , -NR s R h , imidazolyl, pyrazolyl, pyrimidinyl, and pyrrolidinyl; wherein: C3_ 4 cycloalkyl is optionally substituted with one or two pyrrolidinyl is substituted with methyl and a substituent selected from -C(0)OCi_ 3 alkyl , -C(0)Ci_ 6 alkyl, and -C(0) HC 1-6 alkyl, wherein-C(0)Ci_ 6 alkyl is substituted with - HC(0)OC 1-3 alkyl, -OR", -NR d R e , or heterocycle.
• R 4 is -C(0)R 5 wherein R 5 is selected from, -O-tert-butyl, cyclopropyl, tert-butyl, -NHCH 3 , 2,2-dimethylcyclopropyl, pyrimidinyl, pyrazolyl, imidazolyl, -CH2-pyrazolyl, 1 -acetylpyrrolidinyl, 2-methylpyrrolidine- 1 - carboxylic acid methyl ester, l-cyclopropyl-2-methylpyrrolidine, l-(2,2- dimethylcyclopropyl)-2-methylpyrrolidine, and [-2-methyl- 1 -(2-methyl-pyrrolidine- 1 - carbonyl)-propyl]-carbamic acid methyl ester.
• R 4 is -C(0)R 5 wherein R 5 is selected from, -O-tert- butyl, cyclopropyl, tert-butyl, -NHCH 3 , 2,2-dimethylcyclopropyl, pyrimidinyl, pyrazolyl, imidazolyl, -CH2-pyrazolyl, and 1 -acetylpyrrolidinyl.
• R 4 is -C(0)R 5 wherein R 5 is a five- or six-membered heteroaryl ring;
• R 4 is -C(0)R 5 wherein R 5 is cyclopropyl or 2,2- dimethylcyclopropyl.
• R 4 is -C(0)R 5 wherein R 5 is selected from - ⁇ 3 ⁇ 4 ;
• R 4 is -C(0)R 5 wherein R 5 is selected from - ⁇ 3 ⁇ 4 ;
• R 4 is -C(0)R 5 wherein R 5 is -NHCH 3 .
• R 4 is -S(0)2R 6 wherein R 6 is selected from Ci- 6 alkyl, C3_ 6 cycloalkyl, and heteroaryl.
• R 4 is -S(0)2R 6 wherein R 6 is selected from Ci-6alkyl, C3_ 6 cycloalkyl, and a five- or six-membered heteroaryl.
• R 4 is -S(0)2R 6 wherein R 6 is Ci- 6 alkyl. In yet another specific aspect, R 4 is -S(0) 2 R 6 wherein R 6 is methyl.
• R 7 , R 8 , and R 11 are independently selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, -C(0)OR n , -CH 2 NR a R b , and -CN, wherein Ci_ 6 alkyl and
• Ci_ 6 alkoxy are optionally substituted with one, two, or three halo and wherein Ci- 6 alkoxy is optionally substituted with -OR d .
• R 7 , R 8 , and R 11 are independently selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, -C(0)OR n , -CH 2 NR a R b , and -CN, wherein Ci_ 6 alkyl and
• Ci_ 6 alkoxy are optionally substituted with one, two, or three halo
• R 7 is independently selected from halo, Ci- 6 alkyl, and Ci_ 6 alkoxy wherein Ci_ 6 alkyl and are optionally substituted with one, two, or three halo.
• R 7 is halo
• R 7 is chloro or fluoro.
• R 7 is selected from methyl, -CF 3 , -OCH 3 , -OCF 3 , and fluoro.
• R 7 is selected from fluoro, chloro, -CF 3; and -OCF 3 .
• R 9 is selected from d_ 6 alkyl, -CH 2 OR n , -C(0)NR n R p , and C(0)OR n , wherein Ci- 6 alkyl is optionally substituted with -S(0) 2 Ci_ 3 alkyl or with -SCi_ 3 alkyl.
• R 9 is selected from d_ 6 alkyl, -CH 2 OR n , -C(0)NR n R p , and C(0)OR n .
• R 9 is Ci- 6 alkyl or -CH 2 OR n .
• R 9 is Ci- 6 alkyl.
• R 9 is methyl
• R 10 is selected from hydrogen, halo, Ci- 6 alkyl, -C(0)OR c ,
• R 10 is selected from hydrogen, halo, and Ci_ 6 alkyl.
• R is halo; or R is chloro.
• R is hydrogen
• W, X', Y', and Z' are each CH.
• W, X, Y, and Z are independently carbon or nitrogen wherein any carbon atom is bonded to hydrogen or to R 7 , provided that at least two of W, X, Y, and Z are carbon.
• W, X, Y, and Z are independently carbon or nitrogen wherein any carbon atom is bonded to hydrogen or R 7 , provided that at least three of W, X, Y, and Z are carbon.
• W, X, Y, and Z are each carbon and two of W, X, Y, and Z are CH and two of W, X, Y, and Z are bonded to R 7 .
• W and Z are independently carbon bonded to R 7 and X and Y are CH.
• Q, T, U, and V are independently selected from CH and N.
• Q, U, and V are each CH and T is N.
• a is 1 or 2.
• a is 1.
• a is 0.
• b 0.
• c is 1 or 2.
• c is 2.
• c is 1.
• c 0.
• c is 1.
• d 0.
• the invention provides compounds of formula (I) disclosed in U.S. Provisional Application No. 61/492,267, filed on June 1, 2011.
• the invention provides compounds of formula (II):
• the invention provides compounds of formula (III)
• a particular group of compounds of formula (III) is a group wherein:
• R 1 is selected from Ci- 6 alkyl, phenyl, and C3_ 6 cycloalkyl, wherein Ci- 6 alkyl is optionally substituted with -OR q ;
• R 3 is selected from hydrogen, Ci_ 6 alkyl, -C(0)OCi_ 6 alkyl, -C(0)NR a R b ,
• R 5 is selected from Ci_ 6 alkyl, C 3 - 6 cycloalkyl, Ci_ 6 alkoxy, -C(R k R d )NR e R f , -NR s R h , heteroaryl, heterocycle, and -CH 2 -heteroaryl;
• any heteroaryl or heterocycle has 5 or 6 ring atoms
• Ci- 6 alkyl is optionally substituted with one or two substituents independently selected from -OR c , -NHC(0)Ci_ 3 alkyl, and -NHC(0)OCi_ 3 alkyl;
• Ci_ 6 alkoxy is optionally substituted with -OR d ;
• C 3 - 6 cycloalkyl is optionally substituted with one or two substituents independently selected from Ci_ 3 alkyl and halo;
• any heterocycle is optionally substituted with one, two, or three substituents independently selected from Ci_ 3 alkyl, halo, -C(0)OCi_ 3 alkyl , -C(0)Ci_ 6 alkyl, -C(0)C 3 _ 6 cycloalkyl, -C(0)NHCi_ 6 alkyl,
• any -C(0)Ci_ 6 alkyl is optionally substituted with
• any -C(0)C 3 _ 6 cycloalkyl is optionally substituted with one or two Ci- 3 alkyl, and
• any -C(0)NHCi_ 6 alkyl is optionally substituted with -OR" or
• any heteroaryl is optionally substituted with Ci_ 3 alkyl
• R k , R d , R e , R s , and R h are each independently hydrogen or Ci_ 3 alkyl; R is selected from hydrogen and -C(0)Ci_ 3 alkyl;
• R 7 is selected from halo, Ci_ 3 alkyl, and Ci_ 3 alkoxy wherein Ci- 6 alkyl and
• Ci_ 6 alkoxy are optionally substituted with one, two, or three halo;
• R 9 is Ci_ 3 alkyl
• a is 1 or 2;
• c is 1 or 2; and all other variables are as defined in formula (I).
• Another group of compounds of formula (III) is a group wherein:
• R 5 is selected from C 3 - 4 cycloalkyl, -CH 2 NR e R f , -NR s R h , imidazolyl, pyrazolyl, pyrimidinyl, and pyrrolidinyl;
• C3- 4 cycloalkyl is optionally substituted with one or two Ci_ 3 alkyl;
• pyrrolidinyl is substituted with methyl and a substituent selected from -C(0)OCi_ 3 alkyl , -C(0)Ci_ 6 alkyl, -C(0)NHCi_ 6 alkyl, wherein
• -C(0)Ci_ 6 alkyl is substituted with -NHC(0)OCi_ 3 alkyl, -OR", -NR d R e , or heterocycle;
• R e , R s , and R h are each independently hydrogen or Ci_ 3 alkyl; and R f is selected from hydrogen and -C(0)Ci_ 3 alkyl.
• R 1 is isopropyl, R 2 is hydrogen; R 3 is -C(0)OCH 3 ;
• R 7 is selected from fluoro, chloro, -CF 3 , and -OCF 3; R 9 is methyl; and
• R 5 is selected from -NHCH 3; 2,2-dimethylcyclopropyl, and
• the invention additionally provides compounds of formula (IV):
• the invention provides compounds of formula (V):
• the invention provides the compounds of Examples 1-77 and Tables 1-34 below.
• the invention provides a compound selected from the compounds depicted below
• the invention provides a compound selected from the following compounds
• the compounds of the invention contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like.
• Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated.
• the depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated
• Compounds of formula (I) also contain several basic groups (e.g., amino groups) and therefore, such compounds can exist as the free base or in various salt forms, such a mono-protonated salt form, a di-protonated salt form, a tri-protonated salt form, or mixtures thereof. All such forms are included within the scope of this invention, unless otherwise indicated.
• This invention also includes isotopically-labeled compounds of formula (I), i.e., compounds of formula (I) where an atom has been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass that predominates in nature.
• isotopes that may be incorporated into a compound of formula (I) include, but are not limited to, 2 H, 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 35 S, 36 C1, and 18 F.
• compounds of formula (I) enriched in tritium or carbon-14 which compounds can be used, for example, in tissue distribution studies.
• compounds of formula (I) enriched in deuterium especially at a site of metabolism which compounds are expected to have greater metabolic stability.
• compounds of formula (I) enriched in a positron emitting isotope such as n C, 18 F, 15 0 and 13 N, which compounds can be used, for example, in Positron Emission Tomography (PET) studies.
• PET Positron Emission Tomography
• alkyl means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl (Me), ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec -butyl, isobutyl, tert-butyl (t-Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2- propylpentyl, and the like
• C 1-3 alkyl means an alkyl group having from 1 to 3 carbon atoms wherein the carbon atoms are in any chemically-acceptable configuration, including linear or branched configurations.
• alkoxy means the monovalent group -O-alkyl, where alkyl is defined as above.
• Representative alkoxy groups include, by way of example, methoxy, ethoxy, propoxy, butoxy, and the like.
• cycloalkyl means a monovalent saturated carbocyclic group which may be monocyclic or multicyclic. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl (cPr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
• heterocycle means a monovalent saturated or partially unsaturated cyclic non-aromatic group, having from 3 to 10 total ring atoms, wherein the ring contains from 2 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• Heterocyclic groups may be monocyclic or multicyclic (i.e., fused or bridged).
• heterocyclic groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl, 2-imidazolinyl, 1,2,3,4-tetrahydroisoquinolin- 2-yl, quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom.
• such groups may alternatively be referred to as a non-valent species, i.e. pyrrolidine, piperidine, piperazine, imidazole, etc.
• heteroaryl or “heteroaryl ring” means a monovalent aromatic group having from 5 to 10 total ring atoms, wherein the ring contains from 1 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• Heteroaryl groups may be monocyclic or multicyclic.
• Representative heteroaryl groups include, by way of example, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyridyl (or, equivalently, pyridinyl), pyrimidyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom.
• such groups may alternatively be referred to as a non-valent species, i.e.pyrrole, isoxazole, isothiazole, pyrazole, imidazole, etc.
• halo means fluoro, chloro, bromo or iodo.
• terapéuticaally effective amount means an amount sufficient to effect treatment when administered to a patient in need of treatment.
• treatment means the treatment of a disease, disorder, or medical condition in a patient (such as hepatitis C viral infection), such as a mammal (particularly a human) which includes one or more of the following:
• compositions comprising (d) alleviating the symptoms of the disease, disorder, or medical condition in a patient.
• pharmaceutically acceptable salt means a salt that is acceptable for administration to a patient or a mammal, such as a human (e.g., salts having acceptable mammalian safety for a given dosage regime).
• Representative pharmaceutically acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic,
• salt thereof means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
• the cation can be a protonated form of a compound of formula (I), i.e. a form where one or more amino groups have been protonated by an acid.
• the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
• amino-protecting group means a protecting group suitable for preventing undesired reactions at an amino nitrogen.
• Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl and tri-fluoroacetyl; alkoxycarbonyl groups, such as tert butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and
• arylmethyl groups such as benzyl (Bn), trityl (Tr), and l,l-di-(4'-methoxyphenyl)methyl
• silyl groups such as trimethylsilyl (TMS), tert- butyldimethylsilyl (TBDMS), [2-(trimethylsilyl)ethoxy]methyl (SEM); and the like.
• TMS trimethylsilyl
• TDMS tert- butyldimethylsilyl
• SEM [2-(trimethylsilyl)ethoxy]methyl
• R 4a is an amino-protecting group Pg or R 4a is R 4 as defined in formula (I), and G represents the group Gi
• R 1 , R 2 ; and R 3 are defined as in formula (I), or as an amino-protecting group Pg.
• Aniline intermediate 1-1 is reacted with carboxylic acid 1-2 according to typical amide bond formation conditions to provide a compound of formula 1-3
• the carboxylic acid 1-2 is first converted to an acid chloride and then reacted with aniline intermediate 1-1 to provide a compound of formula 1-3.
• the amide bond formation reaction may utilize coupling agents, such as ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), or as 1,3 dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or benzotriazol-l-yloxytripyrrolidino-phosphonium hexafluorophosphate (PyBop), optionally combined with 1 -hydroxy-7-azabenzotriazole (HOAt).
• coupling agents such as ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), or as 1,3 dicyclohexylcarbodiimide (DCC), l-(3
• the process of Scheme 1 is used to prepare compounds of formula 1-3 in which R 7 is absent (a is 0) or R 7 is an electron rich substituent such as an unsubstituted-alkyl or unsubstituted-alkoxy, and the reaction is performed in the presence of coupling agents EDC and HOAt at a temperature of about 50 to about 60 °C.
• G and R 4a is a protecting group, or, if two protecting groups are present, groups removable under different conditions are used.
• R 4a is defined as R 4 and G is defined as protecting group Pg, for example Boc
• G is defined as protecting group Pg, for example Boc
• the product 1-3 of the reaction of Scheme 1 is a protected intermediate which is then deprotected, for example, by treatment with an acid, and reacted with a reagent X-Gi, where X is a halogen leaving group, or with a carboxylic acid of formula HO— Gi, the latter under amide bond formation conditions as described above, to provide the desired product.
• G represents a protecting group
• coupling with an intermediate X— Gi or HO— Gi provides the final product.
• the biaryl aniline intermediate 1-1 may be prepared by the Suzuki coupling reaction in the presence of a palladium catalyst (Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483).
• a palladium catalyst Moyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483
• either coupling partner may bear the boronate moiety.
• a boronic acid reagent may be used in place of a boronate reagent, such as the pinacol boronate depicted below.
• the reaction of a piperazine with a fluorobenzoic ester or fluoronicotinic ester 4-1, typically a methyl or ethyl ester, may be performed in dimethylsulfoxide in the presence of potassium carbonate at elevated temperature, typically about 100 °C to about 130 °C.
• the resulting intermediate 4-2 is subsequently hydro lyzed to provide protected intermediate 1-2".
• protected intermediate 1-2 where preferably the protecting group is Boc, can be deprotected and then reacted with an acid chloride, carboxylic acid, or isocyanate as in Scheme 2 to provide intermediate 1-2'.
• reaction of a fluoronicotinic acid 5-1 with the protected piperazine 5-2 to provide intermediate l-2a" is typically performed using isopropylmagnesium chloride at a temperature below about -20 °C.
• intermediate l-2a' protected intermediate l-2a", where preferably the protecting group is Boc, can be deprotected and esterified by reaction with sulfuric acid in methanol to provide an ester intermediate 5-3, which is reacted with an acid chloride, carboxylic acid, or isocyanate as in Scheme 2 and subsequently hydrolyzed to provide intermediate 1-2 a'.
• the protecting group is Boc
• Intermediate 2-1 where G represents Gi may be prepared by the process of Scheme 1 where the variable R 4a is defined as protecting group Pg.
• formula 1-3 describes a protected intermediate, which is deprotected to provide intermediate 2-1.
• biphenyl aniline 1-1 is reacted with a fluoropyridine carbonyl chloride 6-1 in the presence of base to provide fluoro intermediate 6-2, which is reacted with an excess of protected piperidine 5-2 to provide protected intermediate 6-3.
• the reaction typically is performed in the presence of base with heating to a temperature of about 80 °C to about 120 °C for a period of about 4 to about 48 hours.
• intermediate 6-3 is deprotected, for example, by treatment with hydrochloric acid in an organic solvent to provide intermediate 2-la as the HC1 salt.
• Yet another alternative process for the preparation of intermediate 2-la utilizes a Suzuki coupling reaction of the boronate reagent 3-2 with intermediate 7-1, followed by a deprotection step, under conditions described above, as shown in Scheme 7.
• the bromo intermediate 7-1 may be prepared, for example, by amide coupling of arylamine 8-1 with a fluoropyridine carbonyl chloride 6-1, followed by reaction with a protected piperazine 5-2 as shown in Scheme 8.
• Scheme 8
• intermediate 7-1 may be prepared by the reaction of 8-1 with the carboxylic acid intermediate 1-2" as given in Scheme 9.
• Reagent 10-1 where X represents bromo or chloro is reacted with a protected proline carboxylic acid 10-2 to provide intermediate 10-3 which is converted to intermediate 3-1", where the variable G represents a protecting group, in the presence of an excess of ammonium acetate.
• the ring closure reaction typically is performed at a temperature between about 100 °C and about 120 °C for a period of about 4 to about 24 hours.
• intermediate 3-1' is typically deprotected to provide intermediate 10-4, which is then coupled with a reagent HO-Gi to provide compound 3-1'.
• intermediate 3-1 is reacted with 11-1 in the presence of a palladium catalyst as shown in Scheme 11.
• boronate intermediate 3-2 may be prepared in situ according to the process of Scheme 11 and then reacted with intermediate 7-1 to provide intermediate 6-3 in a single pot process.
• the acid 12-1 and aniline or aminopyridine 12-2 are reacted under amide bond formation conditions.
• the reaction of Scheme 12 directly provides final compounds of formula (I).
• R 4a represents R 4 and G represents protecting group Pg, for example Boc
• the reaction provides a protected intermediate of formula 12-3 which is then deprotected and reacted with a reagent X-Gi, where X is a halogen leaving group, or with a carboxylic acid of formula HO— Gi, to provide the desired product.
• a compound of formula 12-3 in which G is defined as Gi and R 4a is a protecting group Pg provides a useful intermediate, which is deprotected and reacted, for example, with an acid chloride, carboxylic acid, or isocyanate, as in Scheme 2 to provide final compounds of formula (I).
• the intermediates of Scheme 12 may be prepared by conventional synthetic reactions.
• the biaryl acid intermediate 12-1 may be prepared by the Suzuki coupling reaction of Scheme 13
• a useful process for the preparation of the aminopyridine intermediate 12-2 of Scheme 12 utilizes a nitro substituted-chloropyridine or chlorophenyl 14-1 which is reacted with a protected piperazine 5-2 to provide a protected intermediate 14-2 as shown in Scheme 14.
• this disclosure encompasses compounds of formula (I) when prepared by synthetic processes such as those described above and below or by metabolic processes including those occuring in vivo in human or animal body or in vitro.
• compositions typically used in the form of a pharmaceutical composition or formulation.
• Such pharmaceutical compositions may be administered to a patient by any acceptable route of administration including, but not limited to, oral, rectal, vaginal, nasal, inhaled, topical (including transdermal) and parenteral modes of administration.
• the invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or excipient and a compound of formula (I), where, as defined above, "compound of formula (I)” means a compound of formula (I) or a pharmaceutically-acceptable salt thereof.
• such pharmaceutical compositions may contain other therapeutic and/or formulating agents if desired.
• the “compound of the invention” may also be referred to herein as the "active agent”.
• the term “compound of the invention” is intended to include all compounds encompassed by formula (I) as well as the species embodied in formulas (II), (III), (IV), and (V), and pharmaceutically-acceptable salts thereof
• compositions of the invention typically contain a
• a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.
• such pharmaceutical compositions will contain from about 0.1 to about 95% by weight of the active agent; preferably, from about 5 to about 70% by weight; and more preferably from about 10 to about 60% by weight of the active agent.
• any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.
• the choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts.
• the carriers or excipients used in the pharmaceutical compositions of this invention are commercially-available.
• conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen
• compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically-acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills and the like using conventional procedures and equipment.
• the pharmaceutical compositions of the invention are preferably packaged in a unit dosage form.
• unit dosage form refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units.
• unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration.
• the pharmaceutical compositions of the invention are suitable for oral administration.
• Suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a compound of the present invention as an active ingredient.
• the pharmaceutical compositions of the invention When intended for oral administration in a solid dosage form (i.e., as capsules, tablets, pills and the like), the pharmaceutical compositions of the invention will typically comprise the active agent and one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate.
• such solid dosage forms may also comprise: fillers or extenders, such as starches, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as
• absorbents such as kaolin and/or bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof; coloring agents; and buffering agents.
• Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the
• antioxidants examples include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like; oil- soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, and the like; and metal- chelating agents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid, phosphoric acid, and the like.
• water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like
• oil- soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocop
• Coating agents for tablets, capsules, pills and like include those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acidmethacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like.
• enteric coatings such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acidmethacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like.
• compositions of the invention may also be formulated to provide slow or controlled release of the active agent using, by way of example, hydroxypropyl methyl cellulose in varying proportions; or other polymer matrices, liposomes and/or microspheres.
• the pharmaceutical compositions of the invention may optionally contain opacifying agents and may be formulated so that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active agent can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
• Suitable liquid dosage forms for oral administration include, by way of illustration, pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• Liquid dosage forms typically comprise the active agent and an inert diluent, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• Suspensions in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated is
• microcrystalline cellulose aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• the compounds of this invention can also be administered parenterally (e.g. by intravenous, subcutaneous, intramuscular or intraperitoneal injection).
• parenteral administration the active agent is typically admixed with a suitable vehicle for parenteral administration including, by way of example, sterile aqueous solutions, saline, low molecular weight alcohols such as propylene glycol, polyethylene glycol, vegetable oils, gelatin, fatty acid esters such as ethyl oleate, and the like.
• Parenteral formulations may also contain one or more anti-oxidants, solubilizers, stabilizers, preservatives, wetting agents, emulsifiers, buffering agents, or dispersing agents. These formulations may be rendered sterile by use of a sterile injectable medium, a sterilizing agent, filtration, irradiation, or heat.
• compositions of the invention are formulated for administration by inhalation.
• Suitable pharmaceutical compositions for administration by inhalation will typically be in the form of an aerosol or a powder.
• Such compositions are generally administered using well-known delivery devices, such as a metered-dose inhaler, a dry powder inhaler, a nebulizer or a similar delivery device.
• compositions of the invention will typically comprise the active ingredient and a suitable propellant, such as dichlorodifluoromethane,
• the pharmaceutical composition may be in the form of a capsule or cartridge (made, for example, from gelatin) comprising a compound of the invention and a powder suitable for use in a powder inhaler.
• Suitable powder bases include, by way of example, lactose or starch.
• the compounds of the invention can also be administered transdermally using known transdermal delivery systems and excipients.
• the active agent can be admixed with permeation enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a patch or similar delivery system.
• permeation enhancers such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like
• Additional excipients including gelling agents, emulsifiers and buffers, may be used in such transdermal compositions if desired.
• the compounds of the invention have been shown to inhibit viral replication in HCV replicon assays and therefore are expected to be useful for the treatment of hepatitis C viral infections.
• the invention provides a method of inhibiting replication of the hepatitis C virus in a mammal (e.g., a human), the method comprising
• a therapeutically-effective amount of a compound of the invention or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the invention.
• the invention further provides a method of treating hepatitis C viral infections in a mammal (e.g., a human), the method comprising administering to the mammal a therapeutically-effective amount of compound of the invention or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the invention.
• a mammal e.g., a human
• the compounds of the invention may inhibit viral replication by inhibiting the function of the NS5A protein encoded by the HCV genome.
• the invention provides a method of inhibiting the NS5A protein of HCV in a mammal, the method comprising administering to the mammal, a compound or a composition of the invention.
• the compounds of the invention When used to treat HCV infections, the compounds of the invention will typically be administered orally in a single daily dose or in multiple doses per day, although other forms of administration may be used.
• the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• Suitable doses for treating HCV infections will range from about 1 to about 2000 mg/day of active agent, including from about 5 to about 200 mg/day and from about 10 to about 130 mg per day of active agent for an average 70 kg human.
• Compounds of the invention may also be used in combination with one or more agents which act by the same mechanism or by different mechanisms to effect treatment of HCV.
• Useful classes of agents for combination therapy include, but are not limited to, HCV NS3 protease inhibitors, HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, helicase inhibitors, NS4B protein inhibitors, HCV viral entry inhibitors, cyclophyllin inhibitors, toll-like receptor agonists, inhibitors of heat shock proteins, interfering RNA, antisense RNA, HCV internal ribosome entry site (IRES) inhibitors, thiazolides, nucleoside analogs such as ribavirin and related compounds, interferons and other immunomodulatory agents, inosine 5 '-monophosphate dehydrogenase (IMPDH) inhibitors, and other NS5A protein inhibitors.
• Agents which act to inhibit HCV replication by any other mechanism may also be used in combination with the
• HCV NS3 protease inhibitors which may be used in combination therapy include, but are not limited to, telaprevir (VX-950), boceprevir (SCH-503034), TMC-435, narlaprevir (SCH-900518), vaniprevir (MK-7009), danoprevir (ITMN-191, R-7227), BI- 201335, ABT-450, BMS-650032, GS-9256, ACH-1625, ACH-2684, BMS-605339, VX- 985, PHX-1766, BMS-791325, and IDX-320.
• HCV NS5B nucleoside polymerase inhibitors include, but are not limited to, RG7128, IDX-184, PSI-7977, PSI-7851, PSI-938, ⁇ -189 ( ⁇ -08189), RG7348, MK-0608, TMC-649128, and HCV-796, while, non-nucleoside HCV NS5B polymerase inhibitors, include but are not limited to, filibuvir (PF-8685540), tegobuvir (GS-9190), VX-222, VX-759, ANA-598 (setrobuvir), ABT-072, ABT-333, BI-207127, BMS-791325, MK-3281, IDX-37, and BMS-824393.
• interferons and pegylated interferons including alpha, beta, omega, and gamma interferons, having antiviral, antiproliferative or immunomodulatory effects, can be combined with the present compounds.
• Representative examples include, but are not limited to, Intron® A (interferon-alpha2b), Actimmune® (interferon-gamma- lb), Alferon N, Advaferon®, Roferon-A (interferon alpha-2a) Peglntron® (peginterferon- alpha 2b), Alfaferone, Pegasys® (peginterferon alpha-2a), Alfanative (interferon alpha), ZalbinTM (albinterferon alpha-2b), Infergon® (interferon alfacon-1), Omega DUROS® (omega interferon), LocteronTM (interferon alpha), PEG-rIL-29 (pegylated interferon lambda), and Rebif®
• Nucleoside analog antiviral agents include, but are not limited to, ribavirin (Copegus®, Rebetol®,Virazole®) and Viramidine (taribavirin). Interferons and ribavirin are also provided in in the form of kits which include, for example, but are not limited to, Rebetron® (interferon alpha-2b/ribavirin) and Pegetron® (Peginterferon alpha- 2b/ribavirin)
• Useful compounds acting by other mechanisms include, but are not limited to: cyclophilin inhibitors, such as DEB-025, SCY-635, NIM-81 1, and cyclosporine and derivatives; toll-like receptor agonists, such as resiquimod, IMO-2125, and ANA-773, HCV viral entry inhibitors, such as civacir, thiazolides, such as nitazoxanide, and broad- spectrum viral inhibitors, such as, inosine-5' -monophosphate dehydrogenase (IMPDH) inhibitors.
• cyclophilin inhibitors such as DEB-025, SCY-635, NIM-81 1, and cyclosporine and derivatives
• toll-like receptor agonists such as resiquimod, IMO-2125, and ANA-773
• HCV viral entry inhibitors such as civacir, thiazolides, such as nitazoxanide
• broad- spectrum viral inhibitors such as, inosine-5'
• compounds of the invention may be combined with an NS5A inhibitor, for example, BMS-790052, AZD-7295, PPI-461, PPI-1301, GS-5885, or GSK2336805.
• an NS5A inhibitor for example, BMS-790052, AZD-7295, PPI-461, PPI-1301, GS-5885, or GSK2336805.
• the invention provides a therapeutic combination for use in the treatment of hepatitis C viral infections, the combination comprising a compound of the invention and one or more other therapeutic agents useful for treating HCV.
• the invention provides a combination comprising a compound of the invention and one or more agents selected from HCV NS3 protease inhibitors, HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, interferons and pegylated interferons, and ribavirin and related nucleoside analogs.
• a pharmaceutical composition comprising a compound of the invention and one or more other therapeutic agents useful for treating HCV.
• the invention provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a compound of the invention and one or more other therapeutic agents useful for treating HCV.
• the invention provides a method of inhibiting replication of the hepatitis C virus in a mammal, the method comprising administering to the mammal a compound of the invention and one or more other therapeutic agents useful for inhibiting replication of the hepatitis C virus.
• the invention provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a compound of the invention, an interferon or pegylated interferon, and ribavirin.
• the invention provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a compound of the invention, an interferon or pegylated interferon, ribavirin, and an HCV NS3 protease inhibitor.
• the invention provides a method of treating a hepatitis C viral infection in a mammal, the method comprising administering to the mammal a compound of the invention, ribavirin, and an HCV NS3 protease inhibitor.
• Still other combination therapies include, for example, a compound of the invention, an HCV NS3 protease inhibitor, an HCV NS5B nucleoside polymerase inhibitor, and an HCV NS5B non-nucleoside polymerase inhibitor; and a compound of the invention, an HCV NS5B nucleoside polymerase inhibitor, and an HCV NS5B non- nucleoside polymerase inhibitor.
• the invention provides a method of inhibiting replication of the hepatitis C virus in a mammal, using a compound of the invention in combination with other agents, as described above.
• the agents may be formulated in a single pharmaceutical composition, as disclosed above, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. When administered separately, the agents are administered sufficiently close in time so as to provide a desired therapeutic effect.
• Such compositions can be packaged separately or may be packaged together as a kit. The two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration.
• the compounds of the invention may also find utility as research tools, for example, for discovering new HCV NS5A protein inhibitors or explicating mechanisms of HCV replication.
• Pd(dppf)Cl 2 dichloro( 1,1 ' -bis(diphenylphosphino)- ferrocene)dipalladium(II)
• THF tetrahydrofuran Reagents and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, etc.), and used without further purification. Reactions were run under nitrogen atmosphere, unless noted otherwise. Progress of reaction mixtures was monitored by thin layer chromatography (TLC), analytical high performance liquid chromatography (anal. HPLC), and mass spectrometry. Reaction mixtures were worked up as described specifically in each reaction; commonly they were purified by extraction and other purification methods such as temperature-, and solvent-dependent crystallization, and precipitation. In addition, reaction mixtures were routinely purified by preparative HPLC, typically using CI 8 or BDS column packings and conventional eluents. Typical preparative HPLC conditions are described below.
• Injection volume 100-1500 ⁇
• Triethylamine (2.3 g, 11.4 mmol) was added to a solution of 4-(4-bromo-phenyl)- 2-(5)-pyrrolidin-2-yl-lH- imidazole hydrochloride (2 g, 11.4 mol), (5)-2- methoxycarbonylamino-3-methyl-butyric acid (2.5 g, 7.6 mmol), and HATU (4.3 g, 11.4 mmol) in dimethylformamide (50 mL) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature overnight and treated with ethyl acetate (100 mL) and water (1000 mL).
• Tetrakis(triphenylphosphine)palladium(0) (468 mg, 0.41 mmol) was added. The reaction mixture was purged with nitrogen and then heated at 90 °C overnight. The reaction mixture was cooled to RT, diluted with methanol (10 mL), then filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC to give a white solid. (1.28 g) The crude material was dissolved in methanol (40 mL) and then pumped through a continuous flow hydrogenator at 70 °C using a palladium hydroxide on carbon (20 % w/w) cartridge. The resulting solution was concentrated to ⁇ 10 mL, treated with StratospheresTM PL-C03 resin and stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (680 mg).
• the reaction mixture was warmed to reflux under nitrogen, stirred for 4 h, cooled to RT, filtered, and concentrated. The residue was extracted with ethyl acetate and water, dried with sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 1 : 1 hexane:ethyl acetate, to provide the title compound (7 g, 75% yield) as a yellow solid.
• the TFA salt was dissolved in methanol (10 mL) and treated with StratospheresTM PL-C03 resin and stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to provide the title compound (0.354 g).
• reaction mixture was flushed with nitrogen, and tetrakis(triphenylphosphine)palladium(0) (122 mg, 0.106 mmol) was added under nitrogen.
• the reaction mixture was flushed with nitrogen and then heated at 90 °C overnight under an atmosphere of nitrogen.
• the product from the previous step was combined with the corresponding product of a previous run (total 1.13 g), dissolved in methanol (10.0 mL) and water (2.1 mL) and treated with lithium hydroxide monohydrate (564.5 mg) at 60 °C for 3 h.
• the reaction mixture was concentrated and the residue was treated with 1 : 1 acetic acid:water (8.0 mL), and sonicated. Additional TFA (3.0 mL) was and the reaction mixture was sonicated, resulting in a greyish solid precipitate.
• the reaction mixture was stirred at RT for 10 min and then filtered. The filtrate was extracted with EtOAc (20.0 mL).
• the reaction mixture was cooled with an ice- water bath and treated with water (3 mL). Concentrated HC1 was added dropwise over 45 min until the pH of the mixture was 1.5- 2.0. The cooling bath was removed and stirring was continued while adding concentrated HC1 to maintain the pH of the mixture -1.5-2.0. The reaction mixture was stirred overnight, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by preparative HPLC and washed with ethyl acetate to afford the title compound as a shiny white solid (5 g, 61 % yield).
• the brown oil of the previous step was treated with 4 M HQ in 1,4-dioxane (3.8 mL, 15.3 mmol) and stirred at room temperature for 1 h.
• the reaction mixture was concentrated and evaporated with ethyl acetate (2 x) to produce to produce a brown solid.
• the solid was dissolved in 1 : 1 acetic acid:water solution (4 mL), filtered, and purified by reverse phase HPLC to produce the tri-TFA salt of the title compound as a yellow solid, (m/z): [M+H] + calcd for C 39 H 48 8 0 5 709.37 found 709.9.
• Methyl lithium (24 mL, 0.038 mol) was added to a solution of the product of the previous step (9 g, 0.035 mol) in THF (20 mL) at -78 °C and the reaction mixture was stirred at RT for 12 h.
• Trimethyl phenylammonium tribromide 13 g, 0.036 mol was added to a solution of l-(4-bromo-3-methyl-phenyl)-ethanone (6.3 g, 0.030 mol) in THF (30 mL) and the reaction mixture was stirred at RT for 12 h, filtered, and concentrated to provide the title intermediate (8.6 g, 100 % yield).
• Tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added under nitrogen and then the reaction mixture was capped and heated at 100 °C overnight, cooled to RT and partitioned between ethyl acetate (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (12 g silica gel, 0- 100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title compound as a light yellowish foam (135 mg, 85 % yield), (m/z): [M+H] + calcd for C 28 H 3 5 5 0 3 490.27 found 490.6.
• Oxalyl dichloride (6.1 g, 48 mmol) was added to a solution of 4-bromo-3-fluoro- benzoic acid (7 g, 32 mmol) in DCM (80 mL) at 0 °C followed by DMF (0.2 mL) and the reaction mixture was stirred at RT for 2 h and then conentrated under vacuum to provide crude 4-bromo-3-fluoro-benzoyl chloride.
• Potassium carbonate 300 mg, 2.1 mmol was added to a solution of ((5)-1- ⁇ (5)- 2-[4-(4-bromo-3-fluoro-phenyl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl ⁇ -2-methyl- propyl)-carbamic acid methyl ester (200 mg, 0.4 mmol) and 3-fluoro-4-(4,4,5,5- tetramethyl-[l, 3,2]dioxaborolan-2-yl)-phenylamine(130 mg, 0.55 mmol) dissolved in toluene (0.91 mL, 8.6 mmol) and water (0.38 mL, 21 mmol).
• the red solid was purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to produce the desired product as a yellow solid, containing triphenylphosphine oxide.
• a portion of the yellow solid (50 mg) was dissolved in 1 : 1 acetic acid:water (5 mL) and purified by reverse phase HPLC to produce the TFA salt of the title intermediate as a white powder (210 mg, 99.3 % purity).
• Potassium carbonate (350 mg, 2.5 mmol) was added to a solution of [(5)-2- methyl- 1 -((5)-2- ⁇ 4- [4-(4,4,5 ,5 -tetramethyl- [ 1 ,3 ,2] dioxaborolan-2-yl)-phenyl] - 1 ⁇ - imidazol-2-yl ⁇ -pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (250 mg, 0.50 mmol) and 4-bromo-2-fluoro-5-trifluoromethoxy-phenylamine (140 mg, 0.50 mmol; Preparation 42) dissolved in toluene (2 mL) and water (0.54 mL).
• triphenylphosphine oxide impurity (m/z): [M+H] + calcd for C27H 29 F 4 50 4 564.2 found 564.4.
• Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of [(5)-2- methyl- 1 -((5)-2- ⁇ 4- [4-(4,4,5 ,5 -tetramethyl- [ 1 ,3 ,2] dioxaborolan-2-yl)-phenyl] - 1 ⁇ - imidazol-2-yl ⁇ -pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (340 mg, 0.68 mmol) and (25, 5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)- pyridin-2-yl]-2,5-dimethyl-piperazine-l-carboxylic acid tert-bu yl ester (400 mg, 0.
• Potassium carbonate (280 mg, 2.0 mmol) was added to a solution of [(5)-2- methyl- 1 -((S)-2- ⁇ 4- [4-(4,4,5 ,5 -tetramethyl- [ 1 ,3 ,2] dioxaborolan-2-yl)-phenyl] - 1 H- imidazol-2-yl ⁇ -pyrrolidine- l-carbonyl)-propyl]-carbamic acid methyl ester (200 mg, 0.40 mmol) and 5-amino-2-bromo-4-chlorobenzotrifluoride ( 1 10 mg, 0.40 mmol; Preparation 5 1 ) dissolved in toluene ( 1.3 mL) and water (0.43 mL).
• reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.48 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100 °C for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red solid, which was purified by silica gel chromatography (0- 100% ethyl acetate:hexanes) to produce the desired product as a yellow solid.
• reaction mixture was stirred at RT for 5 min and concentrated to produce ⁇ (5)-l-[(5)-2-(4- ⁇ 5'-chloro-4'-[(6-fluoro ⁇ yridine-3-carbonyl)-amino]-2'-trifluoromethyl- biphenyl-4-yl ⁇ -lH-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2-methyl-propyl ⁇ -carbamic acid methyl ester as a yellow solid.
• reaction mixture was stirred at 55 °C overnight, concentrated by rotary evaporation, and extracted with EtOAc (80 mL) and water (20 mL). The organic layer was washed again with water and then with brine, dried over sodium sulfate, filtered, and concentrated under vacuum, and purified by silica gel
• Lithium hydroxide (618 mg, 12.9 mmol) was added to a solution of the product of the previous step in methanol (15 mL) and water (3 mL), and the resulting mixture was stirred at 40 °C for 5 h, concentrated, and acidified with IN HCl to pH 4. The resulting mixture was extracted with ethyl acetate (2 x 50 mL).
• step a substituting the product of step a (7.6 g) for 2-bromo-l-(4-bromo-3-methyl-phenyl)-ethanone, the title intermediate was prepared (3.5 g) as a yellow foam.
• Example 1 ⁇ (S)-l-[(S)-2-(4- ⁇ 4'-[4-(4-Cyclopropanecarbonyl-piperazin-l-yl)- benzoylamino]-biphenyl-4-yl ⁇ -lH-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2-methyl- propyl ⁇ -carba
• reaction mixture was stirred for 15 min at room temperature, then ((5)-l- ⁇ (5)-2-[4-(4'-amino-biphenyl-4-yl)-lH-imidazol-2-yl]- pyrrolidine- l-carbonyl ⁇ -2-methyl-propyl)-carbamic acid methyl ester (25.0 mg, 0.054 mmol) was added and the mixture was allowed to stir overnight.
• the reaction mixture was concentrated and then dissolved in DCM (5 mL) and washed with saturated aqueous sodium bicarbonate (2 mL). The organic layer was concentrated.
• Example 4 ⁇ (S)-l-[(S)-2-(4- ⁇ 4'-[4-(4-Methanesulfonyl-piperazin-l-yl)- benzoylamino]-biphenyl-4-yl ⁇ -lH-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2-methyl- propyl ⁇ -carba
• Oxalyl chloride (44.0 uL, 0.520 mmol) was added to a solution of 4-(5-carboxy- pyridin-2-yl)-piperazine- l-carboxylic acid tert-butyl ester (70.3 mg, 0.229 mmol) in dichloromethane (6.67 mL, 104 mmol) and N,N-dimethylformamide (2.01 uL, 0.026 mmol)
• the reaction mixture was stirred at room temperature for 20 min and then N,N- diisopropylethylamine (0.181 mL, 1.04 mmol) was added followed by ((5)- l - ⁇ (5)-2-[4- (4'-amino-biphenyl-4-yl)- lH-imidazol-2-yl]-pyrrolidine- l-carbonyl ⁇ -2-methyl-propyl)- carbamic acid methyl ester (100.0 mg, 0.217 mmol).
• the reaction mixture was stirred for 2 h at room temperature, then dried by rotary evaporation.
• the crude material was dissolved in dichloromethane (1 mL) and then washed with saturated aqueous sodium bicarbonate (1 mL).
• the organic layer was concentrated, dissolved in 4.0 M hydrogen chloride in 1,4-dioxane (6.7mL, 27 mmol) and stirred for 1 h at room temperature until completely deprotected.
• the reaction mixture was concentrated and used directly in the next step.
• Example 11 ⁇ (S)-l-[(S)-2-(5-Chloro-4- ⁇ 4'-[4-(4-methylcarbamoyl-piperazin- l-yl)-benzoylamino]- biphenyl-4-yl ⁇ -lH-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2- methyl-propyl -carbamic acid methyl ester
• the reaction mixture was cooled to RT and water (5.0 mL) was added. The resulting mixture was centrifuged and filtered. The solid was combined with the product from a previous reaction in which Reactant A (237.8 mg, 0.383 mmol) was reacted with Reactant B (115.0 mg, 0.574 mmol) under the same conditions. The combined solids were dissolved in 1 : 1 acetic acid:water (20 mL), filtered, and split into three equal portions which were purified separately by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid. (805.5 mg total).
• reaction mixture was stirred at RT for 30 min and then ((5)- l - ⁇ (S)-2-[4-(4'-amino-2,2'- difluoro-biphenyl-4-yl)- lH-imidazol-2-yl]-pyrrolidine- 1 -carbonyl ⁇ -2-methyl-propyl)- carbamic acid methyl ester (10 mg, 0.02 mmol; Preparation 38-B) and N,N- diisopropylethylamine (18 uL, 0.10 mmol) were added and the reaction mixture was stirred at RT overnight.

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