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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/20—Spiro-condensed systems
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
• the invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection.
• the invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention.
• HCV hepatitis C virus
• the HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
• the NS proteins are derived by proteolytic cleavage of the polyprotein [R.
• the HCV NS protein 3 contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decrease viral infectivity [Chambers, T.J. et. al., "Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein", Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)].
• the first 181 amino acids of NS3 have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., "Hepatitis C Virus NS3 Serine Proteinase: Trans- Cleavage Requirements and Processing Kinetics", J. Virol., 68, pp. 8147-8157 (1994)]. [0007]
• the HCV NS3 serine protease and its associated cofactor, NS4A helps process all of the viral enzymes, and is thus considered essential for viral replication.
• inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS 3 protease inhibitors.
• such compounds may be useful as antiviral agents, particularly as anti-HCV agents.
• Each A is -(CXiX 2 ) a -;
• Each B is -(CXiX 2 ) b -;
• Each X 1 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (Ci- 4 )-aliphatic, optionally substituted aryl, or -0-X 1A ;
• Each X 2 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C 1- 4 )-aliphatic, optionally substituted aryl, or -0-X 1B ;
• X 1A and X 1B are each independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• X 1 and X 2 together form an oxo group
• Each R 1 is -Z A R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z A are optionally and independently replaced by -C(O)-, -C(S)-, -C(0)NR A -, -C(0)NR A NR A -, -C(O)O-, -NR A C(0)0-, -O-, -NR A C(0)NR A -, -NR A NR A -, -S-, -SO-, -SO 2 -, -NR A -, -SO 2 NR A -, or -NR A S0 2 NR A - provided that -NR A NR A -, -NR A C(0)NR A -, or -NR A S0 2 NR A - is not directly bound to the nitrogen ring atom of formula I;
• Each R 4 is independently R A , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R 2 is -Z 8 R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z B are optionally and independently replaced by -C(O)-, -C(S)-, -C(0)NR B -, -C(0)NR B NR B -, -C(O)O-, -NR B C(0)0-, -NR B C(0)NR B -, -NR B NR B -, -S-, -SO-, -SO 2 -, -NR B -, -SO 2 NR 8 -, or -NR B S0 2 NR B -, provided that SO, SO 2 , or -S0 2 NR B - is not directly bound to the carbonyl of formula I;
• Each R 5 is independently R B , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• R 1 and R 2 together with the atoms to which they are attached, form an optionally substituted heterocycloaliphatic ring;
• Each R 3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfmyl, sulfonamide, sulfamide, sulfo, -0-R 3A , an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R 3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R 7 is independently R°, halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R is independently hydrogen, or optionally substituted aryl
• Each of a and b is independently 0, 1, 2, or 3; provided that the sum of a and b is 2 or 3.
• the invention features a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to inhibit a serine protease; and an acceptable carrier, adjuvant or vehicle.
• the composition may include an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; and a cytochrome P-450 inhibitor; or combinations thereof.
• the immunomodulatory agent is ⁇ — , ⁇ — , or ⁇ -interferon or thymosin; said antiviral agent is ribavirin, amantadine, or telbivudine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease. Cytochrome P-450 inhibitor may be ritonavir.
• a method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound of formula I.
• the serine protease may be an HCV NS3 protease.
• the methods also inluce treating an HCV infection in a patient by administering a compound of formula I.
• the method may also include administering to said patient an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said additional agent is administered to said patient in the same dosage form as the serine protease inhibitor or as a separate dosage form.
• the immunomodulatory agent is ⁇ -, ⁇ -, or ⁇ -interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
• a method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment includes the step of contacting said biological sample or medical or laboratory equipment with a compound of formula I.
• the sample or equipment may be selected from blood, other body fluids, biological tissue, a surgical instrument, a surgical garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; a blood or other body fluid storage material.
• the compounds of the invention, as described herein, also exhibit advantageous PK properties and/or increased potency.
• the invention also relates to compositions that comprise the above compounds and the use thereof; methods of preparing compounds of formula I, and methods of assaying compounds for serine protease activity.
• Such compositions may be used to pre-treat devices that are to be inserted into a patient, to treat biological samples, and for direct administration to a patient. In each case, the composition will be used to ( lessen the risk of or the severity of the HCV infection.
• aliphatic encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
• an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
• An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.
• An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl ⁇ , heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroa
• substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
• carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
• cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alky
• an "alkenyl” group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
• An alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino al
• substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
• an "alkynyl” group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond.
• An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
• An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulf ⁇ nyl [e.g., aliphaticsulf ⁇ nyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO 2 -, aliphaticamino-SO 2 -, or cycloaliphatic- SO 2 -], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbon
• an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refers to an amido group such as -N(R X )-C(O)-R Y or -C(O)-N(R X ) 2 , when used terminally, and -C(O)- N(R X )- or -N(R X )-C(O> when used internally, wherein R x and R ⁇ are defined below.
• amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
• alkylamido such as alkylcarbonylamino or alkylaminocarbonyl
• heterocycloaliphatic such as alkylcarbonylamino or alkylaminocarbonyl
• heteroaryl heteroaryl
• an "amino" group refers to -NR X R Y wherein each of R x and R ⁇ is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulf ⁇ nyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted.
• amino groups examples include alkylamino, dialkylamino, or arylamino.
• amino When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR X -. R x has the same meaning as defined above.
• an "aryl” group used alone or as part of a larger moiety as in “ aralkyl” , “aralkoxy” or “ aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
• the bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings.
• a benzofused group includes phenyl fused with two or more C 4-8 carbocyclic moieties.
• An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carb
• Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di ( such as p, m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl
• an "araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a (C 1-4 )-alkyl group) that is substituted with an aryl group.
• "Aliphatic,” “alkyl,” and “aryl” are defined herein.
• An example of an araliphatic such as an aralkyl group is benzyl.
• an "aralkyl” group refers to an alkyl group (e.g., a (C 1-4 )-alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above.
• An example of an aralkyl group is benzyl.
• An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifiuoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycl
• a "bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common).
• Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
• a "cycloaliphatic” group encompasses a "cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
• a "cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
• Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyL adamantyl, azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
• a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds.
• Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.
• a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloali ⁇ hatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy,aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloali
• cyclic moiety includes cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been defined previously.
• heterocycloaliphatic encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.
• heterocycloalkyl refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
• heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[6]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.
• a monocyclic heterocycloalkyl group can be fused with a phenyl moiety such as tetrahydroisoquinoline.
• a "heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10- membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
• a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (ary
• a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
• a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
• a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl).
• heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl.
• heteroaryl examples include azetidinyl, pyridyl, IH- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo [b]furyl, benzo [b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo- 1,2,5-thiadiazolyl, or
• monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
• Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
• bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo [b] furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo [b] furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
• Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
• Aheteroaril is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; (cycl
• heterocycloaliphatic aliphatic
• carbonyl or (heteroaraliphatic)carbonyl]
• sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
• sulfinyl e.g., aliphaticsulfinyl
• sulfanyl e.g., aliphaticsulfanyl
• a heteroaryl can be unsubstituted.
• Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heteroaryl)amino)carbonyl)heteroaryl, (
• heteroaralkyl refers to an aliphatic group (e.g., a (C ⁇ -alkyl group) that is substituted with a heteroaryl group.
• aliphatic group e.g., a (C ⁇ -alkyl group
• heteroaryl e.g., a (C ⁇ -alkyl group)
• heteroaryl group refers to an alkyl group (e.g., a (C 1-4 )-alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
• a heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
• an "acyl” group refers to a forniyl group or R X -C(O)- (such as alkyl-C(O)-, also referred to as “alkylcarbonyl”) where R and "alkyl” have been defined previously.
• Acetyl and pivaloyl are examples of acyl groups.
• an "aroyl” or “heteroaroyl” refers to an aryl-C(O)- or a heteroaryl- C(O)-.
• the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
• alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
• a "carbamoyl” group refers to a group having the structure -O-CO- NR X R Y or -NR X -CO-O-R Z wherein R x and R ⁇ have been defined above and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
• a "carboxy” group refers to -COOH, -COOR X -OC(O)H, -OC(O)R X when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.
• haloaliphatic refers to an aliphatic group substituted with 1- 3 halogen.
• haloalkyl includes the group -CF 3 .
• mercapto refers to -SH.
• a "sulfo" group refers to -SO 3 H or -SO 3 R X when used terminally or - S(O) 3 - when used internally.
• a "sulfamide” group refers to the structure -NR X -S(O) 2 -NR Y R Z when used terminally and -NR X -S(O) 2 -NR Y - when used internally, wherein R x , R ⁇ , and R z have been defined above.
• a "sulfonamide” group refers to the structure -S(O) 2 -NR X R Y or -NR X -S(O) 2 -R Z when used terminally; or -S(O) 2 -NR X - or -NR X -S(O) 2 - when used internally, wherein R , R , and R are defined above.
• sulfanyl refers to -S-R x when used terminally and -S- when used internally, wherein R x has been defined above.
• examples of sulfanyls include aliphatic- S-, cycloaliphatic-S-, aryl-S-, or the like.
• sulfinyl groupf refers to -S(O)-R X when used terminally and -S(O)- when used internally, wherein R x has been defined above.
• Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic)) -S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
• a "sulfonyl” group refers to-S(O) 2 -R when used terminally and - S(O) 2 - when used internally, wherein R x has been defined above.
• Exemplary sulfonyl groups include aliphatic-S(O) 2 -, aryl-S(O) 2 -, (cycloaliphatic(aliphatic))-S(O) 2 -, cycloaliphatic-S(O) 2 - , heterocycloaliphatic-S(O) 2 -, heteroaryl-S(O) 2 -, (cycloaliphatic(amido(aliphatic)))-S(O) 2 -or the like.
• a "sulfoxy” group refers to -O-SO-R X or -SO-O-R X , when used terminally and -0-S(O)- or -S(O)-O- when used internally, where R x has been defined above.
• a "halogen” or “halo” group refers to fluorine, chlorine, bromine or iodine.
• an "alkoxycarbonyl,” which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.
• alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
• a "carbonyl” refer to -C(O)-.
• phospho refers to phosphinates and phosphonates.
• phosphinates and phosphonates include — P(O)(R P ) 2 , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
• an "aminoalkyl” refers to the structure (R x ) 2 N-alkyl-.
• a “cyanoalkyl” refers to the structure (NC)-alkyl-.
• a "urea” group refers to the structure -NR X -CO-NR Y R Z and a “thiourea” group refers to the structure -NR X -CS-NR Y R Z when used terminally and -NR X - CO-NR Y - or -NR X -CS-NR Y - when used internally, wherein R x , R ⁇ , and R z have been defined above.
• the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
• the term "geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
• terminal refers to the location of a group within a substituent.
• a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
• Carboxyalkyl i.e., R x O(O)C-alkyl is an example of a carboxy group used terminally.
• a group is internal when the group is present in the middle of a substituent of the chemical structure.
• Alkylcarboxy e.g., alkyl-C(O)O- or alkyl-OC(O)-
• alkylcarboxyaryl e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-
• cyclic group includes mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
• bridged bicyclic ring system refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged.
• bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3 ' 7 ]nonyl.
• a bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heter
• an "aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).
• a straight aliphatic chain has the structure-[CHQ 2 ] V -, where v is 1-6.
• a branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups.
• a branched aliphatic chain has the structure -[CHQ] v - where Q is hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance.
• aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
• the phrase "optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
• compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
• the variables R 1 , R 2 , and R 3 , and other variables contained in formulae described herein encompass specific groups, such as alkyl and aryl.
• each of the specific groups for the variables R 1 , R 2 , and R 3 , and other variables contained therein can be optionally substituted with one or more substituents described herein.
• Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
• an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
• the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
• substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
• Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
• an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
• a ring substituent such as a heterocycloalkyl
• substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
• stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
• a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
• an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al, Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
• patient refers to a mammal, including a human.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 1 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.
• the invention features certain compounds as described generically and specifically below. Such specific descriptions are illustrative only and are not meant to limit scope of the compounds or uses thereof.
• the invention provides compounds of formula I useful for inhibiting serine protease activity and methods of inhibiting serine protease activity.
• Compounds of formula I include:
• Each A is -(CX 1 X 2 ) a -;
• Each B is -(CXiX 2 ) b -;
• Each X 1 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C 1- 4 )-aliphatic, optionally substituted aryl, or -0-X 1A ;
• Each X 2 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C 1- 4 )-aliphatic, optionally substituted aryl, Or-O-X 1B ;
• X 1A and X 1B are each independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• X 1 and X 2 together form an oxo group
• Each R 1 is -Z R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z are optionally and independently replaced by -C(O)-, -C(S)-, -C(0)NR A -, -C(0)NR A NR A -, -C(O)O-, -NR A C(O)O-, -O-, -NR A C(0)NR A -, -NR A NR A -, -S-, -SO-, -SO 2 -, -NR A -, -SO 2 NR A -, or -NR A S0 2 NR A - provided that -NR A NR A -, -NR A C(0)NR A -, or -NR A S0 2 NR A - is not directly bound to the nitrogen ring atom of formula I;
• Each R 4 is independently R A , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R2is-ZBR 5,where inch Z B is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z B are optionally and independently replaced by -C(O)-, -C(S)-, -C(O)NR B -, -C(0)NR B NR B -, -C(O)O-, -NR 8 C(O)O-, -NR B C(0)NR B -, -NR B NR B -, -S-, -SO-, -SO 2 -, -NR B -, -SO 2 NR 8 -, or -NR B SO 2 NR B -, provided that SO, SO 2 , or -SO
• Each R 5 is independently R B , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• R 1 and R 2 together with the atoms to which they are attached, form an optionally substituted heterocycloaliphatic ring;
• Each R 3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfinyl, sulfonamide, sulfamide, sulfo, -0-R 3A , an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R 3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each R 7 is independently R°, halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 ;
• Each R° is independently hydrogen, or optionally substituted aryl
• Each of a and b is independently O, 1, 2, or 3; provided that the sum of a and b is 2 or 3.
• Each R 1 is -Z A R 4 , wherein each Z ⁇ is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z A are optionally and independently replaced by -C(O)-, -C(S)-, -C(0)NR A -, -C(0)NR A NR A -, -C(O)O-, -NR A C(0)0-, -0-, -NR A C(0)NR A -, -NR A NR A -, -S-, -SO-, -SO 2 -, -NR A -, -SO 2 NR A -,or-NR A SO 2 NR A - provided that -NR A NR A -, -NR A C(O)NR A -, or -NR A SO 2 NR A - is not directly bound to the nitrogen ring atom of formula I.
• EaChR 4 is independently R A , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 .
• Each R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• R 1 is optionally substituted with 1 to 4 substituents.
• R 1 is -Q 4 -W 4 -Q 3 -W 3 -Q 2 -W 2 -Q 1 ; wherein each of W 2 , W 3 , and W 4 is independently a bond, -C(O)-, -C(S)-, -C(O)N(Q 5 )-, -C(O)O-, -O-, -N(Q 5 )C(O)N(Q 5 )-, -SO 2 -, -N(Q 5 )SO 2 -, -S-, -N(Q 5 )-, -SO-, -OC(O)-, -N(Q 5 )C(O)O-, or -SO 2 N(Q 5 )-; each Of Q 1 , Q 2 , Q 3 and Q 4 is independently a bond, an optionally substituted C 1-4
• R 1 is an optionally substituted acyl group. In several examples, R 1 is an optionally substituted alkylcarbonyl. Additional examples OfR 1 include (amino)alkylcarbonyl, (halo)alkylcarbonyl, (aryl)alkylcarbonyl,
• R 1 is (heterocycloalkyl(oxy(carbonyl(amino)))alkylcarbonyl, (heteroaryl(carbonyl(amino(alkyl(carbonyl(amino)))))alkylcarbonyl, (bicycloaryl(sulfonyl(amino)))alkylcarbonyl, (aryl(alkoxy(carbonyl(amino))))alkylcarbonyl, (alkyl(carbonyl(amino)))alkylcarbonyl, (alkenyl(alkoxy(carbonyl(amino))))alkylcarbonyl, (cycloaliphatic(alkyl(amino(carbonyl(amino)))))alkylcarbonyl, (heteroaryl
• R 1 is an optionally substituted carboxy group.
• R 1 is optionally substituted alkoxycarbonyl.
• Another example OfR 1 includes (C 1-4 )-alkoxycarbonyl, or (tricyclic aryl)alkoxycarbonyl, each of which is optionally substituted with 1-3 substituents.
• carboxy groups include (aliphatic(oxy))carbonyl, a (heteroaralkyl(oxy))carbonyl, (heterocycloaliphatic(oxy)carbonyl, (aralkyl(oxy))carbonyl, each of which is optionally substituted with 1-3 of halo, alkoxy, aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.
• R 1 is optionally substituted aminocarbonyl.
• R 1 include (alkoxy(aryl(alkyl)))aminocarbonyl, (alkyl)aminocarbonyl, or (aryl(alkoxy(carbonyl(alkyl(amino(carbonyl(alkyl)))))))aminocarbonyl, each of which is optionally substituted with 1-3 substituents.
• R 1 is optionally substituted heteroaryl.
• R 1 is an optionally substituted oxazolyl, pyrrolyl, furyl, thiophenyl, triazinyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.
• R 1 is an alkylsulfonyl, aminosulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloaliphaticsulfonyl, or heterocycloaliphaticsulfonyl, each of which is optionally substituted with 1-4 substituents.
• R 1 is an optionally substituted alkylsulfonyl.
• R 1 include (aryl)alkylsulfonyl, or (alkyl(amino))alkylsulfonyl, each of which is optionally substituted with 1-3 substituents. alkylsulfonyl, aminosulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloaliphaticsulfonyl, or heterocycloaliphaticsulfonyl, each of which is optionally substituted.
• R 1 is an optionally substituted alkylsulfonyl.
• R 1 is (aryl)alkylsulfonyl, or (alkyl(amino))alkylsulfonyl, each of which is optionally substituted.
• R 1 is (amino)alkylcarbonyl, (halo)alkylcarbonyl, (aryl)alkylcarbonyl, (cycloaliphatic)alkylcarbonyl, or (heterocycloaliphatic)alkylcarbonyl, (heterocycloalkyl(oxy(carbonyl(amino))))alkylcarbonyl, (heteroaryl(carbonyl(amino(alkyl(carbonyl(amino))))alkylcarbonyl, (bicycloaryl(sulfonyl(amino)))alkylcarbonyl, (aryl(alkoxy(carbonyl(amino)))alkylcarbonylcarbonyl, (aryl(alkoxy(carbonyl(amin
• R 1 is a heteroarylcarbonyl, a (cycloaliphatic(alkyl(amido(alkyl))))carbonyl, a (heterocycloaliphatic(oxy(amido(alkyl))))carbonyl, an
• R 1 is amido.
• R 1 is (alkoxy(aryl(alkyl)))aminocarbonyl, (alkyl)aminocarbonyl, or
• R 1 is
• each of R 8 , R' 8 and R 9 in each subunit can be independently selected as described above.
• the set OfR 8 , R' 8 and R 9 variables in one subunit need not necessarily be identical to the same set of R 8 , R' 8 and R 9 variables in the other subunit.
• R 1 is QI or QII.
• R in the substituent in QI, QII, QIII, QIV, QV, or QVI is
• R1 is QVI and R is
• R in the substituent in QI, QII, QIII, QIV, QV, or QVI is
• each R 10 and R' 1O is independently hydrogen, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloaliphatic, or optionally substituted cycloaliphatic, or R 10 and R' 10 together with the atom to which they are both bound form an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic; and each K is independently a bond, (C 1-12 )- aliphatic, -O-, -S-, -S(O) 2 -, -NR 14 -, -C(O)-, or -C(O)NR 14 -, wherein R 14 is hydrogen or an optionally substituted (C 1-12 )-aliphatic; and n is 1-3.
• each R 10 can be the same or different.
• R 10 or R' 1O is [(C 3 _ 10 )-cycloalkyl or cycloalkenyl]-(C 1-12 )-aliphatic, (3 to 10 membered)-heterocycloaliphatic, (3 to 10 membered)-heterocycloaliphatic-(C 1-12 )-aliphatic-, (5 to 10 membered)-heteroaryl, or (5 to 10 membered)-heteroaryl-(C 1-12 )-aliphatic-. [0095] In still other embodiments, R in the substituent in QI, QII, QIII, QIV, QV, or QVI is
• R in the substituent in QI, QII, QIII, QIV, QV, or QVI is
• each Z is independently -O-, -S-, -NR50-, or -C(R.5o)2-, is independently a single bond or a double bond
• each R 50 is independently hydrogen, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloaliphatic, or optionally substituted cycloaliphatic
• n is 1 or 2.
• each R is independently hydrogen, amino, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; each R 8 and R'g is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and each R 9 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, or R 8 and R 9 , bound on adjacent atoms, taken together with the atoms to which they are
• R 1 1 and R' ! 1 together with the atom to which they are attached form a 3 to 7 membered ring.
• Non-limiting examples include:
• Non-limiting examples OfR 8 and R 11 include:
• R 8 and R 11 together with the atoms to which they are attached may form an optionally substituted 5 to 7 membered monocyclic heterocycloaliphatic or an optionally substituted 6 to 12 membered bicyclic heterocycloaliphatic, in which each heterocycloaliphatic or aryl ring optionally contains an additional heteroatom selected from O, S and N.
• R 8 and R9 together to with the atoms to which they are attached can form a ring
• R 7 and the ring system formed by R 8 and R 9 form an optionally substituted 8 to 14 membered bicyclic fused ring system
• the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10 to 16 membered tricyclic fused ring system.
• R 1 is: , wherein T is -C(O)-, and R is
• R 1 is a group selected from:
• R 1 is
• R is defined above.
• Each R 2 is -Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight (C 1-12 )-aliphatic chain wherein up to three carbon units of Z B are optionally and independently replaced by -C(O)-, -CS-, -C(O)NR B -, -C(0)NR B NR B -, -C(O)O-, -NR B C(O)O-, -O-, -NR B C(O)NR B -, -NR B NR B -, -NR B C(O)-, -S-, -SO-, -SO 2 -, -NR B -, -SO 2 NR B -, or -NR B SO 2 NR B -.
• Each R 5 is independently R B , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 .
• Each R B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• R 2 is -Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight C 1-12 aliphatic chain wherein up to three carbon units of Z B are optionally and independently replaced by -C(O)-, -C(S)-, -C(O)NR B -, - C(O)NR B NR B -, -C(O)O-, -NR B C(O)O-, -NR B C(O)NR B -, -NR B C(O)NR B -, -NR B NR B -, -S-, -SO-, -SO 2 -, -NR B -, -SO 2 NR B -, or -NR 3 SO 2 NR B -, provided that SO, SO 2 , or -SO 2 NR B - is not directly bound to the carbonyl of formula I.
• Each R 5 is independently R B , halo, -OH, -CN, -NO 2 , - NH 2 , or -OCF 3 .
• Each R B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• R 2 is -Z 1 -V 1 -Z 2 -V 2 -Z 3 -V 3 each of V 1 , V 2 , and V 3 is independently a bond, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, or a hydrogen when V 1 , V 2 , V 3 is the terminal group of R 2 ; each of Z 1 , Z 2 , and Z 3 is independently a bond, -C(O)-, -C(O)C(O)-, -C(S)-, -C(O)N(Q 6 )-, -N(Q 6 )C(O)-, -C(O)C(O)N(Q 6 )-, -O-, , SO-, -SO 2 -, -N(Q 6 )SO 2 -,
• R 2 is an optionally substituted (aliphatic)amino wherein the aliphatic portion of R 2 is -Z 2 -V 2 -Z 3 -V 3 or -Z 3 -V 3 wherein each of Z 2 and Z 3 is independently a bond, -C(O)-, -N(Q 5 )-, -CH(OH)-, -C(O)N(Q 6 )-, or -C(O)C(O)N(Q 6 )-; V 2 is independently a bond, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic; and V 3 is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.
• Z 2 is -CH(OH)-, V 2 is a bond, and Z 3 is -C(O)N(Q 6 )- such that R 2 is -N(Qe)-CH(OH)-C(O)-N(V 3 )(Q 6 ).
• R 2 is an optionally substituted (aliphatic)amino, optionally substituted (cycloaliphatic)amino, an optionally substituted alkoxy, or hydroxy.
• R 2 is an alkoxy optionally substituted with 1-3 of halo, hydroxy, aliphatic, cycloaliphatic, or heterocycloaliphatic.
• R 2 is amino.
• R 2 include a mono-substituted amino. Additional examples of R 2 include (cycloaliphatic(carbonyl(carbonyl(alkyl))))amino (amino(carbonyl(carbonyl(aliphatic))))amino, (aliphatic(carbonyl(carbonyl(aliphatic))))amino, or
• R 2 is -NR 2Z R' 2Z , -SR 2Y , or -NR 2 Y-CR 2x R' 2x -L 1 -NR 2Z -R 2 W, wherein R 2 ⁇ is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; each R 2 w is independently hydrogen, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloaliphatic, or optionally substituted cycloaliphatic; each R 2 ⁇ and R' 2X is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic; or R 2 ⁇ and R'
• each R 2 ⁇ and R' 2 ⁇ is independently hydrogen, or optionally substituted aliphatic, optionally substituted cycloaliphatic, or optionally substituted
• L 1 is -C(O)C(O)- or -SO 2 -.
• each R 2 w is hydrogen or optionally substituted cycloaliphatic.
• R 2 is -NH-CHR 2X -C(O)-C(O)-N(R 2Z )R 2W .
• R 2 is -NH-CHR 2X -CH(OH)-C(O)-N(R 2Z )R 2W .
• R 2 is -NH-CHR 2X -C(O)-C(O)-NHR 2Z wherein -NHR 2Z is
• R 2 is --NR 2Z R' 2Z , -SR 2Z wherein each R 2Z and R' 2Z is independently hydrogen, alkyl, cycloalkyl or aralkyl.
• R 2Z include methyl, ethyl, t-butyl, cyclopentyl, cyclohexyl and benzyl.
• R 2 is (-NH-CR 2x R' 2X - L 1 -C(O)) i -M; wherein each M is independently -OH, R 2x , -NR 2Z R' 2Z , or -OR 2x , each i is 1 or 2, and L 1 , R 2Z , R 2x , and R' 2Z are defined above.
• R 2 is (-NH-CR 2Z R' 2Z - L 1 -C(O)); -M wherein L 1 is -C(O)-, i is 1 and M is independently R 2x , -N(R 2X R' 2X ), -OR 2x , -NHSO 2 R 2x , or -SR 2x .
• R' 2Z is H and R 2Z is aliphatic, (aryl)aliphatic or cycloaliphatic.
• R 2x include hydrogen,
• R' 2X is H and R 2x is optionally substituted aliphatic, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaliphatic or optionally substituted heteroaralkyl.
• R 2x include: [00125] In several embodiments, R 2 is:
• R 2 is
• each R 56 is independently optionally substituted C 1-6 aliphatic; optionally substituted aryl, optionally substituted heteraryl, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic; each R 57 is independently optionally substituted aliphatic, optionally substituted aryl, optionally substituted aliphatic, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted cycloaliphatic or optionally substituted amino; and m is 1 or 2; and each R 2 ⁇ and R' 2 ⁇ is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; or R 2 ⁇ and R' 2 ⁇ together with the atom to which they are both attached form an optionally substituted 3 to 7 membered cycloaliphatic or heterocycloaliphatic ring.
• R 58 and R 59 are each independently selected from optionally substituted aliphatic, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (cycloaliphatic)oxy, optionally substituted (heterocycloaliphatic)oxy optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloaliphatic or optionally substituted amino; and each R 2 ⁇ and R' 2 ⁇ is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; or R 2 ⁇ and R' 2 ⁇ together with the atom to which they are both attached form an optionally substituted 3 to 7 membered cycloaliphatic or heterocycloaliphatic ring.
• a portion OfR 1 can form cyclic structures with a portion of R 2 .
• One non-limiting example includes:
• R 2 is one selected from:
• R 2 is
• X 202 is aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl.
• R 2 is
• R 2 Additional examples of R 2 are illustrated in PCT publications WO 2004/103996 Al, WO 2004/72243 A2, WO 03/064456 Al, WO 03/64455 A2, WO 03/064416 Al, and U.S. Patent Publication US 2005/0090450, as well as those other publications referenced herein, each of which is incorporated in its entirety by reference.
• Each R 3 is an aliphatic, a cycloaliphatic, a heterocycloaliphatic, an aryl, or a heteroaryl, each of which is optionally substituted.
• each R 3 is independently -Z C R 6 , wherein each Z° is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z c are optionally and independently replaced by -C(O)-, -CS-, -C(O)NR C -, -C(O)NR 0 NR 0 -, -C(O)O-, -NR 0 C(O)O-, -O-, -NR C C(O)NR 0 -, -NR 0 NR 0 -, -S-, -SO-, -SO 2 -, -NR 0 -, -SO 2 NR 0 -, or -NR 0 SO 2 NR 0 -.
• Each R 6 is independently R°, halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 .
• Each R° is independently hydrogen, an optionally substituted aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloahphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• Z c is a bond and R 6 is R
• R is independently an optionally substituted aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• each R 3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfinyl, sulfonamide, sulfamide, sulfo, -OR 3A , an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and each R 3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
• R 3 is an optionally substituted aryl.
• R 3 is a monocyclic, bicyclic, or tricyclic aryl, each of which is optionally substituted.
• R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted anthracenyl.
• R 3 is a monocyclic, bicyclic, or tricyclic aryl, each of which is optionally substituted with 1-4 of halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, (aliphatic)oxy, (halo(aliphatic))oxy, (aliphatic(oxy(aryl)))oxy, aryl, heteroaryl, haloaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.
• R 3 is an optionally substituted fused bicyclic aryl.
• R 3 is an optionally substituted fused tricyclic aryl.
• R 3 is an optionally substituted heteroaryl.
• R 3 is a monocyclic or bicyclic heteroaryl, each of which is optionally substituted with 1-4 of halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, (aliphatic)oxy, (halo(aliphatic))oxy, (aliphatic(oxy(aryl)))oxy, aryl, heteroaryl, haloaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.
• R 3 is optionally substituted aliphatic such as methyl, ethyl or propyl, each of which is optionally substituted.
• R 3 is an optionally substituted aliphatic.
• R 3 is an optionally substituted (C 1-5 )-aliphatic.
• R 3 is I
• R 3 is one selected from:
• Each A is -(CX 1 X 2 ) a -, wherein each X 1 and X 2 is independently hydrogen, optionally substituted (C 1-4 )-aliphatic, or optionally substituted aryl; or X 1 and X 2 taken together form an oxo group; and each a is 0 to 3.
• X 1 or X 2 is hydrogen.
• X 1 or X 2 is optionally substituted (C 1-4 )-aliphatic.
• Examples OfX 1 or X 2 include trifluoromethyl, or optionally substituted ethyl, propyl, butyl, or isomers thereof.
• X 1 or X 2 is an optionally substituted aryl.
• Examples OfX 1 or X 2 include optionally substituted phenyl, naphthyl, or azulenyl.
• Each B is -(CX 1 X 2 V, wherein each X 1 and X 2 is independently hydrogen, optionally substituted (C 1-4 )-aliphatic, or optionally substituted aryl; or X 1 and X 2 taken together form an oxo group; and each b is 0 to 3.
• X 1 or X 2 is hydrogen.
• X 1 or X 2 is optionally substituted (C ⁇ -aliphatic.
• Examples OfX 1 or X 2 include trifluoromethyl, or optionally substituted ethyl, propyl, butyl, or isomers thereof. In several additional examples, X 1 or X 2 is an optionally substituted mono- or di- substituted (amino)-(C 1 . 4 )-aliphatic.
• X 1 or X 2 is an optionally substituted aryl.
• Examples OfX 1 or X 2 include optionally substituted phenyl, naphthyl, indenyl, or azulenyl.
• each Y and Y' is independently hydrogen, optionally substituted aliphatic, or optionally substituted aryl.
• Each Y and Y' is independently -Z D R 7 , wherein each Z D is independently a bond or an optionally substituted straight or branched (C 1-6 )-aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -C(O)-, -CS-, -C(O)NR D -, -
• Each R 7 is independently R D , halo, -OH, -CN, -NO 2 , -NH 2 , or -OCF 3 .
• Each R° is independently hydrogen, or optionally substituted aryl.
• one selected from Y and Y' is hydrogen.
• one selected from Y and Y' is optionally substituted aliphatic.
• one selected from Y and Y' is optionally substituted aryl.
• both Y and Y' are hydrogen.
• one of Y or Y' is hydrogen and the other is fluorine.
• both of Y and Y' are fluorine.
• a + b is 2 or 3.
• a is 0 and b is 3; a is 1 and b is 2; a is 2 and b is 1; or a is 3 and b is 0.
• Another aspect of the present invention provides compounds of formula Ia useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula Ia include:
• R 3 , A, B, Y, and Y' are defined above in formula I.
• Each R la is -Q 4 -W 4 -Q 3 -W 3 -Q 2 -W 2 -Q 1 ; wherein each of W 2 , W 3 , and W 4 is independently a bond, -C(O)-, -C(S)-, -C(O)N(Q 5 )-, -C(O)O-, -O-, -N(Q 5 )C(O)N(Q 5 )-, -SO 2 -, -N(Q 5 )SO 2 -, -S-, -N(Q 5 )-, -SO-, -N(Q 5 )C(O)-, -OC(O)-, -N(Q 5 )C(O)O-, or -SO 2 N(Q 5 )-; each of Q1, Q2, Q3 , and Q4 is independently a bond, an optionally substituted C 1-4 aliphatic, an optionally substituted cycloalipha
• Each R 2a is -Z 1 -V 1 -Z 2 -V 2 -Z 3 -V 3 each OfV 1 , V 2 , and V 3 is independently a bond, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, or a hydrogen when V 1 , V 2 , V 3 is the terminal group of R 2 ; each OfZ 1 , Z 2 , and Z 3 is independently a bond, -C(O)-, -C(O)C(O)-, -C(S)-, -C(O)N(Q 5 )-, -N(Q 5 )C(O)-, -C(O)C(O)N(Q 5 )-, -O-, , SO-, -SO 2 -, -N(Q 5 )SO 2 -, -N(Q 5
• R 2a is an optionally substituted (aliphatic)amino, an optionally substituted alkoxy, or hydroxy.
• R 2a is an (aliphatic)amino wherein the nitrogen atom is optionally substituted with -Z 2 -V 2 -Z 3 -V 3 or -Z 3 -V 3 wherein each of Z 2 and Z 3 is independently a bond, -C(O)-, -N(Q 5 )-, or -C(O)C(O)N(Q 5 )-; and each of V 2 and V 3 is independently a bond, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.
• Another aspect of the present invention provides compounds of formula Ib useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula Ib include:
• Each G is a 2 to 15 atom optionally substituted aliphatic chain optionally containing 1 to 3 heteroatoms selected from O, S and N.
• Examples of compounds of formula Ib include:
• T, R, and R 3 are defined above in formula I.
• Another aspect of the present invention provides compounds of formula II useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula II include:
• Each R 3 is an optionally substituted aryl or an optionally substituted heteroaryl
• Each R 2 ⁇ is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Each Rp is independently hydrogen, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloaliphatic, or optionally substituted cycloaliphatic;
• Each R 2x and R' 2 ⁇ is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted cy cloaliphatic , an optionally substituted heterocycloaliphatic; or R 2x and R' 2X together with the atom to which they are both attached form an optionally substituted 3 to 7 membered cycloaliphatic or heterocycloaliphatic ring, or R 2 ⁇ and R 2 ⁇ together with the atoms to which they are attached form an optionally substituted 5 to 7 membered heterocycloaliphatic ring;
• Each R lb is -Z E R 21 , wherein Z E is -CH 2 -, -NH-, -CH(R 12 )-, or -O-, and R 21 is optionally substituted 6-7 membered cycloaliphatic or optionally substituted tert-butyl;
• Each R 1Z is optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl , or optionally substituted heteroaryl;
• Each R 2 z is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or optionally substituted aliphatic;
• Each R 2 w is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or optionally substituted aliphatic, or R 2 z and R 2W , together with the nitrogen atom to which they are attached form an optionally substituted heterocycloaliphatic.
• Compounds of formula III include:
• R' 2e is or hydrogen
• R 3e is optionally substituted aryl or optionally substituted heteroaryl.
• Another aspect of the present invention provides compounds of formula IV useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula IV include:
• Each of R 3f and R' 3f is independently hydrogen, sulfonamide, sulfonyl, sulfinyl, optionally substituted acyl, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl, or R 3f and R' 3f together with the nitrogen atom to which they are attached form an optionally substituted, saturated, partially unsaturated, or full unsaturated, 5-8 membered heterocycloaliphatic or heteroaryl.
• Another aspect of the present invention provides compounds of formula V useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula V include:
• Each D is independently -CR 8 -, N, S, or O, provided that no more than two D are independently, S, or O, and R 8 is defined above in formula I.
• Another aspect of the present invention provides compounds of formula VI useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula VI include:
• R 3g is a substituted aryl or a substituted heteroaryl. In some embodiments, R 3g
• Another aspect of the present invention provides compounds of formula VII useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula VII include:
• R 1 e , R 2e , and R' 2e are defined above in formula III, and R 3g is defined in formula VI.
• Another aspect of the present invention provides compounds of formula VIII useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula VIII include:
• Another aspect of the present invention provides compounds of formula IX useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula IX include:
• Another aspect of the present invention provides compounds of formula X useful for inhibiting serine protease activity and methods inhibiting serine protease activity.
• Compounds of formula X include:
• R 1e , R 2e , and R' 2e are defined above in formula III, and R 3g is defined in formula VI.
• the invention is intended to include compounds wherein R 1 and R 2 contain structural elements of a serine protease inhibitor.
• Compounds having the structural elements of a serine protease inhibitor include, but are not limited to, the compounds of the following publications: WO 97/43310, US 20020016294, WO 01/81325, WO 01/58929, WO 01/32691, WO 02/08198, WO 01/77113, WO 02/08187, WO 02/08256, WO 02/08244, WO 03/006490, WO 01/74768, WO 99/50230, WO 98/17679, WO 02/48157, WO 02/08251, WO 02/07761, WO 02/48172, WO 02/08256, US 20020177725, WO 02/060926, US 20030008828, WO 02/48116, WO 01/64678, WO 01/07407, WO 98/46630, WO 00/599
• Compounds of Formula I may be readily synthesized from commercially available starting materials using the exemplary synthetic routes provided below.
• Exemplary synthetic routes to produce compounds Formula I are provided below in the Preparations, Methods, Examples, and Schemes.
• the spiroisoxazoline moiety may be prepared by 1,3- dipolar addition between a nitrile oxide and a methylene proline as reported by Kurth, MJ., et. al, in J.Org.Chem., 2002, 67, pp. 5673-5677, and as illustrated in Scheme 1 below.
• the nitrile oxides can be generated from cholooximes or nitroalkanes using known methods.
• Scheme I provides a general representation of processes for preparing compounds of Formula I. Its overall strategy is to construct a compound of formula Ih followed by selective removal of the protecting group PG 1 in the presence of PG 2 to provide the intermediate Ij. The substituent R 1 may then be coupled to Ij, which provides intermediates of formula Ik containing R 1 .
• R 1 may itself contain a protecting group which may be selectively removed in the presence of PG 2 , followed by further elaboration. Subsequent to the addition of the R 1 moiety, the PG 2 group is removed to provide the intermediate Im. Coupling of Im with an R 2 moiety then provides the peptidomimetic compounds of Formula I.
• the hydroxy proline Ia is protected as the Boc derivative (i.e., step ia) to provide the protected proline Ib, wherein PG 1 is t- butyloxycarbonate, using known methods. See, e.g., T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons, Inc. (1999).
• Oxidation of Ib i.e., step ib
• the oxidation is achieved with a suitable reagent such as, for example, sodium hypochlorite in the presence of TEMPO.
• a suitable protecting group such as, for example, a t-butyl ester under known conditions (ibid) to provide the intermediate Ie.
• syn- means that the 2-carboxyl moiety of the proline ring and the oxygen of the isoxazoline ring are on the same side of a plane as described by the proline ring.
• anti- means that the 2-carboxyl moiety of the proline ring and the oxygen of the isoxazoline ring are on the opposite side of a plane as described by the proline ring.
• PG 1 when PG 1 is Boc and PG 2 is t-butoxy, selective removal of the protecting group PG 1 from Ig and Ih in the presence of the protecting group PG 2 may be achieved with a sulfonic acid such as, for example, methane sulfonic acid in a suitable organic solvent at temperatures from about -40 0 C to about 40 0 C, from about -20 0 C to about 20 0 C and from about -5 0 C to about 5 0 C.
• suitable organic solvents include, for example, methylene chloride and tetrahydrofuran.
• the isomers 1i and 1j may be separated advantageously by crystallization of a mixture of the corresponding organic acid salts which avoids more complicated methods such as, e.g., chromatography.
• Suitable organic salts include those of organic carboxylic acids, e.g., acetic acid, optionally substituted benzoic acids, tartaric acid, malonic acid, fumaric acid, oxalic acid, mandelic acid, citric acid, p-toluoyl tartaric acid and maleic acid; organic sulfonic acids, e.g., methane sulfonic acid, optionally substituted benzene sulfonic acids, trifluromethane sulfonic acid and camphor sulfonic acid.
• organic carboxylic acids e.g., acetic acid, optionally substituted benzoic acids, tartaric acid, malonic acid, fumaric acid, oxalic acid, mandelic acid, citric acid, p-to
• a single spiroisoxazoline isomer, for example Ij, is coupled with an acid R 1 COOH in the presence of a coupling reagent such as, for example, EDCI to provide the intermediate spiroisoxazoline Ik.
• a coupling reagent such as, for example, EDCI
• Selective removal of the protecting group PG 2 of Ik to give Im with minimum racemization or cleavage of the R 1 side chain is achieved by a suitable mineral acid in a suitable organic solvent at temperatures from about -40 °C to about 40 °C, from about - 20° C to about 20 °C and from about -5 °C to about 5 °C.
• Suitable mineral acids include, for example, concentrated hydrochloric acid or concentrated sulfuric acid.
• Suitable organic solvents include, for example, methylene chloride and tetrahydrofuran.
• the spiroisoxazoline Im is then coupled with an amine moiety R 2 to provide the compounds of Formula I.
• PG 1 (CO)- can be an amine protecting group, wherein PG 1 is, for example, methoxycarbonyl, t-butyloxycarbonyl, 9-flourenylmethyloxycarbonyl, or benzyloxycarbonyl.
• PG 2 (CO)- can be an acid or acid protecting group wherein PG 2 is, for example, -OH, methoxy, t-butyloxy or benzyloxy.
• Each OfPG 1 and PG 2 groups may be incorporated into the core spiroisoxazoline structure either individually or together using known methods and as further described herein.
• the desired R 1 substituted is a group other than a PG 1 group (e.g., a protecting group)
• the PG 1 group may be removed to provide a compound with a free amine group.
• That amine group and an appropriate moiety may be coupled under known coupling conditions to provide a compound wherein R 1 is a moiety of a protease inhibitor.
• the protecting group may be removed and an R 2 moiety may be incorporated.
• step iia simultaneous deprotection of both the amine and acid may be achieved by contacting the proline Ie with an acid, for example, trifluoroacetic acid in methylene chloride to give the amino acid 2a.
• an acid for example, trifluoroacetic acid in methylene chloride
• Preparation of the resin bound peptide 2d may be accomplished by reacting the Fmoc derivative 2b with the DHP resin bound amino-alcohol 2c, step iiic, which reacts with the free acid 2b, in the presence of a coupling reagent such as, for example, O-Benzotriazole- N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), a racemization suppressant, such as 1-hydroxybenzotriazole (HOBT) and a tertiary amine, such as di-isopropylethyl amine (DIEA).
• a coupling reagent such as, for example, O-Benzotriazole- N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), a racemization suppressant, such as 1-hydroxybenzotriazole (HOBT) and a tertiary amine, such as di
• an R 3 -substituted nitrile oxide If may undergo a dipolar cycloaddition reaction with the resin bound peptide 2d to provide two isomers, syn- and anti-, of the compound 2e.
• the Fmoc protecting group is removed by contacting 2e with a secondary amine such as, for example, piperidine in a polar solvent such as dimethylformamide to give 2f.
• Formation of the peptide 2g, via step iie, can be achieved through reaction of 2f with a carboxylic acid in the presence of a coupling reagent such as HBTU, a racemization suppressant such as HOBt, and a tertiary amine such as DIEA.
• Cleavage of the peptide-resin 2g, step iif, to give the alpha-hydroxy-amide 2h can be achieved by contacting 2g with a strong acid such as, for example, trifluoroacetic acid and water.
• the alpha-hydroxy-amide 2h is oxidized to 2i using a Dess- Martin periodinane oxidation or a Pfitzner-Moffat oxidation.
• Preparation of the resin bound peptide 2e may be accomplished by reaction of the Fmoc derivative 3a with the DHP resin bound amino-alcohol 2c, via step iiib, which reacts with a free acid 3b, in the presence of a coupling reagent (e.g., O-Benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate (HBTU)), a racemization suppressant (e.g., 1- hydroxybenzotriazole (HOBT)), and a tertiary amine (e.g., di-isopropylethyl amine (DIEA)).
• a coupling reagent e.g., O-Benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate (HBTU)
• HBTU O-Benzotriazole-N,N,N',
• step iid the Fmoc protecting group is removed by contacting 2e with a secondary amine such as, e.g., piperidine in a polar solvent such as dimethylformamide to give 2f.
• a secondary amine such as, e.g., piperidine
• a polar solvent such as dimethylformamide
• Formation of the peptide 2g can be achieved, e.g., by reacting 2f with a carboxylic acid in the presence of a coupling reagent (e.g., HBTU), a racemization suppressant (e.g., HOBt) and a tertiary amine (e.g., DIEA). Cleavage of the peptide-resin 2g to give the free peptide 2b.
• a coupling reagent e.g., HBTU
• a racemization suppressant e.g., HOBt
• a tertiary amine e.g.,
• the alcohol of 2h can be oxidized to 2i, e.g., with Dess-Martin periodinane or sodium hypochlorite and TEMPO.
• Scheme 4 illustrates a synthetic pathway for compounds of Formula I in which R 1 and R 2 , together with the atoms to which they are attached, form an optionally substituted macrocyclic heterocycloaliphatic.
• the spiroisoxazoline acid E4 reacts with the amino ester Hl in the presence of a coupling reagent to provide the intermediate H2. Macrocyclization of H2 results in compound H3. Hydrolysis of the ester H2 provides acid H4. Reaction of acid H4 with a sulfonamide or sulfamide in the presence of a coupling reagent provides the product H5.
• the hydroxy-spiroisoxazoline intermediate 5f may be alkylated to provide the intermediate 5k which may be similarly converted to compounds of the invention.
• the intermediate 6b. may be brominated to give 6j, alkylated to provide 6k or oxidized to provide 6m using the reagents illustrated.
• the Wittig product 9a undergoes a dipolar addition to provide the spiroisoxazoline 9b.
• Reduction of 9b with, for example, DIBAL provides the alcohol 9c which may be alkylated to provide the intermediate 9e which subsequently may be converted to compounds of the invention by methods previously described.
• Hydrolysis of ester 9b with, e.g., LiOH, will provide carboxylic acid 9d which can be converted to compounds of formula I as described herein.
• Scheme 10 :
• Another embodiment of this invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula I or pharmaceutically acceptable salts or mixtures of salts thereof.
• the compound of Formula I is present in an amount effective to decrease the viral load in a sample or in a patient, wherein said virus encodes a serine protease necessary for the viral life cycle, and a pharmaceutically acceptable carrier.
• salts of the compounds of this invention are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, oxalate
• Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N methyl D glucamine, and salts with amino acids such as arginine, lysine, and so forth.
• the basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil soluble or dispersible products are thereby obtained.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
• dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
• long chain halides such
• compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
• modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.
• ion exchangers alumina, aluminum stearate, lecithin
• serum proteins such as human serum albumin
• buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride
• compositions of this invention are formulated for pharmaceutical administration to a mammal.
• said mammal is a human being.
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra articular, intra synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally or intravenously.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• dosage levels of between about 0.01 and about 100 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
• dosage levels of between about 0.5 and about 75 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
• the pharmaceutical compositions of this invention 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.
• compositions of this invention comprise a combination of a compound of formula I and one or more additional therapeutic or prophylactic agents
• both the compound and the additional agent should be present at dosage levels of between about 10 to 100% of the dosage normally administered in a monotherapy regimen.
• the additional agent should be present at dosage levels of between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• carriers that are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried cornstarch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• compositions of this invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
• a suitable non irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
• Such materials include cocoa butter, beeswax and polyethylene glycols.
• the pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
• Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically trans
• the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
• the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
• the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
• the pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation.
• compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
• the pharmaceutical compositions are formulated for oral administration.
• compositions of this invention additionally comprise another anti-viral agent, preferably an anti-HCV agent.
• anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ , ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of U.S.
• PEG-INTRON® peginteferon alfa-2b, available from Schering Corporation, Kenilworth, NJ
• Intron means INTRON-A®, interferon alfa-2b available from Schering Corporation, Kenilworth, NJ;
• ribavirin means ribavirin (l-beta-D-ribofuranosyl-lH-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, CA; described in the Merck Index, entry 8365, Twelfth Edition; also available as REBETROL® from Schering Corporation, Kenilworth, NJ, or as COPEGASUS® from Hoffmann-La Roche, Nutley, NJ; "Pagasys” means PEGASYS®, peginterferon alfa-2a available Hoffmann-La Roche, Nutley, NJ;
• Roferon mean ROFERON®, recombinant interferon alfa-2a available from Hoffmann-La Roche, Nutley, NJ;
• Berefor means BEREFOR®, interferon alfa 2 available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, CT;
• SUMIFERON® a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan;
• WELLFERON® interferon alpha nl available from Glaxo_Wellcome LTd., Great Britain;
• ALFERON® a mixture of natural alpha interferons made by Interferon Sciences, and available from Purdue Frederick Co., CT.
• interferon means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response, such as interferon alpha, interferon beta, or interferon gamma.
• the interferon is ⁇ -interferon.
• a therapeutic combination of the present invention utilizes natural alpha interferon 2a.
• the therapeutic combination of the present invention utilizes natural alpha interferon 2b.
• the therapeutic combination of the present invention utilizes recombinant alpha interferon 2a or 2b.
• the interferon is pegylated alpha interferon 2a or 2b.
• Interferons suitable for the present invention include:
• protease inhibitor would be preferably administered orally. Interferon is not typically administered orally. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime. Thus, each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
• the protease inhibitor and interferon are administered in separate dosage forms.
• any additional agent is administered as part of a single dosage form with the protease inhibitor or as a separate dosage form.
• the specific amounts of each compound may be dependent on the specific amounts of each other compound in the combination.
• dosages of interferon are typically measured in IU (e.g., about 4 million IU to about 12 million IU).
• agents whether acting as an immunomodulatory agent or otherwise
• agents include, but are not limited to, AlbuferonTM (albumin-Interferon alpha) available from Human Genome Sciences; PEG-INTRON® (peginterferon alfa-2b, available from Schering Corporation, Kenil worth, NJ); INTRON-A®, (interferon alfa-2b available from Schering Corporation, Kenilworth, NJ); ribavirin (l-beta-D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, CA; described in the Merck Index, entry 8365, Twelfth Edition); REBETROL® (Schering Corporation, Kenilworth, NJ), COPEGUS® (Hoffmann- La Roche, Nutley, NJ); PEGASYS® (peginterferon alfa-2a available Hoffmann-La Roche, Nutley, NJ
• non-immunomodulatory or immunomodulatory compounds may be used in combination with a compound of this invention including, but not limited to, those specified in WO 02/18369, which is incorporated herein by reference (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11).
• Still other agents include those described in various published U.S. Patent Applications. These publications provide additional teachings of compounds and methods that could be used in combinatio wnith VX-950 in the methods of this invention, particularly for the treatment of hepatitis. It is contemplated that any such methods and compositions may be used in combination with the methods and compositions of the present invention. For brevity, the disclosure the disclosures from those publications is referred to be reference to the publication number but it should be noted that the disclosure of the compounds in particular is specifically incorporated herein by reference. Exemplary such publications include U.S. Patent Publication No. 20040058982; U.S. Patent Publication No. 20050192212; U.S. Patent Publication No. 20050080005; U.S.
• This invention may also involve administering a cytochrome P450 monooxygenase inhibitor.
• CYP inhibitors may be useful in increasing liver concentrations and/or increasing blood levels of compounds that are inhibited by CYP.
• any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention.
• CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436), ketoconazole, ⁇ oleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
• Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
• ritonavir see U.S. Pat. No. 6,037, 157, and the documents cited therein: U.S. Pat. No. 5,484,801, U.S. Application Serial No. 08/402,690, WO 95/07696 and WO 95/09614.
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
• a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
• the amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti- viral agent in the composition.
• the invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention, hi one embodiment, the methods of this invention are used to treat a patient suffering from a HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof. In another embodiment, the patient is a human being.
• the methods of this invention additionally comprise the step of administering to said patient an anti- viral agent preferably an anti-HCV agent.
• anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ — , ⁇ — , and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other antiviral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors andNS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including but not limited to helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX- 497 and other IMPDH inhibitors disclosed in U.S.
• IMPDH inhibitors e.g., VX- 497 and other IMPDH inhibitors
• Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent.
• compositions may also be prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patients supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
• a pack comprising at least one compound of formula I (in dosages according to this invention) and an information insert containing directions on the use of the combination of the invention.
• Any composition, dosage form, therapeutic regimen or other embodiment of this invention may be presented in a pharmaceutical pack.
• the pharmaceutical pack further comprises one or more of additional agent as described herein.
• the additional agent or agents may be provided in the same pack or in separate packs.
• kits for a patient to use in the treatment of HCV infection or in the prevention of HCV infection comprising: a single or a plurality of pharmaceutical formulation of each pharmaceutical component; a container housing the pharmaceutical formulation(s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.
• a kit will comprise, e.g. a composition of each compound and optional additional agent(s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.
• a packaged kit is provided that contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration.
• kits will typically include means for packaging the individual kit components, i.e., the dosage forms, the container means, and the written instructions for use.
• packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
• a kit according to this invention could embody any aspect of this invention such as any composition, dosage form, therapeutic regimen, or pharmaceutical pack.
• the packs and kits according to this invention optionally comprise a plurality of compositions or dosage forms. Accordingly, included within this invention would be packs and kits containing one composition or more than one composition.
• the present invention provides a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention.
• biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
• the invention provides methods of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle.
• This method comprises the step of contacting said material with a compound according to the invention.
• materials include, but are not limited to, surgical instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratory instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); blood collection apparatuses and materials; and invasive devices, such as, for example, shunts and stents.
• the compounds of this invention may be used as laboratory tools to aid in the isolation of a virally encoded serine protease.
• This method comprises the steps of providing a compound of this invention attached to a solid support; contacting said solid support with a sample containing a viral serine protease under conditions that cause said protease to bind to said solid support; and eluting said serine protease from said solid support.
• the viral serine protease isolated by this method is HCV NS3-NS4A protease.
• WO 04/113294 (1 g, 3.65 mmol) in cone.
• HCl (12 niL) was heated to reflux for 18 hours.
• the reaction was concentrated in vacuo to afford the desired amino acid as an HCl salt (1.7 g) which was used in the next step without further purification.
• a solution of the above HCl salt in THF was treated with DIPEA (2.68 g) and Z-OSu (5.16 g). The reaction mixture was stirred at room temperature for 8 hours.
• the organic layer was extracted with sat. NaHCO 3 (50 mL, twice).
• the combined organic layer was dried and concentrated in vacuo to afford the title compound (0.6 g). (M+ 1) 308.
• Step 1 Preparation of benzyl (2S)-l-cyano-3-cyclopropyl-l- hydroxypropan-2-ylcarbamate.
• Step 2 Preparation of (3S)-methyI 3-(benzyloxycarbonyIamino)-4- cyclopropyl-2-hydroxybutanoate.
• Step 4 Preparation of benzyl (2S)-l-cyclopropyl-3-hydroxy-4- (methyIamino)-4-oxobutan-2-ylcarbamate.
• Intermediate XX15 was prepared according to the procedure for preparing intermediate XXlO, step b, except for using substrate XX14 instead of XX9.
• Glycine methyl ester hydrochloride (50.0 g) was suspended in MTBE (300 mL) at RT. To this was added benzaldehyde (40.5 niL) and anhydrous Na2SO4 (33.9 g). The suspension was cooled in an ice-water bath for 20 minutes, then triethylamine (80 mL) was added dropwise over 15 minutes. After 5 minutes, the reaction was removed from the ice- water bath, and stirred at RT for 24 hours. The reaction was quenched with 200 mL ice- water mixture and the organic layer was separated. The aqueous layer was extracted with MTBE (200 mL).
• Lithium tert-butoxide (15.13 g) was suspended in dry toluene (200 mL) at room remperature. To this was added dropwise a solution of the N-benzyl imine of glycine methyl ester (16.89 g) and l,4-dibromo-2-butene (19.28 g) in toluene (100 mL) over 40 minutes. The red solution was stirred for 100 minutes, then quenched with H 2 O (200 mL). The contents were transferred to a separatory funnel and diluted with MTBE (200 mL). The layers were separated and the aqueous layer was extracted with MTBE.
• the combined organic layers were stirred with 1 N HCl (aq.) (500 mL) for 3 hours. The layers were separated and the organic layer was extracted with H 2 O (100 mL). The aqueous layers were combined, NaCl (250 g) and MTBE (700 mL) were added and the pH was brought to -13 with IO N NaOH (aq). The organic layer was separated and the aqueous layer was extracted with MTBE (twice, 300 mL each). The organic layers were combined, dried (MgSO 4 ), and concentrated to a volume of -400 mL. To the solution was added di-tert-butyl dicarbonate (25.0 g) and the reaction was stirred for 3 days.
• Racemic N-Boc-(lR,2S)/(lS,2R)-l-amino-2-vinylcyclopropane carboxylic acid methyl ester (4.2 g) was dissolved in acetone (80 mL) and then diluted with water (160 mL). The pH was adjusted to 7.8 with 0.2N NaOH (aq). Subtilisin A (product P-5380 from Sigma, St. Louis, MO, USA) (4.5 g) was added to the solution. Its pH was maintained between 7.4 and 8.7 for 3 days by the dropwise addition of 0.1 N NaOH (aq.).
• PS-Wang resin (2.Og, l.Oeq.) swelled in DMF (enough to cover).
• 5-chloronicotinaldehyde was prepared according to methods described by D.L.
• aldehydes such as 2-fluoro-5-chlorobenzaldehyde, 2-methoxy-3- methyl benzaldehyde, 2-methoxynicotinaldehyde, 2,3-dihydrobenofuran-7-carbaldehyde can be made from corresponding acid based on following procedure:
• the reaction was quenched with saturated NaHCO 3 (5 vol) and water (2 vol) and the aqueous layer was separated.
• the organic layer was extracted with saturated NaHCO 3 /water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite ® .
• the aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol).
• the organic phase was dried (MgSO 4 ) and the solvent removed.
• the crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol).
• Methanesulfonic acid 150 mL was slowly added maintaining 20 to 30 °C. The mixture was stirred at 25 °C and quenched after 7 hours by carefully adding a solution K 2 CO 3 (300 g) in water (1 L). The phases were separated and the aqueous phase was extracted with isopropyl acetate (1 L). The organic phases were combined and approximately half of the solvent removed under vacuum. The solution was washed with a 1 : 1 mixture of saturated brine (250 mL) and water (250 mL). The aqueous phase was extracted with isopropyl acetate (200 mL) and the organic phases combined then dried over K 2 CO 3 and filtered to afford a homogeneous solution.
• the solution volume was made up to 3 L by adding isopropyl acetate and then a solution of oxalic acid (20 g) in isopropyl acetate (400 mL) was slowly added.
• the solid was isolated by filtration and dried in a vacuum oven.
• the solid was suspended in isopropyl acetate (1.5 L) and water (1.0 L) then K 2 CO 3 was added slowly until the solids fully dissolved.
• the organic layer was isolated, dried over K 2 CO 3 , filtered then a solution of oxalic acid (12.5 g) in isopropyl acetate (250 mL) was added slowly.
• R 4 may contain an amine functionality. Where R 4 contains a protected amine, deprotection of the protected amine to give a free amine, following by a reaction with an activated acid, provides a further elaborated R 4 . Alternatively, a free amine in R 4 may be converted to the corresponding p-nitrophenylcarbamate followed by ractions with an amine or alcohol to provide R4 compounds containing carbamate or urea functionarity.
• Step 1 AUyI l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-ylcarbamate (MlA).
• the resin was washed with DCM (200 mL) and the combined filtrate were concentrated in vacuo to give the resin MlB, which was additionally washed with DCM (twice), DMF (thrice), DCM-MeOH (thrice in succession), Et 2 O, and dried under vacuum overnight to yield a light brown resin.
• the loading of the resin MlB was determined by cleavage of an aliquot (176mg) of the resin with 90% aq. TFA. Loading: 0.48 mmol/g.
• Step 1 3-Amino-N-cyclopropyl-2-hydroxyhexanamide bound resin (MlD).
• Step 2 (9H-Fluoren-9-yl)methyl 2-(l-(cycIopropylamino)-2-hydroxy-l- oxohexan-3-ylcarbamoyl)-4-methylenepyrrolidine-l-carboxyIate bound resin (MlE).
• the resin MlF was shaken in 20% piperidine/DMF for 10 minutes, filtered, and washed with DMF and DCM.
• the THP resin bound spiroisoxazoline proline (0.14 mmol, 0.3g) was mixed with FMOC-L-3-benzothienyl-ALA(0.56 mmol, 0.25g), HOBT (0.56 mmol, 0.075g), N,N-diisopropylethylamine (0.56 mmol, 0.072g), HBTU (0.56 mmol, 0.2Ig) in DMF 2.3 mL and was agitated for 48 hours.
• the resin was filtered and washed with DMF, dichloromethane, and ether to yield the resin compound MlG.
• the resin was filtered and washed with DMF, dichloromethane, and ether.
• the resin obtained was then mixed with a solution of (50:45:5) trifluoroacetic acid, dichloromethane, and triisopropyl silane (3 mL) and was agitated overnight.
• the reaction was filtered and washed with dichloromethane.
• the filtrate was concentrated under vacuum and purified via silica gel chromatography using a gradient of 40% ethyl acetate/60% dichloromethane to 100% ethyl acetate to produce the alcohol MlH.
• Step 1 Fmoc Protected Phenyl-Substituted Isoxazoline bound resin (MIL).
• the THP resin MlM (0.065 mmol) was shaken in 20% piperidine/DMF for 10 minutes, and then filtered and washed with DMF and DCM. The resulting resin was shaken overnight with a solution of 2-(pyridm-3-yl)acetic acid (0.25 mmol 3.0 eq.), HOBT (0.5 mL of 0.5 M in DMF, 3.85 eq.), HBTU (0.5 niL of 0.5 M in DMF, 3.85 eq.), and DIEA (0.5 mmol, 7.69 eq.). The resin was then filtered and washed with DMF and DCM and was shaken with 90% TFA in water for 30 minutes. The resulting solution was concentrated in vacuo to give the hydroxyl amide compound MlP (0.065 mmol) which was used in the next reaction without further purification. (M+ 1) 647.
• the Fmoc derivative A3 is prepared as described in Method 1. Reaction of A3 with the resin bound imino amide Dl in the presence of a coupling reagent provides the compound bound resin D2.
• the resin bound imino amide Dl may be prepared from the diketo compound X31 by reaction with an amino resin such as, for example, a derivatized aminomethylated polystyrene, e.g., X32. Deprotection of D2 provides D3 which reacts with an R 1 carboxylic acid in the presence of a coupling reagent to provide D4 wherein R 1 is R 4 C(O)-. Reaction of D4 with the nitrile oxide If provides D5 which on hydroysis from the resin provides AlO.
• N-Fmoc-4- methyleneproline (3.0 g, 8.8 mmol), HBTU (3.3 g, 8.8 mml) and HOBt (1.1 g, 8.8 mmol) and DIEA (1.6 mL, 8.8 mmol) were dissolved in DMF (100 mL). The solution was added to the resin and shaken overnight. The resin was then drained, washed with DMF (10 times), DCM (4 times) and dried to afford resin M4B.
• the intermediate compound Bl is transformed into amino acid ester E6.
• Reaction of E6 with an R 1 carboxylic acid in the presence of a coupling reagent provides E7 wherein R 1 is R 4 C(O)-.
• E7 is deprotected to provide E2 which is converted to AlO as described in Method 1.
• Example 11 Compound No. 562.
• Boc-t-butylglycine (686 mg, 3.0 mmol), EDC'HCl (659 mg, 3.43 mmol), HOBt (460 mg, 3.4 mmol), and DIEA (1.2 mL, 6.89 mmol) and stirred at room temperature overnight. The reaction was then transferred to a separatory funnel and diluted with EtOAc. The organic layer was washed with 1 N HCl (twice, 20 mL each), sat. aq. NaHCO 3 (25 mL), water (10 mL), brine (10 mL), dried over MgSO 4 and concentrated.
• Example 15 Compound No. 600
• Compound 600 has the same structure as compound 266 in Table A.
• Example 16 Compound No. 602
• Compound 602 has the same structure as compound 212 in Table A.
• Table 5 Additional Compounds of Formula I Produced by Methods 5a and 5b.
• the intermediate Al is converted to the Boc-methyl ester Fl.
• Removal of the Boc group from Fl provides the amine-ester F2 which is reacted with an R 1 carboxylic acid in the presence of a coupling reagent to provide F3 wherein R 1 is R 4 C(O)-.
• F3 reacts with a nitrile oxide If to provide the spiroisoxazoline acid E4 after hydrolysis of the corresponding methyl ester E3. Conversion of E4 to E7 is achieved as described in Method 5a.
• the Cbz hydroxy acid Gl is converted to the methyl ester G2 and deprotected to provide the amino-ester G3.
• Reaction of G3 with the spiroisoxazoline acid G4 in the presence of a coupling reagent provides the intermediate G5.
• Hydrolysis of the methyl ester of G5 provides the hydroxy acid G6 which is oxidized with, for example, Dess-Martin periodinane to provide the ketoacid G7.
• Reaction of G7 with an amine R 13 R 10 NH in the presence of a coupling reagent provides the final product G8.
• Step 3 Preparation of Compound No. 275
• Example 20 Compound No. 181.

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• 2011
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