WO2009142842A2 - Novel macrocyclic inhibitors of hepatitis c virus replication - Google Patents

Novel macrocyclic inhibitors of hepatitis c virus replication Download PDF

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Publication number
WO2009142842A2
WO2009142842A2 PCT/US2009/040565 US2009040565W WO2009142842A2 WO 2009142842 A2 WO2009142842 A2 WO 2009142842A2 US 2009040565 W US2009040565 W US 2009040565W WO 2009142842 A2 WO2009142842 A2 WO 2009142842A2
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Prior art keywords
alkyl
group
optionally substituted
separately
compound
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PCT/US2009/040565
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French (fr)
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WO2009142842A9 (en
WO2009142842A3 (en
Inventor
Scott Seiwert
Leonid Beigelman
Brad Buckman
Antitsa Dimitrova Stoycheva
Steven B. Porter
Williamson Ziegler Bradford
Vladimir Serebryany
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Intermune, Inc.
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Publication date
Priority to EA201071034A priority Critical patent/EA201071034A1/en
Priority to BRPI0911260A priority patent/BRPI0911260A2/en
Application filed by Intermune, Inc. filed Critical Intermune, Inc.
Priority to JP2011505148A priority patent/JP2011519364A/en
Priority to CN2009801189874A priority patent/CN102046622A/en
Priority to AU2009249443A priority patent/AU2009249443A1/en
Priority to AP2010005416A priority patent/AP2010005416A0/en
Priority to MX2010011306A priority patent/MX2010011306A/en
Priority to CA2720729A priority patent/CA2720729A1/en
Priority to EP09751072A priority patent/EP2282762A2/en
Publication of WO2009142842A2 publication Critical patent/WO2009142842A2/en
Publication of WO2009142842A3 publication Critical patent/WO2009142842A3/en
Priority to IL208529A priority patent/IL208529A0/en
Priority to ZA2010/07256A priority patent/ZA201007256B/en
Priority to MA33242A priority patent/MA32225B1/en
Priority to TNP2010000468A priority patent/TN2010000468A1/en
Publication of WO2009142842A9 publication Critical patent/WO2009142842A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/217—IFN-gamma
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • C07K5/123—Tripeptides

Definitions

  • the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • HCV infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States.
  • Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
  • Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using pegylated IFN- ⁇ plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders (NR) or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.
  • HCV is an enveloped positive strand RNA virus in the Flaviviridae family.
  • the single strand HCV RNA genome is approximately 9500 nucleotides in lingth and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non- structural (NS) proteins of the virus.
  • ORF open reading frame
  • NS structural and non- structural
  • the generation of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
  • the first viral protease cleaves at the NS2-NS3 junction of the polyprotein.
  • the second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as "NS3 protease").
  • NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein).
  • NS 3 protease exhibits activity both in cis, at the NS 3 -NS 4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites.
  • the NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • the formation of the complex between NS3 and NS4A is necessary for NS3-mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3.
  • the NS3 protease also exhibits nucleoside triphosphatase and RNA of HCV RNA.
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C 2 -6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(O)R
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(0) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(0)R 2a , -C(0)0R 2a , -NHC(O
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalky
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C 1 - 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6; alkyl, -(CH 2 ) q C3_7cycloalkyl, -(CH 2 ) q C6 or 1 0 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 )tC3_
  • Z is selected from the group consisting of
  • R 19 is hydrogen, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond; with the proviso that the compound of formula I is not
  • R 1 is hydrogen
  • R 2 is hydrogen, -C(O)R 4 or selected from the group consisting of Ci -6 alkyl, aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl, Ci -6 alkoxy, C 2 -6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci -6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb ,
  • R 4 is Ci- 6 alkyl or polycyclic moiety optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH 2 ) q C3_7cycloalkyl, C 2 _6 alkenyl, hydroxyl-Ci_6 alkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R 4 is -NR 90a R 90b or Ci_ 6 alkyl optionally substituted with up to 5 fluoro; wherein R 90a and R 90b are each separately a hydrogen atom or Q -6 alkyl; or R 90a and R 90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 -6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci_ 6 alkyl, C ? ,- ⁇ cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 -6 alkenyl, -(CH 2 ) q C3 -7 cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci -6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4a is imidazolyl or pyrazolyl;
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each q is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; wherein R 9c is Ce or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9d is Ce or 1 0 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or 1 0 aryl, and C ⁇
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 19 is hydrogen, -SO m R 2a , or Ci_ 6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 1 is hydrogen; fluoro;
  • R 4 is -NR 90a R 90b , or Ci_ 6 alkyl optionally substituted with up to 5 fluoro;
  • R 90a and R 90b are each separately a hydrogen atom, or Ci_ 6 alkyl; or R 90a and R 90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 - 7 cycloalkyl substituted with methyl; or R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; wherein R 9c is Ce or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
  • R 9d is Ce or 1 0 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or 1 0 aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of C ⁇ -e alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 3 is a -CONR 100a R 100b ;
  • each m is separately 0, 1 or 2;
  • each q is separately 0, 1 or 2;
  • each t is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 100a is hydrogen, and R 100b is a hydrogen, or -(CH 2 ) v CONR 200a R 200b ; or R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • each p is separately an integer selected from 1-6;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (o) Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci_ 6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 1 is-(CR 5 R 6 ) n R 4 ;
  • n 0, 1 or 2;
  • R 2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C 2 -6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3_6 heterocycloalkyl, -S(O) 2 NR la R lb , -NHC(O)NR la R lb , -NHC(S)NR la R lb , -C(O)NR la R lb , -NR la R lb , -C(O)R 2a , -C(O)OR 2a , -NHC(O)R 2a , -NHC(O)OR 2a , -SO m R 2a ,
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(0) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(S
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, Q -6 alkoxy, phenyl, and hydroxy-C ⁇ tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci_ 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • each R 4a is separately imidazolyl or pyrazolyl
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each r is separately an integer selected from 1-6;
  • R 3 is -P(O)R 10a R 10b , wherein R 1Oa and R 1Ob are each separately selected from the group consisting of hydroxy, -(O) v -Ci_6 alkyl, -(O) v - (CH 2 ) q C3_7cycloalkyl, - (O) v -aryl, and -(O) v -heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3-7 cycloalkyl, C 2 - ⁇ alkenyl, Ci_ 6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
  • each t is separately 0, 1 or 2;
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci_ 6 alkyl, phenyl, Ci_ 6 alkyl substituted with up to 5 fluoro, and Ci_ 6 alkoxy substituted with up to 5 fluoro; or R 5 and R 6 are taken together with the carbon to which they are attached to form a C 3 _ 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH 2 ) u C3_7cycloalkyl,
  • R 19 is hydrogen, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(O)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, Ce or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 2a is separately selected from the group consisting of Ci -6 alkyl, C 3 _ 7 cycloal
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C 1 - 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6; group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkoxy, C 2 _ 6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C3 -7 cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR 7 R 8 , -NHC(O)NR 7 R 8 , -NHC(S)NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -C(O)R 13 , -C(O)OR 13 , -NHC(O)R 13 , -NHC(O)OR 13
  • R 7 and R 8 are each separately a hydrogen, or separately selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3_7 cycloalkyl, C 4 - I o alkylcycloalkyl, C 2 _6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and C O o r 1 0 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 _6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 13 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the the tetrahydropyran ring;
  • R 14 and R 15 are each separately selected from hydrogen and Ci_ 6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 16 is separately imidazolyl or pyrazolyl;
  • V is selected from the group consisting of -O-, -S-, and -NR 15 -;
  • W is -N- or -CR 15 -; wherein R 15 is H, or selected from the group consisting of Ci_ 6 alkyl, (CH 2 ) q C 3-7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci -6 alkyl, Ci -6 alkoxy, or phenyl; each u is separately 0, 1 or 2;
  • Z is selected from the group consisting of
  • R 19 is hydrogen, Ci -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • R 1 is hydrogen
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci-6 alkyl, -(CH 2 ) q C3_7cycloalkyl, Ce or 1 0 aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is
  • R 9a and R 9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and Ce o r io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH 2 ) t C3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci -6 alkyl substituted with up to 5 fluoro, and Ci -6 alkoxy substituted with up to 5 fluoro, or R 9a and R 9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated hetero
  • R 9d is Ce or 1 0 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or 1 0 aryl, and Q -6 alkyl optionally substituted with up to 5 fluoro; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of C ⁇ -e alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 3 is a -CONR 100a R 100b ; or R 3 is a carboxy
  • each t is separately 0, 1 or 2;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and C ⁇ -e alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl, Ci_ 6 alkoxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 _ 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(O) 2 NR 7 R 8 , -NHC(O)NR 7 R 8 , -NHC(S)NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -C(O)OR 13 , -NHC(O)R 13
  • R and R are each separately a hydrogen, or separately selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3-7 cycloalkyl, C 4 - 1 0 alkylcycloalkyl, C 2 _6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is selected from the group consisting of Q -6 alkyl, C 3 _ 7 cycloalkyl, and Ce o r 1 0 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, Ci_ 6 alkoxy, phenyl, and hydroxy-Ci_ 6 alkyl; or R 13 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 13 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 14 and R 15 are each separately selected from hydrogen and Ci_ 6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 16 is imidazolyl or pyrazolyl
  • (q) V is selected from the group consisting of -0-, -S-, and -NR 23 -;
  • (r) R 23 is H, or selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally consisting of halo, cyano, nitro, Ci_ 6 alkyl, Ci_ 6 alkoxy, or phenyl; wherein said phenyl as an optional substituent is further optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 30 is H, or selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci -6 alkyl, Ci -6 alkoxy, or phenyl;
  • R 19 is hydrogen, -SO m R 2a , or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, C 2 -6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, Ce or 1 0 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 ) t C3 -7 cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci -6 al
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C3 -7 cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C 1-6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -C(O)R 2a , -C(O)OR 2a , -NHC(O)R 23 , -NHC(O)OR 23 , -SO 1n R 23
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, Cj,. ⁇ cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C 1 - 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) u C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, Ci_ 6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R 5 and R 6 are taken together with the carbon to which they are attached to form a C 3 _ 7 cycloalkyl, optionally substituted with one or cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy,
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl, Ci_ 6 alkoxy, C 2 _ 6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3 -7 cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR 7 R 8 , -NHC(O)NR 7 R 8 , -NHC(S)NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -C(O)R 13 , -C(O)OR 13 , -NHC(O)R 13 , -
  • R and R are each separately a hydrogen, or separately selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C3-7 cycloalkyl, C 4- 1 0 alkylcycloalkyl, C 2 _6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with
  • R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C3 -7 cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R 13 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 13 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 14 and R 15 are each separately selected from hydrogen and Ci -6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 16 is separately imidazolyl or pyrazolyl; -(CH 2 ) q C 3 - 7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and -NR la R lb ;
  • E and F are independently -N- or -CR -; when E is -CR 18 -, F is -N-; when F is -CR 18 -, E is -N-; each R 18 is separately a hydrogen, or selected from the group consisting of Ci -6 alkyl, (CH 2 ) q C 3 _ 7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; each u is independently 0, 1 or 2;
  • Z is selected from the group consisting of
  • R 19 is hydrogen, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C 1-6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R l
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; cycloalkyl, and Ce or 10 aiyl, each optionally substituted with one or more substituents each
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C 1 - 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of d_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci-6 alkyl, phenyl, Ci -6 alkyl substituted with up to 5 fluoro, and Ci -6 alkoxy substituted with up to 5 fluoro; or R 5 and R 6 are taken together with the carbon to which they are attached to form a C 3 - 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) u C 3-7 cycloalkyl, C 2
  • R 19 is hydrogen, Ci -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 - 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 -6 alkenyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, Q -6 alkoxy, phenyl, and hydroxy-C ⁇ alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • each m is separately 0, 1 or 2; (e each q is separately 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci-6 alkyl, -(CH 2 ) q C3_7cycloalkyl, Ce or io aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is
  • R 9a and R 9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and Ce o r io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH 2 ) t C3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci -6 alkyl substituted with up to 5 fluoro, and Ci -6 alkoxy substituted with up to 5 fluoro, or R 9a and R 9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated hetero
  • each t is separately 0, 1 or 2;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of: and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Q -6 alkyl, Q -6 alkoxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 _ 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(O) 2
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 - 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken piperidinyl, piperazinyl, or morpholinyl;
  • each R 2a is separately selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C 2 _6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci -6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4a is imidazolyl or pyrazolyl
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each q is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 20 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, C ⁇ -e alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C 1-6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , --NH
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; wherein R 9c is Ce or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
  • R 9e is selected from the group consisting of hydrogen, Ce or 1 0 aryl, and Ci_ 6 alkyl optionally substituted with up to 5 fluoro; or R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl substituted with methyl; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or
  • each t is separately 0, 1 or 2;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (r) Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y is within 4 A or less of at least one moiety selected from NS3 protease His57 imidazole moiety and NS3 protease GIy 137 nitrogen atom;
  • Pi' is a moiety, different from Y, having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Pi' is within 6 A consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43;
  • L is a moiety consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
  • P 2 is a moiety selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic;
  • P 2 is positioned by L such that, upon binding of the compound to NS 3 protease, at least one atom of P 2 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Tyr56, His57, Val78, Asp79, Gln80, Asp81, Argl55 and Alal56;
  • R 50 is H and R 60 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; or R 50 and R 60 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
  • R 50 and R 60 are positioned such that, upon binding of the compound to NS3 protease, at least one atom of R 50 or R 60 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Argl23, Alal56, Alal57, Vall58, Cysl59, and Aspl68.
  • hepatic fibrosis used interchangeably herein with “liver fibrosis,” refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.
  • the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
  • liver function refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'- nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
  • serum proteins e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transa
  • sustained viral response refers to the response of an individual to a viral response” refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
  • Treatment failure patients generally refers to HCV- infected patients who failed to respond to previous therapy for HCV (referred to as “non- responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers").
  • the previous therapy generally can include treatment with IFN- ⁇ monotherapy or IFN- ⁇ combination therapy, where the combination therapy may include administration of IFN- ⁇ and an antiviral agent such as ribavirin.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • Type I interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor.
  • Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non- peptide chemical agonists; and the like. naturally occurring or non-naturally occurring ligand of human Type II interferon receptor that binds to and causes signal transduction via the receptor.
  • Type II interferon receptor agonists include native human interferon- ⁇ , recombinant IFN- ⁇ species, glycosylated IFN- ⁇ species, pegylated IFN- ⁇ species, modified or variant IFN- ⁇ species, IFN- ⁇ fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
  • a Type El interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of humanIL-28 receptor ⁇ ("IL- 28R”), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.
  • IL- 28R humanIL-28 receptor ⁇
  • interferon receptor agonist refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III interferon receptor agonist.
  • dosing event refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device.
  • the term "dosing event,” as used herein includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
  • Continuous delivery as used herein (e.g., in the context of “continuous delivery of a substance to a tissue”) is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
  • Controlled release as used herein (e.g., in the context of “controlled drug release”) is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN- ⁇ ) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use.
  • substance e.g., a Type I or Type III interferon receptor agonist, e.g., IFN- ⁇
  • Controlled release thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
  • a pattern generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection).
  • a pre-selected period of time e.g., other than a period associated with, for example a bolus injection.
  • “Patterned” or “temporal” drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
  • controlled drug delivery device is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
  • substantially continuous as used in, for example, the context of “substantially continuous infusion” or “substantially continuous delivery” is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero.
  • substantially continuous drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
  • substantially steady state as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average).
  • the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUC8hr average for the serum concentration of the drug over the time course.
  • alkyl refers to a radical of a fully saturated hydrocarbon, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,
  • alkyl as used herein includes radicals of fully saturated hydrocarbons defined by the following general formula's: the general formula for linear or branched fully saturated hydrocarbons not containing a cyclic structure is C n H 2n+2 ; the general formula for a fully saturated hydrocarbon containing one ring is C n H 2n ; the general formula for a fully saturated hydrocarbon containing two rings is C n H 2(n -i ) ; the general formula for a saturated hydrocarbon containing three rings is C n H 2 ( n - 2 ).
  • halo refers to fluoro, chloro, bromo, or iodo.
  • alkoxy refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an — O— linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • alkenyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond including, like.
  • alkynyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like.
  • polycyclic moiety refers a bicyclic moiety or tricyclic moiety optionally containing one or more heteroatoms wherein at least one of the rings is not an aryl or heteroaryl ring.
  • the bicyclic moiety contains two rings wherein the rings are fused, the bicyclic moiety can be appended at any position of the two rings.
  • bicyclic moiety may refer to a radical including but not limited to: ,
  • the tricyclic moiety contains a bicyclic moiety with an additional fused ring, the tricyclic moiety can be appended at any position of the three rings.
  • tricyclic moiety may refer to a radical including but not limited to:
  • aryl refers to homocyclic aromatic radical whether one ring or multiple fused rings.
  • aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, naphthacenyl, and the like.
  • cycloalkyl used herein refers to saturated aliphatic ring system radical having three to twenty carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.0]hexyl, and the like.
  • cycloalkenyl refers to aliphatic ring system radical having three to twenty carbon atoms having at least one carbon-carbon double bond in the ring.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • polycycloalkyl refers to saturated aliphatic ring system radical having at least two rings that are fused with or without bridgehead carbons.
  • examples of polycycloalkyl groups include, but are not limited to, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, adamantyl, norbornyl, and the like.
  • polycycloalkenyl refers to aliphatic ring system radical having at least two rings that are fused with or without bridgehead carbons in which at least one of the rings has a carbon-carbon double bond.
  • examples of polycycloalkenyl groups include, but are not limited to, norbornylenyl, l,l'-bicyclopentenyl, and the like.
  • polycyclic hydrocarbon refers to a ring system radical in which all of the ring members are carbon atoms. Polycyclic hydrocarbons can be aromatic or can contain less than the maximum number of non-cumulative double bonds. Examples of polycyclic hydrocarbon include, but are not limited to, naphthyl, dihydronaphthyl, indenyl, fluorenyl, and the like. herein refers to cyclic non-aromatic ring system radical having at least one ring in which one or more ring atoms are not carbon, namely heteroatom. In fused ring systems, the one or more heteroatoms may be present in only one of the rings.
  • heterocyclic groups include, but are not limited to, morpholinyl, tetrahydrofuranyl, dioxolanyl, pyrolidinyl, pyranyl, piperidyl, piperazyl, and the like.
  • heteroaryl refers to an aromatic heterocyclic group, whether one ring or multiple fused rings. In fused ring systems, the one or more heteroatoms may be present in only one of the rings.
  • heteroaryl groups include, but are not limited to, benzothiazyl, benzoxazyl, quinazolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyridinyl, pyrrolyl, oxazolyl, indolyl, and the like.
  • arylalkyl refers to one or more aryl groups appended to an alkyl radical.
  • arylalkyl groups include, but are not limited to, benzyl, phenethyl, phenpropyl, phenbutyl, and the like.
  • cycloalkylalkyl refers to one or more cycloalkyl groups appended to an alkyl radical.
  • examples of cycloalkylalkyl include, but are not limited to, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, and the like.
  • heteroarylalkyl refers to one or more heteroaryl groups appended to an alkyl radical.
  • heteroarylalkyl include, but are not limited to, pyridylmethyl, furanylmethyl, thiopheneylethyl, and the like.
  • heterocyclylalkyl refers to one or more heterocyclyl groups appended to an alkyl radical.
  • heterocyclylalkyl include, but are not limited to, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, tetrahydrofuranylmethyl, pyrrolidinylpropyl, and the like.
  • aryloxy used herein refers to an aryl radical covalently bonded to the parent molecule through an --O-- linkage.
  • alkylthio refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an -S-- linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • arylthio refers to an aryl radical covalently bonded to the parent molecule through an -S- linkage. More alkyl groups attached thereto.
  • monoalkylamino refers to nitrogen radical with one alkyl group attached thereto and dialkylamino refers to nitrogen radical with two alkyl groups attached thereto.
  • cyanoamino used herein refers to nitrogen radical with nitrile group attached thereto.
  • sulfamyl used herein refers to -SO 2 NH 2 .
  • thiocarboxy used herein refers to CSOH.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term "radical” can be used interchangeably with the terms “group” and "moiety.”
  • a substituted group is derived from the unsubstituted parent structure in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • the substituent group(s) is (are) one or more group(s) individually and independently selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, C 3 -C 7 cycloalkyl (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO 2 -alkyl, -CF 3 , and -OCF 3 ), C 3 -C 6 heterocycloalkyl (e.g., tetrahydrofuryl) (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO 2 -alkyl, -CF 3 , and -OCF 3 ), aryl (optionally substituted with
  • Asymmetric carbon atoms may be present in the compounds described. All such isomers, including diastereomers and enantiomers, as well as the mixtures thereof are intended to be included in the scope of the recited compound. In certain cases, compounds can exist in tautomeric forms. All tautomeric forms are intended to be included in the scope. Likewise, when compounds contain an alkenyl or alkenylene group, there exists the possibility of cis- and trans- isomeric forms of the compounds. Both cis- and trans- isomers, as well as the mixtures of cis- and trans- isomers, are contemplated. Thus, reference herein to a compound includes all of the aforementioned isomeric forms unless the context clearly dictates otherwise.
  • Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitely disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • a polymorph is a composition having the same chemical formula, but a different structure.
  • a solvate is a composition formed by solvation (the combination of solvent molecules with molecules or ions of the solute).
  • a hydrate is a compound formed by an incorporation of water.
  • a conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond. Salts of compounds can be prepared by methods known to those skilled in the art.
  • salts of compounds can be prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compound.
  • a prodrug is a compound that undergoes biotransformation (chemical conversion) before exhibiting its specialized protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.
  • the present embodiments provide compounds of Formulae I, II, IE, IV, V, VI, VII, and X, as well as pharmaceutical compositions and formulations comprising any compound of Formulae I, II, EI, IV, V, VI, VII, and X.
  • a subject compound is useful for treating HCV infection and other disorders, as discussed below.
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(0)R 2a
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(0) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 - ⁇ alkenyl, hydroxy-Ci_6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloal
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci_ 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of d_ 6 alkyl, -(CH 2 ) q C3_7cycloalkyl, -(CH 2 ) q C6 or 1 0 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 )tC3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is substituted
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R 5 and R 6 are taken together with the carbon to more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxy-Ci_6 alkyl,
  • Z is selected from the group consisting of , a anndd
  • R 19 is hydrogen, Ci -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond; with the proviso that the compound of formula I is not
  • Some embodiments include compounds of Formula I having the structure:
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , and -C(O)R 2a .
  • R 4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and R 3 is -C(O)NHS(O) 2 R 9 where R 9 is C 3 _7cycloalkyl optionally substituted with Ci_6 alkyl.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro.
  • R 4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci_ 6 alkyl optionally substituted with up to 5 fluoro.
  • R 4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF 3 .
  • R 2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkoxy, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2
  • R 2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci_ 6 alkoxy, -(CH 2 ) q C 3 _ 7 cycloalkyl, aryl and heteroaryl; wherein said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of Ci -6 alkyl, and -NR la R lb , wherein q is 0 and R la and R lb are each separately a hydrogen atom or Ci -6 alkyl.
  • R 2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci- 6 alkoxy, -(CH 2 ) q C 3 _ 7 cycloalkyl, phenyl, thiazole, oxazole, thiophene, and pyridine; wherein said thiazole and oxazole as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of Ci_ 6 alkyl, and -NR la R lb , wherein q is 0 and R la and R lb are each separately a hydrogen atom or Ci -6 al
  • n is 0 or 1;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen, -C(O)CH 3 , or -SO 2 CH 3 .
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl optionally substituted with one or more substituents each independently selected from fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; and R 20 is hydrogen.
  • n is 0 or 1 ;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more fluoro and optionally substituted with CF 3 ; and R 20 is hydrogen.
  • Z is propyl
  • R 3 is carboxylic acid
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is C3_7cycloalkyl optionally substituted with Ci -6 alkyl or Ci -6 alkoxy.
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl or phenyl optionally substituted with CF 3 ; m is 0 or 1; and q is 0 or l.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -NR 9a R 9b and R 9a and R 9b are each independently a hydrogen atom or Ci -6 alkyl or -NR 9a R 9b is a pyrrolidine or piperidine.
  • Formula I (alternative 1)
  • R 1 is hydrogen
  • R 2 is hydrogen, -C(O)R 4 or selected from the group consisting of Ci -6 alkyl, aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl, Ci -6 alkoxy, C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3 -7 cycloalkyl, C 3 _6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci -6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, C 2 -6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci_ 6 alkyl, C ? ,- ⁇ cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 -6 alkenyl, -(CH 2 ) q C3 -7 cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci -6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4a is imidazolyl or pyrazolyl;
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; wherein R 9c is Ce or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of
  • R 9d is Ce or io aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or io aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 3 is a -CONR 100a R 100b ;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, C ⁇ -e alkyl optionally substituted with up to 5 fluoro, and C ⁇ -e alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and C ⁇ -e alkoxy optionally substituted with up to 5 fluoro;
  • (q) Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 20 is selected from the group consisting of -SO m R 2a , and -C(0)R 2a .
  • R 20 is -C(O)OR 2a .
  • R 2a is Ci_ 6 alkyl.
  • Z is
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl substituted with methyl.
  • R 3 is -CONR 100a R 100b .
  • R 100a and R 100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH 2 )vCONR 300a R 300b .
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C6 or io aryl; v is 0; and p is 1.
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen, or -(CH 2 ) v CONR 200a R 200b .
  • R 2 is hydrogen. optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxyl-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro.
  • substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxyl-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro.
  • R 4 is a dihydroisoindole optionally substituted with one or more substituents each separately selected from the group consisting of halo, Ci_ 6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro.
  • R 2 is -C(O)R 4 where R 4 is Ci_ 6 alkyl.
  • R 2 is Ci -6 alkyl.
  • R 2 is -C(O)R 4 where R 4 is -NR 90a R 90b ; wherein R 90a and R 90b are each separately a hydrogen atom or Ci_ 6 alkyl; or R 90a and R 90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring.
  • R 90a and R 90b are each separately a hydrogen atom or C 1-6 alkyl.
  • Formula I (alternative 2)
  • R 1 is hydrogen
  • R 2 is -C(O)R 4 , hydrogen, or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 is -NR 90a R 90b , or Ci_ 6 alkyl optionally substituted with up to 5 fluoro;
  • R 90a and R 90b are each separately a hydrogen atom, or Ci_ 6 alkyl; or R 90a and R 90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 - 7 cycloalkyl substituted with methyl; or R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; substituents each separately selected from the group consisting of
  • R 9d is Ce or 1 0 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or 1 0 aryl, and C ⁇ -e alkyl optionally substituted with up to 5 fluoro; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 3 is a -CONR 100a R 100b ;
  • each m is separately 0, 1 or 2;
  • each q is separately 0, 1 or 2;
  • each t is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 100a is hydrogen, and R 100b is a hydrogen, or -(CH 2 ) v CONR 200a R 200b ; or R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) p C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, C ⁇ -e alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • each p is separately an integer selected from 1-6;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and C ⁇ -e alkoxy optionally substituted with up to 5 fluoro;
  • (o) Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 20 is -C(0)0R 2a .
  • R 2a is Ci -6 alkyl.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl substituted with methyl.
  • R 3 is -CONR 100a R 100b .
  • R 100a and R 100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH 2 )vCONR 300a R 300b .
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C6 or io aryl; v is 0; and p is 1.
  • R 100a is hydrogen
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b .
  • R 2 is Ci -6 alkyl.
  • R 2 is -C(O)R 4 ;
  • R 4 is -NR 90a R 90b or Ci_ 6 alkyl; and
  • R 90a and R 90b are each separately a hydrogen atom, or Ci_ 6 alkyl; or
  • R 90a and R 90b are taken heterocycle.
  • R 90a and R 90b are each separately a hydrogen atom or C 1-6 alkyl.
  • R 90a and R 90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle.
  • Formula I (alternative 3)
  • R 1 is-(CR 5 R 6 ) n R 4 ;
  • n 0, 1 or 2;
  • R 2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(O)NR la R lb , -NR la R lb , -C(C(
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb ,
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 - ⁇ alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C 2 _6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci -6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • each R 4a is separately imidazolyl or pyrazolyl
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each r is separately an integer selected from 1-6;
  • R 3 is -P(O)R 10a R 10b , wherein R 1Oa and R 1Ob are each separately selected from the group consisting of hydroxy, -(O) v -Ci_6 alkyl, -(O) v - (CH 2 ) q C3 -7 cycloalkyl, -(O) v -aryl, and -(O) v -heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 ) t C3 -7 cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, alkoxy optionally substituted with up to 5 fluoro;
  • each t is separately 0, 1 or 2;
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxyl-C !
  • R 5 and R 6 are taken together with the carbon to which they are attached to form a C 3 - 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro;
  • R 19 is hydrogen, Ci -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(O)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 1Oa is hydroxy.
  • R 1Ob is -0-C 1-6 alkyl.
  • R i ⁇ D is -Ci -6 alkyl.
  • R lOb is methyl or ethyl.
  • R 1Oa is hydroxy or -0-Ci -6 alkyl and R 1Ob is Ci_ 6 alkyl.
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, C 6 or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 -6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R l
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C 1 - 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R 5 and R 6 are taken together with the carbon to which they are attached to form a C 3 - 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl,
  • R 7 and R 8 are each separately a hydrogen, or separately selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3-7 cycloalkyl, C 4 - 1 0 alkylcycloalkyl, C 2 _6 alkenyl, hydroxy-Ci-6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 13 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 13 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 14 and R 15 are each separately selected from hydrogen and Ci_ 6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 16 is separately imidazolyl or pyrazolyl;
  • V is selected from the group consisting of -0-, -S-, and -NR 15 -;
  • W is -N- or -CR 15 -; wherein R 15 is H, or selected from the group consisting of Ci_ 6 alkyl, (CH 2 ) q C 3 - 7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl; each u is separately 0, 1 or 2;
  • Z is selected from the group consisting of
  • R , 19 is hydrogen, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, or
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(O)OR 2a , -C(O)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • the compound of Formula II has the structure:
  • R is selected from the group consisting of hydrogen, -SO m R 2a , and -C(0)R 2a .
  • R 4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro.
  • R 4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci_ 6 alkyl optionally substituted with up to 5 fluoro.
  • R 4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF 3 .
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy, and -(CH 2 ) q C 3 _ 7 cycloalkyl where q is 0.
  • n is 0 or 1;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen, -C(O)CH 3 , or -SO 2 CH 3 .
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_ 6 alkyl optionally substituted with up to 5 fluoro; and R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more fluoro and optionally substituted with CF 3 ; and R 20 is hydrogen.
  • Z is propyl.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is C 3 _ 7 cycloalkyl optionally substituted with Ci_ 6 alkyl or Ci_ 6 alkoxy.
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl or phenyl optionally substituted with CF 3 ; m is 0 or 1; and q is 0 or l.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -NR 9a R 9b and R 9a and R 9b are each independently a hydrogen atom or Ci_ 6 alkyl or -NR 9a R 9b is a pyrrolidine or piperidine.
  • Formula II (alternative)
  • R 1 is hydrogen
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each q is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci-6 alkyl, -(CH 2 ) q C3_7cycloalkyl, Ce or 1 0 aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is
  • R 9a and R 9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and Ce o r 1 0 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH 2 ) t C3_7cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci_ 6 alkyl substituted with up to 5 fluoro, and Ci_ 6 alkoxy substituted with up to 5 fluoro, or R 9a and R 9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- four heteroatoms selected from the group consisting
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl, Ci_ 6 alkoxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR 7 R 8 , -NHC(O)NR 7 R 8 , -NHC(S)NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -C(O)R 13 , -C(O)OR 13 , -NHC(O)R 13 ,
  • R 7 and R 8 are each separately a hydrogen, or separately selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C3-7 cycloalkyl, C 4- 1 0 alkylcycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci_ 6 alkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; Ce or io aryl, each optionally substituted with one or more substituents
  • R 14 and R 15 are each separately selected from hydrogen and Ci_ 6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 16 is imidazolyl or pyrazolyl
  • (q) V is selected from the group consisting of -O-, -S-, and -NR 23 -;
  • R 23 is H, or selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3-7 cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_ 6 alkyl, Ci_ 6 alkoxy, or phenyl; wherein said phenyl as an optional substituent is further optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 30 is H, or selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3-7 cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_ 6 alkyl, Ci_ 6 alkoxy, or phenyl;
  • (u) Z is selected from the group consisting of fluoro
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C3 -7 cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring; and
  • R 20 is selected from the group consisting of -SO m R 2a , and -C(0)R 2a .
  • R 20 is -C(O)OR 2a .
  • R 2a is Ci -6 alkyl.
  • Z is
  • R 3 is an acylsulfonamide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl optionally substituted with Ci_ 6 alkyl.
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is optionally substituted aryl and m is 0.
  • R 9a and R 9b are each independently a hydrogen atom or Ci_ 6 alkyl or -NR 9a R 9b is pyrrolidine or piperidine.
  • V is selected from the group consisting of -O- and -S-; and W is -N-.
  • V is -NR 21 -; R 21 is H, Ci -6 alkyl, or arylalkyl; and W is -N-.
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy, and -(CH 2 ) q C 3 _ 7 cycloalkyl where q is 0.
  • R 1 is-(CR 5 R 6 ) n R 4 ; n is 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 6 or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is -NR 9a R 9b ; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group optionally
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(0) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(0)R 2a , -C(0)0R 2a , -NHC(O)R 2a , -NHC(0)0R 2
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci -6 alkyl, C 3 - 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C i_ 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy which they are attached to form a C 3 - 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxy-Ci_6
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl, Ci -6 alkoxy, C 2 _6 alkenyl, C 2 - ⁇ alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 _ 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR 7 R 8 , -NHC(O)NR 7 R 8 , -NHC(S)NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -C(O)R 13 , -C(O)OR 13 , -NHC(O)R 13 ,
  • R 7 and R 8 are each separately a hydrogen, or separately selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C 3 _7 cycloalkyl, C 4 - I o alkylcycloalkyl, C 2 _ 6 alkenyl, hydroxy-C ⁇ alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is selected from the group consisting of Ci -6 alkyl, C 3 _ 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C 3 _7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R 13 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 13 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 14 and R 15 are each separately selected from hydrogen and Ci -6 alkyl; or R 14 and R 15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 17 is a hydrogen, or selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and -NR la R lb ;
  • E and F are independently -N- or -CR 18 -; when E is -CR 18 -, F is -N-; when F is -CR 18 -, E is -N-; each R 18 is separately a hydrogen, or selected from the group consisting of Ci -6 alkyl, (CH 2 ) q C 3 _ 7 cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; each u is independently 0, 1 or 2;
  • Z is selected from the group consisting of
  • R 19 is hydrogen, Ci -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • Some embodiments include a compound of Formula IE having the structure:
  • Some embodiments include a compound of Formula IV having the structure:
  • R is selected from the group consisting of hydrogen, -SO m R 2a , and -C(O)R 2a .
  • R 4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and R 3 is -C(O)NHS(O) 2 R 9 where R 9 is C 3 _ 7 cycloalkyl optionally substituted with Ci_6 alkyl.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro.
  • R 4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF 3 .
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, Ci_ 6 alkyl, and Ci_ 6 alkoxy.
  • R 11 and R 12 are each separately selected from the group consisting of hydrogen, methyl and methoxy.
  • R 17 is a hydrogen, or selected from the group consisting of phenyl, thiazole, thiophene, oxazole and pyridine, each optionally substituted with one or more substituents each independently selected from the group consisting Ci_ 6 alkyl and -NR la R lb , wherein R la and R lb are each separately a hydrogen atom or Ci -6 alkyl.
  • n is 0 or 1;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen, -C(O)CH 3 , or -SO 2 CH 3 .
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_ 6 alkyl optionally substituted with up to 5 fluoro; and R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more fluoro and optionally substituted with CF 3 ; and R 20 is hydrogen.
  • Z is propyl
  • R 3 is carboxylic acid. C3-7cycloalkyl optionally substituted with Ci -6 alkyl or Ci -6 alkoxy.
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl or phenyl optionally substituted with CF 3 ; m is 0 or 1; and q is 0 or l.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -NR 9a R 9b and R 9a and R 9b are each independently a hydrogen atom or Ci_ 6 alkyl or -NR 9a R 9b is a pyrrolidine or piperidine.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 -6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C 1-6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C ?
  • R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 2a is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and C i_ 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C3_7cycloalkyl, Ce or 1 0 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci -6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 _6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substitute
  • R 5 and R 6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3 -7 cycloalkyl, C 2 _6 alkenyl, Ci -6 alkoxy, hydroxyl-Ci_ 6 alkyl, phenyl, Ci_ 6 alkyl substituted with up to 5 fluoro, and Ci_ 6 alkoxy which they are attached to form a C 3 - 7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, -(CH 2 ) u C3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxy-Ci_6
  • Z is selected from the group consisting of
  • R 19 is hydrogen, Q -6 alkyl optionally substituted with up to 5 fluoro, or -SO m R 2a ;
  • R 20 is selected from the group consisting of hydrogen, -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
  • n is 0 or 1;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Q -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen, -C(O)CH 3 , or -SO 2 CH 3 .
  • n is 0 or 1;
  • R 5 and R 6 are each hydrogen;
  • R 4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and
  • R 20 is hydrogen.
  • R 20 is hydrogen.
  • n is 0 or 1; R 5 and R 6 are each hydrogen; R 4 is phenyl substituted with one or more fluoro and optionally substituted with CF 3 ; and R 20 is hydrogen.
  • Z is propyl
  • R 3 is carboxylic acid
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is C3_7cycloalkyl optionally substituted with Ci -6 alkyl or Ci -6 alkoxy.
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl or phenyl optionally substituted with CF 3 ; m is 0 or 1; and q is 0 or l.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -NR 9a R 9b and R 9a and R 9b are each independently a hydrogen atom or Q -6 alkyl or -NR 9a R 9b is a pyrrolidine or piperidine.
  • Formulas V and VI (alternative)
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 2 _ 6 alkenyl, -(CH 2 ) q C 3 _7cycloalkyl, Ci -6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R 2a is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; ring;
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6; (e each q is separately 0, 1 or 2;
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Ci-6 alkyl, -(CH 2 ) q C3_7cycloalkyl, Ce or io aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_ 6 alkyl, -(CH 2 ) t C 3 _ 7 cycloalkyl, C 2 -6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is
  • R 9a and R 9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, and Ce o r 1 0 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH 2 )tC3_7cycloalkyl, C 2 -6 alkenyl, Ci -6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci -6 alkyl substituted with up to 5 fluoro, and Ci -6 alkoxy substituted with up to 5 fluoro, or R 9a and R 9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic
  • each R ld is separately selected from the group consisting of a hydrogen atom
  • R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci -6 alkyl, -(CH 2 ) q C3 -7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 3 is a -CONR 100a R 100b ; or R 3 is a carboxylic acid;
  • each t is separately 0, 1 or 2;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20 is selected from the group consisting of -SO m R 2a , -C(0)0R 2a , -C(0)R 2a , -C(0)NR la R lb , and -C(S)NR la R lb ;
  • R 21 and R 21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
  • R 20 is selected from the group consisting of -SO m R 2a , and -C(0)R 2a .
  • R 20 is -C(O)OR 2a .
  • R 2a is Ci_ 6 alkyl.
  • Z is
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl optionally substituted with Ci -6 alkyl.
  • R 3 is carboxylic acid
  • R 3 is -C(O)NHO(CH 2 ) m R 10 where R 10 is Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, or phenyl optionally substituted with CF 3 ; m is 0 or 1; and q is 0 or 1.
  • R 3 is -C(O)NHS(O) 2 R 9 where R 9 is -NR 9a R 9b and R 9a and R 9b are each independently a hydrogen atom or Ci_ 6 alkyl or -NR 9a R 9b is a pyrrolidine or piperidine.
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of: and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl, Ci -6 alkoxy, C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 3 - 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci -6 alkylthio, -N[(CH 2 ) p OH][(CH 2 ) r OH], -S(0) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR la R lb , -NR la R lb , -C(0)R 2a
  • R la and R lb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, C 2 _ 6 alkenyl, hydroxy-Ci-6 alkyl, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R la and R lb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • each R 2a is separately selected from the group consisting of Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, alkyl;
  • R 3a and R 3b are each separately selected from the group consisting of hydrogen and Ci_ 6 alkyl; or R 3a and R 3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4a is imidazolyl or pyrazolyl
  • each m is separately 0, 1 or 2;
  • each p is separately an integer selected from 1-6;
  • each q is separately 0, 1 or 2;
  • each r is separately an integer selected from 1-6;
  • R 20 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci_ 6 alkoxy optionally substituted with up to 5 fluoro, C 2 -6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) q C3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_ 6 alkylthio, -N[(CH 2 ) p 0H][(CH 2 ) r 0H], -S(O) 2 NR la R lb , -NHC(0)NR la R lb , -NHC(S)NR la R lb , -C(0)NR
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of -(CH 2 ) r C(O)NHR 9c , -(CH 2 ) r C(O)OR 9c , and -(CH 2 ) q R 9d ; wherein R 9c is Ce or 1 0 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
  • R 9d is Ce or 1 0 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH 2 ) q C(O)NHR 9e and -NH(CH 2 ) q C(O)NHR 9e ; wherein R 9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; with methyl; or R 3 is a -CONHO(CH 2 ) m R 10 where R 10 is selected from the group consisting of Ci_ 6 alkyl, -(CH 2 ) q C 3 _ 7 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 3 is a -CONR 100a R 100b ; or R 3 is carboxylic acid;
  • each t is separately 0, 1 or 2;
  • R 100a is -(CH 2 ) v CONR 200a R 200b
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b
  • R 100a and R 100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH 2 ) v CONR 300a R 300b ;
  • each v is separately 0, 1, 2, 3, 4, 5, or 6;
  • R 200a and R 200b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C 6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro;
  • (r) Z is selected from the group consisting of
  • R 19 is hydrogen, -SO m R 2a , or Ci_ 6 alkyl optionally substituted with up to 5 fluoro; they are attached form an optionally substituted cyclopropyl; and
  • R 2 is selected from the group consisting of and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, hydroxy, Ci -6 alkyl, and Ci_ 6 alkoxy.
  • R 3 is -C(O)NHS(O) 2 R 9 , where R 9 is -(CH 2 ) q C 3 _ 7 cycloalkyl substituted with methyl.
  • R 3 is -CONR 100a R 100b .
  • R 100a and R 100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH 2 )vCONR 300a R 300b .
  • R 300a and R 300b are each separately hydrogen or -(CH 2 ) P C6 or io aiyl; v is 0; and p is 1.
  • R 100a is hydrogen
  • R 100b is a hydrogen or -(CH 2 ) v CONR 200a R 200b .
  • R 20 is selected from the group consisting of phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substitutents each independently selected from the group consisting of halo, cyano, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
  • R 20 is phenyl optionally substituted with one or more substitutents each independently selected from the group consisting of halo, cyano, Ci -6 alkyl optionally substituted with up to 5 fluoro, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
  • R 20 is phenyl substituted with one or more substitutents each independently selected from the group consisting of halo and Ci_ 6 alkyl optionally substituted with up to 5 fluoro.
  • R 20 is phenyl substituted with one or more fluoro and optionally substituted with CF 3 .
  • Z is * * .
  • an NS 3 protease Sl' pocket moiety refers to a moiety of the NS 3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease SEQ ID NO: 1).
  • NS3 protease e.g., the NS3 protease SEQ ID NO: 1
  • exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43, see Yao. et. al., Structure 1999, 7, 1353.
  • an NS3 protease S2 pocket moiety refers to a moiety of the NS 3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLEVVT-STWVLV, SEQ ID NO: 1).
  • exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Argl55, Val78, Asp79, Gln80 and Asp81, see Yao. et. al., Structure 1999, 7, 1353.
  • Embodiments described herein include compounds containing moieties having a size, configuration and/or position selected to interact and/or be in proximity to particular regions, particular amino acid residues, and/or particular atoms of NS3 protease, upon binding of the compound to NS3 protease.
  • Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y is within 4 A or less of at least one moiety selected from NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom.
  • Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y forms a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease, including, but not limited to, NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom.
  • Y may be configured to form a hydrogen bond with both the NS3 protease His57 imidazole moiety and the NS3 protease GIy 137 nitrogen atom.
  • the moiety -NH-SO 2 - is an example of a Y moiety.
  • the Pi' moiety different from Y, has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of Pi' is within 6 A or less of at least one NS3 protease Sl' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43.
  • the Pi' moiety different from Y, has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease Sl' pocket.
  • the Pi' moiety may form a non-polar interaction with at least one amino acid selected from Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43.
  • the moieties C 3 _ 7 cycloalkyl, C 4 _i 0 alkylcycloalkyl and di(Ci_ 4 alkyl)amine are examples of Pi' moieties.
  • Examples of Y-Pi' include -NH-SO 2 - methylcyclopropyl and -NH-SO 2 -N(CH 3 ) 2 .
  • the P 2 moiety has a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of P 2 is within 5 A or less of any backbone or side chain atom of at least one NS3 protease residue selected from the group consisting of Tyr56, His57, Val78, Asp79, Gln80, Asp81, Argl55 and Alal56.
  • L is a moiety consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
  • L is an oxygen atom.
  • L may contain 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
  • Specific exemplary moieties for L include, but are not limited to, ester, amide, carbamate, thioester, and thioamide.
  • P 2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
  • the P 2 moiety has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of P 2 forms a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket.
  • the P 2 moiety may form a non-polar interaction with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81.
  • the P 2 moiety also may be configured to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS 3 protease S2 pocket.
  • the P 2 moiety may form a hydrogen bond with at instances, P 2 may form both a non-polar interaction and a hydrogen bond with peptide backbone or side chain moieties or atoms located in the substrate binding pocket of NS3 protease, such amino acids selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81.
  • P 2 is positioned by L to provide this configuration, where L is a moiety as described above.
  • P 2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
  • the R 50 and R 60 moieties have a size, configuration and/or positioning such that, upon binding of the compound to NS3 protease, at least one atom of R 50 or R 60 is within 5 A or less of any backbone or side chain atom of at least one NS3 protease residue selected from the group consisting of Argl23, Alal56, Alal57, Vall58, Cysl59, and Aspl68.
  • R 50 is H and R 60 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; or R 50 and R 60 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
  • compositions including pharmaceutical compositions, comprising compounds of the general Formulae I, ⁇ , IE, IV, V, VI, VII, or X.
  • a subject pharmaceutical composition comprises a subject compound; and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7 th ed., Lippincott, Williams, & Wilkins; and Pharmaceutical Assoc.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • the present embodiments provide for a method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound disclosed herein.
  • the present embodiments provide for a method of treating hepatitis by modulating NS3/NS4 protease comprising contacting a NS3/NS4 protease with a compound disclosed herein.
  • Example compounds of Formulae I, ⁇ , III, IV, V, VI, and VII include Compound Numbers 101-492, 701, 1001-1075, and 1077-1147 as set forth herein.
  • Preferred embodiments provide a method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
  • Preferred embodiments provide a method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
  • Preferred embodiments provide a method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
  • a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) NS3 protease. Whether a subject compound inhibits HCV NS3 protease can be readily determined using any known method. Typical methods involve a determination of whether an HCV polyprotein or other polypeptide comprising an NS 3 recognition site is cleaved by NS 3 in the presence of the agent.
  • HCV hepatitis virus C
  • a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound.
  • an HCV NS3 protease with an IC 50 of less than about 50 ⁇ M e.g., a subject compound inhibits an HCV NS3 protease with an IC 50 of less than about 40 ⁇ M, less than about 25 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.
  • a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) NS3 helicase. Whether a subject compound inhibits HCV NS3 helicase can be readily determined using any known method. In many embodiments, a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound.
  • HCV hepatitis virus C
  • a subject compound inhibits HCV viral replication.
  • a subject compound inhibits HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to HCV viral replication in the absence of the compound.
  • Whether a subject compound inhibits HCV viral replication can be determined using methods known in the art, including an in vitro viral replication assay.
  • Whether a subject method is effective in treating an HCV infection can be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.
  • an effective amount of a compound of Formulae I, ⁇ , IE, IV, V, VI, V ⁇ , or X, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy. determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
  • the method involves administering an effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, optionally in combination with an effective amount of one or more additional antiviral agents.
  • an effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
  • an effective amount of a compound of Formulae I, II, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.
  • an effective amount of a compound of Formulae I, E, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.
  • an effective amount of a compound of Formulae I, E, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to achieve a sustained viral response, e.g., non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • a sustained viral response e.g., non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months,
  • liver fibrosis As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
  • ALT levels of serum alanine aminotransferase are measured, using standard assays.
  • an ALT level of less than about 45 compound of Formulae I, ⁇ , EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU/mL serum.
  • a therapeutically effective amount of a compound of Formulae I, ⁇ , III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual.
  • Methods of measuring serum markers include immunological -based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • an effective amount of a compound of Formulae I, ⁇ , EI, IV, V, VI, Vn, or X and an additional antiviral agent is a synergistic amount.
  • the additional antiviral agent may itself be a combination of antiviral agents, e.g., a combination of pegylated interferon-alfa and ribavirin.
  • a "synergistic combination” or a “synergistic amount" of a compound of Formulae I, ⁇ , EI, IV, V, VI, VII, or X and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of Formulae I, ⁇ , IE, IV, V, VI, VII, or X when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
  • a selected amount of a compound of Formulae I, II, HI, IV, V, VI, VII, or X and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount of the compound of Formulae I, II, EI, IV, V, VI, VII, or X and/or the selected amount of the additional antiviral agent is ineffective when used in monotherapy for the disease.
  • the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount of the compound of Formulae I, II, IE, IV, V, VI, additional antiviral agent provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of the compound of Formulae I, II, IE, IV, V, VI, V ⁇ , or X enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of Formulae I, ⁇ , III, IV, V, VI, VII, or X provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of Formulae I, II, III, IV, V, VI, VII, or X and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of Formulae I, II, IE, IV, V, VI, VII
  • a "synergistically effective amount" of a compound of Formulae I, ⁇ , EI, IV, V, VI, VII, or X and an additional antiviral agent, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (l)-(3) above. Fibrosis
  • the embodiments provides methods for treating liver fibrosis (including forms of liver fibrosis resulting from, or associated with, HCV infection), generally involving administering a therapeutic amount of a compound of Formulae I, ⁇ , III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents.
  • Effective amounts of compounds of Formulae I, II, IE, IV, V, VI, VII, or X, with and without one or more additional antiviral agents, as well as dosing regimens, are as discussed below.
  • liver fibrosis reduction is determined by analyzing a liver biopsy sample.
  • An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage” as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol.
  • the METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity).
  • each stage in the METAVIR system is as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
  • Knodell's scoring system also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis.
  • scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.
  • the Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696- 699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
  • the benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
  • a therapeutically effective amount of a compound of Formulae I, ⁇ , IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that effects a change of one unit or more in the fibrosis stage based on pre- and post- therapy liver biopsies.
  • a therapeutically effective amount of a compound of Formulae I, II, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents reduces liver fibrosis by at least one unit in the METAVEl, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
  • indices of liver function can also be used to evaluate the efficacy of treatment with a compound of Formulae I, II, IE, IV, V, VI, VE, or X. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.
  • An effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual.
  • Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
  • Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method.
  • Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen EI peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin.
  • Additional biochemical markers of liver fibrosis include ⁇ -2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
  • IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual.
  • ELISA enzyme-linked immunosorbent assays
  • radioimmunoassays radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
  • a "complication associated with cirrhosis of the liver” refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but it not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
  • a therapeutically effective amount of a compound of Formulae I, ⁇ , III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount that is effective in reducing the incidence (e.g., the likelihood that an individual will develop) of a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or to a placebo-treated individual.
  • the embodiments provide methods for increasing liver function, generally involving administering a therapeutically effective amount of a compound of Formulae I, II, IE, IV, V, VI, V ⁇ , or X, and optionally one or more additional antiviral agents.
  • Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5 '-nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
  • proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5
  • liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function.
  • markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays.
  • Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods.
  • Metabolic functions can be measured by measuring the level of ammonia in the serum.
  • Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples.
  • the normal level of alanine transaminase is about 45 IU per milliliter of serum.
  • the normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum.
  • Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL.
  • Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L.
  • Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.
  • IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more.
  • a therapeutically effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is an amount effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.
  • a therapeutically effective amount of a compound of Formulae I, ⁇ , III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.
  • the active agent(s) e.g., compound of Formulae I, II, in, IV, V, VI, V ⁇ , or X, and optionally one or more additional antiviral agents
  • the agent may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect.
  • the agent can be incorporated into a variety of formulations for therapeutic administration.
  • the agents of the embodiments can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • appropriate, pharmaceutically acceptable carriers or diluents such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • compositions are provided in formulation with a pharmaceutically acceptable excipient(s).
  • a pharmaceutically acceptable excipient A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein.
  • Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7 th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3 rd ed. Amer. Pharmaceutical Assoc.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • an agent is formulated in an aqueous buffer.
  • Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from about 5 mM to about 100 mM.
  • the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars e.g., mannitol, dextrose, sucrose, and the like.
  • the aqueous buffer further includes a non-ionic surfactant such as polysorbate 20 or 80.
  • the formulations may further include a preservative.
  • Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4°C. Formulations may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored over extended periods of time, even at ambient temperatures.
  • administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration.
  • administration is by bolus injection, e.g., subcutaneous bolus injection, intramuscular bolus injection, and the like.
  • compositions of the embodiments can be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred.
  • Subcutaneous administration of a pharmaceutical composition of the embodiments is accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328.
  • a combination of a of the embodiments to a patient through the port is referred to herein as "a subcutaneous injection port delivery system.”
  • subcutaneous administration is achieved by bolus delivery by needle and syringe.
  • the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • the agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers isotonic agents
  • suspending agents emulsifying agents, stabilizers and preservatives.
  • the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • the compounds of the embodiments can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors.
  • unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • units suitable as unitary dosages for human and animal subjects each unit containing a predetermined quantity of compounds of the embodiments calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of the embodiments depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • a subject method will in some embodiments be carried out by administering an NS3 inhibitor that is a compound of Formulae I, II, IE, IV, V, VI, V ⁇ , or X, and optionally one or more additional antiviral agent(s).
  • the method further includes administration of one or more interferon receptor agonist(s).
  • Interferon receptor agonists are described herein.
  • the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described herein.
  • Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs.
  • Non-limiting examples include azidothymidine (AZT) (zidovudine), and analogs and derivatives thereof; 2',3'- dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof; 2',3'- dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof; 2'3,'- didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and analogs and derivatives thereof; combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs; and the like.
  • the method further includes administration of ribavirin.
  • Ribavirin, l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771.
  • Some embodiments also involve use of derivatives of ribavirin (see, e.g., U.S. the same or different administration form and in the same or different route as the NS-3 inhibitor compound.
  • the method further includes administration of ritonavir.
  • Ritonavir 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l-methylethyl)-4- thiazolyl]-3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5- thiazolylmethyl ester [5S-(5R*,8R*,lOR*,llR*)], available from Abbott Laboratories, is an inhibitor of the protease of the human immunodeficiency virus and also of the cytochrome P450 3A and P450 2D6 liver enzymes frequently involved in hepatic metabolism of therapeutic molecules in man.
  • ritonavir at doses below the normal therapeutic dosage may be combined with other protease inhibitors to achieve therapeutic levels of the second protease inhibitor while reducing the number of dosage units required, the dosing frequency, or both.
  • Coadministration of low-dose ritonavir may also be used to compensate for drug interactions that tend to decrease levels of a protease inhibitor metabolized by CYP3A. Its structure, synthesis, manufacture and formulation are described in U.S. Pat. No. 5,541,206 U.S. Pat. No. 5,635,523 U.S. Pat. No. 5,648,497 U.S. Pat. No. 5,846,987 and U.S. Pat. No. 6,232,333.
  • the ritonavir may be administered orally in capsule or tablet or oral solution form, or in the same or different administration form and in the same or different route as the NS-3 inhibitor compound.
  • an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment.
  • an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment can begin before the NS 3 inhibitor compound treatment begins and end before the NS 3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS 3 inhibitor additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end before the NS 3 inhibitor compound treatment ends; or the additional antiviral agent treatment can begin before the NS 3 inhibitor compound treatment begins and end after the NS 3 inhibitor compound treatment ends.
  • the NS3 inhibitor compounds described herein may be used in acute or chronic therapy for HCV disease.
  • the NS3 inhibitor compound is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • the NS 3 inhibitor compound can be administered 5 times per day, 4 times per day, tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.
  • an NS3 inhibitor compound of the embodiments is administered orally.
  • an NS 3 inhibitor compound as described herein may be administered to the patient at a dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
  • the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
  • the amount of active ingredient that may be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration.
  • a typical pharmaceutical preparation can contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the pharmaceutical preparation can contain from about 20% to about 80% active ingredient.
  • dose levels can vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the susceptibility readily determinable by those of skill in the art by a variety of means.
  • a preferred means is to measure the physiological potency of a given interferon receptor agonist.
  • multiple doses of NS3 inhibitor compound are administered.
  • an NS3 inhibitor compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ribavirin.
  • Ribavirin can be administered in dosages of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day.
  • One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of ribavirin for the duration of the desired course of NS3 inhibitor compound treatment.
  • Another embodiment provides any of the above-described methods modified to include co-administering to the patient about 800 mg to about 1200 mg ribavirin orally per day for the duration of the desired course of NS3 inhibitor compound treatment.
  • any of the above-described methods may be modified to include coadministering to the patient (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally per day if the patient has a body weight greater than or equal to 75 kg, where the daily dosage of ribavirin is optionally divided into to 2 doses for the duration of the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of levovirin.
  • Levovirin is generally administered in an amount ranging from about 30 from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
  • levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of viramidine.
  • Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
  • viramidine is administered orally in dosages of about 800 mg, or about 1600 mg per day for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ritonavir.
  • Ritonavir is generally administered in an amount ranging from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, or from about 500 mg to about 600 mg, twice per day.
  • ritonavir is administered orally in dosages of about 300 mg, or about 400 mg, or about 600 mg twice per day for the desired course of NS3 inhibitor compound treatment.
  • Suitable ⁇ -glucosidase inhibitors include any of the above-described imino-sugars, including long-alkyl chain derivatives of imino sugars as disclosed in U.S. Patent Publication No. 2004/0110795; inhibitors of endoplasmic reticulum-associated ⁇ - glucosidases; inhibitors of membrane bound ⁇ -glucosidase; miglitol (Glyset®), and active derivatives, and analogs thereof; and acarbose (Precose®), and active derivatives, and analogs thereof.
  • NS3 inhibitor compound as described above, and an effective amount of an ⁇ -glucosidase inhibitor administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • An ⁇ -glucosidase inhibitor can be administered 5 times per day, 4 times per day, tid (three times daily), bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, an ⁇ -glucosidase inhibitor is administered as a continuous infusion.
  • an ⁇ -glucosidase inhibitor is administered orally.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ⁇ - glucosidase inhibitor administered to the patient at a dosage of from about 10 mg per day to about 600 mg per day in divided doses, e.g., from about 10 mg per day to about 30 mg per day, from about 30 mg per day to about 60 mg per day, from about 60 mg per day to about 75 mg per day, from about 75 mg per day to about 90 mg per day, from about 90 mg per day to about 120 mg per day, from about 120 mg per day to about 150 mg per day, from about 150 mg per day to about 180 mg per day, from about 180 mg per day to about 210 mg per day, from about 210 mg per day to about 240 mg per day, from about 240 mg per day to about 270 mg per day, from about
  • the methods provide for combination therapy comprising administering an NS 3 inhibitor compound as described above, and an effective amount of ⁇ -glucosidase inhibitor administered in a dosage of about 10 mg three times daily.
  • an ⁇ -glucosidase inhibitor is administered in a dosage of about 15 mg three times daily.
  • an ⁇ -glucosidase inhibitor is administered in a administered in a dosage of about 25 mg three times daily.
  • an ⁇ - glucosidase inhibitor is administered in a dosage of about 30 mg three times daily.
  • an ⁇ -glucosidase inhibitor is administered in a dosage of about 40 mg three times daily.
  • an ⁇ -glucosidase inhibitor is administered in a dosage of about 50 mg three times daily. In some embodiments, an ⁇ -glucosidase inhibitor is administered in a dosage of about 100 mg three times daily. In some embodiments, an ⁇ - glucosidase inhibitor is administered in a dosage of about 75 mg per day to about 150 mg per day in two or three divided doses, where the individual weighs 60 kg or less. In some embodiments, an ⁇ -glucosidase inhibitor is administered in a dosage of about 75 mg per day to about 300 mg per day in two or three divided doses, where the individual weighs 60 kg or more.
  • the amount of active ingredient (e.g., ⁇ -glucosidase inhibitor) that may be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration.
  • a typical pharmaceutical preparation can contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the pharmaceutical preparation can contain from about 20% to about 80% active ingredient.
  • dose levels can vary as a function of the specific ⁇ -glucosidase inhibitor, the severity of the symptoms and the susceptibility of the subject to side effects.
  • Preferred dosages for a given ⁇ -glucosidase inhibitor are readily determinable by those of skill in the art by a variety of means. A typical means is to measure the physiological potency of a given active agent.
  • multiple doses of an ⁇ -glucosidase inhibitor are administered.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ⁇ - glucosidase inhibitor administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight years, or more.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of thymosin- ⁇ .
  • Thymosin- ⁇ (ZadaxinTM) is generally administered by subcutaneous injection.
  • Thymosin- ⁇ can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously for the desired course of NS3 inhibitor compound treatment.
  • thymosin- ⁇ is administered twice per week for the desired course of NS 3 inhibitor compound treatment.
  • Effective dosages of thymosin- ⁇ range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg.
  • thymosin- ⁇ is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
  • Thymosin- ⁇ can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • thymosin- ⁇ is administered for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of an interferon receptor agonist.
  • a compound of Formulae I, II, HI, IV, V, VI, VII, or X and a Type I or El interferon receptor agonist are co-administered in the treatment methods described herein.
  • Type I interferon receptor agonists suitable for use herein include any interferon- ⁇ (IFN- ⁇ ).
  • the interferon- ⁇ is a PEGylated interferon- ⁇ .
  • the interferon- ⁇ is a consensus interferon- ⁇ is a monoPEG (30 kD, linear)-ylated consensus interferon.
  • Effective dosages of an IFN- ⁇ range from about 3 ⁇ g to about 27 ⁇ g, from about 3 MU to about 10 MU, from about 90 ⁇ g to about 180 ⁇ g, or from about 18 ⁇ g to about 90 ⁇ g.
  • Effective dosages of Infergen® consensus IFN- ⁇ include about 3 ⁇ g, about 6 ⁇ g, about 9 ⁇ g, about 12 ⁇ g, about 15 ⁇ g, about 18 ⁇ g, about 21 ⁇ g, about 24 ⁇ g, about 27 ⁇ g, or about 30 ⁇ g, of drug per dose.
  • Effective dosages of IFN- ⁇ 2a and IFN- ⁇ 2b range from 3 million Units (MU) to 10 MU per dose.
  • Effective dosages of PEGAS YS ® PEGylated IFN- ⁇ 2a contain an amount of about 90 ⁇ g to 270 ⁇ g, or about 180 ⁇ g, of drug per dose.
  • Effective dosages of PEG-INTRON®PEGylated IFN- ⁇ 2b contain an amount of about 0.5 ⁇ g to 3.0 ⁇ g of drug per kg of body weight per dose.
  • Effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of about 18 ⁇ g to about 90 ⁇ g, or from about 27 ⁇ g to about 60 ⁇ g, or about 45 ⁇ g, of CIFN amino acid weight per dose of PEG-CIFN.
  • Effective dosages of monoPEG (30 kD, linear)-ylated CIFN contain an amount of about 45 ⁇ g to about 270 ⁇ g, or about 60 ⁇ g to about 180 ⁇ g, or about 90 ⁇ g to about 120 ⁇ g, of drug per dose.
  • IFN- ⁇ can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • the Type I or Type El interferon receptor agonist and/or the Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations.
  • Some embodiments provide any of the above- described methods in which the desired dosage of IFN- ⁇ is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration.
  • any of the above-described methods may be practiced in which the desired dosage of PEGylated IFN- ⁇ (PEG-IFN- ⁇ ) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration.
  • receptor agonist are co-administered in the treatment methods of the embodiments.
  • Type II interferon receptor agonists suitable for use herein include any interferon- ⁇ (IFN- ⁇ ).
  • Effective dosages of IFN- ⁇ can range from about 0.5 ⁇ g/m 2 to about 500 ⁇ g/m 2 , usually from about 1.5 ⁇ g/m 2 to 200 ⁇ g/m 2 , depending on the size of the patient. This activity is based on 10 international units (U) per 50 ⁇ g of protein. IFN- ⁇ can be administered daily, every other day, three times a week, or substantially continuously or continuously.
  • IFN- ⁇ is administered to an individual in a unit dosage form of from about 25 ⁇ g to about 500 ⁇ g, from about 50 ⁇ g to about 400 ⁇ g, or from about 100 ⁇ g to about 300 ⁇ g. In particular embodiments of interest, the dose is about 200 ⁇ g IFN- ⁇ . In many embodiments of interest, IFN- ⁇ lb is administered.
  • the amount of IFN- ⁇ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 ⁇ g IFN- ⁇ per kg body weight to about 1.48 ⁇ g IFN- ⁇ per kg body weight.
  • the body surface area of subject individuals generally ranges from about 1.33 m 2 to about 2.50 m 2 .
  • an IFN- ⁇ dosage ranges from about 150 ⁇ g/m 2 to about 20 ⁇ g/m 2 .
  • an IFN- ⁇ dosage ranges from about 20 ⁇ g/m 2 to about 30 ⁇ g/m , from about 30 ⁇ g/m to about 40 ⁇ g/m , from about 40 ⁇ g/m to about 50 ⁇ g/m 2 , from about 50 ⁇ g/m 2 to about 60 ⁇ g/m 2 , from about 60 ⁇ g/m 2 to about 70 ⁇ g/m 2 , from about 70 ⁇ g/m to about 80 ⁇ g/m , from about 80 ⁇ g/m to about 90 ⁇ g/m , from about 90 ⁇ g/m 2 to about 100 ⁇ g/m 2 , from about 100 ⁇ g/m 2 to about 110 ⁇ g/m 2 , from about 110 ⁇ g/m 2 to about 120 ⁇ g/m 2 , from about 120 ⁇ g/m 2 to about 130 ⁇ g/m 2 , from about 130 ⁇ g/m 2 to about 140 ⁇ g/m 2 , or from about 140 ⁇ g/m 2 to about
  • a Type I or a Type IE interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen.
  • the first dosing regimen of Type I or a Type El interferon receptor agonist generally involves administration of a higher dosage of the Type I or Type IE interferon receptor agonist.
  • the first dosing regimen can encompass a single dosing event, or at least two or more dosing events.
  • the first dosing regimen of the Type I or Type IE interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • the first dosing regimen of the Type I or Type III interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
  • the second dosing regimen of the Type I or Type El interferon receptor agonist (also referred to as "the maintenance dose”) generally involves administration of a lower amount of the Type I or Type IE interferon receptor agonist.
  • the second dosing regimen comprises administering CE 7 N at a dose of at least about 3 ⁇ g, at least about 9 ⁇ g, at least about 15 ⁇ g, or at least about 18 ⁇ g.
  • the second dosing regimen can encompass a single dosing event, or at least two or more dosing events.
  • the second dosing regimen of the Type I or Type EI interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • a "priming" dose of a Type E interferon receptor agonist (e.g., IFN- ⁇ ) is included.
  • IFN- ⁇ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type EI interferon receptor agonist. This period of time is referred to as the "priming" phase.
  • the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type IE interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type IE interferon receptor agonist. In these embodiments, the total time of treatment with Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to ⁇ interferon receptor agonist treatment is discontinued once Type I or a Type El interferon receptor agonist treatment begins.
  • the Type I or Type IE interferon receptor agonist is administered in single dosing regimen.
  • the dose of CIFN is generally in a range of from about 3 ⁇ g to about 15 ⁇ g, or from about 9 ⁇ g to about 15 ⁇ g.
  • the dose of Type I or a Type EI interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously.
  • the dose of the Type I or Type III interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
  • a "priming" dose of a Type E interferon receptor agonist (e.g., IFN- ⁇ ) is included.
  • IFN- ⁇ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type IE interferon receptor agonist. This period of time is referred to as the "priming" phase.
  • the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist.
  • the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist.
  • the total time of treatment with the Type E interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days.
  • Type E interferon receptor agonist treatment is discontinued once Type I or a Type EI interferon receptor agonist treatment begins.
  • an NS 3 inhibitor compound, a Type I or IE interferon receptor agonist, and a Type E interferon receptor agonist are co-administered for the desired duration of treatment in the methods described herein.
  • an NS3 inhibitor compound, an interferon- ⁇ , and an interferon- ⁇ are co-administered for the desired duration of treatment in the methods described herein.
  • a Type I or Type III interferon receptor agonist, a Type II interferon receptor agonist, and an NS3 inhibitor compound effective for the treatment of HCV infection in a patient.
  • Some embodiments provide methods using an effective amount of an IFN- ⁇ , IFN- ⁇ , and an NS3 inhibitor compound in the treatment of HCV infection in a patient.
  • One embodiment provides a method using an effective amount of a consensus IFN- ⁇ , IFN- ⁇ and an NS 3 inhibitor compound in the treatment of HCV infection in a patient.
  • an effective amount of a consensus interferon (CIFN) and IFN- ⁇ suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 ⁇ g CIFN: 10 ⁇ g IFN- ⁇ , where both CIFN and IFN- ⁇ are unPEGylated and unglycosylated species.
  • the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 30 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGENOconsensus IFN- ⁇ and IFN- ⁇ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 9 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • an effective amount of INFERGEN® consensus IFN- ⁇ and IFN- ⁇ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 50 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 9 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 90 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 30 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 200 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 4 ⁇ g to about 60 ⁇ g month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • PEG-CIFN PEGylated consensus IFN- ⁇
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 18 ⁇ g to about 24 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • PEG-CIFN PEGylated consensus IFN- ⁇
  • an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 million Units (MU) IFN- ⁇ 2a or 2b or 2c : 30 ⁇ g IFN- ⁇ , where both IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ are unPEGylated and unglycosylated species.
  • MU 1 million Units
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 600 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYSOPEGylated IFN- ⁇ 2a and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 ⁇ g to about 360 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYSOPEGylated IFN- ⁇ 2a and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 ⁇ g of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 25 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 200 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 25 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • NS3 inhibitor comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • any of the above-described methods involving administering an NS3 inhibitor, a Type I interferon receptor agonist (e.g., an IFN- ⁇ ), and a Type II interferon receptor agonist (e.g., an IFN- ⁇ ), can be augmented by administration of an effective amount of a TNF- ⁇ antagonist (e.g., a TNF- ⁇ antagonist other than pirfenidone or a pirfenidone analog).
  • a TNF- ⁇ antagonists e.g., a TNF- ⁇ antagonist other than pirfenidone or a pirfenidone analog.
  • Exemplary, non-limiting TNF- ⁇ antagonists that are suitable for use in such combination therapies include ENBREL®, REMICADE®, and HUMIRATM.
  • One embodiment provides a method using an effective amount of ENBREL®; an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 ⁇ g to about 23 mg per dose, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
  • One embodiment provides a method using an effective amount of REMICADE®, an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously or continuously or
  • One embodiment provides a method using an effective amount of HUMIRATM, an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 ⁇ g to about 35 mg, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of pirfenidone or a pirfenidone analog.
  • an NS3 inhibitor compound, one or more interferon receptor agonist(s), and pirfenidone or pirfenidone analog are co-administered in the treatment methods of the embodiments.
  • an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
  • an NS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
  • Type I interferon receptor agonists suitable for use herein include any IFN- ⁇ , such as interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and PEGylated IFN- ⁇ ' s, such as peginterferon alfa-2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as monoPEG (30 kD, linear)-ylated consensus interferon.
  • Type II interferon receptor agonists suitable for use herein include any interferon- ⁇ .
  • Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally in one to five divided doses per day.
  • Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.
  • One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS 3 inhibitor compound treatment.
  • Combination therapies with TNF- ⁇ antagonists include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS 3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of TNF- ⁇ antagonist, in combination therapy for treatment of an HCV infection.
  • Effective dosages of a TNF- ⁇ antagonist range from 0.1 ⁇ g to 40 mg per dose, e.g., from about 0.1 ⁇ g to about 0.5 ⁇ g per dose, from about 0.5 ⁇ g to about 1.0 ⁇ g per dose, from about 1.0 ⁇ g per dose to about 5.0 ⁇ g per dose, from about 5.0 ⁇ g to about 10 ⁇ g per dose, from about 10 ⁇ g to about 20 ⁇ g per dose, from about 20 ⁇ g per dose to about 30 ⁇ g per dose, from about 30 ⁇ g per dose to about 40 ⁇ g per dose, from about 40 ⁇ g per dose to about 50 ⁇ g per dose, from about 50 ⁇ g per dose to about 60 ⁇ g per dose, from about 60 ⁇ g per dose to about 70 ⁇ g per dose, from about 70 ⁇ g to about 80 ⁇ g per dose, from about 80 ⁇ g per dose to about 100 ⁇ g per dose, from about 100 ⁇ g to about 150 ⁇ g per dose, from about 150 ⁇
  • effective dosages of a TNF- ⁇ antagonist are expressed as mg/kg body weight.
  • effective dosages of a TNF- ⁇ antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.
  • a TNF- ⁇ antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • the TNF- ⁇ antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
  • a TNF- ⁇ antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to more.
  • a TNF- ⁇ antagonist and an NS3 inhibitor are generally administered in separate formulations.
  • a TNF- ⁇ antagonist and an NS 3 inhibitor may be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
  • One embodiment provides a method using an effective amount of a TNF- ⁇ antagonist and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • One embodiment provides a method using an effective amount of ENB REL® and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 ⁇ g to about 23 mg per dose, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • One embodiment provides a method using an effective amount of REMIC ADE® and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once the desired duration of treatment with
  • One embodiment provides a method using an effective amount of HUMIR ATM and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 ⁇ g to about 35 mg, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with
  • the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of thymosin- ⁇ , in combination therapy for treatment of an HCV infection.
  • Effective dosages of thymosin- ⁇ range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg.
  • thymosin- ⁇ is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
  • One embodiment provides a method using an effective amount of ZADAXINTM thymosin- ⁇ and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of ZADAXINTM containing an amount of from about 1.0 mg to about 1.6 mg per dose, subcutaneously twice per week for the desired duration of treatment with the NS 3 inhibitor compound.
  • Some embodiments provide a method of treating an HCV infection in an individual having an HCV infection, the method comprising administering an effective amount of one or more interferons.
  • One embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • One embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN- ⁇ and a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 30 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN- ⁇ and a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 9 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 4 ⁇ g to about 60 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • PEG-CIFN PEGylated consensus IFN- ⁇
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 18 ⁇ g to about 24 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • PEG-CIFN PEGylated consensus IFN- ⁇
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGAS YS ®PEGylated IFN- ⁇ 2a and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 ⁇ g to about 360 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGAS YS ®PEGylated IFN- ⁇ 2a and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 ⁇ g to about 3.0 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Combination therapies with other antiviral agents with other antiviral agents
  • HCV NS3 helicase Other agents such as inhibitors of HCV NS3 helicase are also attractive drugs for combinational therapy, and are contemplated for use in combination therapies described herein.
  • Ribozymes such as HeptazymeTM and phosphorothioate oligonucleotides which are complementary to HCV protein sequences and which inhibit the expression of viral core proteins are also suitable for use in combination therapies described herein.
  • the additional antiviral agent(s) is administered during the entire course of treatment with the NS3 inhibitor compound described herein, and the beginning and end of the treatment periods coincide. In other embodiments, the additional antiviral agent(s) is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., treatment with the additional antiviral agent(s) begins before the NS 3 inhibitor compound treatment begins and ends before the NS 3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS 3 inhibitor compound treatment begins and ends after the NS 3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS 3 inhibitor compound treatment begins and ends before the NS 3 inhibitor compound treatment ends; or treatment with the additional antiviral agent(s) begins before the NS 3 inhibitor compound treatment begins and ends after the NS 3 inhibitor compound treatment ends.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneous Iy once daily or three times per week for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration with an NS 3 inhibitor compound.
  • a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon- 1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon- 1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
  • an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) a
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) a
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) a
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
  • an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or
  • an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 ⁇ g of drug per dose, subcutaneously once weekly for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN- ⁇ can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 ⁇ g to 1.5 ⁇ g of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods can be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods can be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with an NS 3 inhibitor compound.
  • any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
  • any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
  • any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
  • any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
  • any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
  • an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
  • any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS 5 B inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
  • the present embodiments provide for a method of treating a hepatitis C virus infection comprising administering to a human dosages of peginterferon alfa-2a and ribavirin under a standard of care protocol (SOC) in combination with ITMN- 191 or a pharmaceutically acceptable salt thereof.
  • SOC standard of care protocol
  • ITMN- 191 The chemical structure of ITMN- 191 is shown below.
  • the peginterferon alfa-2a and ribavirin in combination with ITMN-191 or a pharmaceutically acceptable salt thereof are administered in combination and provide HCV RNA levels below about 43 IU/mL, below about 25 IU/mL, or below about 9.3 IU/mL after 14 days of treatment.
  • the dosage of peginterferon alfa-2a can be about 180 ⁇ g of peginterferon alfa-2a per dose, administered subcutaneously once weekly for the desired treatment duration. In some embodiments, the dosage of peginterferon alfa-2a can be an amount in the range of about 1.0 ⁇ g to about 1.5 ⁇ g of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with the ITMN-191 and the ribavarin.
  • the dosage of ribavirin can be about 400 mg, about 800 mg, about 1000 mg or about 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the peginterferon alfa-2a and ITMN-191.
  • the dosage of ribavirin can be an amount of about 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or an amount of about 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with the peginterferon alfa-2a and ITMN-191.
  • the amounts of peginterferon alfa-2a and ribavirin administered in the SOC protocol can be lowered due to combination with ITMN-191. For by about 10% to about 75% during the combination treatment.
  • the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.
  • some embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.
  • inventions provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a na ⁇ ve patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
  • HCVL high viral load
  • One embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
  • the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, about 60 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
  • Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks.
  • treatment of an HCV infection where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks.
  • Any of the above treatment regimens can be administered to individuals who have been diagnosed with an HCV infection. Any of the above treatment regimens can be administered to individuals who have failed previous treatment for HCV infection ("treatment failure patients," including non-responders and relapsers).
  • Individuals who have been clinically diagnosed as infected with HCV are of particular interest in many embodiments.
  • Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum.
  • Such individuals include anti-HCV ELISA-positive individuals, and individuals with a positive recombinant immunoblot assay (RIBA).
  • RIBA positive recombinant immunoblot assay
  • Individuals who are clinically diagnosed as infected with HCV include na ⁇ ve individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN- ⁇ -based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients).
  • Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy, or a previous pegylated IFN- ⁇ and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy, or a previous pegylated IFN- ⁇ and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
  • non-responders i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy,
  • individuals have an HCV titer of at least about 10 5 , at least about 5 x 10 5 , or at least about 10 6 , or at least about 2 x 10 6 , genome copies of HCV per milliliter of serum.
  • the patient may be infected with any HCV genotype (genotype 1, including Ia and Ib, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), subtypes and quasispecies.
  • HCV-positive individuals are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child' s-Pugh class A or less), or more advanced cirrhosis (decompensated, Child' s-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti- viral treatment with IFN- ⁇ -based therapies or who cannot tolerate IFN- ⁇ -based therapies, or who have a contraindication to such therapies.
  • HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods described herein.
  • individuals suitable for treatment with the methods of the embodiments are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation.
  • individuals suitable for treatment with the methods described herein include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.).
  • HCV protease inhibitors in the following sections can be prepared according to the procedures and schemes shown in each section.
  • the numberings in each of the following Preparation of NS3 Inhibitor sections including the General Method or General Procedure designations, are meant for that specific section only, and should not be construed or confused with the same numberings, if any, in other sections.
  • Macrocyclics of general structures I-D and I-E can be synthesized as shown in Scheme I.
  • the isoindoline carbamate 1 can be treated under basic conditions to hydrolyse the isoindoline carbamate thereby providing alcohol 2.
  • the alcohol 2 can be treated with a heteroaryl chloride, such as 2-chlorobenzothiazole, 2-chloro-6- methylbenzothiazole, 2,6-dichlorobenzothiazole, 6-bromo-2-chlorobenzothiazole,

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Abstract

The embodiments provide compounds of the general Formulae I, II, III, IV, V, VI, VII, and X, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Description

NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Nos. 61/045,220, filed April 15, 2008; 61/105,736, filed October 15, 2008; 61/105,751, filed October 15, 2008; 61/143,728, filed January 9, 2009; and 61/150,693, filed February 6, 2009; all of which are incorporated herein by reference in their entirety.
SEQUENCE LISTING
[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled INTMU-049VPC.TXT, created April 14, 2009, which is 4 Kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION Field of the Invention
[0003] The present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
Description of the Related Art
[0004] Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
[0005] Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using pegylated IFN-α plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders (NR) or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.
[0006] The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965-1985.
[0007] HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in lingth and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non- structural (NS) proteins of the virus. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first viral protease cleaves at the NS2-NS3 junction of the polyprotein. The second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as "NS3 protease"). NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein). NS 3 protease exhibits activity both in cis, at the NS 3 -NS 4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. Apparently, the formation of the complex between NS3 and NS4A is necessary for NS3-mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3. The NS3 protease also exhibits nucleoside triphosphatase and RNA of HCV RNA.
SUMMARY QF THE INVENTION [0008] The present embodiments provide compounds of the general Formula I:
Figure imgf000004_0001
(I) or a pharmaceutically acceptable salt or prodrug thereof wherein:
R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and C1-6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, Ci_6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C 1-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6; alkyl, -(CH2)qC3_7cycloalkyl, -(CH2)qC6 or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; each u is separately 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000007_0001
Figure imgf000007_0002
R19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond; with the proviso that the compound of formula I is not
Figure imgf000008_0001
[0009] The present embodiments also provide compounds of the general Formula I wherein:
(a) R1 is hydrogen;
(b) R2 is hydrogen, -C(O)R4 or selected from the group consisting of Ci-6 alkyl, aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(c) R4 is Ci-6 alkyl or polycyclic moiety optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxyl-Ci_6 alkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R4 is -NR90aR90b or Ci_6 alkyl optionally substituted with up to 5 fluoro; wherein R90a and R90b are each separately a hydrogen atom or Q-6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(d) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(e) R2a is selected from the group consisting of Ci_6 alkyl, C?,-η cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(f) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(g) R4a is imidazolyl or pyrazolyl; (h) each m is separately 0, 1 or 2;
(i) each p is separately an integer selected from 1-6; (j) each q is separately 0, 1 or 2; (k) each r is separately an integer selected from 1-6;
(1) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and C\-e alkyl optionally substituted with up to 5 fluoro; (m) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(n) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(o) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(p) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(q) Z is selected from the group consisting of
Figure imgf000010_0001
Figure imgf000010_0002
(r) R19 is hydrogen, -SOmR2a, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(s) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(t) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond.
[0010] The present embodiments also provide compounds of the general Formula I wherein:
(a) R1 is hydrogen; fluoro;
(c) R4 is -NR90aR90b, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(d) R90a and R90b are each separately a hydrogen atom, or Ci_6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(e) R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3-7cycloalkyl substituted with methyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of C\-e alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b;
(f) each m is separately 0, 1 or 2;
(g) each q is separately 0, 1 or 2;
(h) each t is separately 0, 1 or 2;
(i) each r is separately an integer selected from 1-6;
(J) R100a is hydrogen, and R100b is a hydrogen, or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b; (1) R200a and R200b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(m) each p is separately an integer selected from 1-6;
(n) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(o) Z is selected from the group consisting of
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
(p) R19 is hydrogen, -SOmR2a, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(q) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(r) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(s) the dashed line represents an optional double bond.
[0011] The present embodiments also provide compounds of the general Formula I wherein:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, -S(O)2NRlaRlb, -NHC(O)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(O)R2a, -NHC(O)OR2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and Ci_6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(d) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(O)OR23, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(e) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Q-6 alkoxy, phenyl, and hydroxy-C^ tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(g) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(h) each R4a is separately imidazolyl or pyrazolyl;
(i) each m is separately 0, 1 or 2;
(j) each p is separately an integer selected from 1-6;
(k) each q is separately 0, 1 or 2;
(1) each r is separately an integer selected from 1-6;
(m) R3 is -P(O)R10aR10b, wherein R1Oa and R1Ob are each separately selected from the group consisting of hydroxy, -(O)v-Ci_6 alkyl, -(O)v- (CH2)qC3_7cycloalkyl, - (O)v-aryl, and -(O)v-heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3-7cycloalkyl, C2-β alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(n) wherein each v is separately 0 or 1 ;
(o) each t is separately 0, 1 or 2;
(p) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; (r) Z is selected from the group consisting of
Figure imgf000015_0001
Figure imgf000015_0002
(s) R19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
(t) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(u) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(v) the dashed line represents an optional double bond. [0012] The present embodiments provide compounds of the general Formula II:
Figure imgf000015_0003
II or a pharmaceutically acceptable salt or prodrug thereof wherein:
R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, C1-6 alkyl, -(CH2)qC3-7cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, C1-6 alkyl, and -(CH2)qC3-7cycloalkyl; each m is separately 0, 1 or 2; each q is separately 0, 1 or 2; each t is separately 0, 1 or 2; substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R2a is separately selected from the group consisting of Ci-6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-β alkenyl, -(CH2)qC3_7cycloalkyl, Q-6 alkoxy, phenyl, and hydroxy-C^ alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C 1-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6; group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-β alkenyl, Q-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro;
R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C2_6 alkenyl, C2-6 alkynyl, -(CH2)qC3-7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)PNR14R15], -S[(CH2)pNR14R15], -(CH2)pNR14R15, -(CH2)PR16, -O(CH2)PR16, and Ci_6 alkyl optionally substituted with up to 5 fluoro;
R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3_7 cycloalkyl, C4-Io alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R13 is selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and CO or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the the tetrahydropyran ring;
R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R16 is separately imidazolyl or pyrazolyl;
V is selected from the group consisting of -O-, -S-, and -NR15-;
W is -N- or -CR15-; wherein R15 is H, or selected from the group consisting of Ci_6 alkyl, (CH2)qC3-7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, or phenyl; each u is separately 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000019_0001
Figure imgf000019_0002
R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
[0013] The present embodiments also provide compounds of the general Formula π wherein:
(a) R1 is hydrogen;
(b) each m is separately 0, 1 or 2;
(c) each p is separately an integer selected from 1-6; (e) each r is separately an integer selected from 1-6;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is
-NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each separately selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or each Rld is separately selected from the group consisting of a hydrogen atom,
Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Q-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of C\-e alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is a carboxylic acid;
(g) each t is separately 0, 1 or 2;
(h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(J) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and C\-e alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(1) R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)pNR14R15], -S[(CH2)pNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
(m) R and R are each separately a hydrogen, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(n) R13 is selected from the group consisting of Q-6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(0) R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(p) R16 is imidazolyl or pyrazolyl;
(q) V is selected from the group consisting of -0-, -S-, and -NR23-;
(r) R23 is H, or selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl; wherein said phenyl as an optional substituent is further optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(s) W is -N- or -CR30-;
(t) R30 is H, or selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, or phenyl;
(u) Z is selected from the group consisting of
Figure imgf000023_0001
Figure imgf000023_0002
(v) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(w) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(x) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
(y) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, C2-6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring; and
(aa) the dashed line represents an optional double bond. [0014] The present embodiments provide compounds of the general Formula III or
IV:
Figure imgf000024_0001
III IV or a pharmaceutically acceptable salt or prodrug thereof wherein: R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;or R3 is a carboxylic acid; selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and (CH2)qC3-7cycloalkyl; each m is separately 0, 1 or 2; each q is separately 0, 1 or 2; each t is separately 0, 1 or 2;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3-7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -C(O)R2a, -C(O)OR2a, -NHC(O)R23, -NHC(O)OR23, -SO1nR23, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, Cj,.η cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R2a is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C 1-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro;
R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3-7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)pNR14R15], -S[(CH2)pNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
7 S
R and R are each separately a hydrogen, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C3-7 cycloalkyl, C4- 10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with
7 S up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R13 is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R14 and R15 are each separately selected from hydrogen and Ci-6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R16 is separately imidazolyl or pyrazolyl; -(CH2)qC3-7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and -NRlaRlb;
E and F are independently -N- or -CR -; when E is -CR18-, F is -N-; when F is -CR18-, E is -N-; each R18 is separately a hydrogen, or selected from the group consisting of Ci-6 alkyl, (CH2)qC3_7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; each u is independently 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000028_0001
R19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
[0015] The present embodiments provide compounds of the general Formula V or VI:
Figure imgf000029_0001
or a pharmaceutically acceptable salt or prodrug thereof wherein: R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; cycloalkyl, and Ce or 10 aiyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C 1-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of d_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)tC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3_7cycloalkyl; each t is separately 0, 1 or 2;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; each u is separately 0, 1 or 2; Z is selected from the group consisting of
Figure imgf000032_0001
R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
[0016] The present embodiments also provide compounds of the general Formula V or VI wherein:
(a) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(b) R2a is selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Q-6 alkoxy, phenyl, and hydroxy-C^ alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(c) each m is separately 0, 1 or 2; (e each q is separately 0, 1 or 2;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or io aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is
-NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each separately selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or each Rld is separately selected from the group consisting of a hydrogen atom,
Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is a carboxylic acid;
(g) each t is separately 0, 1 or 2;
(h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(J) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(1) Z is selected from the group consisting o
Figure imgf000034_0002
Figure imgf000034_0001
(m m)) RR1199 iiss hhyyddrrooggeenn,, --SSOOmmRR22aa,, oorr CCui-6 alkyl optionally substituted with up to 5 fluoro; -C(O)R2a, -C(O)NRlaRlb, and -C(S)NRlaRlb;
(o) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(p) the dashed line represents an optional double bond. [0017] The present embodiments provide compounds of the general Formula VII:
Figure imgf000035_0001
VII or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is hydrogen;
(b) R2 is selected from the group consisting of:
Figure imgf000035_0002
and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Q-6 alkyl, Q-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(c) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken piperidinyl, piperazinyl, or morpholinyl;
(d) each R2a is separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl;
(e) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R4a is imidazolyl or pyrazolyl;
(g) each m is separately 0, 1 or 2;
(h) each p is separately an integer selected from 1-6;
(i) each q is separately 0, 1 or 2;
(j) each r is separately an integer selected from 1-6;
(k) R20 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, C\-e alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(1) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci_6 alkyl optionally substituted with up to 5 fluoro; or R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is carboxylic acid;
(m) each t is separately 0, 1 or 2;
(n) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(o) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(p) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(q) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; (r) Z is selected from the group consisting of
Figure imgf000038_0001
(s) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(t) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond. [0018] The present embodiments provide compounds of the general Formula X:
Figure imgf000038_0002
(X) rmaceutically acceptable salt, prodrug, or ester thereof wherein:
(a) Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y is within 4 A or less of at least one moiety selected from NS3 protease His57 imidazole moiety and NS3 protease GIy 137 nitrogen atom;
(b) Pi' is a moiety, different from Y, having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Pi' is within 6 A consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43;
(c) L is a moiety consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
(d) P2 is a moiety selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic;
(e) the dashed line represents an optional double bond;
(f) P2 is positioned by L such that, upon binding of the compound to NS 3 protease, at least one atom of P2 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Tyr56, His57, Val78, Asp79, Gln80, Asp81, Argl55 and Alal56;
(g) R50 is H and R60 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; or R50 and R60 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
(h) R50 and R60 are positioned such that, upon binding of the compound to NS3 protease, at least one atom of R50 or R60 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Argl23, Alal56, Alal57, Vall58, Cysl59, and Aspl68.
DETAILED DESCRIPTION QF THE EMBODIMENTS
Definitions
[0019] As used herein, common organic abbreviations are defined as follows: Ac Acetyl
Ac2O Acetic anhydride aq. Aqueous
Bn Benzyl
Bz Benzoyl
BOC or Boc tert-Butoxycarbonyl cat. Catalytic
Cbz Carbobenzyloxy
CDI 1,1' -carbonyldiimidazole
Cy (C-C6H11) Cyclohexyl
0C Temperature in degrees Centigrade
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DCE 1 ,2-Dichloroethane
DCM methylene chloride
DIEA Diisopropylethylamine
DMA Dimethylacetamide
DMAP 4-(Dimethylamino)pyridine
DME Dimethoxyethane
DMF N,N'-Dimethylformamide
DMSO Dimethylsulfoxide
Et Ethyl
EtOAc Ethyl acetate g Gram(s) h Hour (hours)
HATU 2-( lH-7-azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3-tetramethyl uronium hexafluorophosphate
HOBT 1 -Ηydroxybenzotriazole
HPLC High performance liquid chromatography iPr Isopropyl
IU International Units
LCMS Liquid chromatography-mass spectrometry
LDA Lithium diisopropylamide mCPBA meta-Chloroperoxybenzoic Acid
MeOH Methanol
MeCN Acetonitrile mL Milliliter(s)
MTBE Methyl tertiary-butyl ether
NH4OAc Ammonium acetate Pd/C Palladium on activated carbon ppt Precipitate
PyBOP (Benzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate
RCM Ring closing metathesis rt Room temperature sBuLi sec-Butylithium
TEA Triethylamine
TCDI l,l'-Thiocarbonyl diimidazole
Tert, t tertiary
TFA Trifluoracetic acid
THF Tetrahydrofuran
TLC Thin-layer chromatography
TMEDA Tetramethylethylenediamine μL Microliter(s)
[0020] As used herein, the term "hepatic fibrosis," used interchangeably herein with "liver fibrosis," refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.
[0021] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
[0022] As used herein, the term "liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'- nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
[0023] The term "sustained viral response" (SVR; also referred to as a "sustained response" or a "durable response"), as used herein, refers to the response of an individual to a viral response" refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
[0024] "Treatment failure patients" as used herein generally refers to HCV- infected patients who failed to respond to previous therapy for HCV (referred to as "non- responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as "relapsers"). The previous therapy generally can include treatment with IFN- α monotherapy or IFN- α combination therapy, where the combination therapy may include administration of IFN-α and an antiviral agent such as ribavirin.
[0025] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
[0026] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
[0027] As used herein, the term "a Type I interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non- peptide chemical agonists; and the like. naturally occurring or non-naturally occurring ligand of human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include native human interferon-γ, recombinant IFN-γ species, glycosylated IFN-γ species, pegylated IFN-γ species, modified or variant IFN-γ species, IFN-γ fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
[0029] As used herein, the term "a Type El interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of humanIL-28 receptor α ("IL- 28R"), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.
[0030] As used herein, the term "interferon receptor agonist" refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III interferon receptor agonist.
[0031] The term "dosing event" as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term "dosing event," as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
[0032] "Continuous delivery" as used herein (e.g., in the context of "continuous delivery of a substance to a tissue") is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
[0033] "Controlled release" as used herein (e.g., in the context of "controlled drug release") is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-α) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "Controlled release" thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals). delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). "Patterned" or "temporal" drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
[0035] The term "controlled drug delivery device" is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
[0036] By "substantially continuous" as used in, for example, the context of "substantially continuous infusion" or "substantially continuous delivery" is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, "substantially continuous" drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
[0037] By "substantially steady state" as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average). The AUC8hr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time course (total/3days), i.e., q = (AUCtotal)/ (total/3days). For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUC8hr average for the serum concentration of the drug over the time course.
[0038] The term "alkyl" as used herein refers to a radical of a fully saturated hydrocarbon, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-hexyl,
Figure imgf000045_0001
h jf
Figure imgf000045_0002
For example, the term "alkyl" as used herein includes radicals of fully saturated hydrocarbons defined by the following general formula's: the general formula for linear or branched fully saturated hydrocarbons not containing a cyclic structure is CnH2n+2; the general formula for a fully saturated hydrocarbon containing one ring is CnH2n; the general formula for a fully saturated hydrocarbon containing two rings is CnH2(n-i); the general formula for a saturated hydrocarbon containing three rings is CnH2(n-2).
[0039] The term "halo" used herein refers to fluoro, chloro, bromo, or iodo.
[0040] The term "alkoxy" used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an — O— linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
[0041] The term "alkenyl" used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond including, like.
[0042] The term "alkynyl" used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like.
[0043] The term "polycyclic moiety" used herein refers a bicyclic moiety or tricyclic moiety optionally containing one or more heteroatoms wherein at least one of the rings is not an aryl or heteroaryl ring. The bicyclic moiety contains two rings wherein the rings are fused, the bicyclic moiety can be appended at any position of the two rings. For
example, bicyclic moiety may refer to a radical including but not limited to: ,
Figure imgf000046_0001
Figure imgf000046_0002
, and . The tricyclic moiety contains a bicyclic moiety with an additional fused ring, the tricyclic moiety can be appended at any position of the three rings.
For example, tricyclic moiety may refer to a radical including but not limited to:
Figure imgf000046_0003
Figure imgf000047_0001
[0044] The term "aryl" used herein refers to homocyclic aromatic radical whether one ring or multiple fused rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, naphthacenyl, and the like.
[0045] The term "cycloalkyl" used herein refers to saturated aliphatic ring system radical having three to twenty carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.0]hexyl, and the like.
[0046] The term "cycloalkenyl" used herein refers to aliphatic ring system radical having three to twenty carbon atoms having at least one carbon-carbon double bond in the ring. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
[0047] The term "polycycloalkyl" used herein refers to saturated aliphatic ring system radical having at least two rings that are fused with or without bridgehead carbons. Examples of polycycloalkyl groups include, but are not limited to, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, adamantyl, norbornyl, and the like.
[0048] The term "polycycloalkenyl" used herein refers to aliphatic ring system radical having at least two rings that are fused with or without bridgehead carbons in which at least one of the rings has a carbon-carbon double bond. Examples of polycycloalkenyl groups include, but are not limited to, norbornylenyl, l,l'-bicyclopentenyl, and the like.
[0049] The term "polycyclic hydrocarbon" used herein refers to a ring system radical in which all of the ring members are carbon atoms. Polycyclic hydrocarbons can be aromatic or can contain less than the maximum number of non-cumulative double bonds. Examples of polycyclic hydrocarbon include, but are not limited to, naphthyl, dihydronaphthyl, indenyl, fluorenyl, and the like. herein refers to cyclic non-aromatic ring system radical having at least one ring in which one or more ring atoms are not carbon, namely heteroatom. In fused ring systems, the one or more heteroatoms may be present in only one of the rings. Examples of heterocyclic groups include, but are not limited to, morpholinyl, tetrahydrofuranyl, dioxolanyl, pyrolidinyl, pyranyl, piperidyl, piperazyl, and the like.
[0051] The term "heteroaryl" used herein refers to an aromatic heterocyclic group, whether one ring or multiple fused rings. In fused ring systems, the one or more heteroatoms may be present in only one of the rings. Examples of heteroaryl groups include, but are not limited to, benzothiazyl, benzoxazyl, quinazolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyridinyl, pyrrolyl, oxazolyl, indolyl, and the like.
[0052] The term "arylalkyl" used herein refers to one or more aryl groups appended to an alkyl radical. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, phenpropyl, phenbutyl, and the like.
[0053] The term "cycloalkylalkyl" used herein refers to one or more cycloalkyl groups appended to an alkyl radical. Examples of cycloalkylalkyl include, but are not limited to, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, and the like.
[0054] The term "heteroarylalkyl" used herein refers to one or more heteroaryl groups appended to an alkyl radical. Examples of heteroarylalkyl include, but are not limited to, pyridylmethyl, furanylmethyl, thiopheneylethyl, and the like.
[0055] The term "heterocyclylalkyl" used herein refers to one or more heterocyclyl groups appended to an alkyl radical. Examples of heterocyclylalkyl include, but are not limited to, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, tetrahydrofuranylmethyl, pyrrolidinylpropyl, and the like.
[0056] The term "aryloxy" used herein refers to an aryl radical covalently bonded to the parent molecule through an --O-- linkage.
[0057] The term "alkylthio" used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an -S-- linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
[0058] The term "arylthio" used herein refers to an aryl radical covalently bonded to the parent molecule through an -S- linkage. more alkyl groups attached thereto. Thus, monoalkylamino refers to nitrogen radical with one alkyl group attached thereto and dialkylamino refers to nitrogen radical with two alkyl groups attached thereto.
[0060] The term "cyanoamino" used herein refers to nitrogen radical with nitrile group attached thereto.
[0061] The term "carbamyl" used herein refers to RNHC(O)O--.
[0062] The term "keto" and "carbonyl" used herein refers to C=O.
[0063] The term "carboxy" used herein refers to -COOH.
[0064] The term "sulfamyl" used herein refers to -SO2NH2.
[0065] The term "sulfonyl" used herein refers to -SO2-.
[0066] The term "sulfinyl" used herein refers to -SO-.
[0067] The term "thiocarbonyl" used herein refers to C=S.
[0068] The term "thiocarboxy" used herein refers to CSOH.
[0069] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term "radical" can be used interchangeably with the terms "group" and "moiety."
[0070] As used herein, a substituted group is derived from the unsubstituted parent structure in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when substituted, the substituent group(s) is (are) one or more group(s) individually and independently selected from Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, C3-C7 cycloalkyl (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO2-alkyl, -CF3, and -OCF3), C3-C6 heterocycloalkyl (e.g., tetrahydrofuryl) (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO2-alkyl, -CF3, and -OCF3), aryl (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO2-alkyl, -CF3, and - OCF3), heteroaryl (optionally substituted with halo, alkyl, alkoxy, carboxyl, CN, -SO2-alkyl, -CF3, and -OCF3), halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, Ci-C6 alkoxy, aryloxy, sulfhydryl (mercapto), Ci-C6 alkylthio, arylthio, mono- and di-(Ci-C6)alkyl amino, quaternary ammonium salts, amino(Ci-C6)alkoxy, hydroxy(Ci-C6)alkylamino, amino(Ci- C6)alkylthio, cyanoamino, nitro, carbamyl, keto (oxo), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and combinations substituents are known to those of skill in the art and can be found in references such as Greene and Wuts Protective Groups in Organic Synthesis; John Wiley and Sons: New York, 1999. Wherever a substituent is described as "optionally substituted" that substituent can be substituted with the above substituents unless the context clearly dictates otherwise.
[0071] Asymmetric carbon atoms may be present in the compounds described. All such isomers, including diastereomers and enantiomers, as well as the mixtures thereof are intended to be included in the scope of the recited compound. In certain cases, compounds can exist in tautomeric forms. All tautomeric forms are intended to be included in the scope. Likewise, when compounds contain an alkenyl or alkenylene group, there exists the possibility of cis- and trans- isomeric forms of the compounds. Both cis- and trans- isomers, as well as the mixtures of cis- and trans- isomers, are contemplated. Thus, reference herein to a compound includes all of the aforementioned isomeric forms unless the context clearly dictates otherwise.
[0072] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitely disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0073] Various forms are included in the embodiments, including polymorphs, solvates, hydrates, conformers, salts, and prodrug derivatives. A polymorph is a composition having the same chemical formula, but a different structure. A solvate is a composition formed by solvation (the combination of solvent molecules with molecules or ions of the solute). A hydrate is a compound formed by an incorporation of water. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond. Salts of compounds can be prepared by methods known to those skilled in the art. For example, salts of compounds can be prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compound. A prodrug is a compound that undergoes biotransformation (chemical conversion) before exhibiting its specialized protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule. Thus, reference herein to a compound includes all of the aforementioned forms unless the context clearly dictates otherwise.
[0074] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the embodiments. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the embodiments.
[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the embodiments, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[0076] It must be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods and reference to "a dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.
[0077] The present embodiments provide compounds of Formulae I, II, IE, IV, V, VI, VII, and X, as well as pharmaceutical compositions and formulations comprising any compound of Formulae I, II, EI, IV, V, VI, VII, and X. A subject compound is useful for treating HCV infection and other disorders, as discussed below. Formula I
[0078] The embodiments provide a compound having the structure of Formula I:
Figure imgf000052_0001
(I) or a pharmaceutically acceptable salt or prodrug thereof wherein:
R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and Ci-6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, Ci_6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(O)OR23, -SOmR2a, -NHS(O)2R23, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-β alkenyl, hydroxy-Ci_6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of d_6 alkyl, -(CH2)qC3_7cycloalkyl, -(CH2)qC6 or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and -(CH2)qC3-7cycloalkyl; each t is separately 0, 1 or 2;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; each u is separately 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
, a anndd
Figure imgf000055_0004
R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond; with the proviso that the compound of formula I is not
Figure imgf000055_0005
[0079] Some embodiments include compounds of Formula I having the structure:
Figure imgf000056_0001
[0080] In some embodiments, R20 is selected from the group consisting of hydrogen, -SOmR2a, and -C(O)R2a.
[0081] In another embodiment, R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl.
[0082] In another embodiment, R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro.
[0083] In some embodiments, R4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro.
[0084] In another embodiment, wherein R4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF3.
[0085] In another embodiment, R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(O)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(O)R2a, -NHC(O)OR2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, Ci_6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro.
[0086] In still another embodiment, R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkoxy, -(CH2)qC3_7cycloalkyl, aryl and heteroaryl; wherein said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of Ci-6 alkyl, and -NRlaRlb, wherein q is 0 and Rla and Rlb are each separately a hydrogen atom or Ci-6 alkyl.
[0087] In some embodiments, R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-6 alkoxy, -(CH2)qC3_7cycloalkyl, phenyl, thiazole, oxazole, thiophene, and pyridine; wherein said thiazole and oxazole as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of Ci_6 alkyl, and -NRlaRlb, wherein q is 0 and Rla and Rlb are each separately a hydrogen atom or Ci-6 alkyl.
[0088] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_ 6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen, -C(O)CH3, or -SO2CH3.
[0089] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl optionally substituted with one or more substituents each independently selected from fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0090] In still another embodiment, n is 0 or 1 ; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci-6 alkyl optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0091] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and R20 is hydrogen.
[0092] In some embodiments, Z is propyl.
[0093] In another embodiment, R3 is carboxylic acid.
[0094] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy.
[0095] In another embodiment, R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3; m is 0 or 1; and q is 0 or l.
[0096] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci-6 alkyl or -NR9aR9b is a pyrrolidine or piperidine. Formula I (alternative 1)
[0097] In an alternative embodiment of Formula I:
(a) R1 is hydrogen;
(b) R2 is hydrogen, -C(O)R4 or selected from the group consisting of Ci-6 alkyl, aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3-7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(O)R2a, -NHC(O)OR2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a; more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxyl-Ci_6 alkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or R4 is -NR90aR90b or Ci_6 alkyl optionally substituted with up to 5 fluoro; wherein R90a and R90b are each separately a hydrogen atom or Ci-6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(d) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, C2-6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(e) R2a is selected from the group consisting of Ci_6 alkyl, C?,-η cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(f) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(g) R4a is imidazolyl or pyrazolyl; (h) each m is separately 0, 1 or 2;
(i) each p is separately an integer selected from 1-6; (k) each r is separately an integer selected from 1-6;
(1) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or io aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or io aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONR100aR100b;
(m) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(n) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(o) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, C\-e alkyl optionally substituted with up to 5 fluoro, and C\-e alkoxy optionally substituted with up to 5 fluoro;
(p) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and C\-e alkoxy optionally substituted with up to 5 fluoro; (q) Z is selected from the group consisting of
Figure imgf000061_0001
(r) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(s) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(t) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond.
[0098] In another embodiment, R20 is selected from the group consisting of -SOmR2a, and -C(0)R2a.
[0099] In another embodiment, R20 is -C(O)OR2a. [0100] In another embodiment, R2a is Ci_6 alkyl.
[0101] In another embodiment, Z is
Figure imgf000061_0002
[0102] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl.
[0103] In another embodiment, R3 is -CONR100aR100b.
[0104] In another embodiment, R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
[0105] In another embodiment, R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl; v is 0; and p is 1.
[0106] In another embodiment, R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen, or -(CH2)vCONR200aR200b.
[0107] In another embodiment, R2 is hydrogen. optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxyl-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
[0109] In another embodiment, R4 is a dihydroisoindole optionally substituted with one or more substituents each separately selected from the group consisting of halo, Ci_6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
[0110] In another embodiment, R2 is -C(O)R4 where R4 is Ci_6 alkyl.
[0111] In another embodiment, R2 is Ci-6 alkyl.
[0112] In another embodiment, R2 is -C(O)R4 where R4 is -NR90aR90b; wherein R90a and R90b are each separately a hydrogen atom or Ci_6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring.
[0113] In another embodiment, R90a and R90b are each separately a hydrogen atom or C 1-6 alkyl. Formula I (alternative 2)
[0114] In an alternative embodiment of Formula I:
(a) R1 is hydrogen;
(b) R2 is -C(O)R4, hydrogen, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(c) R4 is -NR90aR90b, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(d) R90a and R90b are each separately a hydrogen atom, or Ci_6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(e) R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3-7cycloalkyl substituted with methyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and C\-e alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b;
(f) each m is separately 0, 1 or 2;
(g) each q is separately 0, 1 or 2;
(h) each t is separately 0, 1 or 2;
(i) each r is separately an integer selected from 1-6;
(J) R100a is hydrogen, and R100b is a hydrogen, or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(k) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(1) R200a and R200b are each separately hydrogen or -(CH2)pC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, C\-e alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(m) each p is separately an integer selected from 1-6;
(n) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and C\-e alkoxy optionally substituted with up to 5 fluoro; (o) Z is selected from the group consisting of
Figure imgf000064_0001
(p) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(q) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(r) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(s) the dashed line represents an optional double bond.
[0115] In another emboimdent, R20 is -C(0)0R2a. [0116] In another emboimdent, R2a is Ci-6 alkyl.
[0117] In another emboimdent, Z is
Figure imgf000064_0002
[0118] In another emboimdent, R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_ 7cycloalkyl substituted with methyl.
[0119] In another emboimdent, R3 is -CONR100aR100b.
[0120] In another emboimdent, R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
[0121] In another emboimdent, R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl; v is 0; and p is 1.
[0122] In another emboimdent, R100a is hydrogen, and R100b is a hydrogen or -(CH2)vCONR200aR200b.
[0123] In another emboimdent, R2 is Ci-6 alkyl.
[0124] In another emboimdent, R2 is -C(O)R4; R4 is -NR90aR90b or Ci_6 alkyl; and R90a and R90b are each separately a hydrogen atom, or Ci_6 alkyl; or R90a and R90b are taken heterocycle.
[0125] In another emboimdent, R90a and R90b are each separately a hydrogen atom or C 1-6 alkyl.
[0126] In another emboimdent, R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle. Formula I (alternative 3)
[0127] In an alternative embodiment of Formula I:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(O)R2a, -NHC(O)OR2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and d_6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, Ci_6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(d) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -(CH2)pR4a and -O(CH2)pR4a;
(e) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-β alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(g) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(h) each R4a is separately imidazolyl or pyrazolyl;
(i) each m is separately 0, 1 or 2;
(j) each p is separately an integer selected from 1-6;
(k) each q is separately 0, 1 or 2;
(1) each r is separately an integer selected from 1-6;
(m) R3 is -P(O)R10aR10b, wherein R1Oa and R1Ob are each separately selected from the group consisting of hydroxy, -(O)v-Ci_6 alkyl, -(O)v- (CH2)qC3-7cycloalkyl, -(O)v-aryl, and -(O)v-heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, alkoxy optionally substituted with up to 5 fluoro;
(n) wherein each v is separately 0 or 1 ;
(o) each t is separately 0, 1 or 2;
(p) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-C!_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro;
(q) each u is separately 0, 1 or 2;
Figure imgf000067_0001
(s) R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
(t) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(u) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(v) the dashed line represents an optional double bond. [0128] In another embodiment, R1Oa is hydroxy. [0129] In another embodiment, R1Ob is -0-C1-6 alkyl. [0131] In another embodiment, RiυD is -Ci-6 alkyl.
[0132] In another embodiment, R lOb is methyl or ethyl.
[0133] In another embodiment, R1Oa is hydroxy or -0-Ci-6 alkyl and R1Ob is Ci_6 alkyl. Formula II
[0134] The embodiments provide a compound of Formula II:
Figure imgf000068_0001
II or a pharmaceutically acceptable salt or prodrug thereof wherein:
R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, C6 or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and C6 or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3_7cycloalkyl; each m is separately 0, 1 or 2; each q is separately 0, 1 or 2; each t is separately 0, 1 or 2;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(O)OR23, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a; the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R2a is separately selected from the group consisting of Ci-6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-β alkenyl, -(CH2)qC3_7cycloalkyl, Q-6 alkoxy, phenyl, and hydroxy-C^ alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C 1-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2_6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)pOH], -O[(CH2)pNR14R15], -S[(CH2)pNR14R15], -(CH2)pNR14R15, -(CH2)PR16, -O(CH2)PR16, and Ci_6 alkyl optionally substituted with up to 5 fluoro;
R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R13 is selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R16 is separately imidazolyl or pyrazolyl;
V is selected from the group consisting of -0-, -S-, and -NR15-;
W is -N- or -CR15-; wherein R15 is H, or selected from the group consisting of Ci_6 alkyl, (CH2)qC3-7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl; each u is separately 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000072_0001
R , 19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or
-SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(O)OR2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond. [0135] In some embodiments, the compound of Formula II has the structure:
Figure imgf000072_0002
[0136] In some embodiments, R is selected from the group consisting of hydrogen, -SOmR2a, and -C(0)R2a.
[0137] In another embodiment, R »4 i •s selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl fluoro; n is 0; and R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with Ci-6 alkyl.
[0138] In another embodiment, R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
[0139] In another embodiment, R4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro.
[0140] In another embodiment, R4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF3.
[0141] In another embodiment, R11 and R12 are each separately selected from the group consisting of hydrogen, halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy, and -(CH2)qC3_7cycloalkyl where q is 0.
[0142] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen, -C(O)CH3, or -SO2CH3.
[0143] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0144] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0145] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and R20 is hydrogen.
[0146] In another embodiment, Z is propyl. [0148] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl or Ci_6 alkoxy.
[0149] In another embodiment, R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3; m is 0 or 1; and q is 0 or l.
[0150] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine. Formula II (alternative)
[0151] In an alternative embodiment of Formula II:
(a) R1 is hydrogen;
(b) each m is separately 0, 1 or 2;
(c) each p is separately an integer selected from 1-6;
(d) each q is separately 0, 1 or 2;
(e) each r is separately an integer selected from 1-6;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is
-NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each separately selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is C1-6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and C\-e alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; (g) each t is separately 0, 1 or 2;
(h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(J) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(1) R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)PNR14R15], -S[(CH2)PNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
(m) R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C3-7 cycloalkyl, C4- 10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(0) R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(p) R16 is imidazolyl or pyrazolyl;
(q) V is selected from the group consisting of -O-, -S-, and -NR23-;
(r) R23 is H, or selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl; wherein said phenyl as an optional substituent is further optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(s) W is -N- or -CR30-;
(t) R30 is H, or selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl;
(u) Z is selected from the group consisting of
Figure imgf000077_0001
Figure imgf000077_0002
fluoro;
(w) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(x) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
(y) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(z) R2a is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring; and
(aa) the dashed line represents an optional double bond.
[0152] In another embodiment, R20 is selected from the group consisting of -SOmR2a, and -C(0)R2a.
[0153] In another embodiment, R20 is -C(O)OR2a. [0154] In another embodiment, R2a is Ci-6 alkyl.
[0155] In another embodiment, Z is
Figure imgf000078_0001
[0156] In another embodiment, R3 is an acylsulfonamide of the formula -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl optionally substituted with Ci_6 alkyl.
[0157] In another embodiment, R3 is a -CONHO(CH2)mR10 where R10 is optionally substituted aryl and m is 0. R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is pyrrolidine or piperidine.
[0159] In another embodiment, V is selected from the group consisting of -O- and -S-; and W is -N-.
[0160] In another embodiment, V is -NR21-; R21 is H, Ci-6 alkyl, or arylalkyl; and W is -N-.
[0161] In another embodiment, R11 and R12 are each separately selected from the group consisting of hydrogen, halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy, and -(CH2)qC3_7cycloalkyl where q is 0. Formulas III and IV
[0162] The embodiments provide a compound having the structure of Formula III or Formula IV:
Figure imgf000079_0001
III IV or a pharmaceutically acceptable salt or prodrug thereof wherein: R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C6 or io aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group optionally substituted heteroaryl;or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and (CH2)qC3-7cycloalkyl; each m is separately 0, 1 or 2; each q is separately 0, 1 or 2; each t is separately 0, 1 or 2;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R2a is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C i_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each p is separately an integer selected from 1-6; each r is separately an integer selected from 1-6;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro;
R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl, Ci-6 alkoxy, C2_6 alkenyl, C2-β alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)pNR14R15], -S[(CH2)pNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3_7 cycloalkyl, C4-Io alkylcycloalkyl, C2_6 alkenyl, hydroxy-C^ alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R13 is selected from the group consisting of Ci-6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R14 and R15 are each separately selected from hydrogen and Ci-6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; R17 is a hydrogen, or selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and -NRlaRlb;
E and F are independently -N- or -CR18-; when E is -CR18-, F is -N-; when F is -CR18-, E is -N-; each R18 is separately a hydrogen, or selected from the group consisting of Ci-6 alkyl, (CH2)qC3_7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; each u is independently 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000083_0001
R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
[0163] Some embodiments include a compound of Formula IE having the structure:
Figure imgf000084_0001
[0164] Some embodiments include a compound of Formula IV having the structure:
Figure imgf000084_0002
[0165] In another embodiment, R is selected from the group consisting of hydrogen, -SOmR2a, and -C(O)R2a.
[0166] In another embodiment, R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl.
[0167] In another embodiment, R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro. substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro.
[0169] In another embodiment, R4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF3.
[0170] In another embodiment, R11 and R12 are each separately selected from the group consisting of hydrogen, Ci_6 alkyl, and Ci_6 alkoxy.
[0171] In another embodiment, R11 and R12 are each separately selected from the group consisting of hydrogen, methyl and methoxy.
[0172] In another embodiment, R17 is a hydrogen, or selected from the group consisting of phenyl, thiazole, thiophene, oxazole and pyridine, each optionally substituted with one or more substituents each independently selected from the group consisting Ci_6 alkyl and -NRlaRlb, wherein Rla and Rlb are each separately a hydrogen atom or Ci-6 alkyl.
[0173] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci- 6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen, -C(O)CH3, or -SO2CH3.
[0174] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0175] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0176] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and R20 is hydrogen.
[0177] In another embodiment, Z is propyl.
[0178] In another embodiment, R3 is carboxylic acid. C3-7cycloalkyl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy.
[0180] In another embodiment, R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3; m is 0 or 1; and q is 0 or l.
[0181] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine. Formulas V and VI
[0182] The embodiments provide a compound having the structure of Formula V or VI:
Figure imgf000086_0001
(V) (VI) or a pharmaceutically acceptable salt or prodrug thereof wherein: R1 is-(CR5R6)nR4; n is 0, 1 or 2;
R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R2a is separately selected from the group consisting of Ci_6 alkyl, C?,-η cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
R3a and R3b are each separately selected from the group consisting of hydrogen and C i_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R4a is separately imidazolyl or pyrazolyl; each m is separately 0, 1 or 2; each p is separately an integer selected from 1-6; each q is separately 0, 1 or 2; each r is separately an integer selected from 1-6;
R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; each t is separately 0, 1 or 2;
R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; each u is separately 0, 1 or 2;
Z is selected from the group consisting of
Figure imgf000089_0001
Figure imgf000089_0002
R19 is hydrogen, Q-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and the dashed line represents an optional double bond.
[0183] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Q-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen, -C(O)CH3, or -SO2CH3.
[0184] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and R20 is hydrogen. phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and R20 is hydrogen.
[0186] In another embodiment, n is 0 or 1; R5 and R6 are each hydrogen; R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and R20 is hydrogen.
[0187] In another embodiment, Z is propyl.
[0188] In another embodiment, R3 is carboxylic acid.
[0189] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy.
[0190] In another embodiment, R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3; m is 0 or 1; and q is 0 or l.
[0191] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Q-6 alkyl or -NR9aR9b is a pyrrolidine or piperidine. Formulas V and VI (alternative)
[0192] In some alternative embodiments of Formulas V and VI:
(a) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(b) R2a is selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; ring;
(c) each m is separately 0, 1 or 2;
(d) each p is separately an integer selected from 1-6; (e each q is separately 0, 1 or 2;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or io aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is
-NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or
-(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom,
C1-6 alkyl, and -(CH2)qC3-7cycloalkyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is a carboxylic acid;
(g) each t is separately 0, 1 or 2;
(h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(J) R200a and R200b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; (1) Z is selected from the group consisting of
Figure imgf000093_0001
(m) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(n) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(o) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(p) the dashed line represents an optional double bond.
[0193] In another embodiment, R20 is selected from the group consisting of -SOmR2a, and -C(0)R2a.
[0194] In another embodiment, R20 is -C(O)OR2a. [0195] In another embodiment, wherein R2a is Ci_6 alkyl.
[0196] In another embodiment, Z is
Figure imgf000093_0002
[0197] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl optionally substituted with Ci-6 alkyl.
[0198] In another embodiment, R3 is carboxylic acid.
[0199] In another embodiment, R3 is -C(O)NHO(CH2)mR10 where R10 is Ci_6alkyl, -(CH2)qC3_7cycloalkyl, or phenyl optionally substituted with CF3; m is 0 or 1; and q is 0 or 1.
[0200] In another embodiment, R3 is -C(O)NHS(O)2R9 where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine. Formula VII
[0201] Some embodiments provide a compound having the structure of Formula VII:
Figure imgf000094_0001
VII or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is hydrogen;
(b) R2 is selected from the group consisting of:
Figure imgf000094_0002
and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(c) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(d) each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, alkyl;
(e) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R4a is imidazolyl or pyrazolyl;
(g) each m is separately 0, 1 or 2;
(h) each p is separately an integer selected from 1-6;
(i) each q is separately 0, 1 or 2;
(j) each r is separately an integer selected from 1-6;
(k) R20 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(1) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; with methyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is carboxylic acid;
(m) each t is separately 0, 1 or 2;
(n) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(o) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(p) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(q) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(r) Z is selected from the group consisting of
Figure imgf000096_0001
Figure imgf000096_0002
(s) R19 is hydrogen, -SOmR2a, or Ci_6 alkyl optionally substituted with up to 5 fluoro; they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond. [0202] In another embodiment, R2 is selected from the group consisting of
Figure imgf000097_0001
and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, hydroxy, Ci-6 alkyl, and Ci_6 alkoxy.
[0203] In another embodiment, R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl.
[0204] In another embodiment, R3 is -CONR100aR100b.
[0205] In another embodiment, R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
[0206] In another embodiment, R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aiyl; v is 0; and p is 1.
[0207] In another embodiment, R100a is hydrogen, and R100b is a hydrogen or -(CH2)vCONR200aR200b.
[0208] In another embodiment, R20 is selected from the group consisting of phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substitutents each independently selected from the group consisting of halo, cyano, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
[0209] In another embodiment, R20 is phenyl optionally substituted with one or more substitutents each independently selected from the group consisting of halo, cyano, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
[0210] In another embodiment, R20 is phenyl substituted with one or more substitutents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro.
[0211] In another embodiment, R20 is phenyl substituted with one or more fluoro and optionally substituted with CF3. [0212] In another embodiment, Z is ** .
Formula X
[0213] Some embodiments provide a compound of Formula X:
Figure imgf000098_0001
(X) or a pharmaceutically acceptable salt, prodrug, or ester thereof.
[0214] Some embodiments of the compound of Formula X have the structure of Formula Xa:
Figure imgf000098_0002
(Xa) or a pharmaceutically acceptable salt, prodrug, or ester thereof.
[0215] As used herein, an NS 3 protease Sl' pocket moiety refers to a moiety of the NS 3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease SEQ ID NO: 1). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43, see Yao. et. al., Structure 1999, 7, 1353.
[0216] As used herein, an NS3 protease S2 pocket moiety refers to a moiety of the NS 3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLEVVT-STWVLV, SEQ ID NO: 1). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Argl55, Val78, Asp79, Gln80 and Asp81, see Yao. et. al., Structure 1999, 7, 1353.
[0217] Embodiments described herein include compounds containing moieties having a size, configuration and/or position selected to interact and/or be in proximity to particular regions, particular amino acid residues, and/or particular atoms of NS3 protease, upon binding of the compound to NS3 protease. For example, in an embodiment of the compound of the general formulae (X) and (Xa), Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y is within 4 A or less of at least one moiety selected from NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom. In another embodiment of the compound of the general formulae (X) and (Xa), Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y forms a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease, including, but not limited to, NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom. In some instances, Y may be configured to form a hydrogen bond with both the NS3 protease His57 imidazole moiety and the NS3 protease GIy 137 nitrogen atom. The moiety -NH-SO2- is an example of a Y moiety.
[0218] In a similar fashion, in an embodiment of the compound of the general formulae (X) and (Xa), the Pi' moiety, different from Y, has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of Pi' is within 6 A or less of at least one NS3 protease Sl' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43. In another embodiment of the compound of the general formulae (X) and (Xa), the Pi' moiety, different from Y, has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease Sl' pocket. For example the Pi' moiety may form a non-polar interaction with at least one amino acid selected from Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43. The moieties C3_7 cycloalkyl, C4_i0 alkylcycloalkyl and di(Ci_4 alkyl)amine are examples of Pi' moieties. Examples of Y-Pi' include -NH-SO2- methylcyclopropyl and -NH-SO2-N(CH3)2.
[0219] In a similar fashion, in an embodiment of the compound of the general formulae (X) and (Xa), the P2 moiety has a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of P2 is within 5 A or less of any backbone or side chain atom of at least one NS3 protease residue selected from the group consisting of Tyr56, His57, Val78, Asp79, Gln80, Asp81, Argl55 and Alal56. In an embodiment of the compound of the general formulae (X) and (Xa), P2 is positioned by L to provide this configuration, where L is a moiety consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. In an embodiment, L is an oxygen atom. In another embodiment, L may contain 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L may contain a moiety having the formula -W-C(=V)-, where V and W are each individually selected from O, S or NH. Specific exemplary moieties for L include, but are not limited to, ester, amide, carbamate, thioester, and thioamide. In some embodiments, P2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
[0220] In another embodiment of the compound of the general formulae (X) and (Xa), the P2 moiety has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of P2 forms a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket. For example the P2 moiety may form a non-polar interaction with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81. The P2 moiety also may be configured to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS 3 protease S2 pocket. For example the P2 moiety may form a hydrogen bond with at instances, P2 may form both a non-polar interaction and a hydrogen bond with peptide backbone or side chain moieties or atoms located in the substrate binding pocket of NS3 protease, such amino acids selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81. Such hydrogen bond and non-polar interactions may occur with the same amino acid residue or with different amino acid residues in the NS 3 protease S 2 pocket. In an embodiment of the compound of the general formulae (X) and (Xa), P2 is positioned by L to provide this configuration, where L is a moiety as described above. In some embodiments, P2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
[0221] In another embodiment of the compound of the general formulae (X) and (Xa), the R50 and R60 moieties have a size, configuration and/or positioning such that, upon binding of the compound to NS3 protease, at least one atom of R50 or R60 is within 5 A or less of any backbone or side chain atom of at least one NS3 protease residue selected from the group consisting of Argl23, Alal56, Alal57, Vall58, Cysl59, and Aspl68. In an embodiment, R50 is H and R60 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; or R50 and R60 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
Compositions
[0222] The present embodiments further provide compositions, including pharmaceutical compositions, comprising compounds of the general Formulae I, π, IE, IV, V, VI, VII, or X.
[0223] A subject pharmaceutical composition comprises a subject compound; and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Pharmaceutical Assoc.
[0224] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
[0225] The present embodiments provide for a method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound disclosed herein.
[0226] The present embodiments provide for a method of treating hepatitis by modulating NS3/NS4 protease comprising contacting a NS3/NS4 protease with a compound disclosed herein.
[0227] Example compounds of Formulae I, π, III, IV, V, VI, and VII include Compound Numbers 101-492, 701, 1001-1075, and 1077-1147 as set forth herein.
[0228] Preferred embodiments provide a method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
[0229] Preferred embodiments provide a method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
[0230] Preferred embodiments provide a method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.
[0231] In many embodiments, a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) NS3 protease. Whether a subject compound inhibits HCV NS3 protease can be readily determined using any known method. Typical methods involve a determination of whether an HCV polyprotein or other polypeptide comprising an NS 3 recognition site is cleaved by NS 3 in the presence of the agent. In many embodiments, a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound. an HCV NS3 protease with an IC50 of less than about 50 μM, e.g., a subject compound inhibits an HCV NS3 protease with an IC50 of less than about 40 μM, less than about 25 μM, less than about 10 μM, less than about 1 μM, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.
[0233] In many embodiments, a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) NS3 helicase. Whether a subject compound inhibits HCV NS3 helicase can be readily determined using any known method. In many embodiments, a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound.
[0234] In many embodiments, a subject compound inhibits HCV viral replication. For example, a subject compound inhibits HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to HCV viral replication in the absence of the compound. Whether a subject compound inhibits HCV viral replication can be determined using methods known in the art, including an in vitro viral replication assay.
Treating a hepatitis virus infection
[0235] The methods and compositions described herein are generally useful in treatment of an of HCV infection.
[0236] Whether a subject method is effective in treating an HCV infection can be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.
[0237] In general, an effective amount of a compound of Formulae I, π, IE, IV, V, VI, Vπ, or X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy. determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
[0239] The method involves administering an effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, optionally in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum. In some embodiments, an effective amount of a compound of Formulae I, II, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.
[0240] In some embodiments, an effective amount of a compound of Formulae I, E, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.
[0241] In many embodiments, an effective amount of a compound of Formulae I, E, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a sustained viral response, e.g., non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
[0242] As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
[0243] As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 compound of Formulae I, π, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount effective to reduce ALT levels to less than about 45 IU/mL serum.
[0244] A therapeutically effective amount of a compound of Formulae I, π, III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Methods of measuring serum markers include immunological -based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
[0245] In many embodiments, an effective amount of a compound of Formulae I, π, EI, IV, V, VI, Vn, or X and an additional antiviral agent is a synergistic amount. The additional antiviral agent may itself be a combination of antiviral agents, e.g., a combination of pegylated interferon-alfa and ribavirin. As used herein, a "synergistic combination" or a "synergistic amount" of a compound of Formulae I, π, EI, IV, V, VI, VII, or X and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of Formulae I, π, IE, IV, V, VI, VII, or X when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
[0246] In some embodiments, a selected amount of a compound of Formulae I, II, HI, IV, V, VI, VII, or X and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount of the compound of Formulae I, II, EI, IV, V, VI, VII, or X and/or the selected amount of the additional antiviral agent is ineffective when used in monotherapy for the disease. Thus, the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount of the compound of Formulae I, II, IE, IV, V, VI, additional antiviral agent provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of the compound of Formulae I, II, IE, IV, V, VI, Vπ, or X enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of Formulae I, π, III, IV, V, VI, VII, or X provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of Formulae I, II, III, IV, V, VI, VII, or X and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of Formulae I, II, IE, IV, V, VI, VII, or X and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease. As used herein, a "synergistically effective amount" of a compound of Formulae I, π, EI, IV, V, VI, VII, or X and an additional antiviral agent, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (l)-(3) above. Fibrosis
[0247] The embodiments provides methods for treating liver fibrosis (including forms of liver fibrosis resulting from, or associated with, HCV infection), generally involving administering a therapeutic amount of a compound of Formulae I, π, III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents. Effective amounts of compounds of Formulae I, II, IE, IV, V, VI, VII, or X, with and without one or more additional antiviral agents, as well as dosing regimens, are as discussed below.
[0248] Whether treatment with a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is effective in reducing liver fibrosis is determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Liver fibrosis reduction is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade" as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage" as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a Knodell, Scheuer, Ludwig, and Ishak scoring systems.
[0249] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
[0250] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.
[0251] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.
[0252] The Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696- 699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
[0253] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
[0254] In some embodiments, a therapeutically effective amount of a compound of Formulae I, π, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that effects a change of one unit or more in the fibrosis stage based on pre- and post- therapy liver biopsies. In particular embodiments, a therapeutically effective amount of a compound of Formulae I, II, EI, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, reduces liver fibrosis by at least one unit in the METAVEl, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
[0255] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a compound of Formulae I, II, IE, IV, V, VI, VE, or X. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.
[0256] An effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
[0257] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen EI peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include α-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase. IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
[0259] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
[0260] As used herein, a "complication associated with cirrhosis of the liver" refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but it not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
[0261] A therapeutically effective amount of a compound of Formulae I, π, III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount that is effective in reducing the incidence (e.g., the likelihood that an individual will develop) of a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or to a placebo-treated individual.
[0262] Whether treatment with a compound of Formulae I, II, in, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is effective in reducing the those skilled in the art.
[0263] Reduction in liver fibrosis increases liver function. Thus, the embodiments provide methods for increasing liver function, generally involving administering a therapeutically effective amount of a compound of Formulae I, II, IE, IV, V, VI, Vπ, or X, and optionally one or more additional antiviral agents. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5 '-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
[0264] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.
[0265] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal level of alanine transaminase is about 45 IU per milliliter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control. IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a compound of Formulae I, II, IE, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is an amount effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. A therapeutically effective amount of a compound of Formulae I, π, III, IV, V, VI, VII, or X, and optionally one or more additional antiviral agents, is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.
Dosages, Formulations, and Routes of Administration
[0267] In the subject methods, the active agent(s) (e.g., compound of Formulae I, II, in, IV, V, VI, Vπ, or X, and optionally one or more additional antiviral agents) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents of the embodiments can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols. Formulations
[0268] The above-discussed active agent(s) can be formulated using well-known reagents and methods. Compositions are provided in formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.
[0269] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
[0270] In some embodiments, an agent is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from about 5 mM to about 100 mM. In some embodiments, the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars e.g., mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further includes a non-ionic surfactant such as polysorbate 20 or 80. Optionally the formulations may further include a preservative. Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4°C. Formulations may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored over extended periods of time, even at ambient temperatures.
[0271] As such, administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In many embodiments, administration is by bolus injection, e.g., subcutaneous bolus injection, intramuscular bolus injection, and the like.
[0272] The pharmaceutical compositions of the embodiments can be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred.
[0273] Subcutaneous administration of a pharmaceutical composition of the embodiments is accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination of a of the embodiments to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In many embodiments, subcutaneous administration is achieved by bolus delivery by needle and syringe.
[0274] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.
[0275] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
[0276] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
[0277] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the embodiments can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
[0278] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier. units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the embodiments calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the novel unit dosage forms of the embodiments depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
[0280] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
Other antiviral or antifibrotic agents
[0281] As discussed above, a subject method will in some embodiments be carried out by administering an NS3 inhibitor that is a compound of Formulae I, II, IE, IV, V, VI, Vπ, or X, and optionally one or more additional antiviral agent(s).
[0282] In some embodiments, the method further includes administration of one or more interferon receptor agonist(s). Interferon receptor agonists are described herein.
[0283] In other embodiments, the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described herein.
[0284] Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs. Non-limiting examples include azidothymidine (AZT) (zidovudine), and analogs and derivatives thereof; 2',3'- dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof; 2',3'- dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof; 2'3,'- didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and analogs and derivatives thereof; combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs; and the like.
[0285] In some embodiments, the method further includes administration of ribavirin. Ribavirin, l-β-D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. Some embodiments also involve use of derivatives of ribavirin (see, e.g., U.S. the same or different administration form and in the same or different route as the NS-3 inhibitor compound. Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, intravenously, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
[0286] In some embodiments, the method further includes administration of ritonavir. Ritonavir, 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l-methylethyl)-4- thiazolyl]-3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5- thiazolylmethyl ester [5S-(5R*,8R*,lOR*,llR*)], available from Abbott Laboratories, is an inhibitor of the protease of the human immunodeficiency virus and also of the cytochrome P450 3A and P450 2D6 liver enzymes frequently involved in hepatic metabolism of therapeutic molecules in man. Because of its strong inhibitory effect on cytochrome P450 3A and the inhibitory effect on cytochrome P450 2D6, ritonavir at doses below the normal therapeutic dosage may be combined with other protease inhibitors to achieve therapeutic levels of the second protease inhibitor while reducing the number of dosage units required, the dosing frequency, or both.
[0287] Coadministration of low-dose ritonavir may also be used to compensate for drug interactions that tend to decrease levels of a protease inhibitor metabolized by CYP3A. Its structure, synthesis, manufacture and formulation are described in U.S. Pat. No. 5,541,206 U.S. Pat. No. 5,635,523 U.S. Pat. No. 5,648,497 U.S. Pat. No. 5,846,987 and U.S. Pat. No. 6,232,333. The ritonavir may be administered orally in capsule or tablet or oral solution form, or in the same or different administration form and in the same or different route as the NS-3 inhibitor compound. Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, intravenously, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
[0288] In some embodiments, an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment. In other embodiments, an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment can begin before the NS 3 inhibitor compound treatment begins and end before the NS 3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS 3 inhibitor additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end before the NS 3 inhibitor compound treatment ends; or the additional antiviral agent treatment can begin before the NS 3 inhibitor compound treatment begins and end after the NS 3 inhibitor compound treatment ends.
Methods of Treatment Monotherapies
[0289] The NS3 inhibitor compounds described herein may be used in acute or chronic therapy for HCV disease. In many embodiments, the NS3 inhibitor compound is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The NS 3 inhibitor compound can be administered 5 times per day, 4 times per day, tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.
[0290] In many embodiments, an NS3 inhibitor compound of the embodiments is administered orally.
[0291] In connection with the above-described methods for the treatment of HCV disease in a patient, an NS 3 inhibitor compound as described herein may be administered to the patient at a dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day. In some embodiments, the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
[0292] The amount of active ingredient that may be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration. A typical pharmaceutical preparation can contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the pharmaceutical preparation can contain from about 20% to about 80% active ingredient.
[0293] Those of skill will readily appreciate that dose levels can vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the susceptibility readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given interferon receptor agonist.
[0294] In many embodiments, multiple doses of NS3 inhibitor compound are administered. For example, an NS3 inhibitor compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. Combination therapies with ribavirin
[0295] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ribavirin. Ribavirin can be administered in dosages of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day.
[0296] One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of ribavirin for the duration of the desired course of NS3 inhibitor compound treatment.
[0297] Another embodiment provides any of the above-described methods modified to include co-administering to the patient about 800 mg to about 1200 mg ribavirin orally per day for the duration of the desired course of NS3 inhibitor compound treatment. In another embodiment, any of the above-described methods may be modified to include coadministering to the patient (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally per day if the patient has a body weight greater than or equal to 75 kg, where the daily dosage of ribavirin is optionally divided into to 2 doses for the duration of the desired course of NS3 inhibitor compound treatment. Combination therapies with levovirin
[0298] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of levovirin. Levovirin is generally administered in an amount ranging from about 30 from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment. Combination therapies with viramidine
[0299] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of viramidine. Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, viramidine is administered orally in dosages of about 800 mg, or about 1600 mg per day for the desired course of NS3 inhibitor compound treatment. Combination therapies with ritonavir
[0300] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ritonavir. Ritonavir is generally administered in an amount ranging from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, or from about 500 mg to about 600 mg, twice per day. In some embodiments, ritonavir is administered orally in dosages of about 300 mg, or about 400 mg, or about 600 mg twice per day for the desired course of NS3 inhibitor compound treatment. Combination therapies with alpha- glucosidase inhibitors
[0301] Suitable α-glucosidase inhibitors include any of the above-described imino-sugars, including long-alkyl chain derivatives of imino sugars as disclosed in U.S. Patent Publication No. 2004/0110795; inhibitors of endoplasmic reticulum-associated α- glucosidases; inhibitors of membrane bound α-glucosidase; miglitol (Glyset®), and active derivatives, and analogs thereof; and acarbose (Precose®), and active derivatives, and analogs thereof. comprising administering an NS3 inhibitor compound as described above, and an effective amount of an α-glucosidase inhibitor administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
[0303] An α-glucosidase inhibitor can be administered 5 times per day, 4 times per day, tid (three times daily), bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, an α-glucosidase inhibitor is administered as a continuous infusion.
[0304] In many embodiments, an α-glucosidase inhibitor is administered orally.
[0305] In connection with the above-described methods for the treatment of a flavivirus infection, treatment of HCV infection, and treatment of liver fibrosis that occurs as a result of an HCV infection, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of α- glucosidase inhibitor administered to the patient at a dosage of from about 10 mg per day to about 600 mg per day in divided doses, e.g., from about 10 mg per day to about 30 mg per day, from about 30 mg per day to about 60 mg per day, from about 60 mg per day to about 75 mg per day, from about 75 mg per day to about 90 mg per day, from about 90 mg per day to about 120 mg per day, from about 120 mg per day to about 150 mg per day, from about 150 mg per day to about 180 mg per day, from about 180 mg per day to about 210 mg per day, from about 210 mg per day to about 240 mg per day, from about 240 mg per day to about 270 mg per day, from about 270 mg per day to about 300 mg per day, from about 300 mg per day to about 360 mg per day, from about 360 mg per day to about 420 mg per day, from about 420 mg per day to about 480 mg per day, or from about 480 mg to about 600 mg per day.
[0306] In some embodiments, the methods provide for combination therapy comprising administering an NS 3 inhibitor compound as described above, and an effective amount of α-glucosidase inhibitor administered in a dosage of about 10 mg three times daily. In some embodiments, an α-glucosidase inhibitor is administered in a dosage of about 15 mg three times daily. In some embodiments, an α-glucosidase inhibitor is administered in a administered in a dosage of about 25 mg three times daily. In some embodiments, an α- glucosidase inhibitor is administered in a dosage of about 30 mg three times daily. In some embodiments, an α-glucosidase inhibitor is administered in a dosage of about 40 mg three times daily. In some embodiments, an α-glucosidase inhibitor is administered in a dosage of about 50 mg three times daily. In some embodiments, an α-glucosidase inhibitor is administered in a dosage of about 100 mg three times daily. In some embodiments, an α- glucosidase inhibitor is administered in a dosage of about 75 mg per day to about 150 mg per day in two or three divided doses, where the individual weighs 60 kg or less. In some embodiments, an α-glucosidase inhibitor is administered in a dosage of about 75 mg per day to about 300 mg per day in two or three divided doses, where the individual weighs 60 kg or more.
[0307] The amount of active ingredient (e.g., α-glucosidase inhibitor) that may be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration. A typical pharmaceutical preparation can contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the pharmaceutical preparation can contain from about 20% to about 80% active ingredient.
[0308] Those of skill will readily appreciate that dose levels can vary as a function of the specific α-glucosidase inhibitor, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given α-glucosidase inhibitor are readily determinable by those of skill in the art by a variety of means. A typical means is to measure the physiological potency of a given active agent.
[0309] In many embodiments, multiple doses of an α-glucosidase inhibitor are administered. For example, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of α- glucosidase inhibitor administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight years, or more.
Combination therapies with thymosin-α
[0310] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of thymosin-α. Thymosin-α (Zadaxin™) is generally administered by subcutaneous injection. Thymosin-α can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously for the desired course of NS3 inhibitor compound treatment. In many embodiments, thymosin-α is administered twice per week for the desired course of NS 3 inhibitor compound treatment. Effective dosages of thymosin-α range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-α is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
[0311] Thymosin-α can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In one emobidment, thymosin-α is administered for the desired course of NS3 inhibitor compound treatment. Combination therapies with interferon(s)
[0312] In many embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of an interferon receptor agonist. In some embodiments, a compound of Formulae I, II, HI, IV, V, VI, VII, or X and a Type I or El interferon receptor agonist are co-administered in the treatment methods described herein. Type I interferon receptor agonists suitable for use herein include any interferon-α (IFN-α). In certain embodiments, the interferon-α is a PEGylated interferon-α. In certain other embodiments, the interferon-α is a consensus interferon-α is a monoPEG (30 kD, linear)-ylated consensus interferon.
[0313] Effective dosages of an IFN-α range from about 3 μg to about 27 μg, from about 3 MU to about 10 MU, from about 90 μg to about 180 μg, or from about 18 μg to about 90 μg. Effective dosages of Infergen® consensus IFN-α include about 3 μg, about 6 μg, about 9 μg, about 12 μg, about 15 μg, about 18 μg, about 21 μg, about 24 μg, about 27 μg, or about 30 μg, of drug per dose. Effective dosages of IFN-α2a and IFN-α2b range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGAS YS ® PEGylated IFN- α2a contain an amount of about 90 μg to 270 μg, or about 180 μg, of drug per dose. Effective dosages of PEG-INTRON®PEGylated IFN-α2b contain an amount of about 0.5 μg to 3.0 μg of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of about 18 μg to about 90 μg, or from about 27 μg to about 60 μg, or about 45 μg, of CIFN amino acid weight per dose of PEG-CIFN. Effective dosages of monoPEG (30 kD, linear)-ylated CIFN contain an amount of about 45 μg to about 270 μg, or about 60 μg to about 180 μg, or about 90 μg to about 120 μg, of drug per dose. IFN-α can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0314] In many embodiments, the Type I or Type El interferon receptor agonist and/or the Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations. Some embodiments provide any of the above- described methods in which the desired dosage of IFN-α is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration. In other embodiments, any of the above-described methods may be practiced in which the desired dosage of PEGylated IFN-α (PEG-IFN-α) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration. receptor agonist are co-administered in the treatment methods of the embodiments. Type II interferon receptor agonists suitable for use herein include any interferon-γ (IFN-γ).
[0316] Effective dosages of IFN-γ can range from about 0.5 μg/m2 to about 500 μg/m2, usually from about 1.5 μg/m2 to 200 μg/m2, depending on the size of the patient. This activity is based on 10 international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week, or substantially continuously or continuously.
[0317] In specific embodiments of interest, IFN-γ is administered to an individual in a unit dosage form of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 100 μg to about 300 μg. In particular embodiments of interest, the dose is about 200 μg IFN-γ. In many embodiments of interest, IFN-γlb is administered.
[0318] Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.
[0319] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m2 to about 20 μg/m2. For example, an IFN-γ dosage ranges from about 20 μg/m2 to about 30 μg/m , from about 30 μg/m to about 40 μg/m , from about 40 μg/m to about 50 μg/m2, from about 50 μg/m2 to about 60 μg/m2, from about 60 μg/m2 to about 70 μg/m2, from about 70 μg/m to about 80 μg/m , from about 80 μg/m to about 90 μg/m , from about 90 μg/m2 to about 100 μg/m2, from about 100 μg/m2 to about 110 μg/m2, from about 110 μg/m2 to about 120 μg/m2, from about 120 μg/m2 to about 130 μg/m2, from about 130 μg/m2 to about 140 μg/m2, or from about 140 μg/m2 to about 150 μg/m2. In some embodiments, the dosage groups range from about 25 μg/m2 to about 100 μg/m2. In other embodiments, the dosage groups range from about 25 μg/m2 to about 50 μg/m2.
[0320] In some embodiments, a Type I or a Type IE interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I or a Type El interferon receptor agonist (also referred to as "the induction regimen") generally involves administration of a higher dosage of the Type I or Type IE interferon receptor agonist. For example, in the case of Infergen® consensus IFN-α about 18 μg, or about 27 μg. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I or Type IE interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0321] The first dosing regimen of the Type I or Type III interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
[0322] The second dosing regimen of the Type I or Type El interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I or Type IE interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CE7N at a dose of at least about 3 μg, at least about 9 μg, at least about 15 μg, or at least about 18 μg. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.
[0323] The second dosing regimen of the Type I or Type EI interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0324] In some embodiments, where an "induction'V'maintenance" dosing regimen of a Type I or a Type EI interferon receptor agonist is administered, a "priming" dose of a Type E interferon receptor agonist (e.g., IFN-γ) is included. In these embodiments, IFN- γ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type EI interferon receptor agonist. This period of time is referred to as the "priming" phase.
[0325] In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type IE interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type IE interferon receptor agonist. In these embodiments, the total time of treatment with Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to π interferon receptor agonist treatment is discontinued once Type I or a Type El interferon receptor agonist treatment begins.
[0326] In other embodiments, the Type I or Type IE interferon receptor agonist is administered in single dosing regimen. For example, in the case of CE7N, the dose of CIFN is generally in a range of from about 3 μg to about 15 μg, or from about 9 μg to about 15 μg. The dose of Type I or a Type EI interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously. The dose of the Type I or Type III interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
[0327] In some embodiments, where a single dosing regimen of a Type I or a Type EI interferon receptor agonist is administered, a "priming" dose of a Type E interferon receptor agonist (e.g., IFN-γ) is included. In these embodiments, IFN-γ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type IE interferon receptor agonist. This period of time is referred to as the "priming" phase. In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total time of treatment with the Type E interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, Type E interferon receptor agonist treatment is discontinued once Type I or a Type EI interferon receptor agonist treatment begins.
[0328] In additional embodiments, an NS 3 inhibitor compound, a Type I or IE interferon receptor agonist, and a Type E interferon receptor agonist are co-administered for the desired duration of treatment in the methods described herein. In some embodiments, an NS3 inhibitor compound, an interferon-α, and an interferon-γ are co-administered for the desired duration of treatment in the methods described herein. a Type I or Type III interferon receptor agonist, a Type II interferon receptor agonist, and an NS3 inhibitor compound, effective for the treatment of HCV infection in a patient. Some embodiments provide methods using an effective amount of an IFN-α, IFN-γ, and an NS3 inhibitor compound in the treatment of HCV infection in a patient. One embodiment provides a method using an effective amount of a consensus IFN-α, IFN-γ and an NS 3 inhibitor compound in the treatment of HCV infection in a patient.
[0330] In general, an effective amount of a consensus interferon (CIFN) and IFN-γ suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 μg CIFN: 10 μg IFN-γ, where both CIFN and IFN-γ are unPEGylated and unglycosylated species.
[0331] In one embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-α and IFN-γ in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0332] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGENOconsensus IFN-α and IFN-γ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 μg to about 9 μg, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 10 μg to about 100 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound. modified to use an effective amount of INFERGEN® consensus IFN- α and IFN-γ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 10 μg to about 50 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0334] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-α and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 9 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 90 μg to about 100 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0335] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-α and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 200 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0336] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-α and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 4 μg to about 60 μg month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 30 μg to about 1,000 μg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0337] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-α and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 18 μg to about 24 μg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 100 μg to about 300 μg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0338] In general, an effective amount of IFN-α 2a or 2b or 2c and IFN-γ suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 million Units (MU) IFN-α 2a or 2b or 2c : 30 μg IFN-γ, where both IFN-α 2a or 2b or 2c and IFN-γ are unPEGylated and unglycosylated species.
[0339] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 30 μg to about 600 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0340] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in of IFN-γ, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0341] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-γ containing an amount of about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0342] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYSOPEGylated IFN-α2a and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 30 μg to about 1,000 μg, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0343] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYSOPEGylated IFN-α2a and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 μg of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 100 μg to about 300 μg, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0344] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN-α2b and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 30 μg to about 1,000 μg of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0345] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN-α2b and IFN-γ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 μg of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-γ containing an amount of about 100 μg to about 300 μg of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0346] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0347] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0348] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; 100 μg Actimmune® human IFN-γlb administered subcutaneously embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0349] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0350] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0351] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; 25 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0352] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; 200 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0353] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; and 25 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks. comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 μg INFERGEN® consensus IFN-α administered subcutaneously qd or tiw; and 200 μg Actimmune® human IFN-γlb administered subcutaneous Iy tiw, where the duration of therapy is 48 weeks.
[0355] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0356] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0357] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0358] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0359] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0360] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0361] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0362] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0363] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an administered subcutaneously every 10 days or qw; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0364] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0365] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0366] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0367] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more. comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0369] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days or qw; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0370] Any of the above-described methods involving administering an NS3 inhibitor, a Type I interferon receptor agonist (e.g., an IFN-α), and a Type II interferon receptor agonist (e.g., an IFN-γ), can be augmented by administration of an effective amount of a TNF-α antagonist (e.g., a TNF-α antagonist other than pirfenidone or a pirfenidone analog). Exemplary, non-limiting TNF-α antagonists that are suitable for use in such combination therapies include ENBREL®, REMICADE®, and HUMIRA™.
[0371] One embodiment provides a method using an effective amount of ENBREL®; an effective amount of IFN-α; an effective amount of IFN-γ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 μg to about 23 mg per dose, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
[0372] One embodiment provides a method using an effective amount of REMICADE®, an effective amount of IFN-α; an effective amount of IFN-γ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
[0373] One embodiment provides a method using an effective amount of HUMIRA™, an effective amount of IFN-α; an effective amount of IFN-γ; and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRA™ containing an amount of from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRA™, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment. Combination therapies with pirfenidone
[0374] In many embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, an NS3 inhibitor compound, one or more interferon receptor agonist(s), and pirfenidone or pirfenidone analog are co-administered in the treatment methods of the embodiments. In certain embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. In other embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. Type I interferon receptor agonists suitable for use herein include any IFN-α, such as interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and PEGylated IFN-α' s, such as peginterferon alfa-2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as monoPEG (30 kD, linear)-ylated consensus interferon. Type II interferon receptor agonists suitable for use herein include any interferon-γ.
[0375] Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
[0376] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally in one to five divided doses per day. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.
[0377] One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS 3 inhibitor compound treatment. Combination therapies with TNF-α antagonists
[0378] In many embodiments, the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of TNF-α antagonist, in combination therapy for treatment of an HCV infection.
[0379] Effective dosages of a TNF-α antagonist range from 0.1 μg to 40 mg per dose, e.g., from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, from about 1.0 μg per dose to about 5.0 μg per dose, from about 5.0 μg to about 10 μg per dose, from about 10 μg to about 20 μg per dose, from about 20 μg per dose to about 30 μg per dose, from about 30 μg per dose to about 40 μg per dose, from about 40 μg per dose to about 50 μg per dose, from about 50 μg per dose to about 60 μg per dose, from about 60 μg per dose to about 70 μg per dose, from about 70 μg to about 80 μg per dose, from about 80 μg per dose to about 100 μg per dose, from about 100 μg to about 150 μg per dose, from about 150 μg to about 200 μg per dose, from about 200 μg per dose to about 250 μg per dose, from about 250 μg to about 300 μg per dose, from about 300 μg to about 400 μg per dose, from about 600 μg to about 700 μg per dose, from about 700 μg to about 800 μg per dose, from about 800 μg to about 900 μg per dose, from about 900 μg to about 1000 μg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
[0380] In some embodiments, effective dosages of a TNF-α antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-α antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.
[0381] In many embodiments, a TNF-α antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-α antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
[0382] In many embodiments, multiple doses of a TNF-α antagonist are administered. For example, a TNF-α antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to more.
[0383] A TNF-α antagonist and an NS3 inhibitor are generally administered in separate formulations. A TNF-α antagonist and an NS 3 inhibitor may be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
[0384] One embodiment provides a method using an effective amount of a TNF-α antagonist and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0385] One embodiment provides a method using an effective amount of ENB REL® and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 μg to about 23 mg per dose, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0386] One embodiment provides a method using an effective amount of REMIC ADE® and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once the desired duration of treatment with an NS3 inhibitor compound.
[0387] One embodiment provides a method using an effective amount of HUMIR A™ and an effective amount of an NS 3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRA™ containing an amount of from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRA™, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound. Combination therapies with thvmosin-α
[0388] In many embodiments, the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of thymosin-α, in combination therapy for treatment of an HCV infection.
[0389] Effective dosages of thymosin-α range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-α is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
[0390] One embodiment provides a method using an effective amount of ZADAXIN™ thymosin-α and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of ZADAXIN™ containing an amount of from about 1.0 mg to about 1.6 mg per dose, subcutaneously twice per week for the desired duration of treatment with the NS 3 inhibitor compound. Combination therapies with a TNF-α antagonist and an interferon
[0391] Some embodiments provide a method of treating an HCV infection in an individual having an HCV infection, the method comprising administering an effective amount of one or more interferons.
[0392] One embodiment provides any of the above-described methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0393] One embodiment provides any of the above-described methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN-γ containing an amount of about 10 μg to about 100 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0394] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN-γ containing an amount of about 30 μg to about 1,000 μg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0395] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0396] One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN-α and a TNF-α antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0397] One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN-α and a TNF-α antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 μg to about 9 μg, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0398] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-α and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 4 μg to about 60 μg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0399] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-α and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 18 μg to about 24 μg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0400] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0401] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound. modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0403] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGAS YS ®PEGylated IFN-α2a and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0404] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGAS YS ®PEGylated IFN-α2a and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0405] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN-α2b and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg of drug per kilogram of body weight per dose of PEG-INTRON®, a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
[0406] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN-α2b and an effective amount of a TNF-α antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 μg of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-α antagonist containing an amount of from about 0.1 μg to about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound. Combination therapies with other antiviral agents
[0407] Other agents such as inhibitors of HCV NS3 helicase are also attractive drugs for combinational therapy, and are contemplated for use in combination therapies described herein. Ribozymes such as Heptazyme™ and phosphorothioate oligonucleotides which are complementary to HCV protein sequences and which inhibit the expression of viral core proteins are also suitable for use in combination therapies described herein.
[0408] In some embodiments, the additional antiviral agent(s) is administered during the entire course of treatment with the NS3 inhibitor compound described herein, and the beginning and end of the treatment periods coincide. In other embodiments, the additional antiviral agent(s) is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., treatment with the additional antiviral agent(s) begins before the NS 3 inhibitor compound treatment begins and ends before the NS 3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS 3 inhibitor compound treatment begins and ends after the NS 3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS 3 inhibitor compound treatment begins and ends before the NS 3 inhibitor compound treatment ends; or treatment with the additional antiviral agent(s) begins before the NS 3 inhibitor compound treatment begins and ends after the NS 3 inhibitor compound treatment ends. simultaneously in separate formulations; simultaneously in the same formulation; administered in separate formulations and within about 48 hours, within about 36 hours, within about 24 hours, within about 16 hours, within about 12 hours, within about 8 hours, within about 4 hours, within about 2 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes or less) one or more additional antiviral agents.
[0410] As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
[0411] As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
[0412] As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS 3 inhibitor compound.
[0413] As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration with an NS 3 inhibitor compound.
[0414] As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneous Iy once daily or three times per week for the desired treatment duration with an NS 3 inhibitor compound.
[0415] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0416] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0417] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0418] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0419] As non-limiting examples, any of the above-described methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration with an NS 3 inhibitor compound.
[0420] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0421] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0422] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0423] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0424] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0425] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0426] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0427] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound. an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0429] As non- limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon- 1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0430] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon- 1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0431] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0432] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0433] As non- limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0434] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0435] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS 3 inhibitor compound.
[0436] As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound. an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0438] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0439] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0440] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0441] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0442] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0443] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0444] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound. an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0446] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0447] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0448] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0449] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0450] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0451] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0452] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound. an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0454] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0455] As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0456] As non-limiting examples, any of the above-described methods featuring an IFN- α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0457] As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS 3 inhibitor compound.
[0458] As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0459] As non-limiting examples, any of the above-described methods featuring an IFN- α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0460] As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0461] As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0462] As non- limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0463] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 μg of drug per dose, subcutaneously once weekly for the desired treatment duration with an NS 3 inhibitor compound.
[0464] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 μg to 1.5 μg of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with an NS3 inhibitor compound.
[0465] As non- limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0466] As non- limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with an NS 3 inhibitor compound.
[0467] As non- limiting examples, any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
[0468] As non- limiting examples, any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
[0469] As non- limiting examples, any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
[0470] As non- limiting examples, any of the above-described methods can be modified to replace the subject NS 3 inhibitor regimen with an NS 3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
[0471] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0472] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound. an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0474] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS 5 B inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0475] The present embodiments provide for a method of treating a hepatitis C virus infection comprising administering to a human dosages of peginterferon alfa-2a and ribavirin under a standard of care protocol (SOC) in combination with ITMN- 191 or a pharmaceutically acceptable salt thereof. The chemical structure of ITMN- 191 is shown below. In some embodiments, the peginterferon alfa-2a and ribavirin in combination with ITMN-191 or a pharmaceutically acceptable salt thereof are administered in combination and provide HCV RNA levels below about 43 IU/mL, below about 25 IU/mL, or below about 9.3 IU/mL after 14 days of treatment. In some embodiments, the dosage of peginterferon alfa-2a can be about 180 μg of peginterferon alfa-2a per dose, administered subcutaneously once weekly for the desired treatment duration. In some embodiments, the dosage of peginterferon alfa-2a can be an amount in the range of about 1.0 μg to about 1.5 μg of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with the ITMN-191 and the ribavarin. In some embodiments, the dosage of ribavirin can be about 400 mg, about 800 mg, about 1000 mg or about 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the peginterferon alfa-2a and ITMN-191. In some embodiments, the dosage of ribavirin can be an amount of about 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or an amount of about 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with the peginterferon alfa-2a and ITMN-191.
[0476] In some embodiments, the amounts of peginterferon alfa-2a and ribavirin administered in the SOC protocol can be lowered due to combination with ITMN-191. For by about 10% to about 75% during the combination treatment.
Patient Identification
[0477] In certain embodiments, the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.
[0478] Thus, some embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.
[0479] Other embodiments provide any of the above-described methods for HCV in which the subject method is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.
[0480] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.
[0481] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naϊve patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
[0482] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naϊve patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.
[0483] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naϊve patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where "HVL" refers to an HCV viral load of greater than 2 x 106 HCV genome copies per mL serum, and where the patient receives a 48 week course of therapy.
[0484] One embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
[0485] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
[0486] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
[0487] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
[0488] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks. treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per mL of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
[0490] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
[0491] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
[0492] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per mL of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 48 weeks.
[0493] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, about 60 weeks.
[0494] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
[0495] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
[0496] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.
[0497] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
[0498] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks. treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks. Subjects Suitable for Treatment
[0500] Any of the above treatment regimens can be administered to individuals who have been diagnosed with an HCV infection. Any of the above treatment regimens can be administered to individuals who have failed previous treatment for HCV infection ("treatment failure patients," including non-responders and relapsers).
[0501] Individuals who have been clinically diagnosed as infected with HCV are of particular interest in many embodiments. Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum. Such individuals include anti-HCV ELISA-positive individuals, and individuals with a positive recombinant immunoblot assay (RIBA). Such individuals may also, but need not, have elevated serum ALT levels.
[0502] Individuals who are clinically diagnosed as infected with HCV include naϊve individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN-α-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients). Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
[0503] In particular embodiments of interest, individuals have an HCV titer of at least about 105, at least about 5 x 105, or at least about 106, or at least about 2 x 106, genome copies of HCV per milliliter of serum. The patient may be infected with any HCV genotype (genotype 1, including Ia and Ib, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), subtypes and quasispecies.
[0504] Also of interest are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child' s-Pugh class A or less), or more advanced cirrhosis (decompensated, Child' s-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti- viral treatment with IFN-α-based therapies or who cannot tolerate IFN-α-based therapies, or who have a contraindication to such therapies. In particular embodiments of interest, HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods described herein. In other embodiments, individuals suitable for treatment with the methods of the embodiments are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation. In still other embodiments, individuals suitable for treatment with the methods described herein include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.).
Preparation of NS3 Inhibitors METHODOLOGY
[0505] The HCV protease inhibitors in the following sections can be prepared according to the procedures and schemes shown in each section. The numberings in each of the following Preparation of NS3 Inhibitor sections including the General Method or General Procedure designations, are meant for that specific section only, and should not be construed or confused with the same numberings, if any, in other sections.
Example 1 General Synthesis A Scheme I
Figure imgf000170_0001
[0506] Macrocyclics of general structures I-D and I-E can be synthesized as shown in Scheme I. The isoindoline carbamate 1 can be treated under basic conditions to hydrolyse the isoindoline carbamate thereby providing alcohol 2. The alcohol 2 can be treated with a heteroaryl chloride, such as 2-chlorobenzothiazole, 2-chloro-6- methylbenzothiazole, 2,6-dichlorobenzothiazole, 6-bromo-2-chlorobenzothiazole,
1-chloroisoquinoline and the like, under basic conditions to afford a compound of general structure I-A. The compound of general structure I-A can be treated with acid in methanol to remove the Boc protecting group and form a methyl ester thereby providing a compound of general structure I-B. The compound of general structure I-B can be treated with optionally substituted aryl boronic acids under Cu2+-catalyzed conditions thereby providing N-aryl under basic conditions to hydrolyse the methyl ester thereby providing carboxylic acids of general structure I-D. Finally, acids of general structure I-D can be coupled with sulfonamides (or sulfamides, not shown) thereby providing compounds of general structure I-
E.
Example 1-1:
General Procedure A
[0507] Compound l ( 10 g, 15.9 mmol.) was dissolved in methanol (100 mL), 5
M NaOH solution (95 mL) was added , the resulting mixture was heated to 50 0C and stirred overnight, after completion of the reaction. The mixture was cooled by ice water, 2 M HCl was added to acidify the mixture to pH=3-4, then the mixture was extracted by EtOAc, the organic layers were combined, washed by brine, dried, the solvent was removed under reduced pressure, the crude compound 2 (7.5 g) was used directly in the next step.
Example 1-2:
General Procedure B
[0508] A solution of Compound 2 (5 g, 1 mL/100 mg) in DMF was added slowly to a mixture of NaH was dissolved in DMF (1.5 mL/100 mg NaH), cooled to 0-5 0C. The mixture was stirred for 2 h at 0-5 0C, then heteroaryl halide (2c) was added, the resulting mixture was warmed to room temperature and stirred for 12 h. The mixture was cooled to 0 0C (ice water bath), then 2 M HCl was carefully added to lower the pH (pH=3-4). The acidic mixture was extracted by EtOAc. The combined organic layers were washed by brine and dried. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford general compound I-A (3.0 g, 60-70% yield).
Example 1-3:
General Procedure C
[0509] General compound I-A (3.0 g) was dissolved in HCl in MeOH (25 niL/g, compound I-A), the resulting mixture was stirred at room temperature for 12 h. The solvent was removed then aqueous NaHCθ3 was added to neutralize any remaining acid. The basic mixture was extracted by EtOAc. The EtOAc layer was dried and then the solvent was further purification in the next step.
Example 1-4:
General Procedure D
[0510] A mixture of general compound I-B (400 mg, 0.80 mmol.), phenylboronic acid (146.8 mg, 1.2 mmol.), Cu(OAc)2 (188 mg, 1.0 mmol.), pyridine (316 mg, 4 mmol.), pyridine N-Oxide (76 mg, 0.8 mmol.) and molecular sieves 4A in dichloromethane (10 mL) was stirred for 12 h at room temperature in a vessel opened to the air. During this time period, the reaction was monitored by LC-MS. Subsequently, another 1.5 eq boronic acid was added with continued stirring. After completion of the reaction, the solvent was removed and the crude mixture was purified by prep-HPLC to give the pure general compound I-C (80 mg, isolated yield 15%). If excessive boronic acid was used, N,N diphenyl product was obtained.
Example 1-5:
General Procedure E
[0511] General compound I-C was dissolved in methanol (10 mIVl g compound I-C), 2 M aqueous NaOH (8 mL/1 g compound I-C) was added to the methanol solution and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0 0C (ice water bath), then 2 M HCl was carefully added to lower the pH (pH=3-4). The acidic mixture was extracted by EtOAc. The combined organic layers were washed by brine and dried. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC (EtOAc/methanol=10:l) to afford general compound I-D (yield, 90- 100%).
Example 1-6:
General Procedure F
[0512] General compound I-D (60 mg, 0.14 mmol. in 2 mL dichloromethane) was added to CDI (45.6 mg, 0.28 mmol.) dissolved in dichloromethane (1 mL) and then stirred 1 h. Subsequently, cyclopropyl sulfonamide (25.4 mg, 0.21 mmol.) and DBU (0.2 mL, 5.0 eq) were added, the resulting mixture was stirred at room temperature for another 12 h monitoring by LCMS. The solvent was then removed and the crude product was purified by prep-HPLC to give the pure general compound I-E as a white solid (-50% yield). Example 1-7:
Figure imgf000173_0001
324
[0513] Compound 324 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 610.7.
Example 1-8:
Figure imgf000173_0002
325
[0514] Compound 325 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 650.8.
Figure imgf000174_0001
326
[0515] Compound 326 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 767.9.
Example 1-10:
Figure imgf000174_0002
327
[0516] Compound 327 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 624.7.
Example 1-11:
Figure imgf000174_0003
328 F, and the yield was 50%. MS (ESI) m/e (M+H+) 727.8.
Example 1-12:
Figure imgf000175_0001
235
[0518] Compound 235 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 709.8.
Example 1-13:
Figure imgf000175_0002
222
[0519] Compound 222 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 759.8.
Figure imgf000176_0001
244
[0520] Compound 244 was prepared in a manner analogous to General Procedure F, and the yield was 50 %. MS (ESI) m/e (M+H+) 721.9.
Example 1-15:
Figure imgf000176_0002
329
[0521] Compound 329 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 642.7.
Example 1-16:
Figure imgf000176_0003
330 F, and the yield was 50%. MS (ESI) m/e (M+H+) 759.8.
Example 1-17:
Figure imgf000177_0001
331
[0523] Compound 331 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 609.1.
Example 1-18:
Figure imgf000177_0002
332
[0524] Compound 332 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 726.3.
Figure imgf000178_0001
333
[0525] Compound 333 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 643.6.
Example 1-20:
Figure imgf000178_0002
334
[0526] Compound 334 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 760.8.
Example 1-21:
Figure imgf000178_0003
335 E, and the yield was 85%. MS (ESI) m/e (M+H+) 609.1.
Example 1-22:
Figure imgf000179_0001
336
[0528] Compound 336 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 827.8.
Example 1-23:
Figure imgf000179_0002
337
[0529] Compound 337 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 726.3.
Figure imgf000180_0001
338
[0530] Compound 338 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 710.7.
Example 1-25:
Figure imgf000180_0002
339
[0531] Compound 339 was prepared in a manner analogous to General Procedure F, and the yield was 85%. MS (ESI) m/e (M+H+) 709.9.
Example 1-26:
Figure imgf000180_0003
340 F, and the yield was 50%. MS (ESI) m/e (M+H+) 760.8.
Example 1-27:
Figure imgf000181_0001
341
[0533] Compound 341 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 727.8.
Example 1-28:
Figure imgf000181_0002
342
[0534] Compound 342 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 741.9.
Figure imgf000182_0001
343
[0535] Compound 343 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 610.7.
Example 1-30:
Figure imgf000182_0002
344
[0536] Compound 344 was prepared in a manner analogous to General Procedure E, and the yield was 85%. MS (ESI) m/e (M+H+) 643.6.
Figure imgf000183_0001
218
[0537] Compound 218 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 705.9.
Example 1-32:
Figure imgf000183_0002
217
[0538] Compound 217 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 726.3.
Figure imgf000184_0001
227
[0539] Compound 227 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 773.9.
Example 1-34:
Figure imgf000184_0002
226
[0540] Compound 226 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 794.3.
Figure imgf000185_0001
223
[0541] Compound 223 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 838.8.
Example 1-36:
Figure imgf000185_0002
345
[0542] Compound 345 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 777.8.
Figure imgf000186_0001
214
[0543] Compound 214 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 770.8.
Example 1-38:
Figure imgf000186_0002
346
[0544] Compound 346 was prepared in a manner analogous to General Procedure F, and the yield was -45%. MS (ESI) m/e (M+H+) 772.2.
Example 1-39:
Figure imgf000186_0003
347 F, and the yield was -45%. MS (ESI) m/e (M+H+) 772.2.
Example 1-40:
Figure imgf000187_0001
220
[0546] Compound 220 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 791.9.
Example 1-41:
Figure imgf000187_0002
348
[0547] Compound 348 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 695.
Example 1-42:
Figure imgf000188_0001
349
[0548] Compound 349 was prepared in a manner analogous to General Procedure F, and the yield was 50%. MS (ESI) m/e (M+H+) 709.
PREPARATION OF NS3 INHIBITORS: SECTION II Example 2 Scheme II
Figure imgf000188_0002
[0549] R1 = O-aryl or SO2cycloalkyl; R1 = O-aryl or SO2cycloalkyl; R" =
(CH2)naryl or (CH2)nheteroaryl; and n = 0, 1, or 2. R11, R12, V, and W are as defined above.
[0550] Macrocyclics of general structures H-D can be synthesized as shown in Scheme II. The alcohol 2 can be treated with a heteroaryl chloride of formula H-A, such as 2-chlorobenzothiazole, and the like, under basic conditions to afford a compound of general structure H-B. The compound of general structure H-B can be coupled with sulfonamides (or sulfamides not shown) or optionally substituted O-alkyl or aryl hydroxylamines thereby providing compounds of general structure H-C. The Boc protected compounds of general structure H-C can be treated with acid in an appropriate solvent to remove the Boc protecting groupto provide the free amine. The free amine can then be coupled under appropriate conditions providing an N-substituted compound of general structure I-D.
Example 2-1: General Method A
Figure imgf000189_0001
[0551] To a solution of compound 2 (1 g, 2.2 mmol.) in 10 mL of dry DMF was added sodium hydride (0.53 g, 13.2 mmol.) at 0 0C. The resulting mixture was stirred at this temperature for 1 h before the addition of 2-chloro-benzothiazole, the mixture was then allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched by careful addition of methanol (10 mL) and water (30 mL). The resulting solution was stirred for 15 min, extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford a residue. The residue was purified by Prep-HPLC to afford compound 3-B as a white solid 0.78 g (yield 60.5 %). 1H NMR (400 MHz, DMSO-4) δ 12.22 (bra, 1 H), 8.61 (s, 2 H), 7.83 (d, / = 7.6 Hz, 1 H), 7.67 (d, / = 7.6 Hz, 1 H), 7.36 (t, / = 7.2 Hz, 1 H), 7.24 (t, / = 7.2 Hz, 1 H), 6.94 (d, / = 6.8 Hz, 1 H), 5.74 (s, 1 H), 5.46 (q, / = 8 Hz, 1 H), 5.25 (t, / = 9.2 Hz, 1 H), 4.51 (d, / = 12.8 Hz, 1 H), 4.41 (t, / = 8 Hz, 1 H), 4.00 (t, / = 10 Hz, 1 H), 3.87 (d, / = 9.6 Hz, 1 H), 2.29-2.30 (m, 1 H), 2.14-2.16 (m, 1 H), 1.43-1.47 (m, 2 H), 1.29-1.14 (m, 16H). MS (ESI) m/e (M+H+) 598.7. General Method C
Figure imgf000190_0001
3-B 3-E
[0552] To a solution of compound 3-B (100 mg, 0.17 mmol.) in 5 mL of dry DMF was added PyBOP (177 mg, 0.34 mmol.) and HOBT (46 mg, 0.34 mmol.) at room temperature, the resulting mixture was stirred 2 h at the same temperature. Subsequently, the stirring mixture was treated with O-phenylhydroxylamine hydrochloride (26.9 mg, 0.19 mmol.) and DIEA (88 mg, 0.68 mmol.), the resulting mixture was stirred overnight at rt. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to get a residue, which was purified by Prep-HPLC to give compound 3-E as white solid 50 mg (yield 32.5%). MS (ESI) m/e (M+H+) 690.3.
Example 4 General Method D
Figure imgf000190_0002
4-B 4-C
[0553] To a solution of compound 4-B (100 mg, 0.17 mmol.) in dry DCM (3 mL) was added CDI (55 mg, 0.34 mmol.) at 25 0C, the mixture was stirred 1 h at the same temperature. Subsequently, the stirring mixture was treated with methylcyclopropanyl sulfonamide (46 mg, 0.34 mmol.) and DBU (0.1 mL, 0.85 mmol.), the resulting mixture was Prep-HPLC to give 4-C as white solid 50 mg (yield 43%). MS (ESI) m/e (M+H+) 700.3.
Example 5- Synthesis of N- Substituted Aryl Ethers Scheme III
Figure imgf000191_0001
[0554] R" = (CH2)naryl or (CH2)nheteroaryl; n= 0, 1, or 2; and R1 = O-aryl or SO2cycloalkyl. R11, R12, V, and W are as defined above.
[0555] Macrocyclics of general structures IH-C can be synthesized as shown in Scheme III. The Boc protected carboxylic acids of the general structure IH-A can be treated with an acid in an appropriate solvent to remove the Boc protecting group to provide the free amine. The free amine can then be coupled under appropriate conditions providing an N- substituted compound of general structure IH-B. The compound of general structure IH-B can be coupled with sulfonamides (or sulf amides; not shown) or optionally substituted O- alkyl or aryl hydroxylamines thereby providing compounds of general structure III-C. General Method E
Figure imgf000192_0001
3-B 5
[0556] A solution of compound 3-B (1 g, 1.67 mmol.) in DCM (5 mL) was treated with TFA (5 mL) at 25 0C. After stirring 2h, the solvent was removed to afford a residue of 5 (1.Og, 100%), which was used in the next step without further purification. MS (ESI) m/e (M+H+) 499.2.
Example 5-2 General Method F
Figure imgf000192_0002
[0557] To a solution of compound 5 (100 mg, 0.2 mmol.) in DCM (5 mL) was added benzaldehyde (13 mg, 0.24 mmol.), NaHB(OAc)3 (81 mg, 0.38 mmol.), and AcOH (0.02 mL) at 25 0C. The resulting mixture was stirred overnight at 25 0C. The solvent was removed to afford a residue, which was purified by Prep-HPLC to give 141 as white solid 50 mg (yield 43.2%). 1H NMR (400 MHz, OMSO-d6) δ 12.43 (br, IH ), 9.29 (br, 1 H), 9.16 (br, 1 H), 8.89 (s, 1 H), 7.90 (d, 1 H), 7.70 (d, / = 8.0 Hz, 1 H), 7.42 (t, / = 7.2 Hz, 1 H), 7.36- 7.23 (m, 6 H), 5.83 (s, 1 H), 5.49 (q, / = 10.4 Hz, 1 H), 5.33 (t, / = 10 Hz, 1 H), 4.44 (t, (m, 3 H), 1.77 (br, 3 H), 1.47-1.23 (m, 9H). MS (ESI) m/e (M+H+) 589.4
Example 5-3
Figure imgf000193_0001
141 253
[0558] The acylsulfonamide 253 was prepared following General Method D, the product was isolated as a white solid. Yield =45.3% MS (ESI) m/e (M+H+) 706.3.
Example 5-4
Figure imgf000193_0002
141 197
[0559] The acylsulfonamide 197 was prepared following General Method D, the product was isolated as a white solid. Yield = 43%. MS (ESI) m/e (M+H+) 792.3.
Figure imgf000194_0001
141 309
[0560] The hydroxamate 309 was prepared following General Method C.
Example 5-5 General Method G
Figure imgf000194_0002
253 315
[0561] A solution of compound 253 (100 mg, 0.14 mmol.) in DCM (5 niL) was cooled to 0 0C, then Et3N (85 mg, 0.84 mmol.) was added, followed by slow addition acetyl chloride (55 mg, 0.7 mmol.). After complete addition, the mixture was allowed to reach room temperature and stirred overnight. The mixture was diluted with EtOAc (20 mL), then washed with 5% NaHCU3, water and brine. The organic solvent mixture was dried over Na2SO4 and then the solid was removed by filtration. The organic solvent was removed to afford a crude product mixture, which was applied to Prep-HPLC to afford compound 315 as a white solid 19 mg (isolated yield 20%). MS (ESI) m/e (M+H+) 748.3.
Figure imgf000195_0001
197 316
[0562] The amide 316 was prepared following General Method G. Isolated Yield
=16%. MS (ESI) m/e (M+H+) 734.3.
Example 5-7
Figure imgf000195_0002
197 317
[0563] The sulfonamide 317 was prepared following General Method G, using methansulfonyl chloride in place of acetyl chloride. Isolated Yield =15%. MS (ESI) m/e (M+H+) 770.2.
General Method H
Figure imgf000196_0001
[0564] A mixture of compound 5 (400 mg, 0.80 mmol.), phenylboronic acid (147 mg, 1.2 mmol.), Cu(OAc)2 (188 mg, 1.0 mmol.), pyridine (316 mg, 4 mmol.), pyridine N-Oxide (76 mg, 0.8 mmol.) and molecular sieves 4A in dichloromethane (10 mL) was stirred for 12 h at room temperature opened to the air. The reaction was monitored by LC-MS. Another 1.5 eq boronic acid was added and stirred. After completion of the reaction, the solvent was removed and the crude mixture was purified by prep-HPLC to afford compound 101. (80 mg, isolated yield 15%) 1H-NMR (400MHz, CDCl3): δ 8.60 (s, 1 H), 7.91 (d, / = 8 Hz, 1 H), 7.71 (d, / = 8 Hz, 1 H), 7.41 (t, / =7.6Hz, 1 H), 7.29 (t, / = 7.6Hz, 2 H), 6.92 (t, / = 8 Hz, 2 H), 6.59 (d, / = 8 Hz, 2 H), 6.52 (d, 1 H), 5.84 (s, 1 H), 5.54-5.47 (q, 1 H), 5.32-5.27 (t, 1 H), 4.48-4.41 (t, 1 H), 4.35-4.32 (m, 1 H), 4.01-3.82 (m, 2 H), 2.53-2.11 (m, 2 H), 2.26-2.11 (t, 1 H), 2.08-1.18 (br, 11 H). MS-ESI: m/z=575[M+l]+.
Example 6-1
Figure imgf000196_0002
5 132
[0565] The acid 132 was prepared following General Method H. Isolated yield=18%. MS-ESI: m/z=605[M+l]+
Figure imgf000197_0001
[0566] The acid 123 was prepared following General Method H. Isolated yield
12% MS-ESI: m/z=593[M+l]+.
Example 6-3
Figure imgf000197_0002
[0567] The acid 110 was prepared following General Method H. Isolated yield 16% MS-ESI: m/z=643[M+l]+.
Example 7 General Method I
Figure imgf000197_0003
added to CDI (46 mg, 0.28 mmol.) in dichloromethane (1 mL), the resulting mixture was stirred at room temperature for 1 h. Subsequently, the mixture was treated with cyclopropyl sulfonamide (25 mg, 0.21 mmol.) and DBU (0.2 mL, 5.0 eq), the resulting mixture was stirred at room temperature for another 12 h and the reaction was monitored by LCMS. After completion of the reaction, the solvent was removed and the crude was purified by prep- HPLC to afford the pure compound 157 as a white solid. Yield = 20%. MS-ESI m/z = 678.2 [M+l]+.
Example 7-1
Figure imgf000198_0001
[0569] Compound 213 was prepared in a manner analogous to General Method I, and the yield was -45%. MS (ESI) m/e (M+H+) 692.0.
Example 7-2
Figure imgf000198_0002
101 269
[0570] The hydroxamate 269 is prepared following General Method C. Scheme IV
Figure imgf000199_0001
IV-A IV-B
Figure imgf000199_0002
IV-C IV-D
[0571] R' = O-aryl or SO2cycloalkyl; R" = (CH2)naryl or (CH2)nheteroaiyl; and n = 0, 1, or 2. R11, R12, V, and W are as defined above.
[0572] Macrocyclics of general structures IV-D can be synthesized as shown in Scheme IV. The Boc protected carboxylic acid of general structure IV-A can be treated with acid in methanol to remove the Boc protecting group and esterify the carboxylic acid to provide a free amine and a methyl ester. The amino ester can then be coupled under appropriate conditions providing an N-substituted compound of general structure IV-B. The methyl esters of general structure IV-B can be treated under basic conditions to hydrolyse the methyl ester thereby providing carboxylic acids of general structure IV-C. Finally, acids of general structure IV-C can be coupled with sulfonamides (or sulfamides; not shown) or optionally substituted O-alkyl or aryl hydroxylamines thereby providing compounds of general structure IV-D. General Method J
Figure imgf000200_0001
3-B 6-A
[0573] Compound 3-B was dissolved in HCl in MeOH (25 mL/g compound 14), the resulting mixture was stirred at room temperature for 12h, after that, the solvent was removed, aqueous NaHCU3 was added to neutralize the acid, then, EtOAc was added to extract the mixture, the organic layer was dried, the solvent was removed, the crude compound 6-A was used in the next step without further purification.
Example 8-2 General Method K
Figure imgf000200_0002
6-A 7-A
[0574] A mixture of crude compound 6-A (500 mg, 0.98 mmol.), phenylboronic acid (371 mg, 1.95 mmol.), Cu(OAc)2 (249 mg, 1.37 mmol.), pyridine (387 mg, 5 mmol.), pyridine N-Oxide (93 mg, 0.98 mmol.) and molecular sieves 4 A in dichloromethane (10 mL) was stirred for 12 h at room temperature opened to the air. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed and the crude mixture was purified by Prep-HPLC to give the pure compound 7-A. (400 mg, isolated yield 60%). obtained.
Example 8-3 General Method L
Figure imgf000201_0001
7-A 110
[0575] The compound 7-A (400 mg, 0.61 mmol.) was dissolved in methanol (5 mL), then NaOH (488 mg, 12.2 mmol.) and water (1 mL) were added, the resulting mixture was stirred at rt for 12 h, after completion of the reaction, 2M HCl was added to acidify the mixture to pH = 4-5, EtOAc was added to extract the mixture, the organic layer was dried, and the solvent was removed to afford the acid 110.
PREPARATION OF NS3 INHIBITORS: SECTION III
EXAMPLE 9
Scheme V: General Route for Synthesis of Aryl amine precursors
Figure imgf000202_0001
9 8
[0576] Compound 9 can be synthesized as shown in Scheme V. The isoindoline carbamate 6 can be treated under basic conditions, for example sodium hydroxide in ethanol, to hydrolyse the isoindoline carbamate thereby providing alcohol 7. The alcohol 7 can be treated with 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinoline under basic conditions, for example sodium hydride in DMF, to afford compound 8. Compound 8 can be treated under acidic conditions, for example HCl in dioxane, to remove the Boc protecting group thereby forming compound 9.
EXAMPLE 9-1 General Method M
Figure imgf000203_0001
[0577] A mixture of carbamate 6 (8.4 g, 11.3 mmol.), ethanol (60 mL) and 2 N aqueous sodium hydroxide (57 mL) was refluxed for 4 h. Ethanol was removed by evaporation and the residue was dissolved in water. Hydrochloric acid (2N) was added to pH 2-3 and the precipitated compound was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. The residue was crystallized from methanol (30 mL) to give the target hydroxy compound 7 as a white solid. Yield 5.12 g (77.7%). 1H- NMR (DMSO-d6), δ: 10.87 (s, 1 H), 8.98 (s, 1 H), 6.99 (d, 1 H), 5.61 (dt, 1 H), 5.14 (d, 1 H), 4.95 (dd, 1 H), 4.44 (m, 1 H), 4.36 (dd, 1 H), 4.05-4.18 (m, 2 H), 3.74-3.77 (m, 1 H), 3.67 (dd, 1 H), 2.39-2.48 (m, 1 H), 2.31 (dd, 1 H), 1.94-2.08 (m, 2 H), 1.70-1.90 (m, 2 H), 1.60 (dd, 1 H), 1.10-1.52 (m, 21 H), 0.84-0.92 (m, 2 H).
EXAMPLE 9-2 General Method MA
Figure imgf000203_0002
8
[0578] Compound 7 (292 mg, 0.5 mmol.) was co-evaporated with DMF and then dissolved in anhydrous DMF (5 mL). After cooling to 00C sodium hydride (80 mg, 60% mineral oil dispersion, 2 mmol.) was added and the reaction mixture was stirred at room temperature until hydrogen formation subsided (15-20 min). 2-(4-isopropylthiazol-2-yl)-4- stirred overnight at room temperature. The reaction mixture was diluted with water, acidified to pH 2-3 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and evaporated. Compound 8 was isolated by column chromatography in 25% acetone-hexane. Yield 220 mg (50.1%). Pale-yellow foam. 1H-NMR (DMSO-d6), δ: 10.85 (s, 1 H), 9.00 (s, 1 H), 8.08 (d, 1 H), 7.53 (s, 1 H), 7.46 (s, 1 H), 7.28 (d, 1 H), 7.15 (d, 1 H), 5.66 (m, 1 H), 5.60 (dt, 1 H), 5.05 (dd, 1 H), 4.70 (d, 1 H), 4.46 (dd, 1 H), 4.01-4.06 (m, 1 H), 3.93 (s, 3 H), 3.91 (m, 1 H), 3.18 (m, 1 H), 2.62-2.70 (m, 2 H), 2.58 (s, 3 H), 2.30-2.46 (m, 2 H), 1.62-1.80 (m, 2 H), 1.48-1.60 (m, 2 H), 1.25-1.46 (m, 16 H), 1.10-1.22 (m, 11 H), 0.80-0.92 (m, 2 H).
EXAMPLE 9-3 General Method MB
Figure imgf000204_0001
[0579] Compound 8 (220 mg, 0.25 mmol.) was dissolved in DCM (5 niL) and treated with 4N HCl-dioxane (1 mL, 4 mmol.). After stirring for 2 h at room temperature the solid was filtered off, washed with ethyl acetate, and dried in vacuo to provide to desired product compound 9. Yield: 170 mg (83.4%; HCl salt). Yellow solid. 1H-NMR (DMSO-d6), δ: 10.86 (s, 1 H), 9.26 (s, 1 H), 8.29 (m, 3 H), 8.09 (d, 1 H), 7.58 (s, 1 H), 7.49 (s, 1 H), 7.44 (d, 1 H), 5.72 (m, 1 H), 5.62 (dt, 1 H), 5.11 (dd, 1 H), 4.55 (dd, 1 H), 4.32 (d, 1 H), 4.26 (m,
1 H), 4.08 (dd, 1 H), 3.87 (s, 3 H), 3.17 (m, 1 H), 2.74 (dd, 1 H), 2.56 (s, 3 H), 2.40-2.59 (m,
2 H), 2.21 (dt, 1 H), 1.82-1.94 (m, 1 H), 1.64-1.82 (m, 2 H), 1.61 (dd, 1 H), 1.53 (dd, 1 H), 1.16-1.50 (m, 17 H), 0.88 (m, 2 H). Scheme VI: Synthesis of Acylsulfonamide alcohol precursor General Method N
Figure imgf000205_0001
EXAMPLE 10-1
[0580] To a solution of the carbamate 10 (1.00 g, 1.37 mmol.) in methanol (10 mL) was added aqueous NaOH (5 M, 8.6 mL). The mixture was heated to 50 0C, additional methanol (10.0 mL) was added to fully dissolve remaining solids. The resulting clear solution was stirred at 50 0C for 17h, HPLC showed complete reaction: Shimadzu MS 17 3 minute method ELSD 0.23 mins (50%) MH+ 138; 1.90 mins (44%) MH+ 569.
EXAMPLE 10-2
Figure imgf000205_0002
[0581] The solution was cooled below 10 0C and 2 M aqueous hydrochloric was added slowly until pH 4, significant product had precipitated at this stage. The resulting gum and aqueous solution was stirred with ethyl acetate (30 mL) until all was in solution. The aqueous layer was further extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed twice with brine, dried over Na2SO4 and evaporated under reduced pressure to give the crude product 11 as a beige solid - 0.88g. HPLC -ELSD 1.90 mins (99.1%) MH+ 569.
Figure imgf000206_0001
13
[0582] The crude solid 11 was dissolved in dichloromethane and columned on 25 g of silica gel. The solvent was changed to TBME which rapidly eluted a non-polar impurity, 82 mg, pale brown solid, found to be the methylcarbamate derivative 13 of the isoindoline - 31% yield. HPLC -ELSD no signal, UV 1.76 mins (96%) MH+ 196. 1H NMR (250 MHz, CDCl3) δ ppm 7.19 - 7.33 (m, 1 H,), 6.88 - 7.10 (m, 2 H,), 4.74 (dd, / = 9.9, 3.8 Hz, 4 H,), 3.79 (s, 3 H).
EXAMPLE 10-4
Figure imgf000206_0002
[0583] Further elution gave product 11 as a very pale beige solid. Yield 480 mg (62%). Additional product was still eluting slowly. 1H NMR (250 MHz, CDCl3) δ ppm 10.60 (br. s, 0.2 H), 10.46 (s, 0.8 H), 8.48 (br. s, 0.2 H), 7.74 (s, 0.8 H), 6.60 (br. s, 0.2 H), 5.56 - 5.81 (m, 1 H), 5.34 (m, 0.8 H), 4.85 - 5.03 (m, 1 H), 4.41 - 4.73 (m, 2 H), 4.28 (br. s, 1 H), 3.39 - 4.10 (m, 3 H), 2.73 - 2.98 (m, 1 H), 2.06 - 2.63 (m, 4 H), 1.68 - 2.05 (m, 3 H), 1.20 - 1.67 (m, 17 H), 0.65 - 1.13 (m, 4 H).
Scheme VII
Figure imgf000207_0001
VII-B
[0584] Macrocyclics of general structures VII-A and VII-B can be synthesized as shown in Scheme VII. The isoindoline carbamate 1 can be treated with acid in methanol to remove the Boc protecting group and form a methyl ester thereby providing compound 12. Compound 12 can be treated with optionally substituted aryl boronic acids, for example phenyl boranic acid, under Cu2+-catalyzed conditions thereby providing N-aryl compounds, such as compound 13. Compound 13 can be treated under basic conditions to hydrolyse the methyl ester and the isoindoline carbamate thereby providing hydroxy acid 14. The hydroxy acid 14 can be treated with a heteroaryl chloride, such as 2-chlorobenzothiazole, 2-chloro-6- methylbenzothiazole, 6-bromo-2-chlorobenzothiazole, 2,6-dichlorobenzothiazole, 2- chlorobenzoxazole, 2-chloro-l -ethyl- lH-benzoimidazole, and 2-chloro-l-isopropyl-lH- benzoimidazole and the like, under basic conditions to afford a compound of general structure VII-A. Finally, acids of general structure VII-A can be coupled with sulfonamides (or sulfamides, not shown) thereby providing compounds general structure VII-B.
Example 11-1:
General Procedure G 1), the resulting mixture was stirred at room temperature for 12 h. The solvent was removed then aqueous NaHCU3 was added to neutralize any remaining acid. The basic mixture was extracted by EtOAc. The EtOAc layer was dried and then the solvent was removed to afford a crude residue. The crude compound 12 (2.8 g) was used in the next step without further purification.
Example 11-2:
General Procedure O
[0586] A mixture of compound 12 (400 mg, 0.80 mmol.), phenylboronic acid
(146.8 mg, 1.2 mmol.), Cu(OAc)2 (188 mg, 1.0 mmol.), pyridine (316 mg, 4 mmol.), pyridine N-Oxide (76 mg, 0.8 mmol.) and molecular sieves 4A in dichloromethane (10 mL) was stirred for 12 h at room temperature opened to the air. Another 1.5 eq boronic acid was added and the reaction was stirred until completion of the reaction. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed and the crude mixture was purified by Prep-HPLC to afford pure compound 13, (400 mg, isolated yield 75%).
Example 11-3:
General Procedure P
[0587] To a stirring solution of compound 13 (400 mg, 0.56 mmol) in methanol
(10 mL) was added 5 M NaOH solution (2 mL), the resulting mixture was heated to 50 0C and continued stirring overnight. Subsequently, the mixture was cooled to 0 0C (ice water bath), then 2 M HCl was carefully added to lower the pH (pH=3-4). The acidic mixture was extracted by EtOAc. The combined organic layers were washed by brine and dried. The solvent was removed under reduced pressure and the crude compound 14 (380 mg) was used without further purification in the next step.
Example 11-4:
General Procedure Q
[0588] A solution of compound 14 (380 g, 1 mL/100 mg compound 14) in DMF was added slowly to a mixture of NaH was dissolved in DMF (1.5 mL/100 mg NaH), cooled to 0-5 0C. The mixture was stirred for 2 h at 0-5 0C, then heteroaryl halide (R-Cl) was added, the resulting mixture was warmed to room temperature and stirred for 12 h. The mixture was The acidic mixture was extracted by EtOAc. The combined organic layers were washed by brine and dried. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford general compound VII-A (150 mg, 40-70% yield).
Example 11-5:
General Procedure R
[0589] General compound VII-A (1 eq. in 2 mL dichloromethane) was added to
CDI (2-6 equiv.) dissolved in dichloromethane (1 mL) and then stirred 1 h. Subsequently, 1-methylcyclopropane-l- sulfonamide (2-6 equiv.) and DBU (0.1 mL) were added, the resulting mixture was stirred at room temperature for another 12 h monitoring by LCMS. After completion of the reaction, the solvent was then removed and the crude product was purified by prep-TLC to give the general compound VII-B as a white solid (-20-50% yield).
Example 11-6:
Figure imgf000209_0001
350
[0590] Compound 350 was prepared in a manner analogous to General Procedure R, and the yield is 50%. MS (ESI) m/e (M+H+) 792.2.
Figure imgf000210_0001
351
[0591] Compound 351 was prepared in a manner analogous to General Procedure R, and the yield is 50%. MS (ESI) m/e (M+H+) 812.2.
Example 11-8:
Figure imgf000210_0002
352
[0592] Compound 352 was prepared in a manner analogous to General Procedure R, and the yield is 50%. MS (ESI) m/e (M+H+) 856.
Example 11-9:
Figure imgf000210_0003
353
[0593] Compound 353 was prepared in a manner analogous to General Procedure R, and the yield is 50%. MS (ESI) m/e (M+H+) 761. Example 11-10:
Figure imgf000211_0001
318
[0594] Compound 318 was prepared in a manner analogous to General Procedure Q, and the yield is 60%. MS (ESI) m/e (M+H+) 671.3.
Example 11-11:
Figure imgf000211_0002
318 319
[0595] Compound 319 was prepared in a manner analogous to General Procedure R, and the yield is 45%. MS (ESI) m/e (M+H+) 788.3.
Example 11-12:
Figure imgf000211_0003
388. R, to afford 22 mg (22.7%). MS (ESI) m / z (M+H)+ 775.3.
Example 11-13:
Figure imgf000212_0001
320
[0597] Compound 320 was prepared in a manner analogous to General Procedure Q, and the yield is 61%. MS (ESI) m/e (M+H+) 685.3.
Example 11-14:
Figure imgf000212_0002
320 376
[0598] Compound 376 was prepared in a manner analogous to General Procedure R, and the yield was -45%. MS (ESI) m/e (M+H+) 803.3.
Example 11-15:
Figure imgf000212_0003
[0599] Compound 393 was prepared in a manner analogous to General Procedure F, to afford 39.2 mg (49%). MS (ESI) m / z (M+H)+ 789.1.
Example 11-16:
Figure imgf000213_0001
321
[0600] Compound 321 was prepared in a manner analogous to General Procedure Q, and the yield is 45%. MS (ESI) m/e (M+H+) 661.3.
Example 11-17:
Figure imgf000213_0002
322
[0601] Compound 322 was prepared in a manner analogous to General Procedure Q, and the yield is 52%. MS (ESI) m/e (M+H+) 694.2.
Figure imgf000214_0001
323
[0602] Compound 323 was prepared in a manner analogous to General Procedure Q, and the yield is 53%. MS (ESI) m/e (M+H+) 674.2.
Example 11-19:
Figure imgf000214_0002
376 465
General Procedure RH2
[0603] To a solution of compound 376 (47 mg, 0.059 mmol.) in 3mL of EtOAc was added catalyst (Pd/C, 10 mg, 20% wt), the mixture was degassed with hydrogen for 3 times, then the resulting mixture was stirred at room temperature under hydrogen atmosphere for 1.5h, the reaction was monitored by LCMS. After completion of the reaction, the solid was removed by filtration, the solvent was evaporated and the crude product was purified by prep-HPLC to afford compound 465 (2.5 mg, 5.3%). MS (ESI) m / z (M+H)+ 805.5.
Figure imgf000215_0001
466
[0604] Compound 466 was prepared in a manner analogous to General Procedure RH2 to afford 90.6 mg (48%), MS (ESI) m / z (M+H)+ 791.3.
PREPARATION OF NS3 INHIBITORS: SECTION IV EXAMPLE 12 Scheme VIII
Figure imgf000215_0002
18 15
[0605] N-aryl amines, such as compound 15, can be synthesized as shown in Scheme VIII. The isoindoline carbamate 16 can be treated with acid, for example TFA in DCM, to remove the Boc protecting group thereby providing compound 17. Compound 17 can be treated with optionally substituted aryl boronic acids, for example 3-fluoro-5- aryl compounds, such as compound 18. Finally, compound 18 can be treated under basic conditions to hydrolyse the ethyl ester and the isoindoline carbamate thereby providing hydroxy acid 15. The hydroxy acid 15 can be used to synthesize the macrocycles by further methods disclosed herein.
Example 12-1:
General Procedure S
[0606] To a solution of compound 16 (100 mg, 0.15 mmol.) in 3 mL of DCM was added 3 mL of TFA, stirring was continued at rt for 2h. The solvent was removed afford a residue. The residue was treated with water (30 mL) and then aqueous sat. NaHCO3 was added to adjust the pH (pH~10). The basic aqueous solution was extracted with ethyl acetate (3x20 mL). combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford compound 17 as white solid (84.7 mg, yield 100%). MS (ESI) m/e (M+H+) 556.2.
Example 12-2:
General Procedure T
[0607] To a solution of compound 17 (1 g, 1.8 mmol.) in 15 mL of DCM was added 4A molecular sieves D Cu(OAc)2 (0.9 g, 4.5 mmol.), 3-fluoro-5- (trifluoromethyl)phenyl boronic acid (0.75 g, 3.6 mmol.), pyridine (2.8 g, 36 mmol.) and pyridine N-Oxide (0.4 g, 4.5 mmol.) sequentially at 25 0C. The resulting mixture was stirred at same temperature for 48 h. The mixture was concentrated to afford a residue, which was purified by Prep-TLC to afford 18 as white solid (760 mg, yield 58.9%). MS (ESI) m/e (M+H+) 718.3.
Example 12-3:
General Procedure U
[0608] To a solution of compound 18 (100 mg, 0.14 mmol.) in 5 mL of ethanol was added 5 mL of aq. NaOH (20%) at 50 0C. The resulting mixture was stirred at the same temperature overnight. The ethanol was removed under reduced pressure to afford a residue. The residue was treated with water (30 mL), and then aqueous diluted HCl was added to adjust the pH (pH~3). The acidic aqueous layer was extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and (M+H+) 527.
Example 12-4:
Figure imgf000217_0001
354
[0609] Compound 354 was prepared in a manner analogous to General Procedure B, and the yield is 20%. MS (ESI) m/e (M+H+) 760.7.
Example 12-5:
Figure imgf000217_0002
354 355
[0610] Compound 355 was prepared in a manner analogous to General Procedure F, and the yield is 30%. MS (ESI) m/e (M+H+) 877.9. Example 13
Scheme IX: Synthesis of O-Benzothiazole iV-Thiazole Acylsulfonamides
Figure imgf000218_0001
231 [0611] N-thiazole amines, such as compound 231, can be synthesized as shown in
Scheme IX. Compound 19 can be treated with 9-fluorenylmethoxycarbonyl isothiocyanate (FmocΝCS) to afford thiourea 20. Thiourea 20 can be treated with α-bromoketones, for example l-bromo-3,3-dimethylbutan-2-one, under basic conditions thereby providing Ν-thiazole esters, such as compound 21. Compound 21 can be treated under basic conditions to hydrolyse the ethyl ester thereby providing carboxylic acids, such as compound 119. Finally, carboxylic acids, for example compound 119, can be coupled with sulfonamides (or sulfamides, not shown) thereby providing acyl sulfonamides, such as compound 231. Example 13-1:
General Procedure
Figure imgf000219_0001
H 19 20
[0612] To a solution of compound 19 (512 mg, 1 mmol.) and FmocNCS (281 mg, 1 mmol.) in DCM (5 mL) at 0 0C was added Et3N (5 mL, 3 mmol.) in one portion. The reaction mixture was allowed to rt and stirred 0.5 hour. Subsequently, the reaction was purified by prep-TLC to afford 400 mg of desired product 20 as white solid (70% yield).
Example 13-2:
General Procedure I
Figure imgf000219_0002
NaHCO3, EtOH, reflux
Figure imgf000219_0003
Figure imgf000219_0004
20 21
[0613] A mixture of compound 20 (400 mg, 0.7 mmol.), NaHCO3 (120 mg,
1.4 mmol.) and l-bromo-3,3-dimethylbutan-2-one (2.5 mL, 1.4 mmol.) in 6 mL of EtOH was refluxed for 1 hour. The reaction mixture was cooled down and purified by prep-TLC to afford 350 mg of desired product 21 as white solid (77% yield). General Procedure J
Figure imgf000220_0001
21 119
[0614] A mixture of compound 21 (350 mg, 0.5 mmol.), NaOH (100 mg, 2.5 mmol.), H2O (1 mL), and methanol (5 mL) was stirred at rt for 24 hours. The volatiles were removed and the remaining aqueous solution was acidified at 0 0C. Subsequently, the acidic solution was extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 258 mg of compound 119 as white solid. MS (ESI) m/e (M+H+) 638.2.
Example 13-4:
General Procedure K
Figure imgf000220_0002
231
[0615] To the solution of compound 119 (360 mg) in DCM (5 mL) was added CDI (324mg, 2 mmol.) at rt in one portion. The resulting mixture was stirred at rt for 2 hrs. Subsequently, 1-methylcyclopropane-l -sulfonamide (270 mg, 2 mmol.) and DBU (1 mL) were successively added. Stirring was continued for another 20 hrs. After purification, 80 mg of compound 231 was obtained as white solid (yield 21%). MS (ESI) m/e (M+H+) 755.2. Example 14
Scheme X: Preparation of 2-phenyl-4-chloro-7-methoxy-quinoline
Figure imgf000221_0001
[0616] Optionally substituted 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2- phenyl-4-chloro-7-methoxy-quinoline, can be synthesized as shown in Scheme X. A β-keto ester, such as ethyl benzoylacetate, can reacted with an optionally substituted aniline to provide an optionally substituted 2-phenyl-4-hydroxy-7-alkoxy-quinolines, such as 2-phenyl- 4-hydroxy-7-methoxy-quinoline. An optionally substituted 2-phenyl-4-hydroxy-7-alkoxy- quinolines, such as 2-phenyl-4-hydroxy-7-methoxy-quinoline, can be treated with a chlorinating agent, for example oxalyl chloride, thionyl chloride, phosphorus oxychloride and the like, thereby providing optionally substituted 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2-phenyl-4-chloro-7-methoxy-quinoline.
Example 14-1:
General Procedure V
Figure imgf000221_0002
[0617] Preparation of 2-phenyl-4-hydroxy-7-methoxy-quinoline:
[0618] To a solution of ethyl benzoylacetate (10.00 g, 52.0 mmol., 1 eq) and m-anisidine (7.05 g, 57.2 mmol., 1.1 eq) in toluene (85 mL) was added 4M HCl in dioxane (0.520 mL, 2.08 mmol., 0.04 eq) dropwise. The reaction mixture was refluxed for 15 hours while water was collected in a Dean-Stark apparatus. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was suspended in diphenyl ether (28 mL) and the mixture was heated for 2 h at 240 0C. The reaction mixture was then left to cool to ambient temperature and dichloromethane (55 mL) was added, leading to the precipitation of a yellow solid. Stirring was continued at ambient temperature of dichloromethane. The solid was transferred to a 100 mL round bottom flask and stirred with dichloromethane (50 mL) for another 45 min at ambient temperature. After filtration and drying under high vacuum, 2.85 g (22%) of the title compound was isolated as a pale yellow solid. 1H NMR (250 MHz, DMSOd6) δ ppm 11.54 (s, 1 H), 7.99 (d, / = 8.91 Hz, 1 H), 7.73 - 7.90 (m, 2 H), 7.48 - 7.64 (m, 3 H), 7.20 (d, / = 2.32 Hz, 1 H), 6.94 (dd, / = 2.34, 8.97 Hz, 1 H), 6.26 (s, 1 H), 3.86 (s, 3 H). LC-MS: purity 98% (UV), tR 1.52 min, m/z [M+l]+ 252.10.
Example 14-2:
General Procedure WA
Figure imgf000222_0001
[0619] Preparation of 2-phenyl-4-chloro-7-methoxy-quinoline:
[0620] 2-phenyl-4-hydroxy-7-methoxy-quinoline (2.73 g, 10.9 mmol., 1 eq) was suspended in neat phosphorus oxychloride (30 mL). The reaction mixture was heated under reflux. After 2 h, LCMS analysis showed full consumption of the starting material. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was partitioned between ethyl acetate (100 mL) and 2M aqueous sodium hydroxide solution (80 mL). The mixture was stirred at ambient temperature for a further 10 min, and then the two layers were separated. The organic phase was washed with water (2 x 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The obtained beige solid was further dried under high vacuum for 2 hours to give 2.66 g (91%) of the title compound. 1H NMR (250 MHz, DMSOd6) δ ppm 8.25 - 8.35 (m, 2H), 8.21 (s, 1 H), 8.09 (d, / = 9.14 Hz, 1 H), 7.47 - 7.61 (m, 4H), 7.38 (dd, / = 2.55, 9.18 Hz, 1 H), 3.97 (s, 3 H). LC-MS: purity 100% (UV), tø2.58 min, m/z [M+l]+ 270.00.
Example 15
Preparation of 2-(4'-isopropyl-thiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinoline
Scheme XI: Preparation of l-Bromo-3-methyl-but-2-one:
Figure imgf000222_0002
General Procedure WB
Figure imgf000223_0001
[0621] Preparation of l-Bromo-3-methyl-but-2-one:
[0622] To a solution of 3-methyl-butan-2-one (20 g, 232 mmol., 1.0 eq.) in dry methanol (200 mL) previously cooled to 0 0C, bromine (37.11 g, 232 mmol., 1.0 eq.) was added in a rapid fashion, with vigorous stirring, keeping the temperature below 10 0C. Stirring was continued at 10 0C for 2 hours. Water (40 mL) was added and the reaction mixture was left to stir at ambient temperature for 15 hours. A second portion of water (80 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 400 mL). The organic extracts were combined, washed with 10% aqueous potassium carbonate solution (150 mL), dried over sodium sulphate, filtered, and the solvent removed under vacuum to give 27.5 g (72%) of the title compound as a yellow oil which was used in the next step without any further purification. 1H NMR (250 MHz, CDCl3) δ ppm 3.99 (s, 2 H) 2.99 (spt, / = 6.93 Hz, 1 H) 1.17 (d, / = 6.85 Hz, 6 H).
Example 16
Scheme XII: Preparation of 4-isopropylthiazole-2-carbonyl chloride:
Figure imgf000223_0002
[0623] Optionally substituted thiazole-2-carboxylic acid chlorides, such as 4- isopropylthiazole-2-carbonyl chloride, can be synthesized as shown in Scheme XII. Ethyl thioxamate can react with an optionally substituted α-bromo ketone, such as l-bromo-3- methyl-but-2-one thereby providing an optionally substituted thiazole-2-carboxylic ethyl ester, such as ethyl 4-isopropyl-thiazole-2 carboxylate. The optionally substituted thiazole-2- carboxylic ethyl ester, such as ethyl 4-isopropyl-thiazole-2 carboxylate, can then be treated under basic conditions, for example lithium hydroxide in methanol/THF, to provide an acid. Finally, the optionally substituted thiazole-2-carboxylic acids, such as 4-isopropyl- thiazole-2-carboxylic acid, can be reacted with a chlorinating agent, for example oxalyl chloride, thionyl chloride and the like, to provide an optionally substituted thiazole-2- carboxylic acid chloride, such as 4-isopropylthiazole-2-carbonyl chloride.
Example 16-1:
General Procedure X
[0624] Preparation of Ethyl 4-isopropyl-thiazole-2 carboxylate:
Figure imgf000224_0001
[0625] l-Bromo-3-methyl-but-2-one (17.5 g, 106.2 mmol., 1.2 eq.) was added dropwise to a boiling solution of ethyl thioxamate (11.8 g, 88.7 mmol., 1.0 eq.) in ethanol (100 mL). The reaction mixture was stirred under reflux for a further 4 hours by when LCMS analysis showed the reaction to be complete. The reaction mixture was left to cool to ambient temperature and made alkaline by addition of a few drops of concentrated aqueous ammonia. The reaction mixture was then partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected and the aqueous phase further extracted with ethyl acetate (2 x 300 mL). The organic extracts were combined, washed with brine (100 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes: ethyl acetate (9:1 to 85:15). After combining the relevant fractions and solvent removal, 11.1 g (74%) of the title compound was isolated as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.19 (s, 1 H), 4.48 (q, J = IAl Hz, 2 H), 3.25 (spt, / = 6.89 Hz, 1 H), 1.43 (t, J = IAO Hz, 3 H), 1.35 (d, / = 7.02 Hz, 6 H). LC-MS: 90% (UV), tR 1.87 min, m/z [M+l]+ 200.05
Example 16-2:General Procedure Y
Figure imgf000224_0002
[0626] Preparation of 4-Isopropyl-thiazole-2-carboxylic acid: to a solution of ethyl 4-isopropyl-thiazole-2 carboxylate (4.08 g, 20.5 mmol., 1.0 eq.) in tetrahydrofuran (45 mL) and methanol (15 mL). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis of the reaction mixture showed a small amount of methyl ester remaining (zrarø-esterification from ethyl to methyl ester occurred) so lithium hydroxide monohydrate (86 mg, 2.0 mmol., 0.1 eq.) was added and the reaction mixture stirred for a further 3 hours. The reaction mixture was diluted with water (15 mL) and washed with diethyl ether (40 mL). The aqueous phase was cooled to 0 0C, and acidified to pH 3 by slow addition of IM hydrochloric acid. The aqueous layer was extracted with diethyl ether (3 x 50 mL). The organic extracts were combined, dried over sodium sulphate, filtered and the solvent removed under vacuum to give a mixture of the title product 2.5 g (71%) and 0.6 g of the decarboxylated by product. The mixture was used in the next step without further purification. 1H NMR (250 MHz, CDCl3) δ ppm 7.29 (s, 1 H) 3.15 - 3.30 (spt, / = 6.85 Hz, 1 H), 1.35 (d, / = 6.85 Hz, 6 H). LC-MS: 72% (UV), tR 1.21 min, m/z [M+l]+ 171.95.
Analysis for decarboxylated by-product:
[0628] iH NMR (250 MUz CDQ3) § ppm 8 91 (d> j = l i98 Hz i H) 6 97 (dd5
/ = 1.98, 0.76 Hz, 1 H), 3.15 - 3.30 (spt, / = 6.85 Hz, 1 H), 1.35 (d, / = 6.85 Hz, 6 H). LC- MS: 25% (UV), tR 1.37 min, m/z [M+l-C02]+ 128.05.
Example 16-3:
General Procedure YA
Figure imgf000225_0001
Preparation of 4-isopropylthiazole-2-carbonyl chloride
[0629] Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent purification.
Example 17
Scheme XIII: Preparation of 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl- quinoline:
Figure imgf000226_0001
[0630] Optionally substituted 2-(thiazol-2-yl)-4-chloro-7-alkoxy-8-alkyl-quinoline 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2-(4-isopropylthiazol-2-yl)-4-chloro-7- methoxy-8-methyl-quinoline, can be synthesized as shown in Scheme XIII. 3-Alkoxy-2- alkyl- anilines, such as 3-methoxy-2-methyl-aniline, can react with acetonitrile (CH3CN) in the presence of Lewis acids, for example boron trichloride and aluminum trichloride, to provide 2- alkyl- 3 -alkoxy- 6- acetyl- anilines such as 2-methyl-3-methoxy-6-acetyl-aniline. The 2-alkyl-3-alkoxy-6-acetyl-anilines, such as 2-methyl-3-methoxy-6-acetyl-aniline, can be coupled to an an optionally substituted thiazole-2-carboxylic acid chloride, such as 4- isopropylthiazole-2-carbonyl chloride to provide an optionally substiuted l-acetyl-2-[(thiazol- 2-yl)-carbonylamino]-3-alkyl-4-alkoxy-benzene, such as l-acetyl-2-[(4-isopropyl-thiazol-2- yl)-carbonylamino]-3-methyl-4-methoxy-benzene. The optionally substiuted l-acetyl-2- [(thiazol-2-yl)-carbonylamino]-3-alkyl-4-alkoxy-benzene, such as l-acetyl-2-[(4-isopropyl- thiazol-2-yl)-carbonylamino]-3-methyl-4-methoxy-benzene, can be cyclized under basic conditions, for example sodium tert-butoxide in tert-butanol, to provide an optionally substituted 2-(thiazol-2-yl)-4-hydroxy-7-alkoxy-8-alkyl-quinoline, such as 2-(4- isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8-methyl-quinoline. Finally, an optionally isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8-methyl-quinoline can be reacted with a chlorinating agent, for example phosphorous oxychloride, oxalyl chloride, thionyl chloride and the like, to provide an optionally substituted 2-(thiazol-2-yl)-4-chloro-7-alkoxy-8-alkyl- quinoline 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2-(4-isopropylthiazol-2-yl)-4- chloro-7-methoxy-8-methyl-quinoline.
Example 17-1:
General Procedure Z
Figure imgf000227_0001
[0631] Preparation of 2-Methyl-3-methoxy-6-acetyl-aniline:
[0632] Boron trichloride (IM solution in dichloromethane, 31.4 mL, 31.4 mmol., 1.05 eq.) was added dropwise, over 20 minutes, at 0 0C, to a solution of 3-methoxy-2-methyl- aniline (4.10 g, 29.9 mmol., 1.0 eq.) in xylenes (48 mL). The reaction mixture was stirred for 30 minutes at 0 0C, then acetonitrile (4.06 mL, 77.71 mmol., 2.6 eq.) was added dropwise keeping the reaction mixture in the range 0-10 0C. Stirring was continued for a further 30 minutes keeping the temperature bellow 10 0C. The reaction mixture was transferred to a dropping funnel, using dichloromethane (20 mL) to rinse the initial reaction flask. This solution was added dropwise to a stirred suspension of aluminium trichloride (4.18 g, 31.38 mmol., 1.05 eq.) in dichloromethane (10 mL) at 0 0C. The resulting reaction mixture was then heated under reflux for 15 hours. The reaction mixture was cooled to 0 0C and ice cold 2M hydrochloric acid (120 mL) was slowly added giving a light yellow suspension. The suspension was then stirred at 80 0C for around 90 minutes until a clear yellow solution was obtained. The reaction mixture was left to cool to ambient temperature and extracted with dichloromethane (3 x 100 mL). The organic extracts were combined, dried over sodium sulphate, filtered and the solvent removed under vacuum. The obtained solid was washed with diethyl ether (2 x 5 mL) and collected by filtration to give 2.31 g (43%) of the title compound as a beige solid. 1H NMR (250 MHz, CDCl3) δ ppm 7.66 (d, / = 8.98 Hz, 1 H), 6.45 (br. s, 2 H), 6.31 (d, / = 9.14 Hz, 1 H), 3.88 (s, 3 H), 2.55 (s, 3 H), 2.02 (s, 3 H). LC- MS: 97% (UV), tR 1.16 min, m/z [M+l]+ 180.10. General Procedure AA
Figure imgf000228_0001
[0633] Preparation of l-Acetyl-2-[(4-isopropyl-thiazol-2-yl)-carbonylamino]-
3-methyl-4-methoxy-benzene
[0634] Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with dry dioxane (40 mL). Diisopropylethylamine (3.9 g, 30 mmol., 2 eq.) was added dropwise followed by 2-methyl-3- methoxy-6-acetyl-aniline (2.7 g, 15.0 mmol., 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis showed full conversion of the starting material to product. The solvent was removed under vacuum and the residue dissolved with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes: ethyl acetate (4:1 to 6:4). The relevant fractions were combined and the solvent removed under vacuum to give 4.55 g (91%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.28 (br. s, 1 H), 7.76 (d, / = 8.70 Hz, 1 H), 7.17 (s, 1 H), 6.79 (d, / = 8.70 Hz, 1 H), 3.94 (s, 3 H), 3.23 (spt, / = 6.89 Hz, 1 H), 2.59 (s, 3 H), 2.17 (s, 3 H), 1.42 (d, / = 6.87 Hz, 6 H). LC-MS: 99% (UV), tR 2.24 min, m/z [M+l]+ 333.05.
Figure imgf000229_0001
[0635] Preparation of 2-(4-isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8- methyl- quinoline
[0636] Sodium fert-butoxide (3.20 g, 28.6 mmol., 2.1 eq.) was added portion wise, at ambient temperature, to a solution of l-acetyl-2-[(4-isopropyl-thiazol-2-yl)- carbonylamino]-3-methyl-4-methoxy-benzene (4.52 g, 13.6 mmol., 1.0 eq.) in dry tert- butanol (45 mL). The reaction mixture was stirred at 90 0C for 4 hours. LCMS analysis showed the reaction to be complete. The reaction mixture was left to cool to ambient temperature and then diluted with ethyl acetate (100 mL). The organic layer was washed with IM aqueous potassium hydrogen sulphate (75 mL), water (50 mL), brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum to give 4.63 g (99%) of the title compound as an off white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.59 (br. s, 1 H), 8.26 (d, / = 9.16 Hz, 1 H), 7.10 (s, 1 H), 7.03 (d, / = 9.16 Hz, 1 H), 6.77 (s, 1 H), 3.98 (s, 3 H), 3.20 (spt, / = 6.87 Hz, 1 H), 2.43 (s, 3 H), 1.39 (d, / = 7.02 Hz, 6 H). LC-MS: 95% (UV), tR 22A min, m/z [M+l]+ 315.15.
Example 17-4:
General Procedure CC
Figure imgf000229_0002
[0637] Preparation of 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8- methyl- quinoline
[0638] 2-(4-isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8-methyl-quinoline (4.63 g, 13.6 mmol., 1.0 eq.) was charged into a 100 mL round bottom flask. Phosphorous oxychloride (45 mL) was added and the reaction mixture stirred at 90 0C for 3 hours. Monitoring the reaction mixture by 1H NMR showed full consumption of the starting material. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with ethyl acetate (80 mL) and the reaction the pH of the aqueous phase was 14 (stir reaction mixture for 1 min between every NaOH addition). The two layers were separated and the organic layer was further washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulphate, filtered and the solvent removed under vacuum to give 4.1 Ig (91 %) of the title compound as a pale brown solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.28 (s, 1 H), 8.09 (d, / = 9.16 Hz, 1 H), 7.38 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 4.02 (s, 3 H), 3.20 (spt, / = 6.87 Hz, 1 H), 2.73 (s, 3 H), 1.40 (d, / = 6.87 Hz, 6 H).
Example 18
Synthesis of RCM precursor (l/?,2/?)-l-amino-2-vinyl-cvclopropane-l-carbonyl-(l'- methvD-cvclopropane-sulfonamide hydrochloride salt
Scheme XIV: General Route for synthesis of (lR,2/?)-l-amino-2-vinyl-cyclopropane-l- carbonyl-(l '-methyl)-cyclopropane-sulfonamide hydrochloride salt
Figure imgf000230_0001
BocHN,,, Jl 3C/ 2M HCI Cr
A H V in dioxane >
Figure imgf000230_0002
[0639] (l/?,2/?)-l-amino-2-vinyl-cyclopropane-l-carbonyl-(l '-methyl- cyclopropane- sulfonamide hydrochloride salt can be synthesized as shown in Scheme XIV. Ethyl (l^,2^)-l-(ferf-butoxycarbonylamino)-2-vinyl-cyclopropane-l-carboxylate can be treated under basic conditions, for example lithium hydroxide in a water-THF mixture, to hydrolyse the ethyl ester thereby providing (IR,2R)- \-{tert -butoxycarbonylamino)-2- vinyl- cyclopropane- 1-carboxylic acid. (1R,2R)- l-(tert -butoxycarbonylamino)-2- vinyl- cyclopropane- 1-carboxylic acid can be coupled with 1-methyl-cyclopropanesulfonamide, for example using 1 , l'-Carbonyldiimidazole in the presence of DBU, to provide (lR,2R)-l-(tert- butoxycarbonylamino)-2-vinyl-cyclopropane-l-carbonyl-(l'-methyl)- cyclopropanesulfonamide. (IR,2R)- l-(ferz-butoxycarbonylamino)-2- vinyl-cyclopropane- 1- carbonyl-(l'-methyl)-cyclopropanesulfonamide can be treated under acidic conditions, for group thereby providing (l^,2^)-l-amino-2-vinyl-cyclopropane-l-carbonyl-(l'-methyl)- cyclopropane- sulfonamide hydrochloride salt.
Example 18-1:
General Procedure DD
O BocHN,
[0640] Preparation of (l/?,2/?)-l-(fert-butoxycarbonylamino)-2-vinyl- cyclopropane-1-carboxylic acid:
[0641] Ethyl ( \R,2R)- l-(fer/-butoxycarbonylamino)-2- vinyl-cyclopropane- 1 - carboxylate (2.O g, 7.84 mmol., 1.0 eq.), water (60 mL) and tetrahydrofuran (50 mL) were charged into a 250 mL round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (0.523 g, 12.94 mmol., 1.65 eq.) was added portion wise and the reaction mixture heated at 80 0C for 15 hours. TLC analysis of the reaction mixture (heptanes: ethyl acetate, 1:1) showed full consumption of the starting material. The reaction mixture was left to cool down to ambient temperature and diluted with ethyl acetate (50 mL). The organic phase was discarded, and the aqueous phase washed further with ethyl acetate (50 mL). The aqueous phase was acidified to pH 3 by slow addition of IM hydrochloric acid then extracted with ethyl acetate (2 x 80 mL). The organic extracts were pooled, washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated to dryness to give 1.72 g (96%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.67 - 5.86 (m, 1 H), 5.31 (d, / = 17.10 Hz, 1 H), 5.18 - 5.28 (m, 1 H), 5.15 (d, / = 10.32 Hz, 1 H), 2.20 (q, / = 8.86 Hz, 1 H), 1.70 - 1.92 (m, 1 H), 1.50 - 1.65 (m, 1 H), 1.46 (s, 9 H). LC-MS: purity 100% (ELS), tR 1.56 min, m/z [M-H]" 226.10.
Example 18-2:
General Procedure DDLS
[0642] Ethyl ( 1^,25)- 1 -(ferz-butoxycarbonylamino)-2- vinyl-cyclopropane- 1 - carboxylate (61 g, 0.239 mol, 1.0 eq.) and tetrahydrofuran (700 mL) were charged into a 2 L round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (30 g, 0.714 mol, 3.0 eq.) was dissolved in water (800 mL) and added slowly to the mixture. The reaction showed some residual starting material so lithium hydroxide (20 g, 0.476 mol, 2 eq.) was added. The reaction was stirred further for 5 hours and then stirred at room temperature for 2 days. Monitoring the reaction conversion by LCMS showed complete conversion. The reaction mixture was acidified to pH 3 by slow addition of IM hydrochloric acid then extracted with ethyl acetate (4 x 900 mL). The organic extracts were pooled, washed with brine (600 mL), dried over sodium sulfate, filtered and concentrated to dryness. Cyclohexane (100 mL) was added to the dried crude material and concentrated to afford 71.44 g (54.0 g, 100%, corrected for residual solvent) of (17?,2^)-l-(ferf-butoxycarbonylamino)-2- vinyl- cyclopropane- 1-carboxylic acid as a pale yellow solid which contained residual cyclohexane (24.5% w/w as calculated from 1H NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 5.79 (dt, / = 17.01, 9.65 Hz, 1 H), 5.27 (br. s, 1 H), 5.30 (d, / = 17.09 Hz, 1 H), 5.14 (d, / = 10.38 Hz, 1 H), 2.20 (q, / = 8.85 Hz, 1 H), 1.70 - 1.90 (m, 1 H), 1.52 - 1.63 (m, 1 H), 1.45 (s, 9 H). LC-MS: purity 100% (UV), tR 1.60 min, m/z [M+Na]+ 250.00.
Example 18-3:
General Procedure EE
Figure imgf000232_0001
[0643] Preparation of (l/?,2/?)-l-(tert-butoxycarbonylamino)-2-vinyl- cyclopropane-l-carbonyl-(l'-methyl)-cyclopropanesulfonamide:
[0644] (17?,2^)-l-(ferf-Butoxycarbonylamino)-2- vinyl-cyclopropane- 1-carboxylic acid (3.80 g, 16.72 mmol., 1.0 eq.) and dichloroethane (60 mL) were charged into a 100 mL round bottom flask. l,l'-Carbonyldiimidazole (3.80 g, 23.40 mmol., 1.4 eq.) was added portionwise and the reaction mixture stirred at 50 0C for 15 hours. 1-Methyl- cyclopropanesulfonamide (6.10 g, 45.14 mmol., 2.7 eq.) was added portionwise followed by dropwise addition of DBU (6.834 g, 45.14 mmol., 2.7 eq.). Stirring was continued at 50 0C for a further 15 hours by when LCMS analysis of the reaction mixture showed full consumption of the starting material. The solvent was removed under vacuum. The residue was partitioned between dichloromethane (100 mL) and 0.5 M hydrochloric acid (60 mL). solvent removed under vacuum. The residue was purified by flash column chromatography using heptanes: ethyl acetate gradient (9:1 to 6:4) as eluent. After combining the relevant fractions and removing the solvent under vacuum, 4.0 g (70%) of the title compound was isolated as an off-white solid. 1H NMR (250 MHz, CDCl3) δ ppm 9.56 (br. s, 1 H), 5.46 - 5.78 (m, 1 H), 5.11 - 5.41 (m, 3 H), 2.16 (q, / = 8.53 Hz, 1 H), 1.91 (dd, / = 5.94, 8.07 Hz, 1 H), 1.59 - 1.79 (m, 3 H), 1.54 (s, 3 H), 1.50 (s, 9 H), 1.20 - 1.39 (m, 2 H). LC-MS: purity 100% (ELS), tø 1.81 min, m/z [M+Na]+ 367.05.
Example 18-4:
General Procedure EELS
[0645] (1^,25)- l-(ferf-Butoxycarbonylamino)-2- vinyl-cyclopropane- 1-carboxylic acid (54.0 g, 0.239 mol, 1.0 eq., dichloroethane (700 mL) and molecular sieves were charged into a 2.50 L round bottom flask. The mixture was stirred at room temperature for 15 minutes. The molecular sieves were filtered off and washed with dichloromethane (2 x 40 mL). l,l'-Carbonyldiimidazole (54.3 g, 0.334 mol, 1.4 eq.) was added portionwise and the reaction mixture stirred vigorously at 500C for 3 hours until no more gas evolution was noticed. l-Methyl-cyclopropanesulfonamide (48.5 g, 0.358 mol, 1.5 eq.) was added portionwise followed by dropwise addition of DBU (91.0 g, 0.598 mol, 2.5 eq.). Stirring was continued at 500C for a further 20 hours by which time LCMS analysis of the reaction mixture showed full consumption of the starting material. The reaction mixture was washed with 0.05M citric acid (2 x 540 mL) and brine (500 mL), dried over sodium sulfate and filtered. After the solvent was removed under vacuum, 75.6 g (92%) of (l^,2^)-l-(ferz- butoxycarbonylamino)-2-vinyl-cyclopropane-l-carbonyl-(l'-methyl)- cyclopropanesulfonamide was isolated as a pale yellow solid. The compound was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 9.57 (br. s, 1 H), 5.51 - 5.69 (m, 1 H), 5.41 (br. s, 1 H), 5.31 (d, / = 17.09 Hz, 1 H), 5.16 (d, / = 10.38 Hz, 1 H), 2.16 (q, / = 8.54 Hz, I H), 1.91 (dd, / = 7.78, 5.95 Hz, I H), 1.71 (dd, / = 10.53, 5.04 Hz, 1 H), 1.60 - 1.67 (m, 1 H), 1.53 (s, 3 H), 1.46 - 1.51 (m, 9 H), 1.27 - 1.37 (m, 1 H), 0.80 - 0.92 (m, 2 H). LC-MS: purity 95% (UV), tR 1.96 min, m/z [M+Na]+ 367.35. General Procedure FF
Figure imgf000234_0001
[0646] Preparation of (l/?,2/?)-l-amino-2-vinyl-cyclopropane-l-carbonyl-(l'- methyl)-cyclopropane-sulfonamide hydrochloride salt:
[0647] ( 1R,2R)-1 -(7e?t-Butoxycarbonylamino)-2- vinyl-cyclopropane- l-acyl-( 1 ' - methyl)-cyclopropanesulfonamide (4.00 g, 11.6 mmol., 1.0 eq.) and dioxane (20 mL) were charged into a 50 mL round bottom flask. 4 M HCl in dioxane (10 mL) was added dropwise over 5 minutes and the reaction mixture stirred at ambient temperature for 15 hours. LCMS analysis showed full consumption of the starting material. The solvent was removed under vacuum and the residue further dried under high vacuum for 4 hours to give 2.80 g (86%, corrected for solvent content) of the title compound as a white foamy solid which contained residual dioxane (25 % w/w as calculated from NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, DMSOd6) δ ppm 9.06 (br. s, 3H), 5.50 - 5.63 (m, 1 H), 5.35 (d, / = 16.51 Hz, 1 H), 5.21 (d, / = 11.37 Hz, 1 H), 2.35 (q, 1 H), 2.02 (t, / = 6.97 Hz, 1 H), 1.67 (dd, / = 6.79, 9.72 Hz, 1 H), 1.45 - 1.48 (m, 1 H), 1.43 (s, 3 H), 1.30 - 1.38 (m, 1 H), 0.84 - 0.98 (m, 2 H). LC-MS: purity 100% (UV), tR 0.80 min, m/z [M+H]+ 245.00.
Example 18-6:
General Procedure FFLS
[0648] (1^,25)- l-(ferf-Butoxycarbonylamino)-2- vinyl-cyclopropane- 1-carbonyl-
(l'-methyl)-cyclopropanesulfonamide (18.0 g, 52.3 mmol., 1.0 eq.) was charged into a 500 mL round bottom flask placed on top of an ice/water bath, and 4 M HCl in dioxane (180 mL) was added dropwise over 5 min with rapid stirring. The reaction mixture was then stirred at ambient temperature for 15 hours. LCMS analysis showed full consumption of the starting material. The solvent was removed under vacuum and the residue further evaporated from dichloromethane (2 x 100 mL). The crude product was dried further under high vacuum for 4 hours to give 13.98 g (95%) of (l^,2^)-l-amino-2-vinyl-cyclopropane-l-carbonyl-(l'- methyl)-cyclopropane-sulfonamide hydrochloride salt as a beige solid. The compound was used in the next step without further purification. 1H NMR (500 MHz, DMSOd6) δ ppm 2.35 (q, 1 H), 2.02 (t, / = 6.97 Hz, 1 H), 1.67 (dd, / = 6.79, 9.72 Hz, 1 H), 1.45 - 1.48 (m, 1 H), 1.43 (s, 3 H), 1.30 - 1.38 (m, 1 H), 0.84 - 0.98 (m, 2 H). LC-MS: purity 99% (UV), tR 0.85 min, m/z [M+H]+ 245.10.
Example 18-7:
General Procedure GG
Figure imgf000235_0001
[0649] Preparation of (l/?,2/?)-l-(tert-butoxycarbonylamino)-2-vinyl- cyclopropane-l-carbonyl-cyclopropanesulfonamide:
[0650] (l^,2^)-l-(ferf-Butoxycarbonylamino)-2-vinyl-cyclopropane-l-carboxylic acid (1.72 g, 7.57 mmol., 1.0 eq.) and dichloroethane (38 mL) were charged into a 100 mL round bottom flask. 1 , l'-Carbonyldiimidazole (1.72 g, 10.61 mmol., 1.4 eq.) was added portionwise and the reaction mixture stirred at 50 0C for 15 hours. Cyclopropanesulfonamide (2.47 g, 20.4 mmol., 2.7 eq.) was added portionwise followed by dropwise addition of DBU (3.11 g, 20.4 mmol., 2.7 eq.). Stirring was continued at 50 0C for a further 15 hours by when LCMS analysis of the reaction mixture showed full consumption of the starting material. The solvent was removed under vacuum. The residue was partitioned between dichloromethane (50 mL) and 0.5 M hydrochloric acid (20 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using heptanes: ethyl acetate gradient (60:50 to 50:50) as eluent. After combining the relevant fractions and removing the solvent under vacuum, 1.12 g (45%) of the title compound was isolated as a yellow semi solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.71 (br. s, 1 H), 5.61 (br. s, 1 H), 5.32 (d, / = 16.87 Hz, 1 H), 5.20 - 5.28 (m, 1 H), 5.18 (d, / = 10.27 Hz, 1 H), 2.88 - 3.00 (m, 1 H), 2.16 (q, / = 8.44 Hz, 1 H), 1.87 - 1.96 (m, 1 H), 1.51 (s, 9 H), 1.40 - 1.47 (m, 1 H), 1.24 - 1.36 (m, 2 H), 1.07 - 1.16 (m, 1 H), 0.99 - 1.07 (m, 1 H). LC-MS: purity 100% (ELS), tR UA min, m/z [M-H]" 329.10.
Example 18-8:
Figure imgf000236_0001
[0651] Preparation of (l/?,2/?)-l-amino-2-vinyl-cyclopropane-l-carbonyl- cyclopropane-sulfonamide hydrochloride salt:
[0652] (17?,2^)-l-(ferf-Butoxycarbonylamino)-2- vinyl-cyclopropane- 1-acyl- cyclopropane-sulfo-namide (1.12 g, 3.4 mmol., 1.0 eq.) and dioxane (8.5 mL) were charged into a 25 mL round bottom flask. 4M HCl in dioxane (8.5 mL) was added dropwise over 5 minutes and the reaction mixture stirred at ambient temperature for 15 hours. LCMS analysis showed full consumption of the starting material. The solvent was removed under vacuum and the residue further dried under high vacuum for 4 hours to give 1.25g (99% corrected for solvent content) of the title compound as a white foamy solid which contained residual dioxane (25 % w/w as calculated from NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, CD3OD) δ ppm 5.73 (ddd, / = 7.34, 10.13, 17.19 Hz, 1 H), 5.44 (d, / = 17.06 Hz, 1 H), 5.35 (d, / = 10.27 Hz, 1 H), 2.95 - 3.13 (m, 1 H), 2.28 - 2.46 (m, 1 H), 2.20 (t, / = 7.98 Hz, 1 H), 1.69 (dd, / = 7.89, 10.09 Hz, 1 H), 1.26 - 1.34 (m, 1 H), 1.20 - 1.27 (m, 1 H), 1.12 (d, / = 8.07 Hz, 2 H). LC-MS: purity 100% (ELS), tR 0.55 min, m/z [M+H]+ 231.00.
Example 18-9:
Figure imgf000236_0002
[0653] Preparation of (lR,2S)-l-(tert-Butoxycarbonylamino)-2-vinyl- cyclopropane-l-carbonyl-ΛyV-dimethylsulfamide:
[0654] (1^,25)- l-(ferf-Butoxycarbonylamino)-2-vinyl-cyclopropane-l-carboxylic acid (1.3 g, 5.72 mmol, 1.0 eq.), dichloroethane (30 mL) and molecular sieves were charged into a 100 mL round bottom flask. The mixture was stirred at room temperature for 15 minutes. The molecular sieves were filtered off and washed with dichloroethane (2 x 5 mL). l,l'-Carbonyldiimidazole (1.29 g, 8.01 mmol, 1.4 eq.) was added portionwise and the reaction mixture stirred vigorously at 500C for 1 hour until no more gas evolution was noticed. dropwise addition of DBU (3.2 mL, 21.63 mmol, 2.7 eq.). Stirring was continued at 50°C for a further 15 hours by which time LCMS analysis of the reaction mixture showed full consumption of the starting material. The reaction mixture was washed with 0.5 M hydrochloric acid (3 x 50 mL) and brine (50 mL), dried over sodium sulfate and filtered. The residue was purified by flash column chromatography, using a methanol :dichloromethane gradient (from neat dichloromethane to 2% methanol in dichloromethane). After combining the relevant fractions and solvent removal, 1.5 g (78%) of (l/?,25)-l-(tert- Butoxycarbonylamino)-2- vinyl-cyclopropane- 1 -carbonyl-N,N-dimethylsulf amide was isolated as a white solid. 1H ΝMR (500 MHz, CDC13) δ ppm 8.90 - 9.88 (m, 1 H) 5.46 - 5.73 (m, 2 H) 5.14 (d, / = 10.38 Hz, 1 H) 2.90 (s, 6 H) 2.12 (q, / = 8.70 Hz, 1 H) 1.87 (dd, / = 7.93, 5.80 Hz, 1 H) 1.45 (br. s, 9 H) 1.23 - 1.38 (m, 1 H). LC-MS: purity 99% (UV), m/z [M+Νa]+ 356.35.
Example 19
Scheme XV: General Route for synthesis of 2-(3-trifluoromethyl-5-fluoro- phenylamino)-non-8-enoic acid
Figure imgf000237_0001
[0655] N-aryl amino acids, such as 2-(3-trifluoromethyl-5-fluoro-phenylamino)- non-8-enoic acid, can be synthesized as shown in Scheme XV. 2-Amino-non-8-enoic acid methyl ester can be treated with an optionally substituted aryl boronic acids, for example 3- fluoro-5-(trifluoromethyl)phenyl boronic acid, under Cu2+-catalyzed conditions to provide N- aryl amino esters, such as 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid methyl ester. Finally, N-aryl amino esters, such as 2-(3-trifluoromethyl-5-fluoro- phenylamino)-non-8-enoic acid methyl ester can be treated under basic conditions to hydrolyse the methyl ester thereby providing N-aryl amino acids, such as 2-(3- trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid. The N-aryl amino acids can be used to synthesize macrocycles by further methods disclosed herein. General Procedure II
Figure imgf000238_0001
[0656] Preparation of 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8- enoic acid methyl ester:
[0657] Reaction performed in parallel in 8 x 50 mL reaction flasks. Copper (II) acetate (270 mg, 1.48 mmol., 1.1 eq.) and 4A molecular sieves (700 mg) were charged in 50 mL round bottom flask. Dichloromethane (10 mL, previously saturated with air) was added a single portion. 2-amino-non-8-enoic acid methyl ester (250 mg, 1.35 mmol., 1.0 eq.) was added and the reaction mixture was stirred for a further 5 min by when the initial light blue solution had turned dark blue. 3-fluoro-5-trifluoromethylbenzene boronic acid (560 mg, 2.70 mmol., 2 eq.) was added followed by triethylamine (218 mg, 2.70 mmol., 2 eq.). The reaction mixture was stirred over night under an air atmosphere. The 8 reaction mixtures were combined together and IM hydrochloric acid (150 mL) was added. The mixture was stirred for a further 5 min until the aqueous layer turned pale blue and the organic layer turned pale yellow. The organic layer was collected, dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a dichloromethane:heptanes gradient (from neat heptane to 50% dichloromethane in heptanes). After combining the relevant fractions and solvent removal, 970 mg (26%) of the title compound was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.66 (d, / = 8.54 Hz, 1 H), 6.61 (s, 1 H), 6.42 (d, / = 10.83 Hz, 1 H), 5.72 - 5.87 (m, / = 6.71, 6.71, 10.26, 17.05 Hz, 1 H), 5.00 (dd, / = 1.83, 17.09 Hz, 1 H), 4.95 (dt, / = 0.95, 10.15 Hz, 1 H), 4.48 (d, / = 8.54 Hz, 1 H), 4.05 (dt, / = 6.45, 8.32 Hz, 1 H), 3.76 (s, 3H), 2.05 (q, / = 6.92 Hz, 2 H), 1.82 - 1.93 (m, 1 H), 1.71 - 1.82 (m, 1 H), 1.30 - 1.45 (m, 6 H). LC-MS: purity 94% (UV), tR 2.63 min, m/z [M+H]+ 348.00.
Intermediates synthesized according to the preceding General Methods Example 19-2:
Figure imgf000239_0001
[0658] 2-phenylamino-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II, to afford 817 mg (58%), yellow oil. 1H NMR (250 MHz, CDCl3) δ ppm 7.21 - 7.34 (m, 2 H), 6.84 (t, / = 7.31 Hz, 1 H), 6.72 (d, / = 8.22 Hz, 2 H), 5.91 (m, / = 16.98, 10.20, 6.66, 6.66 Hz, 1 H), 4.94 - 5.22 (m, 2 H), 4.24 (br. s, 1 H), 4.09 - 4.22 (m, 1 H), 3.80 (s, 3 H), 2.06 - 2.28 (m, 2 H), 1.67 - 2.06 (m, 2 H), 1.29 - 1.66 (m, 6 H). LC-MS: purity 92% (UV), tR 2.41 min, m/z [M+H]+ 262.20.
Example 19-3:
Figure imgf000239_0002
[0659] Preparation of (5)-2-(3-fluoro-phenylamino)-non-8-enoic acid methyl ester
General Procedure IILS
[0660] 2-(3-fluoro-phenylamino)-non-8-enoic acid methyl ester was also prepared in the following manner. The reaction was performed in parallel in 45 x 50 mL reaction flasks. Copper (II) acetate anhydrous (381 mg, 2.07 mmol, 1.1 eq.), 4A molecular sieves (350 mg) and dichloromethane (20 mL, previously saturated with air) were charged in 50 mL round bottom flask. 2-amino-non-8-enoic acid methyl ester (350 mg, 1.88 mmol, 1.0 eq.) was added and the reaction mixture was stirred for a further 5 min. 3-fluorobenzene boronic acid (545 mg, 3.77 mmol, 2 eq.) was added followed by triethylamine (386 mg, 3.77 mmol, 2 eq.). The reaction mixture was stirred for 18 hours under an air atmosphere. The 45 reaction mixtures were combined together. Sieves was filtered off and washed twice with dichloromethane (30 mL x 2). 2M hydrochloric acid (800 mL) was added. The mixture was stirred for a further 5 min. The organic layer was collected, dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by dry flash chromatography, using a ethylacetate:heptanes gradient (from neat heptanes to 10% ethylacetate in heptanes). After combining the relevant fractions and solvent removal, 10.27 g (43%, not corrected) of 7.14 (m, 1 H) 6.40 - 6.46 (m, 1 H) 6.35 - 6.40 (m, 1 H) 6.30 (dt, / = 11.44, 2.21 Hz, 1 H) 5.80 (m, / = 16.99, 10.24, 6.68, 6.68 Hz, 1 H) 5.00 (dd, / = 17.17, 1.60 Hz, 1 H) 4.95 (d, / = 10.07 Hz, 1 H) 4.15 - 4.29 (m, 1 H) 3.98 - 4.07 (m, 1 H) 3.74 (s, 3 H) 2.05 (q, / = 6.87 Hz, 2 H) 1.80 - 1.91 (m, 1 H) 1.75 (dq, / = 14.21, 7.17 Hz, 1 H) 1.30 - 1.47 (m, 6 H). LC-MS: purity 94% (UV), tR 5.14 min, m/z [M+H]+ 280.40
Example 19-4:
Figure imgf000240_0001
[0661] 2-(3-trifluoromethyl-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II, to afford 931 mg (52%) as a clear oil. 1H NMR (250 MHz, CDCl3) δ ppm 7.14 - 7.40 (m, 1 H), 6.97 (d, / = 7.61 Hz, 1 H), 6.82 (s, 1 H), 6.75 (dd, / = 7.92, 2.44 Hz, 1 H), 5.80 (m, / = 17.06, 10.36, 6.70, 6.70 Hz, 1 H), 4.86 - 5.09 (m, 2 H), 4.33 (br. s, 1 H), 4.09 (t, / = 6.24 Hz, 1 H), 3.75 (s, 3 H), 2.05 (d, / = 7.01 Hz, 2 H), 1.69 - 1.97 (m, 2 H), 1.23 - 1.52 (m, 6 H). LC-MS: purity 99% (UV), tR 2.57 min, m/z [M+H]+ 330.50.
Example 19-5:
Figure imgf000240_0002
[0662] 2-(4-Fluoro-phenyl)-amino-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure π, to afford 1.47 g (49%), yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.88 (t, / = 8.70 Hz, 2 H), 6.49 - 6.63 (m, 2 H), 5.80 (m, / = 17.03, 10.28, 6.71, 6.71 Hz, 1 H), 5.00 (dd, / = 17.09, 1.53 Hz, 1 H), 4.95 (d, / = 10.22 Hz, 1 H), 3.98 (d, / = 4.27 Hz, 2 H), 3.72 (s, 3 H), 2.05 (q, / = 6.82 Hz, 2 H), 1.79 - 1.87 (m, 1 H), 1.71 - 1.78 (m, 1 H), 1.38 - 1.45 (m, 4 H), 1.34 - 1.38 (m, 2 H). LC-MS: 94% (UV), tR 2.44 min, m/z [M+H]+ 280.20.
Example 19-6:
Figure imgf000241_0001
[0663] 2-(3,5-difluoro-phenyl-amino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II, to afford 630 mg (19%), yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.17 (tt, / = 9.16, 2.14 Hz, 1 H), 6.06 - 6.13 (m, 2 H), 5.75 - 5.85 (m, 1 H), 5.00 (dd, / = 17.09, 1.83 Hz, 1 H), 4.95 (d, / = 10.38 Hz, 1 H), 4.34 (d, / = 8.54 Hz, 1 H), 3.96 - 4.02 (m, 1 H), 3.76 (s, 3 H), 2.85 (t, / = 7.32 Hz, 1 H), 2.02 - 2.08 (m, 3 H), 1.79 - 1.90 (m, 1 H), 1.69 - 1.79 (m, 1 H), 1.60 - 1.69 (m, 1 H), 1.38 - 1.43 (m, 2 H), 1.36 (dd, / = 7.02, 3.05 Hz, 1 H). LC-MS: purity 86% (UV), tR 2.52 min, m/z [M+H]+ 298.10.
Example 19-7:
Figure imgf000241_0002
[0664] 2-(2-benzoxazyl-amino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II, to afford 2.28 g (70%), yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.39 (d, / = 7.78 Hz, 1 H), 7.25 - 7.28 (m, 1 H), 7.18 (t, J = 7.55 Hz, 1 H), 7.04 - 7.08 (m, 1 H), 5.78 (m, / = 17.03, 10.24, 6.66, 6.66 Hz, 1 H), 5.64 (br. s, 1 H), 4.98 (dd, / = 17.09, 1.53 Hz, 1 H), 4.93 (d, / = 10.07 Hz, 1 H), 4.61 - 4.66 (m, 1 H), 3.79 (s, 3 H), 1.99 - 2.06 (m, 3 H), 1.79 - 1.87 (m, 1 H), 1.43 - 1.51 (m, 1 H), 1.32 - 1.43 (m, 5 H). LC-MS: purity 87% (UV), tR 4.67 min, m/z [M+H]+ 303.45.
Example 19-8:
Figure imgf000241_0003
[0665] 2-(3,4-Difluoro-phenyl-amino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure π, to afford 522 mg (16%), yellow oil. 1H NMR (250 MHz, CDCl3) δ ppm 6.95 (dt, / = 10.13, 8.87 Hz, 1 H), 6.40 (ddd, / = 12.49, 6.70, 6.70 Hz, 1 H), 4.86 - 5.10 (m, 2 H), 3.87 - 4.19 (m, 2 H), 3.73 (s, 3 H), 1.96 - 2.13 (m, 2 H), 1.64 - 1.94 (m, 2 H), 1.30 - 1.42 (m, 6 H). LC-MS: purity 98% (UV), tR 2.47 min, m/z [M+H]+ 298.45.
Example 19-9:
Figure imgf000242_0001
[0666] 2-(3,5-Dichloro-phenyl-amino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure π, to afford 1.70 g (42%), yellow oil. 1H NMR (250 MHz, CDCl3) δ ppm 6.71 (t, / = 1.75 Hz, 1 H), 6.46 (d, / = 1.68 Hz, 1 H), 5.80 (d, / = 6.85 Hz, 1 H), 5.03 (d, / = 1.68 Hz, 1 H), 4.94 - 4.99 (m, 1 H), 4.21 - 4.38 (m,
1 H), 3.93 - 4.10 (m, 1 H), 3.87 (s, 1 H), 3.76 (s, 3 H), 2.04 - 2.13 (m, 2 H), 1.71 - 1.93 (m,
2 H), 1.32 - 1.41 (m, 6 H). LC-MS: purity 97% (UV), tR 2.74 min, m/z [M+H]+ 330.10.
Example 19-10:
Figure imgf000242_0002
[0667] 2-(3-Trifluoromethyl-4-fluoro-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure π, to afford 550 mg (14%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.00 (t, / = 9.38 Hz, 1 H), 6.77 (dd, / = 5.34, 3.05 Hz, 1 H), 6.66 - 6.74 (m, 1 H), 5.72 - 5.87 (m, 1 H), 5.00 (dd, / = 17.17, 1.30 Hz, 1 H), 4.95 (d, / = 10.07 Hz, 1 H), 4.18 (d, / = 6.71 Hz, 1 H), 4.01 (q, / = 6.41 Hz, 1 H), 3.74 (s, 3 H), 2.05 (q, / = 6.92 Hz, 2 H), 1.80 - 1.92 (m, 1 H), 1.69 - 1.80 (m, 1 H), 1.25 - 1.52 (m, 6 H). LC-MS: purity 100% (UV), tR 2.36 min, m/z [M+H]+ 348.50.
Example 19-11:
Figure imgf000243_0001
[0668] 2-(4-Trifluoromethyl-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II, to afford 1.21 g (23%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.41 (d, / = 8.54 Hz, 2 H), 6.62 (d, / = 8.54 Hz, 2 H), 5.71 - 5.89 (m, 1 H), 5.00 - 5.10 (m, 1 H), 4.95 (d, / = 10.22 Hz, 1 H), 4.45 (d, / = 8.54 Hz, 1 H), 4.07 - 4.15 (m, 1 H), 3.75 (s, 3 H), 2.00 - 2.10 (m, 2 H), 1.83 - 1.93 (m, 1 H), 1.77 (dq, / = 14.13, 7.19 Hz, 1 H), 1.32 - 1.48 (m, 6 H). LC-MS: purity 100% (UV), tR 2.71 min, m/z [M+H]+ 330.20.
Example 19-12:
General Procedure JJ
Figure imgf000243_0002
[0669] Preparation of 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8- enoic acid:
[0670] 2-(3-Trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid methyl ester (1.643 g, 4.73 mmol., 1 eq.) was dissolved in tetrahydrofuran (40 mL). A solution of lithium hydroxide monohydrate (0.596 g, 14.19 mmol., 3 eq.) in water (40 mL) was added dropwise and the reaction mixture stirred for a further 3 hours at ambient temperature by when LCMS analysis of an aliquot showed the reaction to be complete. The reaction mixture volume was reduced by half in vacuo to remove most of the tetrahydrofuran and the obtained solution was diluted with 1.5 M hydrochloric acid (40 mL). The solution was extracted with dichloromethane (2 x 60 mL). The organic extracted were combined, dried over sodium sulfate and the solvent removed in vacuo to give 1.41 g (90%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.68 (d, / = 8.54 Hz, 1 H), 6.63 (s, 1 H), 6.44 (dd, / = 1.98, 10.68 Hz, 1 H), 5.72 - 5.85 (m, / = 6.64, 6.64, 10.28, 17.03 Hz, 1 H), 5.00 (dq, / = 1.66, 17.15 Hz, 1 H), 4.95 (dt, / = 0.97, 10.11 Hz, 1 H), 4.07 (dd, / = 5.80, 6.87 Hz, 1 H), 1.51 (m, 2 H), 1.32 - 1.43 (m, 3 H). LC-MS: purity 98% (UV), ^ 2.33 min, m/z [M+H]4 334.10
Example 19-13:
Figure imgf000244_0001
[0671] 2-phenylamino-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 630 mg (89%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.21 (dd, / = 8.54, 7.32 Hz, 2 H), 6.80 (t, / = 7.32 Hz, 1 H), 6.65 (d, / = 7.93 Hz, 2 H), 5.80 (m, / = 17.01, 10.22, 6.68, 6.68 Hz, 1 H), 5.00 (dq, / = 17.13, 1.72 Hz, 1 H), 4.92 - 4.96 (m, 1 H), 4.03 (dd, / = 7.48, 5.65 Hz, 1 H), 2.05 (q, / = 7.02 Hz, 2 H), 1.88 - 1.98 (m, 1 H), 1.74 - 1.83 (m, 1 H), 1.48 (td, / = 6.87, 2.75 Hz, 2 H), 1.38 - 1.43 (m, 2 H), 1.32 - 1.38 (m, 2 H). LC-MS: purity 92% (UV), tR 2.09 min, m/z [M+H]+ 248.20.
Example 19-14:
Figure imgf000244_0002
[0672] 2-(3-fluoro-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 259 mg (94%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.09 - 7.15 (m, 1 H), 6.46 (td, / = 8.35, 2.21 Hz, 1 H), 6.40 (dd, / = 8.16, 2.06 Hz, 1 H), 6.33 (dt, / = 11.29, 2.29 Hz, 1 H), 5.79 (m, / = 17.03, 10.24, 6.66, 6.66 Hz, 1 H), 5.00 (dd, / = 17.09, 1.83 Hz, 1 H), 4.92 - 4.97 (m, 1 H) 4.03 (dd, / = 7.02, 5.80 Hz, 1 H), 2.05 (q, / = 6.97 Hz, 2 H), 1.88 - 1.97 (m, 1 H), 1.74 - 1.84 (m, 1 H), 1.43 - 1.52 (m, 2 H), 1.34 - 1.43 (m, 4 H). LC-MS: purity 97% (UV), tR 2.14 min, m/z [M+H]+ 266.15.
General Procedure JJLS
[0673] The preceding compound was also prepared in the following manner. (3-
Fluorophenylamino)-non-8-enoic acid methyl ester (9.9 g, 35 mmol, 1 eq.) was dissolved in tetrahydrofuran (300 mL). A solution of lithium hydroxide monohydrate (4.47 g, 106 mmol, 3 ambient temperature by when LCMS analysis of an aliquot showed the reaction to be complete. The reaction mixture volume was reduced by half under vacuum to remove most of the tetrahydrofuran and the obtained solution was diluted with 1.0M hydrochloric acid. The solution was extracted with dichloromethane (2 xl50 mL). The organic extracted were combined, dried over sodium sulfate and the solvent removed under vacuum to give 9 g (95%) of the title compound as a yellow solid which contained unknown impurities. 1H NMR (500 MHz, CDCl3) δ ppm 7.12 (q, 1 H) 6.45 (td, /=8.35, 2.06 Hz, 1 H) 6.40 (dd, /=8.16, 1.60 Hz, 1 H) 6.32 (dt, /=11.29, 2.14 Hz, 1 H) 5.80 (m, /=17.01, 10.26, 6.66, 6.66 Hz, 1 H) 4.93 - 5.02 (m, 2 H) 4.03 (t, /=6.41 Hz, 1 H) 2.05 (q, /=6.82 Hz, 2 H) 1.89 - 1.96 (m, 1 H) 1.74 - 1.83 (m, 1 H) 1.33 - 1.51 (m, 6 H). LC-MS: purity 100% (UV), tR 4.74 min, m/z [M+H]+ 266.05.
Example 19-15:
Figure imgf000245_0001
[0674] 2-(3-trifluoromethyl-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 820 mg (92%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (t, / = 7.93 Hz, 1 H), 7.00 (d, / = 7.63 Hz, 1 H), 6.84 (s, 1 H), 6.76 (dd, / = 8.24, 2.14 Hz, 1 H), 5.73 - 5.85 (m, 1 H), 5.00 (dq, / = 17.09, 1.73 Hz, 1 H), 4.95 (m, / = 10.19, 2.10, 1.18, 1.18 Hz, 1 H), 4.10 (dd, / = 7.02, 5.80 Hz, 1 H), 2.05 (q, / = 7.02 Hz, 2 H), 1.89 - 1.98 (m, 1 H), 1.80 (dq, /=14.61, 7.24 Hz, 1 H), 1.44 - 1.52 (m, 2 H), 1.31 - 1.44 (m, 4 H). LC-MS: purity 97% (UV), tR 2.30 min, m/z [M+H]+ 316.10.
Example 19-16:
Figure imgf000245_0002
[0675] 2-(4-Fluoro-phenyl)-amino-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 1.11 g (74%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 6.91 (t, / = 8.59 Hz, 2 H), 6.59 (dd, / = 8.83, 4.26 Hz, 2 H), 5.80 (m, 1 H), 3.95 (t, / = 6.31 Hz, 1 H), 2.05 (q, / = 6.94 Hz, 2 H), 1.85 - 1.96 (m, 2 H), 1.69 - 1.85 (m, 2 H), 1.45 - 1.52 (m, 2 H), 1.34 - 1.43 (m, 4 H). LC-MS: 93% (UV), tR 2.15 min, m/z [M+H]+ 266.10
Example 19-17:
Figure imgf000246_0001
[0676] 2-(3,5-difluoro-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 667 mg (92%, corrected for residual solvent), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 6.03 - 6.28 (m, 2 H), 5.70 - 5.90 (m, 1 H), 4.82 - 5.08 (m, 2 H), 4.01 (t, / = 6.26 Hz, 1 H), 2.05 (q, = 6.92 Hz, 2 H), 1.89 - 1.98 (m, 1 H), 1.72 - 1.84 (m, 1 H), 1.58 - 1.72 (m, 1 H), 1.15 - 1.55 (m, 6 H). LC-MS: 96% (UV), tR 2.24 min, m/z [M+H]+ 284.15.
Example 19-18:
Figure imgf000246_0002
[0677] (S)-2-(3-(trifluoromethoxy)phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 1.21 g (95%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.17 (t, / = 8.09 Hz, 1 H), 6.61 (d, / = 7.93 Hz, 1 H), 6.53 (dd, / = 8.24, 1.83 Hz, 1 H), 6.46 (s, 1 H), 5.72 - 5.88 (m, 1 H), 4.89 - 5.07 (m, 2 H), 4.05 (dd, / = 7.02, 5.80 Hz, 1 H), 2.00 - 2.14 (m, 2 H), 1.87 - 1.99 (m, 1 H), 1.72 - 1.85 (m, 1 H), 1.31 - 1.58 (m, 6 H). LC-MS: purity 95% (UV), tR 2.35 min, m/z [M+H]+ 332.50.
Example 19-19:
Figure imgf000247_0001
[0678] 2-(2-benzoxazyl-amino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 2.05 g (96%), pale yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 8.96 (br. s, 1 H), 7.32 (t, / = 7.25 Hz, 2 H), 7.22 (t, / = 7.63 Hz, 1 H), 7.06 - 7.13 (m, 1 H), 5.81 (m, / = 17.05, 10.26, 6.71, 6.71 Hz, 1 H), 5.31 (s, 1 H), 4.99 (dd, / = 17.17, 1.45 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.59 (t, / = 5.19 Hz, 1 H), 2.11 - 2.22 (m, 1 H), 1.98 - 2.11 (m, 3 H), 1.62 (dd, / = 11.67, 6.48 Hz, 1 H), 1.51 (dd, / = 11.44, 6.10 Hz, 1 H), 1.35 - 1.48 (m, 4 H). LC-MS: purity 83% (UV), tR 4.30 min, m/z [M+H]+ 289.50.
Example 19-20:
Figure imgf000247_0002
[0679] 2-(3,4-Difluoro-phenyl-amino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 618 mg (92%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 6.89 - 7.06 (m, 1 H), 6.43 (ddd, / = 12.37, 6.54, 2.84 Hz, 1 H), 6.25 - 6.36 (m, 1 H), 5.80 (m, / = 17.00, 10.27, 6.70, 6.70 Hz, 1 H), 4.87 - 5.07 (m, 2 H), 3.95 (dd, / = 6.94, 5.83 Hz, I H), 1.98 - 2.10 (m, 2 H), 1.83 - 1.95 (m, I H), 1.77 (d, / = 7.41 Hz, 1 H), 1.23 - 1.56 (m, 8 H). LC-MS: purity 89% (UV), tR 2.21 min, m/z [M+H]+ 284.10.
Example 19-21:
Figure imgf000247_0003
[0680] 2-(3,5-Dichloro-phenyl-amino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 561 mg (34%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 6.73 (s, 1 H), 6.49 (s, 1 H), 5.74 - 5.86 (m, 1 H), 5.00 (d, / = 18.76 (m, 2 H), 1.85 - 1.98 (m, 1 H), 1.71 - 1.84 (m, 1 H), 1.59 - 1.71 (m, 1 H), 1.28 - 1.52 (m, 7 H). LC-MS: purity 97% (UV), tR 2.44 min, m/z [M+H]+ 316.00.
Example 19-22:
Figure imgf000248_0001
[0681] 2-(3-Trifluoromethyl-4-fluoro-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 520 mg (98%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.02 (t, / = 9.31 Hz, 1 H), 6.80 (dd, / = 5.34, 2.90 Hz, 1 H), 6.70 - 6.75 (m, 1 H), 5.79 (m, / = 17.05, 10.26, 6.71, 6.71 Hz, 1 H), 5.00 (dd, / = 17.17, 1.60 Hz, 1 H), 4.95 (d, / = 10.22 Hz, 1 H), 4.02 (t, / = 6.41 Hz, 1 H), 2.05 (q, / = 6.97 Hz, 2 H), 1.86 - 1.96 (m, 1 H), 1.75 - 1.83 (m, 1 H), 1.44 - 1.52 (m, 2 H), 1.33 - 1.43 (m, 4 H). LC-MS: purity 96% (UV), tR 5.00 min, m/z [M+H]+ 334.45.
Example 19-23:
Figure imgf000248_0002
[0682] 2-(4-Trifluoromethyl-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ, to afford 1.16 g (97%), pale yellow oily solid. 1H NMR (250 MHz, CDCl3) δ ppm 7.42 (d, / = 8.68 Hz, 2 H), 6.64 (d, / = 8.68 Hz, 2 H), 5.79 (m, / = 17.04, 10.26, 6.68, 6.68 Hz, 2 H), 4.87 - 5.08 (m, 3 H), 4.11 (dd, / = 6.85, 5.79 Hz, 1 H), 3.71 - 3.85 (m, 2 H), 1.97 - 2.14 (m, 3 H), 1.83 - 1.92 (m, 3 H). LC-MS: purity 100% (UV), tR 2.43 min, m/z [M+H]+ 316.50. Scheme XVI: General Route for synthesis of Macrocycle.
Figure imgf000249_0001
[0683] Macrocycles, such as compound 346, can be synthesized as shown in Scheme XVI. (2SAR)- l-(ferf-Butoxycarbonylamino)-4-hydroxy-proline can be treated with a heteroaryl chloride, such as 2-phenyl-4-chloro-7-methoxy-quinoline, 1-chloro-isoquinoline and the like, under basic conditions, for example potassium ferf-butoxide in DMSO, to provide heteroaryl ethers, such as (2S£R)- l-(tert-butoxycarbonylamino)-4-(l-isoquinolin-l- oxy)-proline. The heteroaryl ethers, such as (2S,4^)-l-(tert-butoxycarbonylamino)-4-(l- isoquinolin-l-oxy)-proline, can be coupled with amino acylsulfonamides, such as (\R,2R)-\- Amino-2-vinyl-cyclopropane-l-acyl-(l'-methyl)cyclopropanesulfonamide, using a coupling agent, for example using HATU in DMF in the presence of DIPEA, to provide dipeptides such as compound 22. Compound 22 can be treated under acidic conditions, for example HCl in dioxane, to remove the Boc protecting group thereby forming free amines, such as compound 23. Free amines, such as compound 23, can be coupled with N-aryl amino acids, such as 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid, using a coupling agent, for example using HATU in DMF in the presence of DIPEA, to provide macrocyclization precursors, such as compound 24. Finally, the macrocyclization precursors, such as compound 24, can be cyclized in the presence of a catalyst, for example a Zhan catalyst, to provide macrocycles, such as compound 346.
Example 19-25:
Figure imgf000250_0001
[0684] Preparation of (25,4/?)-l-(fert-butoxycarbonylamino)-4-(l-isoquinolin- 1-oxy) -proline:
[0685] (25',4JR)-l-(ferf-Butoxycarbonylamino)-4-hydroxy-proline (1.00 g, 4.64 mmol., 1.0 eq.) and dimethylsulfoxide (40 mL) were charged into a 100 mL round bottom flask. Potassium ferz-butoxide (1.04 g, 9.3 mmol., 2.0 eq.) was added portionwise over 10 minutes at ambient temperature followed by 1-chloro-isoquinoline (0.836 g, 5.11 mmol., 1.1 eq.). Stirring was continued at ambient temperature for a further 15 hrs by when LCMS analysis of the reaction mixture showed the reaction to be complete. The reaction mixture was partitioned between ethyl acetate (80 mL) and water (40 mL). The phases were separated and the aqueous phase further extracted with ethyl acetate (40 mL). The organic phases were combined to give "organic phase 1". The aqueous phase was acidified to pH 3 with IM hydrochloric acid and extracted with ethyl acetate (2 x 50 mL). The organic extracts were combined to give "organic phase 2". Organic phase 1, being contaminated with traces of chloroisoquinoline, was extracted with IM aqueous sodium hydrogen carbonate solution (50 mL). The aqueous phase (pH 8) was washed with ethyl acetate (2 x 40 mL) and acidified to pH 3 with IM hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (2 x 80 mL). The organic extracts were pooled and combined with "organic phase 2". The resulting solution was dried over sodium sulfate, filtered and the solvent removed under vacuum to give 1.86 g (92% corrected for solvent) of the title compound which contained residual dimethylsulfoxide (18% w/w). 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (dd, / = 8.44, 13.39 Hz, 1 H), 7.91 - 8.04 (m, 1 H), 7.71 - 7.82 (m, 1 H), 7.68 (t, / = 7.24 Hz, 1 H), 7.55 (t, / = 7.43 Hz, 1 H), 7.21 - 7.27 (m, 1 H), 5.82 (br. s, 1 H), 4.42 - 4.75 (m, 1 H), 3.77 - 4.00 (m, 2 H), 2.67 - 2.80 (m, 1 H), 2.41 - 2.65 (m, 1 H), 1.46 (s, 9 H). LC-MS: purity 100% (ELS) 92% (UV), tR 1.97 min, m/z [M+H]+ 359.05.
Example 19-26:
Figure imgf000251_0001
[0686] Preparation of Boc protected heteroaryl ether intermediate
[0687] (25,4/?)- 1 -(ferf-Butoxycarbonylamino)-4-( 1-isoquinolin- 1 -oxy)-proline (2.17 g, 6.0 mmol., 1.0 eq.) and N,N-dimethylformamide (25 mL) were charged into a 50 mL round bottom flask under nitrogen. HATU (2.76 g, 7.3 mmol., 1.2 eq.) and diisopropylethylamine (2.34 g, 18.1 mmol., 3.0 eq.) were added and the reaction mixture stirred at ambient temperature for a further 20 minutes. (l/?,2/?)-l-Amino-2- vinyl - cyclopropane-l-acyl-(l'-methyl)cyclopropanesulfonamide hydrochloride salt (1.78 g, 6.35 mmol., 1.05 eq.) was added as a single portion and stirring was continued at ambient temperature for a further 15 hours. Monitoring the reaction extent by LCMS showed full disappearance of the starting material. The solvent was removed under vacuum and the residue partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was further washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a heptanes: ethyl acetate gradient (from 7:3 to 4:6). After combining the relevant fractions and solvent removal, 3.48 g (98%) of compound 22 was isolated as a pale yellow foamy solid. 1H ΝMR (500 MHz, CDCl3) δ ppm 9.88 (br. s, 1 H), 8.14 (d, / = 8.44 Hz, 1 H), 7.98 (d, / = 5.87 Hz, 1 H), 7.72 - 7.82 (m, 1 H), 7.68 (t, / = 7.52 Hz, 1 H), 7.54 (t, / = 7.70 Hz, 1 H), 7.26 (d, / = 5.50 Hz, 1 H), 7.22 (br. s, 1 H), 5.81 - 5.94 (m, 1 H), 5.67 - 5.82 (m, 1 H), 5.30 (d, / = 17.24 Hz, 1 H), 5.16 (d, / = 10.27 Hz, 1 H), 4.42 (t, / = 7.89 Hz, 1 H), 3.67 - 3.96 (m, 2 H), 2.39 - 2.65 (m, 2 H), 2.13 (q, / = 8.56 Hz, 1 H), 1.98 (dd, / = 8.07, 5.50 Hz, 1 H), 1.58 - 1.71 (m, 2 H), 1.51 (s, 3 H), 1.47 (s, 9 H), 1.38 - 1.44 (m, 1 H), 0.86 - 0.92 (m, 1 H), 0.79 - 0.86 (m, 1 H). LC-MS: purity 100% (UV), tR 2.29 min, m/z [M+H]+ 585.25.
Example 19-27:
Figure imgf000252_0001
23
[0688] Preparation of deprotected heteroaryl ether intermediate hydrochloride salt
[0689] Boc protected heteroaryl ether intermediate compound 22 (3.48 g, 5.95 mmol., 1.0 eq.) and dioxane (2.5 mL) were charged into a 25 mL round bottom flask. 4M HCl in dioxane (12.5 mL) was added dropwise over 5 minutes and the reaction mixture stirred at ambient temperature for 2 hours. LCMS analysis showed full consumption of the starting material. The solvent was removed under vacuum and the residue further dried under high vacuum for 4 hours to give 2.70 g (94%) of compound 23 which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-rf6) δ ppm 10.57 - 10.86 (m, 1 H), 9.17 (s, 1 H), 8.87 - 9.01 (m, 1 H), 8.36 (d, / = 7.70 Hz, 1 H), 8.03 (d, / = 5.87 Hz, 1 H), 7.93 (d, /=8.44 Hz, 1 H), 7.80 (td, / = 7.61, 1.28 Hz, 1 H), 7.65 (td, / = 7.70, 1.10 Hz, 1 H), 7.47 (d, / = 5.87 Hz, 1 H), 5.82 (t, / = 3.85 Hz, 1 H), 5.46 - 5.55 (m, 1 H), 5.27 (dd, / = 17.24, 1.47 Hz, 1 H), 5.10 (dd, / = 10.27, 1.83 Hz, 1 H), 4.54 - 4.67 (m, 1 H), 3.67 - 3.77 (m, 1 H), 3.59 - 3.67 (m, 1 H), 3.52 - 3.55 (m, 1 H), 2.75 (dd, / = 14.31, 7.34 Hz, 1 H), 2.29 (q, / = 8.93 Hz, I H), 2.22 (ddd, / = 14.12, 11.19, 4.40 Hz, 1 H), 1.80 (dd, / = 7.89, 4.95 Hz, I H), 1.33 - 1.43 (m, 5 H), 1.27 (dd, / = 9.35, 4.95 Hz, 1 H), 0.85 - 0.94 (m, 2 H). LC-MS: purity 92% (UV), tR 1.43 min, m/z [M+H]+ 485.25.
General Procedure NN
Figure imgf000253_0001
[0690] Preparation of macrocyclization precursor:
[0691] Deprotected heteroaryl ether intermediate compound 23 (HCl salt, 500 mg, 1.03 mmol., 1.0 eq.) and N,N-dimethylformamide (9 mL) were charged into a 25 mL round bottom flask under nitrogen. HATU (505 mg, 1.33 mmol., 1.3 eq.) and diisopropylethylamine (665 mg, 5.15 mmol., 5.0 eq.) were added and the reaction mixture stirred at ambient temperature for a further 15 minutes. 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8- enoic acid (376 mg, 1.13 mmol., 1.1 eq.) was added as a single portion and stirring was continued at ambient temperature for a further 15 hours. Monitoring the reaction extent by LCMS showed full consumption of the starting material. The solvent was removed under vacuum and the residue partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography, using a heptanes: ethyl acetate gradient (from 95:5 to 50:50). After combining the relevant fractions and solvent removal, 531 mg (65%) of compound 24 was isolated as a yellow glassy solid. 1H ΝMR (500 MHz, CDCl3) δ ppm 10.21 (br. s, 1 H), 8.06 (d, / = 8.24 Hz, 1 H), 7.99 (d, / = 5.95 Hz, 1 H), 7.78 (d, / = 8.24 Hz, 1 H), 7.66 - 7.73 (m, 1 H), 7.54 (t, / = 7.55 Hz, 1 H), 7.30 (d, / = 5.80 Hz, 1 H), 6.87 (s, 1 H), 6.61 (d, / = 8.39 Hz, 1 H), 6.58 (s, 1 H), 6.38 (d, / = 10.83 Hz, 1 H), 6.04 (br. s, 1 H), 5.73 - 5.85 (m, 2 H), 5.24 (dd, / = 17.17, 0.99 Hz, 1 H), 5.13 (dd, / = 10.38, 1.22 Hz, 1 H), 5.08 (d, / = 9.77 Hz, 1 H), 4.99 (dd, / = 17.17, 1.75 Hz, 1 H), 4.94 (dt, / = 10.19, 0.93 Hz, 1 H), 4.50 (t, / = 8.39 Hz, 1 H), 4.05 - 4.17 (m, 3 H), 2.53 - 2.65 (m, 2 H), 2.02 - 2.09 (m, 4 H), 1.77 - 1.87 (m, 2 H), 1.68 - 1.75 (m, 2 H), 1.51 (s, 3 H), 1.44 - 1.49 (m, 2 H), 1.32 - 1.43 (m, 4 H), 0.82 - 0.96 (m, 3 H). LC-MS: purity 92% (UV), tR2.19 min, m/z [M+H]+ 800.35. Example 19-29:
General Procedure OO
Figure imgf000254_0001
346
[0692] Preparation of compound 346:
[0693] The macrocyclization precursor compound 24 (200 mg, 0.250 mmol., 1.0 eq.) and toluene (10 mL, previously degassed by bubbling nitrogen through the solvent for 30 min) were charged in a 25 mL round bottom flask previously flushed with nitrogen gas (It is important to keep the reaction mixture under a protective nitrogen atmosphere as much as possible). Zhan catalyst (1.6 mg, 2 mol%) was added and the reaction mixture heated at 65 0C for 1 hour with constant nitrogen gas bubbling through the reaction mixture (via needle). LCMS analysis showed 80% conversion, so a further 1 mol% catalyst was added and the stirring continued at 65 0C. After one 1 hour all starting material had been consumed so heating was stopped and the reaction mixture left to cool down to ambient temperature. N- methyl-ethylenediamine (24 mg, 10 times the catalyst weight) was added and the reaction mixture stirred for a further 15 minutes. The solvent was removed under vacuum and the residue partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was collected and the pH of the aqueous phase adjusted to 6-7 with 0.5M hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography, using a methanol :dichloromethane gradient (from 0.5% to 1% methanol in dichloromethane). After combining the relevant fractions and solvent removal, 40.7 mg (21%) of compound 346 was isolated as a glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.09 (br. s, 1 H), 8.05 (d, / = 8.24 Hz, 1 H), 7.98 (d, / = 5.80 Hz, 1 H), 7.74 (d, / = 8.24 Hz, 1 H), 7.63 - 7.68 (m, 1 H), 7.49 (t, / = 7.63 Hz, 1 H), 7.26 (s, 2 H), 7.00 (br. s, 1 H), 6.55 (s, 1 H), 6.52 (d, / = 8.39 Hz, 1 H), 6.30 (d, / = 10.68 Hz, 1 H), 5.98 / = 7.86 Hz, 1 H), 4.23 (td, / = 3.43, 8.66 Hz, 1 H), 4.13 - 4.20 (m, 2 H), 2.69 (dd, / = 3.43, 7.71 Hz, 2 H), 2.36 - 2.45 (m, 1 H), 2.27 (q, / = 8.80 Hz, 1 H), 2.00 - 2.07 (m, 1 H), 1.84 - 1.92 (m, 2 H), 1.74 - 1.82 (m, 2 H), 1.48 - 1.52 (m, 4 H), 1.39 - 1.48 (m, 4 H), 1.28 - 1.35 (m, 2 H), 0.80 - 0.85 (m, 2 H). LC-MS: purity 93% (UV), tR 5.53 min, m/z [M+H]+ 772.40.
Example 19-30:
Figure imgf000255_0001
375
[0694] Compound 375 was prepared in a manner analogous to General Procedure OO, and the yield was 27%. 1H NMR (500 MHz, CDCl3) δ 10.16 (br. s, 1 H), 8.00 (dd, 2 H), 7.79 (d, / = 8.07 Hz, 1 H), 7.71 (t, / = 7.43 Hz, 1 H), 7.52 (t, / = 7.61 Hz, 1 H), 7.31 (d, / = 5.87 Hz, 1 H), 6.76 (s, 1 H), 6.71 (dd, / = 2.57, 5.14 Hz, 1 H), 6.35 - 6.41 (m, 1 H), 6.29 (t, 1 H), 5.97 (br. s, 1 H), 5.75 (q, 1 H), 5.01 (t, / = 9.45 Hz, 1 H), 4.66 - 4.73 (m, 1 H), 4.31 (d, / = 9.54 Hz, 1 H), 4.24 (d, / = 11.55 Hz, 1 H), 4.09 - 4.18 (m, 2 H), 2.93 (br. s, 1 H), 2.62 - 2.76 (m, 2 H), 2.46 - 2.56 (m, 1 H), 2.25 (d, / = 8.99 Hz, 1 H), 1.93 - 2.04 (m, 2 H), 1.73 - 1.88 (m, 2 H), 1.42 - 1.55 (m, 6 H), 1.28 - 1.38 (m, 3 H), 1.08 - 1.21 (m, 2 H). LC-MS: purity 99% (ELS) 96% (UV), tR 5.29 min, m/z [M+H]+ 758.30.
Example 19-31:
Figure imgf000256_0001
[0695] (2S,4fl)-l-(te^butoxycarbonylamino)-4-(2-phenyl-7-methoxy- quinoline-4-oxy)-proline was prepared in a manner analogous to General Procedure KK, to afford 17.39 g (70%), beige solid. 1H NMR (250 MHz, CD3OD) δ ppm 7.94 - 8.16 (m, 3 H) 7.50 - 7.65 (m, 3 H) 7.36 - 7.48 (m, 1 H) 7.25 - 7.32 (m, 1 H) 7.14 - 7.25 (m, 1 H) 5.36 - 5.61 (m, 1 H) 4.37 - 4.61 (m, 1 H) 3.97 (s, 3 H) 3.85 - 3.94 (m, 2 H) 2.70 - 2.88 (m, 1 H) 2.35 - 2.54 (m, 1 H) 1.34 - 1.53 (m, 9 H). LC-MS: purity 96% (UV), tR 1.53 min m/z [M+H]+ 465.60.
Example 19-32:
Figure imgf000256_0002
[0696] (25,4Λ)-l-(fert-butoxycarbonylamino)-4-[2-(3'-isopropyl-thiazol-2yl)- 7-methoxy-8-methyl-quinoline-4-oxy]-proline was prepared in a manner analogous to General Procedure KK, to afford 6.40 g (99%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.89 - 8.03 (m, 1 H) 7.44 - 7.56 (m, 1 H) 7.24 (d, / = 9.16 Hz, 1 H) 7.04 (br. s, 1 H) 5.39 (br. s, 1 H) 4.69 (s, 1 H) 4.47 - 4.60 (m, 1 H) 4.00 (s, 3 H) 3.98 (br. s, 1 H) 3.78 - 3.88 (m, 1 H) 3.18 - 3.25 (m, 1 H) 2.71 (s, 3 H) 1.47 (s, 9 H) 1.42 - 1.45 (m, 1 H) 1.40 (d, / = 6.71 Hz, 6 H) 1.36 - 1.38 (m, 1 H). LC-MS: purity 100% (UV), tR 2.65 min, m/z [M+H]+ 528.30.
General Procedure KKLS
[0697] A preparation of (25',4^)-l-(ferf-butoxycarbonylamino)-4-[2-(3'-isopropyl- thiazol-2yl)-7-methoxy-8-methyl-quinoline-4-oxy]-proline was also completed using the following procedure: (2S,4^)-l-(?e?t-Butoxycarbonylamino)-4-riydroxy-proline (24.25 g, 105 mmol, 1.0 eq.) and dimethylsulfoxide (350 mL) were charged into a 2 L round bottom flask. at ambient temperature. The reaction mixture was stirred for 1 hour at ambient temperature while the colour changed from pale yellow to dark orange. 2-(4-isopropylthiazol-2-yl)-4- chloro-7-methoxy-8-methyl-quinoline (35.00 g, 105 mmol, 1.0 eq.) was added portionwise leading to the formation of a brown sticky residue. Further dimethylsulf oxide (150 mL) was added to help solubilizing the reagents and the stirring was continued at 350C for a further 20 min. As the reaction mixture remained very thick more dimethylsulf oxide (300 mL) was added. The resulting mixture was stirred at 280C for 15 hours by which time LCMS analysis of the reaction mixture showed the reaction to be complete. The reaction mixture was diluted with methanol (300 mL) and stirred for 30 min. The reaction mixture was left to cool to ambient temperature and split into two portions to ease the work up. Both fractions were treated in the same way as follows. The mixture was diluted with ethyl acetate (500 mL) and water (300 mL). The aqueous phase was acidified to pH 3 with IM hydrochloric acid (~ 80 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were combined, washed with water (5 x 350 mL) and brine (300 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum to give 24 g and 25 g of crude product respectively. Each solid was purified separately by dry flash chromatography onto 500 g of silica and eluting with a dichloromethane: methanol gradient (from neat dichloromethane to 5% methanol in dichloromethane). After combining the relevant fractions and solvent removal 20.6 g (37%) and 21.7 g (39%) of the desired product were isolated as a yellow solid. The combined yield was 42.3 g (76%). 1H NMR (500 MHz, CDCl3) δ ppm 7.89 - 8.03 (m, 1 H) 7.44 - 7.56 (m, 1 H) 7.24 (d, /=9.16 Hz, 1 H) 7.04 (br. s, 1 H) 5.39 (br. s, 1 H) 4.69 (s, 1 H) 4.47 - 4.60 (m, 1 H) 4.00 (s, 3 H) 3.98 (br. s, 1 H) 3.78 - 3.88 (m, 1 H) 3.18 - 3.25 (m, 1 H) 2.71 (s, 3 H) 1.47 (s, 9 H) 1.42 - 1.45 (m, 1 H) 1.40 (d, / = 6.71 Hz, 6 H) 1.36 - 1.38 (m, 1 H). LC-MS: purity 98% (UV), m/z [M+Na]+ 550.15.
Figure imgf000258_0001
25
[0698] The preceding compound was prepared in a manner analogous to General Procedure LL, to afford 4.27 g (%), cream solid. 1H NMR (250 MHz, CDCl3) δ ppm 10.03 (br. s, 1 H) 8.05 (dd, / = 7.99, 1.45 Hz, 2 H), 7.97 (d, / = 9.14 Hz, 1 H), 7.39 - 7.62 (m, 4 H), 7.25 (s, 1 H), 7.13 (dd, / = 9.14, 2.28 Hz, 1 H), 7.00 (s, 1 H), 5.63 - 5.92 (m, 1 H), 5.22 - 5.39 (m, 2 H), 5.16 (d, / = 10.36 Hz, 1 H), 4.37 (t, / = 7.84 Hz, 1 H), 3.97 (s, 3 H), 3.88 (br. s, 2 H), 2.90 - 3.01 (m, 1 H), 2.42 - 2.75 (m, 2 H), 2.13 (q, / = 8.58 Hz, 1 H), 2.00 (dd, / = 7.99, 5.56 Hz, 1 H), 1.56 - 1.88 (m, 1 H), 1.46 (s, 9 H), 1.27 - 1.39 (m, 2 H), 1.05 (d, / = 8.07 Hz, 2 H). LC-MS: purity 100% (UV), tR 3.70 min, m/z [M+H]+ 677.40.
Example 19-34:
Figure imgf000258_0002
26
[0699] The preceding compound was prepared in a manner analogous to General Procedure LL, to afford 2.32 g (86%), yellow solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.65 (dd, / = 4.40, 1.28 Hz, 1 H), 8.34 (dd, / = 8.44, 1.28 Hz, 1 H), 8.12 (d, / = 9.17 Hz, 1 H), 8.05 (d, / = 7.89 Hz, 2 H), 7.57 - 7.60 (m, 3 H), 7.45 - 7.47 (m, 1 H), 7.36 (s, 1 H), 7.27 (dd, / = 9.17, 2.38 Hz, 1 H), 5.69 - 5.80 (m, 1 H), 5.61 (br. s, 1 H), 5.31 (d, / = 17.06 Hz, (dd, / = 13.85, 6.69 Hz, 1 H), 2.38 (ddd, / = 13.98, 9.86, 4.22 Hz, 1 H), 2.25 (q, / = 8.68 Hz, 1 H), 1.81 - 1.89 (m, 1 H), 1.56 - 1.64 (m, 1 H), 1.50 (s, 3 H), 1.47 (s, 9 H), 1.44 - 1.46 (m, 1 H), 1.37 - 1.44 (m, 2 H). LC-MS: purity 95% (UV), tR 1.79 min, m/z [M+H]+ 691.80.
Example 19-35: Preparation of compound 27:
Figure imgf000259_0001
27
General Procedure LLLS
[0700] (25,4/?)- 1 -(fe?t-Butoxycarbonylamino)-4- [2-(3 ' -isopropyl-thiazol-2yl)-7- methoxy-8-methyl-quinoline-4-oxy] -proline (25.00 g, 47.38 mmol., 1.0 eq.) and NN- dimethylformamide (200 mL) were charged into a 1 L round bottom flask under nitrogen. HATU (21.62 g, 56.86 mmol., 1.2 eq.) and diisopropylethylamine (50 mL, 284.3 mmol., 6.0 eq.) were added at 00C and the reaction mixture stirred at ambient temperature for a further 30 minutes. (l/?,25)-l-Amino-2-vinyl-cyclopropane-l-carbonyl-(l'-methyl)cyclopropane- sulfonamide hydrochloride salt (13.98 g, 49.75 mmol., 1.05 eq.), previously dissolved in NN- dimethylformamide (50 mL) was added drop wise over 15 minutes at 00C and stirring was continued for 2 hours ambient temperature. Monitoring the reaction conversion by LCMS showed complete consumption of the starting material. The solvent was removed under vacuum and the residue partitioned between water (0.5 L) and ethyl acetate (0.5 L) leading to the precipitation of a solid. The phases were separated and the solid partitioned between ethyl acetate (1.5 L) and water (3 L). The organic phases were combined, washed with water (2 x 1 L), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by dry flash chromatography, using a heptanes: ethyl acetate gradient (from 4:1 to neat EtOAc). After combining the relevant fractions and solvent removal, 21.0 g (59%) of compound 27 was isolated as a yellow solid. 1H ΝMR (500 MHz, CDCl3) δ ppm 9.79 (br. s, 7.05 (s, 1 H) 5.65 - 5.88 (m, 1 H) 5.37 - 5.48 (m, 1 H) 5.30 (d, / = 17.09 Hz, 1 H) 5.17 (d, / = 10.38 Hz, 1 H) 4.40 (t, / = 7.78 Hz, 1 H) 4.00 (s, 3 H) 3.92 (br. s, 2 H) 3.12 - 3.30 (m, 1 H) 2.71 (s, 3 H) 2.54 - 2.68 (m, 2 H) 2.12 (q, / = 8.70 Hz, 1 H) 1.99 (dd, / = 8.09, 5.80 Hz, 1 H) 1.61 - 1.78 (m, 3 H) 1.52 (s, 2 H) 1.44 - 1.50 (m, 9 H) 1.33 - 1.43 (m, 7 H) 0.76 - 0.95 (m, 2 H). LC-MS: purity 98% (UV), m/z [M+H]+ 754.45.
Example 19-36:
Figure imgf000260_0001
28
[0701] The preceding compound was prepared in a manner analogous to General Procedure MM, to afford 571 mg (99%), yellow solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.56 (d, / = 9.31 Hz, 1 H), 8.11 (d, / = 7.17 Hz, 2 H), 7.71 - 7.81 (m, 3 H), 7.66 (s, 1 H), 7.61 (d, / = 2.29 Hz, I H), 7.51 (dd, / = 9.31, 2.29 Hz, 1 H), 6.01 (br. s, 1 H), 5.64 (ddd, / = 17.13, 10.19, 8.70 Hz, 1 H), 5.34 (dd, / = 17.17, 0.99 Hz, 1 H), 5.16 (dd, / = 10.38, 1.22 Hz, 1 H), 4.81 - 4.84 (m, 1 H), 4.08 (s, 3 H), 4.01 (s, 2 H), 3.11 (dd, / = 14.65, 7.48 Hz, 1 H), 2.91 - 2.99 (m, 1 H), 2.57 (ddd, / = 14.57, 10.68, 4.20 Hz, 1 H), 2.40 (q, / = 8.65 Hz, 1 H), 1.96 (dd, / = 7.93, 5.65 Hz, 1 H), 1.39 (dd, / = 9.46, 5.49 Hz, 1 H), 1.24 - 1.31 (m, 1 H), 0.99 - 1.19 (m, 3 H). LC-MS: purity 99% (UV), tR 1.24 min, m/z [M+H]+ 577.30.
Figure imgf000261_0001
29
[0702] The preceding compound was prepared in a manner analogous to General Procedure MM, to afford 2.24 g (99%), beige solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.61 (dd, / = 4.43, 1.37 Hz, 1 H), 8.39 (d, / = 9.16 Hz, 1 H), 8.30 (dd, / = 8.39, 1.37 Hz, 1 H), 7.95 - 7.98 (m, 2 H), 7.58 - 7.66 (m, 3 H), 7.52 (s, 1 H), 7.46 (d, / = 2.14 Hz, 1 H), 7.36 - 7.41 (m, 2 H), 5.86 (t, / = 3.81 Hz, 1 H), 5.44 - 5.53 (m, 1 H), 5.21 (dd, / = 17.24, 1.37 Hz, 1 H), 5.03 (dd, / = 10.38, 1.53 Hz, 1 H), 4.68 (dd, / = 10.68, 7.32 Hz, 1 H), 3.95 (s, 3 H), 3.83 - 3.88 (m, 2 H), 2.97 (dd, / = 15.11, 7.48 Hz, 1 H), 2.42 (ddd, / = 14.80, 10.53, 4.27 Hz, 1 H), 2.25 (q, / = 8.65 Hz, 1 H), 1.82 (dd, / = 8.09, 5.65 Hz, 1 H), 1.44 - 1.49 (m, 1 H), 1.37 - 1.41 (m, 1 H), 1.37 (s, 3 H), 1.24 (dd, / = 9.61, 5.65 Hz, 1 H), 0.70 - 0.82 (m, 2 H). LC-MS: purity 78% (UV), tR 1.27 min, m/z [M+H]+ 591.30.
Example 19-38:
Figure imgf000261_0002
30
[0703] The preceding compound was prepared in a manner analogous to General Procedure MM, to afford 3.16 g (96%), brown solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.41 (d, / = 9.31 Hz, 1 H), 7.78 (s, 1 H), 7.66 (s, 1 H), 7.61 (d, / = 9.46 Hz, 1 H), 5.88 (br. s, / = 10.60, 7.55 Hz, 1 H), 4.08 (s, 3 H), 3.97 (br. s, 2 H), 3.25 - 3.30 (m, 1 H), 3.06 (dd, / = 14.42, 7.40 Hz, 1 H), 2.64 (s, 3 H), 2.55 (ddd, / = 14.65, 10.60, 4.35 Hz, 1 H), 2.37 (q, / = 8.70 Hz, 1 H), 1.95 (dd, / = 7.93, 5.65 Hz, 1 H), 1.56 - 1.62 (m, 1 H), 1.51 - 1.54 (m, 1 H), 1.50 (s, 3 H), 1.44 (d, / = 7.02 Hz, 6 H), 1.38 (dd, / = 9.46, 5.65 Hz, 1 H), 0.85 - 0.94 (m, 2 H). LC-MS: purity 99% (UV), tR 1.94 min, m/z [M+H]+ 654.10.
Example 19-39:
Figure imgf000262_0001
31
[0704] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 55.0 mg (26%), beige foamy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.19 (br. s, 1 H), 8.01 - 8.07 (m, 1 H), 7.96 - 8.01 (m, 1 H), 7.74 - 7.83 (m, 1 H), 7.71 (t, / = 7.52 Hz, 1 H), 7.61 - 7.68 (m, 1 H), 7.46 - 7.60 (m, 2 H), 7.30 (d, / = 5.87 Hz, 1 H),
6.98 - 7.09 (m, 1 H), 6.89 (d, / = 4.77 Hz, 1 H), 6.75 (s, 1 H), 6.65 (d, / = 8.07 Hz, 1 H), 6.03 (d, / = 2.20 Hz, 1 H), 5.73 - 5.85 (m, 3 H), 5.24 (d, / = 16.87 Hz, 1 H), 5.08 - 5.18 (m, 1 H),
4.99 (d, / = 15.77 Hz, 1 H), 4.94 (d, / = 10.64 Hz, 1 H), 4.83 (br. s, 1 H), 4.44 - 4.57 (m, 1 H), 4.12 - 4.22 (m, 1 H), 4.04 - 4.12 (m, 1 H), 2.59 (d, / = 8.80 Hz, 1 H), 1.96 - 2.11 (m, 3 H), 1.67 - 1.87 (m, 3 H), 1.51 (s, 3 H), 1.44 - 1.49 (m, 2 H), 1.31 - 1.43 (m, 5 H), 1.17 - 1.29 (m, 2 H), 0.83 - 0.98 (m, 2 H). LC-MS: purity 75% (UV), tR 2.77 min, m/z [M+H]+ 782.45.
Example 19-40:
Figure imgf000263_0001
[0705] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 57.4 mg (44%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.17 (br. s, 1 H), 8.06 (d, / = 8.44 Hz, 1 H), 8.00 (d, / = 5.87 Hz, 1 H), 7.75 - 7.80 (m, 1 H), 7.67 - 7.73 (m, 1 H), 7.48 - 7.54 (m, 1 H), 7.29 (d, / = 5.87 Hz, 1 H), 7.19 (s, 1 H), 6.94 (t, / = 7.89 Hz, 2 H), 6.61 (t, / = 7.34 Hz, 1 H), 6.49 (d, / = 7.89 Hz, 2 H), 5.99 (d, / = 2.93 Hz, 1 H), 5.71 - 5.84 (m, 2 H) 5.25 (d, / = 17.06 Hz, 1 H), 5.13 (d, / = 10.27 Hz, 1 H), 4.99 (dd, / = 17.06, 1.65 Hz, 1 H), 4.93 (dd, / = 10.18, 0.83 Hz, 1 H), 4.52 (t, / = 8.34 Hz, 1 H), 4.17 (d, / = 11.92 Hz, 1 H), 4.09 - 4.14 (m, 1 H) 4.06 (dd, / = 11.74, 3.67 Hz, 1 H), 2.55 (dd, / = 8.34, 2.66 Hz, 2 H), 1.98 - 2.09 (m, 4 H), 1.74 - 1.81 (m, 2 H), 1.72 (dd, / = 10.73, 5.04 Hz, 1 H), 1.65 - 1.70 (m, 1 H), 1.51 (s, 3 H), 1.41 - 1.47 (m, 2 H), 1.28 - 1.41 (m, 5 H), 0.79 - 0.95 (m, 3 H). LC-MS: purity 100% (UV), tR 2.64 min, m/z [M+H]+ 714.40.
Example 19-41:
Figure imgf000263_0002
33
[0706] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 432 mg (61%), pale yellow solid. 1H NMR (500 MHz, CDCl3) (m, 1 H), 7.66 - 7.74 (m, 1 H), 7.49 - 7.60 (m, 1 H), 7.30 (d, / = 5.80 Hz, 1 H), 6.99 (s, 1 H) 6.84 - 6.94 (m, 1 H), 6.18 - 6.38 (m, 3 H), 6.01 (s, 1 H), 5.70 - 5.87 (m, 2 H), 5.24 (dd, / = 17.09, 1.22 Hz, 1 H), 5.13 (dd, / = 10.38, 1.37 Hz, 1 H), 4.90 - 5.04 (m, 2 H), 4.70 (br. s,
1 H), 4.51 (t, / = 8.39 Hz, 1 H), 4.01 - 4.21 (m, 3 H), 2.58 (dd, / = 8.39, 2.59 Hz, 2 H), 1.98 - 2.10 (m, 4 H), 1.75 - 1.83 (m, 2 H), 1.62 - 1.75 (m, 4 H), 1.56 (d, /=6.41 Hz, 1 H), 1.51 (s,
2 H) 1.43 - 1.48 (m, 1 H), 1.29 - 1.42 (m, 4 H), 0.80 - 0.97 (m, 2 H). LC-MS: purity 97% (UV), tR 2.65 min, m/z [M+H]+ 732.50.
Example 19-42:
Figure imgf000264_0001
34
[0707] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 528 mg (42%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.21 (br. s, 1 H), 8.06 (d, / = 8.39 Hz, 1 H), 7.99 (d, / = 5.80 Hz, 1 H), 7.78 (d, 1 H), 7.70 (t, / = 7.55 Hz, 1 H), 7.52 (t, / = 7.63 Hz, 1 H), 7.30 (d, / = 5.95 Hz, 1 H), 7.09 (br. s, 1 H), 6.92 (t, / = 8.16 Hz, 1 H), 6.48 (d, / = 8.09 Hz, 1 H), 6.40 (d, / = 8.24 Hz, 1 H), 6.36 (s, 1 H), 6.01 (d, / = 2.44 Hz, 1 H), 5.78 (dd, / = 10.22, 6.71 Hz, 1 H), 5.24 (d, / = 17.09 Hz, 1 H), 5.13 (d, / = 10.53 Hz, 1 H), 4.99 (dd, / = 17.09, 1.68 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.52 (t, / = 8.32 Hz, 1 H), 4.13 (q, / = 7.12 Hz, 3 H), 4.09 (d, / = 3.36 Hz, 1 H), 2.55 - 2.60 (m, 2 H), 2.01 - 2.07 (m, 7 H), 1.65 - 1.84 (m, 5 H), 1.44 - 1.48 (m, 2 H), 1.31 - 1.42 (m, 5 H), 0.88 - 0.95 (m, 1 H), 0.79 - 0.87 (m, 1 H). LC-MS: purity 100% (UV), tR 5.72 min, m/z [M+H]+ 798.50.
Example 19-43:
Figure imgf000265_0001
35
[0708] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 209 mg (42%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.19 (br. s, 1 H), 8.07 (d, / = 8.24 Hz, 1 H), 8.00 (d, / = 5.80 Hz, 1 H), 7.76 (d, / = 8.09 Hz, 1 H), 7.66 (t, / = 7.55 Hz, 1 H), 7.44 (t, J = 7.71 Hz, 1 H), 7.29 (d, / = 5.80 Hz, 1 H), 7.18 (d, / = 7.78 Hz, 1 H), 7.04 - 7.11 (m, 3 H), 6.99 (d, / = 7.32 Hz, 1 H), 6.14 (br. s, 1 H), 6.01 (br. s, 1 H), 5.73 - 5.86 (m, 3 H), 5.25 (d, / = 17.09 Hz, 1 H), 5.14 (d, / = 10.38 Hz, 1 H), 4.87 - 5.03 (m, 4 H), 4.72 (br. s, 1 H), 4.55 (t, J = 8.16 Hz, 1 H), 4.34 (d, / = 11.75 Hz, 1 H), 4.09 - 4.14 (m, 1 H), 2.55 - 2.64 (m, 2 H), 2.07 - 2.13 (m, 1 H), 2.03 (d, / = 5.80 Hz, 2 H), 1.89 - 1.97 (m, 2 H), 1.72 - 1.78 (m, 2 H), 1.65 - 1.71 (m, 1 H), 1.55 (s, 1 H), 1.47 (dd, / = 9.08, 5.57 Hz, 2 H), 1.30 - 1.39 (m, 4 H), 0.88 - 0.95 (m, 1 H), 0.81 - 0.88 (m, 1 H). LC-MS: purity 98% (UV), tR 2.16 min, m/z [M+H]+ 755.40.
Example 19-44:
Figure imgf000265_0002
36
[0709] The preceding compound was prepared in a manner analogous to General
Procedure NN, to afford 103 mg (48%), pale yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 10.20 (br. s, 1 H), 8.02 (d, / = 8.24 Hz, 1 H), 7.97 (d, / = 5.80 Hz, 1 H), 7.74 - 7.78 (m, 1 H), 7.68 (t, / = 7.48 Hz, 1 H), 7.50 (t, / = 7.63 Hz, 1 H), 7.24 - 7.30 (m, 1 H), 6.60 - 6.70 (m), 5.23 (d, / = 17.39 Hz, 1 H), 5.10 (d, / = 10.99 Hz, 1 H), 4.98 (dd, / = 17.09, 1.53 Hz, 1 H), 4.92 (d, / = 10.38 Hz, 1 H), 4.52 (dd, / = 9.61, 7.17 Hz, 1 H), 4.08 - 4.14 (m, 1 H), 4.03 - 4.08 (m, 1 H), 3.99 (dd, / = 8.54, 3.97 Hz, 1 H), 2.54 - 2.62 (m, 1 H), 2.46 - 2.54 (m, 1 H), 1.95 - 2.11 (m, 4 H), 1.59 - 1.83 (m, 4 H), 1.50 - 1.58 (m, 1 H), 1.49 (s, 3 H), 1.17 - 1.47 (m, 8 H), 0.95 - 1.18 (m, 1 H), 0.85 - 0.93 (m, 1 H), 0.76 - 0.84 (m, 1 H). LC-MS: purity 100% (UV), tR 2.23 min, m/z [M+H]+ 750.40.
Example 19-45:
Figure imgf000266_0001
37
[0710] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 142.5 mg (60%), yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 10.36 (s, 1 H), 8.00 - 8.14 (m, 2 H), 7.82 (d, / = 8.98 Hz, 1 H), 7.42 - 7.62 (m, 4 H), 7.11 (dd, / = 2.44, 9.14 Hz, 1 H), 7.04 (s, 1 H), 6.98 (s, 1 H), 6.78 - 6.92 (m, 1 H), 6.73 (dd, / = 2.66, 5.41 Hz, 1 H), 6.52 - 6.68 (m, 1 H), 5.67 - 5.93 (m, 2 H), 5.41 - 5.62 (m, 1 H), 5.23 (dd, / = 1.29, 17.28 Hz, 1 H), 5.12 (dd, / = 1.45, 10.28 Hz, 1 H), 4.87 - 5.05 (m, 2 H), 4.69 (d, / = 10.05 Hz, 1 H), 4.46 (t, / = 8.30 Hz, 1 H), 4.03 - 4.22 (m, 3 H), 3.98 (s, 3 H), 3.50 (s, 1 H), 2.55 - 2.67 (m, 2 H), 1.95 - 2.13 (m, 4 H), 1.65 - 1.87 (m, 2 H), 1.29 - 1.49 (m, 8 H), 1.01 - 1.17 (m, 2 H), 0.79 - 0.95 (m, 1 H). LC-MS: purity 93% (UV), tR 4.58 min, m/z [M+H]+ 892.10.
Example 19-46:
Figure imgf000267_0001
38
[0711] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 297 mg (50%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.28 (br. s, 1 H) 8.07 (d, J = IAl Hz, 2 H) 7.85 (d, / = 9.16 Hz, 1 H) 7.52 - 7.58 (m, 2 H) 7.50 (d, / = 7.02 Hz, 1 H) 7.48 (d, / = 2.44 Hz, 1 H) 7.11 (dd, / = 9.16, 2.44 Hz, 1 H) 7.07 (t, / = 7.86 Hz, 2 H) 7.05 (s, 1 H) 6.94 (s, 1 H) 6.72 (t, / = 7.32 Hz, 1 H) 6.55 (d, / = 7.93 Hz, 2 H) 5.69 - 5.85 (m, 2 H) 5.50 (br. s, 1 H) 5.23 (d, / = 16.94 Hz, 1 H) 5.13 (d, / = 11.14 Hz, 1 H) 4.99 (dd, / = 17.17, 1.60 Hz, 1 H) 4.93 (d, / = 10.07 Hz, 1 H) 4.36 - 4.50 (m, 2 H) 4.23 (d, / = 11.75 Hz, 1 H) 4.14 - 4.21 (m, 1 H) 4.06 (dd, / = 11.67, 3.43 Hz, 1 H) 3.99 (s, 3 H) 2.90 - 2.99 (m, 1 H) 2.55 - 2.67 (m, 2 H) 1.97 - 2.08 (m, 4 H) 1.73 - 1.83 (m, 2 H) 1.44 - 1.54 (m, 2 H) 1.32 - 1.43 (m, 7 H) 1.06 (s, 2 H). LC-MS: purity 100% (UV), tR 2.64 min, m/z [M+H]+ 714.40.
Example 19-47:
Figure imgf000267_0002
39
[0712] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 240 mg (32%), beige solid. 1H NMR (500 MHz, CD3OD) δ ppm Hz, 1 H), 7.30 (s, 1 H), 7.10 (dd, / = 9.16, 2.44 Hz, 1 H), 6.93 - 7.03 (m, 1 H), 6.88 (s, 1 H), 6.77 (d, / = 7.32 Hz, 1 H), 6.69 (dd, / = 8.24, 1.83 Hz, 1 H), 5.70 - 5.86 (m, 2 H), 5.61 - 5.68 (m, 1 H), 5.30 (dd, / = 17.24, 1.37 Hz, 1 H), 5.12 (dd, / = 10.53, 1.37 Hz, 1 H), 4.93 - 4.99 (m, 1 H), 4.87 - 4.91 (m, 1 H), 4.56 (dd, / = 10.22, 6.87 Hz, 1 H), 4.41 (d, / = 12.51 Hz, 1 H), 4.33 (dd, / = 8.09, 5.04 Hz, 1 H), 4.07 (dd, / = 12.36, 3.20 Hz, 1 H), 3.98 (s, 3 H), 2.63 (dd, / = 13.73, 6.41 Hz, 1 H), 2.36 (ddd, / = 13.96, 10.45, 3.97 Hz, 1 H), 2.22 (q, / = 8.85 Hz,
1 H), 1.98 - 2.04 (m, 2 H), 1.78 - 1.91 (m, 2 H), 1.67 - 1.77 (m, 1 H), 1.54 - 1.64 (m, 2 H), 1.52 (s, 3 H), 1.42 - 1.51 (m, 3 H), 1.35 - 1.41 (m, 3 H), 1.26 - 1.35 (m, 3 H), 0.86 - 0.95 (m,
2 H). LC-MS: purity 92% (UV), tR 2.27 min m/z [M+H]+ 888.45.
Example 19-48:
40
[0713] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 220 mg (31%), yellow waxy solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.02 (d, / = 7.02 Hz, 2 H), 7.86 (d, / = 9.16 Hz, 1 H), 7.43 - 7.55 (m, 3 H), 7.35 (d, / = 2.44 Hz, I H), 7.18 (s, 1 H), 7.05 (dd, / = 9.16, 2.14 Hz, 1 H), 6.76 - 6.87 (m, 1 H), 6.18 - 6.31 (m, 3 H), 5.65 - 5.82 (m, 2 H), 5.50 (br. s, 1 H), 5.26 (d, / = 17.70 Hz, 1 H), 5.07 (d, / = 11.29 Hz, 1 H), 4.95 (dd, / = 17.24, 1.68 Hz, 1 H), 4.88 (d, / = 10.38 Hz, 1 H), 4.49 (dd, J = 9.92, 7.17 Hz, 1 H), 4.27 (d, / = 12.21 Hz, 1 H), 4.17 (dd, / = 7.78, 5.34 Hz, 1 H), 4.00 (dd, / = 12.21, 3.05 Hz, 1 H), 3.91 (s, 3 H), 2.56 (dd, / = 12.36, 7.17 Hz, 1 H), 2.27 - 2.38 (m, I H), 2.17 (q, / = 8.85 Hz, I H), 1.99 (q, / = 7.22 Hz, 2 H), 1.83 (dd, / = 7.93, 5.49 Hz, I H), 1.72 - 1.81 (m, 1 H), 1.61 - 1.72 (m, 1 H), 1.50 - 1.61 (m, 2 H), 1.48 (s, 3 H), 1.38 - 1.47 (m, (UV), tR 2.13 min, m/z [M+H]+ 838.45.
Example 19-49:
Figure imgf000269_0001
41
[0714] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 191 mg (25%), yellow waxy solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.03 (d, / = 7.02 Hz, 2 H), 7.90 (d, / = 9.16 Hz, 1 H), 7.46 - 7.55 (m, 3 H), 7.38 (d, / = 2.44 Hz, 1 H), 7.22 (s, 1 H), 7.06 (dd, / = 9.16, 2.44 Hz, 1 H), 6.71 (s, 1 H), 6.51 (d, / = 8.54 Hz, 1 H), 6.46 (d, / = 11.44 Hz, 1 H), 5.67 - 5.82 (m, 2 H), 5.57 (br. s, 1 H), 5.28 (dd, / = 17.17, 0.84 Hz, 1 H), 5.10 (d, / = 11.75 Hz, 1 H), 4.95 (dd, / = 17.17, 1.75 Hz, I H), 4.88 - 4.90 (m, 1 H), 4.54 (dd, / = 10.07, 7.02 Hz, 1 H), 4.27 - 4.38 (m, 2 H), 4.04 (dd, / = 12.05, 3.20 Hz, 1 H), 3.93 (s, 3 H), 2.59 (dd, / = 14.04, 7.02 Hz, 1 H), 2.34 (ddd, / = 13.92, 10.26, 3.89 Hz, 1 H), 2.19 (q, / = 8.95 Hz, 1 H), 2.01 (q, / = 6.87 Hz, 2 H), 1.79 - 1.88 (m, 2 H), 1.67 - 1.77 (m, 1 H), 1.53 - 1.62 (m, 2 H), 1.50 (s, 3 H), 1.43 - 1.49 (m, 2 H), 1.34 - 1.39 (m, 3 H), 1.28 - 1.34 (m, 3 H), 0.82 - 0.94 (m, 2 H). LC-MS: purity 95% (UV), tR 2.29 min, m/z [M+H]+ 906.45.
Figure imgf000270_0001
42
[0715] Compound 42 was prepared in a manner analogous to General Procedure NN, to afford 267 mg (62%), white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.09 (br. s, 1 H), 8.05 (d, / = 7.48 Hz, 2 H), 7.85 (d, / = 9.16 Hz, 1 H), 7.51 - 7.56 (m, 2 H), 7.49 (d, / = 7.02 Hz, 1 H), 7.47 (d, / = 1.83 Hz, 1 H), 7.08 - 7.14 (m, 2 H), 6.99 - 7.04 (m, 2 H), 6.55 (d, / = 7.93 Hz, 1 H), 6.40 - 6.45 (m, 2 H), 5.69 - 5.83 (m, 2 H), 5.49 (br. s, 1 H), 5.22 (d, / = 17.09 Hz, 1 H), 5.11 (d, / = 10.38 Hz, 1 H), 4.90 - 5.00 (m, 2 H), 4.75 (br. s, 1 H), 4.47 (t, / = 8.09 Hz, 1 H), 4.11 - 4.19 (m, 2 H), 4.05 - 4.11 (m, 1 H), 3.97 (s, 3 H), 2.59 (d, / = 7.48 Hz, 2 H), 2.03 (dd, / = 13.12, 5.65 Hz, 4 H), 1.83 - 1.97 (m, 2 H), 1.78 (d, / = 5.49 Hz, 2 H), 1.49 (s, 4 H), 1.29 - 1.43 (m, 6 H), 0.86 - 0.93 (m, 1 H), 0.81 - 0.87 (m, 1 H). LC-MS: purity 99% (UV), tR 1.88 min, m/z [M+H]+ 904.90.
Example 19-51:
Figure imgf000270_0002
[0716] (5)-2-(3-methyl-5-trifluoromethyl-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II to afford 271 mg (64%). 1H NMR (500 MHz, CDCl3) δ ppm 6.80 (s, 1 H) 6.63 (s, 1 H) 6.57 (s, 1 H) 5.75 - 5.85 (m, 1 H) 4.93 - 5.03 (m, 2 H) 4.08 (t, /=6.41 Hz, 1 H) 3.74 (s, 3 H) 2.31 (s, 3 H) 2.02 - 2.08 (m, 2 H) 1.85 (s, 1 H) 1.76 (s, 1 H) 1.33 - 1.46 (m, 7 H). LC-MS: purity 98% (UV), tR 5.65 min, m/z [M+H]+ 344.20. Example 19-52:
Figure imgf000271_0001
[0717] (S)-2-(3-Fluoro-5-trifluoromethoxy-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II to afford 225 mg (41%). 1H NMR (500 MHz, CDCl3) δ ppm 6.31 (d, /=9.16 Hz, 1 H) 6.19 - 6.25 (m, 2 H) 5.74 - 5.85 (m, 1 H) 4.91 - 5.05 (m, 2 H) 4.41 (d, /=8.39 Hz, 1 H) 3.96 - 4.04 (m, 1 H) 3.76 (s, 3 H) 2.00 - 2.10 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.75 (dq, /=14.13, 7.14 Hz, 1 H) 1.29 - 1.46 (m, 6 H). LC-MS: purity 98% (UV), tR 2.69 min m/z [M+H]+ 364.10.
Example 19-53:
Figure imgf000271_0002
[0718] (5)-2-(3-chloro-5-trifluoromethyl-phenylamino)-non-8-enoic acid methyl ester was prepared in a manner analogous to General Procedure II to afford 346 mg (20%). 1H NMR (500 MHz, CDCl3) δ ppm 6.94 (s, 1 H) 6.70 (d, / = 8.70 Hz, 2 H) 5.80 (m, / = 16.98, 10.22, 6.69, 6.69 Hz, 1 H) 4.91 - 5.04 (m, 2 H) 4.44 (d, / = 8.54 Hz, 1 H) 4.02 - 4.10 (m, 1 H) 3.76 (s, 3 H) 2.00 - 2.11 (m, 2 H) 1.82 - 1.92 (m, 1 H) 1.72 - 1.81 (m, 1 H) 1.30 - 1.46 (m, 6 H). LC-MS: purity 98% (UV), tR 2.78 min, m/z [M+H]+ 363.95.
Example 19-54:
Figure imgf000271_0003
[0719] (5)-2-(3-chloro-5-trifluoromethyl-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ to afford 312 mg (94%). 1H NMR 5.04 (m, 2 H) 4.51 (br. s., 1 H) 4.09 (t, /=6.26 Hz, 1 H) 3.73 - 3.81 (m, 1 H) 2.05 (q, /=6.71 Hz, 2 H) 1.90 - 1.98 (m, 1 H) 1.88 (dt, /=6.48, 3.32 Hz, 1 H) 1.80 (dq, /=14.34, 7.32 Hz, 1 H) 1.32 - 1.51 (m, 5 H). LC-MS: purity 100% (UV), tR 2.51 min, m/z [M+H]+ 349.90.
Example 19-55:
Figure imgf000272_0001
[0720] (S)-2-(3-methyl-5-trifluoromethyl-phenylamino)-non-8-enoic acid was prepared in a manner analogous to General Procedure JJ to afford 236 mg (91%). 1H NMR (500 MHz, CDCl3) δ ppm 6.83 (s, 1 H) 6.65 (s, 1 H) 6.59 (s, 1 H) 5.80 (m, / = 17.03, 10.28, 6.71, 6.71 Hz, 1 H) 4.97 - 5.03 (m, 1 H) 4.95 (dd, / = 10.22, 0.92 Hz, 1 H) 4.03 - 4.14 (m, 1 H) 2.32 (s, 3 H) 2.05 (q, / = 6.82 Hz, 2 H) 1.92 (d, / = 5.65 Hz, 1 H) 1.73 - 1.85 (m, 1 H) 1.43 - 1.52 (m, 2 H) 1.32 - 1.43 (m, 4 H). LC-MS: purity 97% (UV), tR 2.43 min, m/z [M+H]+ 330.45.
Example 19-56:
Figure imgf000272_0002
[0721] (S)-2-(3-(trifluoromethoxy)phenylamino)non-8-enoic acid was prepared in a manner analogous to General Procedure JJ to afford 257 mg (92%). 1H NMR (500 MHz, CDCl3) δ ppm 6.34 (d, / = 9.16 Hz, 1 H) 6.20 - 6.26 (m, 2 H) 5.73 - 5.85 (m, 1 H) 4.90 - 5.05 (m, 2 H) 4.02 (t, / = 6.33 Hz, 1 H) 3.75 - 3.84 (m, 1 H) 2.94 (t, / = 7.25 Hz) 1.99 - 2.10 (m, 2 H) 1.85 - 1.98 (m, 1 H) 1.79 (dq, / = 14.50, 7.27 Hz, 1 H) 1.62 - 1.73 (m, 1 H) 1.31 - 1.51 (m, 6 H) LC-MS: purity 93% (UV), tR 5.14 min, m/z [M+H]+ 350.05.
Figure imgf000273_0001
[0722] (S)-methyl 2-(3-(trifluoromethoxy)phenylamino)non-8-enoate was prepared in a manner analogous to General Procedure II to afford 160 mg (39%). 1H NMR (500 MHz, CDCl3) δ ppm 7.15 (t, J = 8.16 Hz, 1 H) 6.58 (d, / = 8.09 Hz, 1 H) 6.52 (dd, / = 8.16, 1.91 Hz, 1 H) 6.43 (br. s, 1 H) 5.80 (m, / = 16.98, 10.22, 6.69, 6.69 Hz, 1 H) 5.00 (dd, / = 17.17, 1.75 Hz, 1 H) 4.95 (d, / = 10.22 Hz, 1 H) 4.27 (br. s, 1 H) 4.01 - 4.07 (m, 1 H) 3.74 (s, 3 H) 2.01 - 2.09 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.76 (dq, / = 14.17, 7.18 Hz, 1 H) 1.30 - 1.46 (m, 6 H). LC-MS: purity 100% (UV), fΛ2.73 min, m/z [M+H]+ 743.30.
Example 19-58:
Figure imgf000273_0002
78 [0723] ( 1^,25)- l-(tert-butoxycarbonylamino)-2- vinyl-cyclopropane- 1-carbonyl-
(l'-methyl)-dimethylsulfonamide (1.5 g, 4.50 mmol, 1.0 eq.) and dioxane (3 mL) were charged into a 50 mL round bottom flask and the reaction mixture cooled on top of an ice bath. 4M HCl in dioxane (15 mL) was added and the reaction mixture stirred at ambient temperature for 1 hour. After this time, LCMS analysis of an aliquot showed the reaction to be complete. The solvent was removed under vacuum and the residue azeotroped with dichloromethane (2 x 30 mL) twice. The residue was used in the next step without further purification.
[0724] (25',4JR)-l-(tert-butoxycarbonyl)-4-(2-(4-isopropylthiazol-2-yl)-7-methoxy- 8-methylquinolin-4-yloxy)pyrrolidine-2-carboxylic acid (2.05 g, 4.05 mmol, 0.9 eq.) and NN- dimethylformamide (20 mL) were charged into a 50 mL round bottom flask and the reaction mixture cooled to 00C. HATU (2.2 g, 5.85 mmol, 1.3 eq.) was added portion wise followed further 15 minutes. A solution of the amino acid residue in N,N-dimethylformamide (5 mL) was then added to the reaction mixture. The reaction mixture was stirred at ambient temperature for a further 2 hours by which time LCMS analysis of an aliquot showed the reaction to be complete. The solvent was removed under vacuum and the residue dissolved in ethyl acetate (100 mL). The organic phase was washed with water (2 x 100 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a ethyl acetate:heptanes gradient (from 1:9 to 7:3 ethyl acetate/heptanes). After combining the relevant fractions and solvent removal, 2.40 g (83%) of compound 79 was isolated as a pale yellow solid. 1H ΝMR (500 MHz, CDCl3) δ ppm 9.82 (s, 1 H) 7.92 (d, / = 9.16 Hz, 1 H) 7.51 (s, 1 H) 7.24 (d, / = 9.16 Hz, 1 H) 7.07 (br. s, 1 H) 7.05 (s, 1 H) 5.71 - 5.85 (m, 1 H) 5.43 (br. s, 1 H) 5.30 (d, / = 17.09 Hz, 1 H) 5.17 (d, / = 10.38 Hz, 1 H) 4.38 (t, / = 7.93 Hz, 1 H) 4.00 (s, 3 H) 3.82 - 3.96 (m, 2 H) 3.20 (spt, / = 6.82 Hz, 1 H) 2.93 (s, 6 H) 2.70 (s, 3 H) 2.60 (d, / = 6.10 Hz, 2 H) 2.11 (q, / = 8.65 Hz, 1 H) 1.97 (dd, / = 8.01, 5.87 Hz, 1 H) 1.47 (s, 9 H) 1.40 - 1.44 (m, 1 H) 1.39 (d, / = 7.78 Hz, 6 H). LC- MS: purity 100% (UV), tø2.48 min, m/z [M+H]+ 743.30.
Example 19-59:
Figure imgf000274_0001
79
[0725] Compound 78 (1.4 g, 1.884 mmol, 1 eq.) and dioxane (3 mL) were charged into a 50 mL round bottom flask and the reaction mixture cooled on top of an ice bath. 4M HCl in dioxane (15 mL) was added and the reaction mixture stirred at ambient temperature for 1.5 hour. After this time, LCMS analysis of an aliquot showed the reaction to be complete. The solvent was removed under vacuum and the residue azeotroped with dichloromethane (2 x 30 mL) twice to give 1.41 g (99%) of compound 79 as a beige solid which was used in the next step without further purification. 1H ΝMR (250 MHz, MeOD) δ 1 H) 5.86 (br. s, 1 H) 5.49 - 5.71 (m, 1 H) 5.22 - 5.37 (m, 1 H) 5.14 (dd, / = 10.36, 1.22 Hz, 1 H) 4.70 - 4.83 (m, 1 H) 4.05 (s, 3 H) 3.96 (s, 2 H) 3.03 (br. s, 1 H) 2.78 - 2.93 (m, 6 H) 2.60 (s, 4 H) 2.31 (s, 1 H) 1.84 - 1.98 (m, 1 H) 1.42 (d, / = 6.85 Hz, 6 H) 1.34 (dd, / = 9.44, 5.63 Hz, 1 H). LC-MS: purity 100% (UV), tR 1.55 min, m/z [M+H]+ 643.25.
Example 20
Scheme XVII: Olefin Metathesis route to N-Aryl Acylsulfonamides
Figure imgf000275_0001
[0726] Macrocycles, such as compound 358, can be synthesized as shown in Scheme XVII. (2SAR)- l-(ferf-Butoxycarbonylamino)-4-hydroxy-proline can be treated with a heteroaryl chloride, such as 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl- quinoline and the like, under basic conditions, for example potassium ferf-butoxide in DMSO, to provide heteroaryl ethers, such as (2S£R)- l-(tert-butoxycarbonylamino)-4-[2-(3'- isopropyl-thiazol-2yl)-7-methoxy-8-methyl-quinoline-4-oxy]-proline. The heteroaryl ethers, such as (2S,AR)- l-(tert-butoxycarbonylamino)-4-[2-(3'-isopropyl-thiazol-2yl)-7-methoxy-8- methyl-quinoline-4-oxy]-proline, can be coupled with amino acylsulfonamides, such as (17?,2^)-l-amino-2-vinyl-cyclopropane-l-acyl-(r-methyl)cyclopropanesulfonamide, using a coupling agent, for example using HATU in DMF in the presence of DIPEA, to provide dipeptides such as compound 43. Compound 43 can be treated under acidic conditions, for example HCl in dioxane, to remove the Boc protecting group thereby forming amines, such as as 2-(3-trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid, using a coupling agent, for example using HATU in DMF in the presence of DIPEA, to provide macrocyclization precursors, such as compound 45. Finally, the macrocyclization precursors, such as compound 45, can be cyclized in the presence of a catalyst, for example a Zhan catalyst, to provide macrocycles, such as compound 358.
Example 20-1:
General Procedure PP
Figure imgf000276_0001
[0727] Synthesis of (25,4/?)-l-(fert-butoxycarbonylamino)-4-[2-(3'-isopropyl- thiazol-2yl)-7-methoxy-8-methyl-quinoline-4-oxy]-proline:
[0728] (25',4JR)-l-(ferf-Butoxycarbonylamino)-4-hydroxy-proline (24.25 g, 105 mmol., 1.0 eq.) and dimethylsulfoxide (350 mL) were charged into a 2 L round bottom flask. Potassium ferz-butoxide (23.56 g, 210 mmol., 2.0 eq.) was added portionwise over 10 min at ambient temperature. The reaction mixture was stirred for 1 hour at ambient temperature while the color changed from pale yellow to dark orange. 2-(4-isopropylthiazol-2-yl)-4- chloro-7-methoxy-8-methyl-quinoline (35.00 g, 105 mmol., 1.0 eq.) was added portionwise leading to the formation of a brown sticky residue. Further dimethylsulfoxide (150 mL) was added to help solubilizing the reagents and the stirring was continued at 350C for a further 20 min. As the reaction mixture remained very thick more dimethylsulfoxide (300 mL) was added. The resulting mixture was stirred at 280C for 15 hours by which time LCMS analysis of the reaction mixture showed the reaction to be complete. The reaction mixture was diluted with methanol (300 mL) and stirred for 30 min. The reaction mixture was left to cool to ambient temperature and split into two portions to ease the work up. Both fractions were treated in the same way as follows. The mixture was diluted with ethyl acetate (500 mL) and mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were combined, washed with water (5 x 350 mL) and brine (300 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum to give 24 g and 25 g of crude product respectively. Each solid was purified separately by dry flash chromatography onto 500 g of silica and eluting with a dichloromethane: methanol gradient (from neat dichloromethane to 5% methanol in dichloromethane). After combining the relevant fractions and solvent removal 20.6 g (37%) and 21.7 g (39%) of the desired product were isolated as a yellow solid. The combined yield was 42.3 g (76%). 1H NMR (500 MHz, CDCl3) δ ppm 7.89 - 8.03 (m, 1 H), 7.44 - 7.56 (m, 1 H), 7.24 (d, / = 9.16 Hz, 1 H), 7.04 (br. s, 1 H), 5.39 (br. s, 1 H), 4.69 (s, 1 H), 4.47 - 4.60 (m, 1 H), 4.00 (s, 3 H), 3.98 (br. s, 1 H), 3.78 - 3.88 (m, 1 H), 3.18 - 3.25 (m, 1 H), 2.71 (s, 3 H), 1.47 (s, 9 H), 1.42 - 1.45 (m, 1 H), 1.40 (d, / = 6.71 Hz, 6 H), 1.36 - 1.38 (m, 1 H). LC-MS: purity 100% (UV), tR 2.65 min, m/z [M+Na]+ 550.20.
Example 20-2:
General Procedure QQ
Figure imgf000277_0001
43 [0729] Synthesis of Compound 43
[0730] (25',4JR)-l-(ferf-Butoxycarbonylamino)-4-[2-(3'-isopropyl-thiazol-2yl)-7- methoxy-8-methyl-quinoline-4-oxy] -proline (25.00 g, 47.38 mmol., 1.0 eq.) and NN- dimethylformamide (200 mL) were charged into a 1 L round bottom flask under nitrogen. HATU (21.62 g, 56.86 mmol., 1.2 eq.) and diisopropylethylamine (50 mL, 284.3 mmol., 6.0 eq.) were added at 00C and the reaction mixture stirred at ambient temperature for a further 30 minutes. (1R,2S)- l-Amino-2-vinyl-cyclopropane-l-carbonyl-(l'-methyl)cyclopropane- sulfonamide hydrochloride salt (13.98 g, 49.75 mmol., 1.05 eq.), previously dissolved in NN- continued for 2 hours ambient temperature. Monitoring the reaction conversion by LCMS showed complete consumption of the starting material. The solvent was removed under vacuum and the residue partitioned between water (0.5 L) and ethyl acetate (0.5 L) leading to the precipitation of a solid. The phases were separated and the solid partitioned between ethyl acetate (1.5 L) and water (3 L). The organic phases were combined, washed with water (2 x 1 L), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by dry flash chromatography, using a heptanes: ethyl acetate gradient (from 4: 1 to neat EtOAc). After combining the relevant fractions and solvent removal, 21.0 g (59%) of compound 43 was isolated as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.79 (br. s, 1 H), 7.93 (d, / = 9.00 Hz, 1 H), 7.51 (br. s, 1 H), 7.24 (d, / = 9.16 Hz, 1 H), 7.16 (br. s, 1 H), 7.05 (s, 1 H), 5.65 - 5.88 (m, 1 H), 5.37 - 5.48 (m, 1 H), 5.30 (d, / = 17.09 Hz, 1 H), 5.17 (d, / = 10.38 Hz, 1 H), 4.40 (t, / = 7.78 Hz, 1 H), 4.00 (s, 3 H), 3.92 (br. s, 2 H), 3.12 - 3.30 (m, 1 H), 2.71 (s, 3 H), 2.54 - 2.68 (m, 2 H), 2.12 (q, / = 8.70 Hz, 1 H), 1.99 (dd, / = 8.09, 5.80 Hz, 1 H), 1.61 - 1.78 (m, 3 H), 1.52 (s, 2 H), 1.44 - 1.50 (m, 9 H), 1.33 - 1.43 (m, 7 H), 0.76 - 0.95 (m, 2 H). LC-MS: purity 98% (UV), tR 2.50 min, m/z [M+H]+ 754.45.
Example 20-3:
General Procedure RR
Figure imgf000278_0001
44 [0731] Synthesis of Compound 44
[0732] Compound 43 (3.61 g, 4.78 mmol., 1.0 eq.) and dichloromethane (45 mL) were charged into a 100 mL round bottom flask. 4M HCl in dioxane (30 mL) was added dropwise over 5 minutes and the dark orange reaction mixture stirred at ambient temperature for 2 hours. LCMS analysis showed full consumption of the starting material. The solvent give 3.70 g (96%, 3.16 g corrected for solvent content) of compound 44 as a brown solid which contained residual dioxane (15% w/w). The product was used in the next step without further purification. 1H NMR (500 MHz, CD3OD) δ ppm 8.41 (d, J = 9.31 Hz, 1 H), 7.78 (s, 1 H), 7.66 (s, 1 H), 7.61 (d, / = 9.46 Hz, 1 H), 5.88 (br. s, 1 H), 5.57 - 5.67 (m, 1 H), 5.33 (d, / = 16.94 Hz, 1 H), 5.16 (d, / = 11.14 Hz, 1 H), 4.81 (dd, / = 10.60, 7.55 Hz, 1 H), 4.08 (s, 3 H), 3.97 (br. s, 2 H), 3.25 - 3.30 (m, 1 H), 3.06 (dd, / = 14.42, 7.40 Hz, 1 H), 2.64 (s, 3 H), 2.55 (ddd, / = 14.65, 10.60, 4.35 Hz, 1 H), 2.37 (q, / = 8.70 Hz, 1 H), 1.95 (dd, / = 7.93, 5.65 Hz, 1 H), 1.56 - 1.62 (m, 1 H), 1.51 - 1.54 (m, 1 H), 1.50 (s, 3 H), 1.44 (d, / = 7.02 Hz, 6 H), 1.38 (dd, / = 9.46, 5.65 Hz, 1 H), 0.85 - 0.94 (m, 2 H). LC-MS: purity 99% (UV), tR 1.95 min, m/z [M+H]+ 654.10.
Example 20-4:
General Procedure SS
Figure imgf000279_0001
45 [0733] Synthesis of Compound 45
[0734] Compound 44 (HCl salt, 670 mg, 0.97 mmol., 1.0 eq.) and N,N-dimethylformamide (10 mL) were charged into a 25 mL round bottom flask under nitrogen. HATU (443 mg, 1.16 mmol., 1.2 eq.) and diisopropylethylamine (1.01 mL, 5.82 mmol., 6.0 eq.) were added at 0°C and the reaction mixture stirred at ambient temperature for a further 15 minutes. (2S)-2-(3-fluoro-5-trifluoromethyl-phenylamino)-non-8- enoic acid (376 mg, 1.13 mmol., 1.1 eq.) was added as a single portion and stirring was continued at ambient temperature for a further 1.5 hours. Monitoring the reaction conversion by LCMS showed full consumption of the starting material. The solvent was removed under organic phase was further washed with water (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography, using a heptanes: ethyl acetate gradient (from 9:1 to 1:1). After combining the relevant fractions and solvent removal, 688 mg (73%) of compound 45 was isolated as a pale yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 10.13 (s, 1 H), 7.82 (d, / = 9.14 Hz, 1 H), 7.56 (s, 1 H), 7.20 (d, / = 9.29 Hz, 1 H), 7.06 (d, / = 0.91 Hz, 1 H), 6.84 (s, 1 H), 6.58 - 6.72 (m, 2 H), 6.40 (dt, / = 10.89, 1.94 Hz, 1 H), 5.68 - 5.89 (m, 2 H), 5.55 - 5.66 (m, 1 H), 5.22 (dd, / = 17.21, 1.37 Hz, 1 H), 5.05 - 5.16 (m, 2 H), 4.88 - 5.05 (m, 2 H), 4.38 - 4.51 (m, 1 H), 4.09 - 4.25 (m, 3 H), 3.99 (s, 3 H), 3.10 - 3.29 (m, 1 H), 2.71 (s, 3 H), 2.59 - 2.69 (m, 2 H), 1.99 - 2.10 (m, 4 H), 1.76 - 1.89 (m, 2 H), 1.67 - 1.76 (m, 2 H), 1.53 - 1.60 (m, 1 H), 1.50 (s, 3 H), 1.45 (br. s, 1 H), 1.36 - 1.45 (m, 10 H), 1.30 - 1.36 (m, 1 H), 0.82 - 0.97 (m, 2 H). LC-MS: purity 100 % (UV), tR 2.55 min, m/z [M+H]+ 969.40.
Example 20-5:
Figure imgf000280_0001
[0735] Synthesis of Compound 46
[0736] Compound 46 was prepared in a manner analogous to General Procedure NN, to afford 346 mg (54%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.38 (br. s, 1 H), 7.82 (d, / = 9.00 Hz, 1 H), 7.55 (s, 1 H), 7.20 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 6.79 (s, 1 H), 6.65 (d, / = 8.39 Hz, 1 H), 6.62 (s, 1 H), 6.38 (d, / = 10.68 Hz, 1 H), 5.80 (ddd, / = 17.09, 10.15, 6.94 Hz, 2 H), 5.61 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.12 (d, / = 10.53 Hz, 1 H), 5.06 (d, / = 9.61 Hz, 1 H), 4.99 (dd, / = 17.01, 1.30 Hz, 1 H), 4.94 (d, / = 10.22 Hz, 1 H), 4.44 (dd, / = 9.38, 7.25 Hz, 1 H), 4.14 - 4.23 (m, 2 H), 4.08 - 4.13 (m, 2.69 (m, 2 H), 1.99 - 2.09 (m, 4 H), 1.80 - 1.89 (m, 1 H), 1.71 - 1.80 (m, 1 H), 1.58 - 1.72 (m, 1 H), 1.43 - 1.58 (m, 3 H), 1.39 - 1.41 (m, 7 H), 1.26 - 1.38 (m, 4 H), 1.08 (t, /=7.86 Hz, 2 H). LC-MS: purity 100% (UV), tR 2.74 min, m/z [M+H]+ 955.30.
Example 20-6:
Figure imgf000281_0001
47
[0737] Synthesis of Compound 47
[0738] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 1.26 g (67%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.08 (s, 1 H), 7.81 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.17 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 6.98 - 7.05 (m, 2 H), 6.68 (t, / = 7.32 Hz, 1 H), 6.53 (d, / = 7.63 Hz, 2 H), 5.70 - 5.84 (m, 2 H), 5.58 (d, / = 2.75 Hz, 1 H), 5.24 (d, / = 17.09 Hz, 1 H), 5.09 - 5.15 (m, 1 H), 4.98 (dd, / = 17.09, 1.83 Hz, 1 H), 4.93 (d, / = 10.07 Hz, 1 H), 4.48 (t, / = 8.24 Hz, 2 H), 4.22 (d, / = 11.90 Hz, 1 H), 4.10 - 4.18 (m, 1 H), 4.05 (dd, J = 11.60, 3.36 Hz, 1 H), 4.00 (s, 3 H), 3.21 (spt, / = 6.92 Hz, 1 H), 2.72 (s, 3 H), 2.57 - 2.65 (m, 2 H), 1.96 - 2.06 (m, 4 H), 1.74 - 1.82 (m, 2 H), 1.68 - 1.75 (m, 2 H), 1.67 (s, 1 H), 1.58 (tt, / = 13.96, 7.25 Hz, 1 H), 1.51 (s, 3 H), 1.43 - 1.49 (m, 1 H), 1.40 (d, / = 6.71 Hz, 6 H), 1.23 - 1.38 (m, 5 H), 0.87 - 0.95 (m, 1 H), 0.81 - 0.87 (m, 1 H). LC-MS: purity 100% (UV), tR 2.43 min, m/z [M+H]+ 883.35.
Example 20-7:
[0739] Synthesis of Compound 48
[0740] Compound 48 was prepared in a manner analogous to General Procedure NN, to afford 2.07 g (60%), white solid. 1H NMR (250 MHz, CDCl3) δ ppm 10.33 (br. s, 1 H), 7.81 (d, / = 9.14 Hz, 1 H), 7.55 (s, 1 H), 7.17 (d, / = 9.29 Hz, 1 H), 6.95 - 7.09 (m, 4 H), 6.60 - 6.74 (m, 1 H), 6.52 (d, / = 7.61 Hz, 2 H), 5.68 - 5.88 (m, 2 H), 5.58 (d, / = 2.13 Hz, 1 H), 5.24 (dd, / = 17.06, 1.37 Hz, 1 H), 5.13 (dd, / = 10.36, 1.52 Hz, 1 H), 4.84 - 5.07 (m, 2 H), 4.47 (t, / = 8.22 Hz, 2 H), 4.18 - 4.27 (m, 1 H), 4.10 - 4.18 (m, 1 H), 4.02 - 4.10 (m, 1 H), 3.99 (s, 3 H), 3.21 (spt, / = 6.73 Hz, 1 H), 2.87 - 3.02 (m, 1 H), 2.71 (s, 3 H), 2.55 - 2.65 (m, 2 H), 1.94 - 2.10 (m, 5 H), 1.68 - 1.84 (m, 3 H), 1.44 - 1.61 (m, 2 H), 1.40 (d, / = 6.85 Hz, 6 H), 1.34 (d, / = 6.40 Hz, 5 H), 1.00 - 1.10 (m, 2 H). LC-MS: purity 84% (UV), tR 2.71 min, m/z [M+H]+ 869.00.
Example 20-8: Synthes
Figure imgf000282_0002
General Procedure SSLS
[0741] Compound 44 (HCl salt, 4 g, 5.3 mmol, 1.0 eq.) and N,N- dimethylformamide (80 mL) were charged into a 250 mL round bottom flask under nitrogen. HATU (2.65 g, 6.4 mmol, 1.2 eq.) and diisopropylethylamine (6 mL, 32 mmol, 6.0 eq.) were added at 0°C and the reaction mixture stirred at ambient temperature for a further 15 minutes. (25)-2-(3-trifluoromethyl-phenylamino)-non-8-enoic acid (2.01 g, 6.4 mmol, 1.2 eq.) was added as a single portion and stirring was continued at ambient temperature for a further 2 hours. Monitoring the reaction conversion by LCMS showed full consumption of the starting material. The solvent was removed under vacuum and the residue partitioned between ethyl acetate (80 mL) and water (80 mL). The organic phase was further washed with water (80 mL x 4), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography, using a dichloromethane: ethyl acetate gradient (from neat dichloromethane to 10% ethylacetate in dichloromethane). After combining the relevant fractions the solvent was removed under vacuum to give 3.08g (61%) of compound 49 as a yellow solid.
[0742] The residue was dissolved in toluene (300 mL) and decolorizing charcoal (924 mg, -30 wt% of the residue mass) was added. The slurry was heated at 65°C for 30 minutes and the charcoal removed by filtration while still hot. The mixture was used in the next step. 1H NMR (500 MHz, CDCl3) δ ppm 10.12 (s, 1 H) 7.80 (d, / = 9.14 Hz, 1 H) 7.56 (br. s, 1 H) 7.17 (d, / = 9.30 Hz, 1 H) 7.07 - 7.12 (m, 1 H) 7.06 (s, 1 H) 6.88 - 6.95 (m, 2 H) 6.80 (s, 1 H) 6.67 (d, / = 8.04 Hz, 1 H) 5.71 - 5.83 (m, 2 H) 5.60 (br. s, 1 H) 5.23 (d, / = 17.18 Hz, 1 H) 5.12 (d, / = 10.40 Hz, 1 H) 4.98 (d, / = 17.18 Hz, 1 H) 4.93 (d, / = 10.09 Hz,
1 H) 4.86 (d, / = 9.14 Hz, 1 H) 4.46 (t, / = 8.28 Hz, 1 H) 4.19 (d, J = 11.35 Hz, 2 H) 4.06 - 4.15 (m, 1 H) 3.99 (s, 3 H) 3.21 (spt, / = 6.78 Hz, 1 H) 2.71 (s, 3 H) 2.64 (d, / = 7.25 Hz,
2 H) 1.97 - 2.08 (m, 4 H) 1.75 - 1.88 (m, 2 H) 1.71 (br. s, 2 H) 1.62 - 1.70 (m, 1 H) 1.54 - 1.62 (m, 1 H) 1.51 (s, 3 H) 1.29 - 1.45 (m, 10 H) 1.23 - 1.29 (m, 1 H) 0.89 - 0.95 (m, 1 H) 0.82 - 0.87 (m, 1 H). LC-MS: purity 100% (UV), tR 5.60 min, m/z [M+H]+ 951.31.
Figure imgf000284_0001
[0743] Synthesis of Compound 50
[0744] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 385 mg (61%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.38 (s, 1 H), 7.80 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.17 (d, / = 9.16 Hz, 1 H), 7.09 (t, 1 H), 7.06 (s, 1 H), 6.93 (d, / = 7.63 Hz, 1 H), 6.86 (s, 1 H), 6.79 (s, 1 H), 6.66 (d, / = 8.24 Hz, 1 H), 5.74 - 5.84 (m, 2 H), 5.61 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.12 (d, / = 10.53 Hz, 1 H), 4.99 (d, / = 15.72 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.83 (d, / = 9.77 Hz, 1 H), 4.42 - 4.48 (m, 1 H), 4.20 (d, / = 11.60 Hz, 2 H), 4.07 - 4.11 (m, 1 H), 3.99 (s, 3 H), 3.20 (spt, / = 6.82 Hz, 1 H), 2.91 - 2.99 (m, 1 H), 2.71 (s, 3 H), 2.60 - 2.67 (m, 2 H), 1.98 - 2.05 (m, 2 H), 1.79 - 1.88 (m, 1 H), 1.71 - 1.79 (m, 1 H), 1.47 - 1.60 (m, 2 H), 1.45 (dd, / = 8.39, 4.58 Hz, 1 H), 1.40 (d, / = 6.87 Hz, 8 H), 1.32 - 1.38 (m, 4 H), 1.30 (d, / = 7.48 Hz, 1 H), 1.03 - 1.11 (m, 2 H), 0.79 - 0.87 (m, 1 H). LC-MS: purity 100% (UV), tR 2.72 min, m/z [M+H]+ 937.35.
Figure imgf000285_0001
51 [0745] Synthesis of Compound 51
[0746] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 344 mg (50%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.09 (br. s, 1 H) 7.83 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.20 (d, /=9.16 Hz, 1 H), 7.06 (s, 1 H), 6.97 (q, / = 7.83 Hz, 1 H), 6.90 (s, 1 H), 6.40 (td, /= 8.39, 1.68 Hz, 1 H), 6.33 (dd, /=8.16, 1.30 Hz, 1 H), 6.27 (d, /= 11.29 Hz, 1 H), 5.77 (dd, /= 17.09, 7.02 Hz, 2 H), 5.60 (d, /=2.14 Hz, 1 H), 5.23 (d, /= 17.09 Hz, 1 H), 5.12 (d, /= 10.68 Hz, 1 H), 4.99 (dd, /= 17.09, 1.37 Hz, 1 H), 4.93 (d, /=9.92 Hz, 1 H), 4.69 (d, /=9.77 Hz, 1 H), 4.46 (t, /=8.32 Hz, 1 H), 4.20 (d, /= 11.75 Hz, 1 H), 4.13 (q, /= 6.87 Hz, 1 H), 4.07 (dd, /= 11.75, 3.20 Hz, 1 H), 4.00 (s, 3 H) 3.21 (spt, /= 6.71 Hz, 1 H), 2.71 (s, 3 H), 2.65 (d, /= 8.24 Hz, 2 H), 1.95 - 2.08 (m, 4 H), 1.79 (d, / = 6.87 Hz, 2 H), 1.71 (s, 2 H) 1.53 - 1.58 (m, 1 H), 1.51 (s, 3 H), 1.45 - 1.49 (m, 1 H), 1.42 - 1.46 (m, 1 H), 1.40 (d, /=6.87 Hz, 6 H), 1.28 - 1.37 (m, 4 H), 0.91 - 0.95 (m, 1 H), 0.81 - 0.87 (m, 1 H). LC-MS: purity 99% (UV), tR 2.48 min, m/z [M+H]+ 901.45.
Figure imgf000286_0001
52
[0747] Synthesis of Compound 52
[0748] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 754 mg (58%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.10 (br. s, 1 H), 7.80 (d, / = 9.00 Hz, 1 H), 7.54 (s, 1 H), 7.19 (d, / = 9.31 Hz, 1 H), 7.14 (s,
1 H), 7.06 (s, 1 H), 6.62 - 6.68 (m, 2 H), 6.39 - 6.44 (m, 2 H), 6.03 (br. s, 1 H), 5.72 - 5.83 (m,
2 H), 5.58 (d, / = 3.81 Hz, 1 H), 5.26 (d, / = 16.94 Hz, 1 H), 5.09 - 5.14 (m, 1 H), 4.97 (dd, / = 17.09, 1.68 Hz, 1 H), 4.92 (dd, / = 10.07, 0.76 Hz, 1 H), 4.52 (dd, / = 9.92, 6.87 Hz, 1 H), 4.13 - 4.19 (m, 1 H), 4.07 (d, / = 3.20 Hz, 1 H), 4.01 - 4.05 (m, 1 H), 4.00 (s, 3 H), 3.89 - 3.98 (m, 1 H), 3.64 - 3.74 (m, 4 H), 3.19 - 3.24 (m, 1 H), 3.17 (q, / = 7.48 Hz, 3 H), 2.71 (s, 3 H), 2.61 - 2.69 (m, 1 H), 2.52 - 2.60 (m, 1 H), 2.11 (q, / = 8.85 Hz, 1 H), 2.00 - 2.05 (m, 3 H), 1.61 - 1.68 (m, 1 H), 1.52 - 1.60 (m, 1 H), 1.51 (s, 3 H), 1.44 (d, / = 7.48 Hz, 6 H), 1.25 - 1.29 (m, 1 H), 0.93 (dt, / = 8.96, 6.12 Hz, 1 H), 0.80 - 0.89 (m, 1 H). LC-MS: purity 91% (UV), tR 2.66 min, m/z [M+H]+ 901.45..
Figure imgf000287_0001
[0749] Synthesis of Compound 53
[0750] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 685 mg (52%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.34 (br. s, 1 H), 7.74 (d, / = 8.99 Hz, 1 H), 7.56 (s, 1 H), 7.07 (s, 1 H), 6.86 (s, 1 H), 6.69 (t, / = 8.67 Hz, 2 H), 6.44 (dd, / = 8.91, 4.33 Hz, 2 H), 5.71 - 5.86 (m, 2 H), 5.60 (br. s, 1 H), 5.24 (d, / = 17.18 Hz, 1 H), 5.13 (d, / = 10.40 Hz, 1 H), 4.99 (dd, / = 17.18, 1.89 Hz, 1 H), 4.93 (dd, / = 10.09, 0.95 Hz, 1 H), 4.45 (t, / = 8.35 Hz, 1 H), 4.30 - 4.41 (m, 1 H), 4.19 (d, / = 11.82 Hz, 1 H), 4.02 - 4.10 (m, 2 H), 4.01 (s, 3 H), 3.21 (spt, / = 6.88 Hz, 1 H), 2.90 - 2.99 (m, 1 H), 2.72 (s, 3 H), 2.62 (d, / = 8.51 Hz, 2 H), 1.99 - 2.09 (m, 4 H), 1.74 (d, / = 4.89 Hz, 2 H), 1.53 - 1.59 (m, 1 H), 1.48 - 1.53 (m, 1 H), 1.45 (dt, / = 8.63, 4.28 Hz, 2 H), 1.40 (m, / = 6.94 Hz, 8 H), 1.30 - 1.37 (m, 4 H), 1.07 (d, / = 8.04 Hz, 2 H). LC-MS: purity 100% (UV), tR 2.63 min, m/z [M+H]+ 887.40.
Figure imgf000288_0001
54 [0751] Synthesis of Compound 54
[0752] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 272 mg (51%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.09 (br. s, 1 H), 7.84 (d, / = 9.14 Hz, 1 H), 7.56 (s, 1 H), 7.21 (d, / = 9.14 Hz, 1 H), 7.06 (s,
1 H), 6.93 (s, 1 H), 6.17 (tt, / = 9.08, 2.03 Hz, 1 H), 6.05 - 6.13 (m, 2 H), 5.70 - 5.85 (m,
2 H), 5.60 (br. s, 1 H), 5.22 (dd, / = 17.02, 0.79 Hz, 1 H), 5.09 - 5.15 (m, 1 H), 4.99 (dd, / = 17.10, 1.81 Hz, 1 H), 4.92 (t, J = 10.01 Hz, 2 H), 4.43 - 4.49 (m, 1 H), 4.16 - 4.21 (m,
1 H), 4.06 - 4.10 (m, 1 H), 4.00 (s, 3 H), 3.20 (spt, / = 6.86 Hz, 1 H), 2.71 (s, 3 H), 2.59 - 2.69 (m, 2 H), 1.95 - 2.04 (m, 3 H), 1.75 - 1.85 (m, 2 H), 1.68 - 1.74 (m, 2 H), 1.53 - 1.60 (m,
2 H), 1.50 (s, 3 H), 1.46 - 1.49 (m, 1 H), 1.42 - 1.46 (m, 2 H), 1.38 - 1.42 (m, 8 H), 1.34 - 1.38 (m, 2 H), 1.29 - 1.34 (m, 2 H). LC-MS: 100% (UV), tR 2.49 min, m/z [M+H]+ 919.35.
Example 20-14:
Figure imgf000288_0002
[0753] Synthesis of Compound 55
[0754] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 359 mg (64%), orange oil. 1H NMR (500 MHz, CDCl3) δ ppm 10.10 (br. s, 1 H), 7.81 (d, / = 9.00 Hz, 1 H), 7.56 (s, 1 H), 7.19 (d, / = 9.31 Hz, 1 H), 7.06 (s, 1 H), 7.00 (t, / = 8.09 Hz, 1 H), 6.93 (br. s, 1 H), 6.54 (d, / = 8.24 Hz, 1 H), 6.38 - 6.47 (m, 2 H), 5.69 - 5.85 (m, 2 H), 5.60 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.12 (d, / = 10.68 Hz, 1 H), 4.98 (d, / = 17.09 Hz, 1 H), 4.93 (d, / = 10.07 Hz, 1 H), 4.80 (br. s, 1 H), 4.47 (t, / = 8.32 Hz, 1 H), 4.05 - 4.22 (m, 3 H), 3.99 (s, 3 H), 3.21 (spt, / = 6.82 Hz, 1 H), 2.71 (s, 3 H), 2.64 (d, / = 7.78 Hz, 2 H), 1.98 - 2.07 (m, 4 H), 1.75 - 1.88 (m, 3 H), 1.62 - 1.69 (m, 2 H), 1.53 - 1.61 (m, 2 H), 1.51 (s, 3 H), 1.42 - 1.45 (m, 1 H), 1.40 (d, / = 6.87 Hz, 6 H), 1.37 - 1.39 (m, 1 H), 1.30 - 1.36 (m, 2 H), 0.82 - 0.95 (m, 2 H). LC-MS: purity 98% (UV), tR 2.56 min, m/z [M+H]+ 967.40.
Example 20-15:
Figure imgf000289_0001
56 [0755] Synthesis of Compound 56
[0756] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 266 mg (42%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.38 (br. s, 1 H), 7.81 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.19 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 7.00 (t, / = 8.16 Hz, 1 H), 6.84 (s, 1 H), 6.54 (d, / = 8.09 Hz, 1 H), 6.42 (d, / = 8.24 Hz, 1 H), 6.40 (s, 1 H), 5.72 - 5.86 (m, 2 H), 5.61 (br. s, 1 H), 5.23 (d, / = 17.24 Hz, 1 H), 5.13 (d, / = 10.38 Hz, 1 H), 4.99 (dd, / = 17.09, 1.53 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.77 (d, / = 9.61 Hz, 1 H), 4.45 (t, / = 8.32 Hz, 1 H), 4.17 - 4.20 (m, 1 H), 4.12 - 4.17 1 H), 2.71 (s, 3 H), 2.58 - 2.68 (m, 2 H), 2.00 - 2.10 (m, 4 H), 1.78 - 1.86 (m, 1 H), 1.68 - 1.78 (m, 1 H), 1.48 - 1.58 (m, 2 H), 1.43 - 1.48 (m, 2 H), 1.39 - 1.41 (m, 7 H), 1.29 - 1.38 (m, 4 H), 1.02 - 1.12 (m, 2 H). LC-MS: purity 100% (UV), tR 2.73 min, m/z [M+H]+ 953.25.
Example 20-16:
Figure imgf000290_0001
57
[0757] Synthesis of Compound 57
[0758] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 996 mg (73%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.11 (s, I H), 7.81 (d, / = 9.14 Hz, 1 H), 7.55 (s, 1 H), 7.20 (d, / = 7.88 Hz, 1 H), 7.07 - 7.13 (m, 2 H), 7.04 - 7.07 (m, 1 H), 6.94 - 7.03 (m, 3 H), 6.02 (d, / = 7.57 Hz, 1 H), 5.68 - 5.90 (m, 2 H), 5.54 - 5.64 (m, 1 H), 5.23 (d, / = 16.87 Hz, 1 H), 5.13 (d, / = 11.35 Hz, 1 H), 4.98 (dd, / = 17.02, 1.58 Hz, 1 H), 4.92 (dd, / = 10.17, 1.02 Hz, 1 H), 4.76 (td, / = 8.28, 5.36 Hz, 1 H), 4.48 - 4.52 (m, 1 H), 4.43 - 4.48 (m, 1 H), 4.12 (dd, / = 11.66, 3.47 Hz, 1 H), 3.92 (s, 3 H), 3.17 - 3.22 (m, 1 H), 2.69 (s, 3 H), 2.53 - 2.68 (m, 2 H), 1.97 - 2.10 (m, 4 H), 1.81 - 1.96 (m, 2 H), 1.67 - 1.80 (m, 2 H), 1.52 (s, 5 H), 1.43 - 1.47 (m, 1 H), 1.35 - 1.43 (m, 10 H), 0.89 - 0.97 (m, 1 H), 0.81 - 0.89 (m, 1 H). LC-MS: purity 99% (UV), tR 2.49 min, m/z [M+H]+ 924.55.
Figure imgf000291_0001
58 [0759] Synthesis of Compound 58
[0760] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 96 mg (23%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.15 (br. s, 1 H), 7.84 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.19 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H) 6.99 (br. s, 1 H), 6.67 (s, 1 H), 6.47 - 6.51 (m, 1 H), 6.45 (d, / = 1.68 Hz, 2 H), 5.72 - 5.84 (m, 2 H), 5.56 - 5.62 (m, 1 H), 5.22 (d, / = 17.24 Hz, 1 H), 5.12 (d, / = 10.38 Hz, 1 H), 4.99 (dd, / = 17.17, 1.60 Hz, 1 H), 4.94 (dd, / = 10.22, 1.07 Hz, 1 H), 4.81 - 4.92 (m, 1 H), 4.45 (t, 1 H), 4.05 - 4.20 (m, 4 H), 3.98 (s, 4 H), 3.20 (spt, / = 6.87 Hz, 1 H), 2.70 (s, 3 H), 2.59 - 2.67 (m, 2 H), 2.01 - 2.06 (m, 5 H), 1.82 - 1.97 (m, 2 H), 1.76 - 1.81 (m, 2 H), 1.71 (br. s, 2 H), 1.52 - 1.61 (m, 1 H), 1.50 (s, 3 H), 1.42 - 1.48 (m, 1 H), 1.28 - 1.38 (m, 3 H), 0.77 - 0.96 (m, 2 H). LC-MS: purity 90% (UV), tR 2.63 min, m/z [M+H]+ 951.30.
Example 20-18:
Figure imgf000291_0002
[0762] The preceding compound was prepared in a manner analogous to General Procedure SS, to afford 920 mg (66%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.12 (s, 1 H), 7.75 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.19 (d, / = 9.16 Hz, 1 H), 7.07 (s, 1 H), 6.84 (s, 1 H), 6.74 - 6.80 (m, 2 H), 6.57 - 6.62 (m, 1 H), 5.73 - 5.83 (m, 2 H), 5.62 (br. s, 1 H), 5.22 (d, / = 17.09 Hz, 1 H), 5.13 (d, / = 10.38 Hz, 1 H), 4.99 (d, / = 17.09 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.72 (d, / = 10.38 Hz, 1 H), 4.45 (t, / = 8.32 Hz, 1 H), 4.17 (d, 1 H), 4.08 (d, / = 6.56 Hz, 1 H), 4.00 (s, 3 H), 3.20 (quin, / = 6.90 Hz, 1 H), 2.72 (s, 3 H), 2.61 - 2.65 (m, 2 H), 1.98 - 2.08 (m, 4 H), 1.75 - 1.82 (m, 2 H), 1.72 (br. s, 2 H), 1.50 (s, 3 H), 1.43 (d, / = 5.34 Hz, 2 H), 1.40 (d, /=6.87 Hz, 6 H), 1.30 - 1.38 (m, 3 H), 1.24 - 1.30 (m, 3 H), 0.86 - 0.91 (m, 2 H). LC-MS: purity 89% (UV), tR 5.57 min, m/z [M+H]+ 969.39.
Example 20-19:
Figure imgf000292_0001
[0763] Synthesis of Compound 60
[0764] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 310 mg (48%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.38 (br. s, 1 H), 7.75 (d, / = 9.16 Hz, 1 H), 7.56 (s, 1 H), 7.19 (d, J = 9.31 Hz, 1 H), 7.07 (s, 1 H), 6.74 - 6.80 (m, 3 H), 6.56 - 6.60 (m, 1 H), 5.75 - 5.84 (m, 2 H), 5.62 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.13 (d, / = 10.68 Hz, 1 H), 4.99 (dd, / = 17.17, 1.45 Hz, 1 H), 4.92 - 4.95 (m, 1 H), 4.68 (d, / = 9.16 Hz, 1 H), 4.45 (t, J = 8.39 Hz, 1 H), 4.16 - 4.19 (m, 1 H), 4.06 - 4.11 (m, 2 H), 4.00 (s, 3 H), 3.17 - 3.25 (m, 1 H), 2.93 - 2.99 (m, 1 H), 2.72 (s, 3 H), 2.59 - 2.69 (m, 2 H), 1.99 - 2.09 (m, 4 H), 1.78 - 1.85 (m, 1 H), 1.69 - 1.77 (m, 1 H), 1.42 LC-MS: purity 96% (UV), tR 5.45 min, m/z [M+H]+ 955.11.
Example 20-20:
Figure imgf000293_0001
[0765] Synthesis of Compound 61
[0766] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 499 mg (60%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.04 (br. s, 1 H), 7.81 (d, / = 9.16 Hz, 1 H), 7.58 (s, 1 H), 7.16 - 7.20 (m, 2 H), 7.07 (s, 1 H), 6.93 (s, 1 H), 6.49 (d, / = 8.39 Hz, 2 H), 5.77 (dd, / = 10.15, 7.10 Hz, 2 H), 5.63 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.12 (d, / = 10.38 Hz, 1 H), 4.98 (d, / = 17.09 Hz, 1 H), 4.93 (d, / = 10.07 Hz, 1 H), 4.85 (d, / = 9.61 Hz, 1 H), 4.48 (t, / = 8.39 Hz, 1 H), 4.23 (d, / = 11.75 Hz, 1 H), 4.10 - 4.19 (m, 1 H), 4.06 (dd, / = 11.75, 2.59 Hz, 1 H), 3.99 (s, 3 H), 3.21 (spt, / = 6.84 Hz, 1 H), 2.72 (s, 3 H), 2.64 (d, / = 7.93 Hz, 2 H), 1.99 - 2.08 (m, 4 H), 1.77 - 1.85 (m, 2 H), 1.68 - 1.73 (m, 2 H), 1.53 - 1.60 (m, 2 H), 1.50 (s, 3 H), 1.39 - 1.42 (m, 8 H), 1.34 - 1.37 (m, 2 H), 0.82 - 0.95 (m, 4 H). LC-MS: purity 94% (UV), tR 2.72 min, m/z [M+H]+ 951.40.
Figure imgf000294_0001
[0767] Synthesis of Compound 62
[0768] The preceding compound was prepared in a manner analogous to General Procedure NN, to afford 245 mg (67%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.29 (br. s, 1 H), 7.80 (d, J = 9.16 Hz, 1 H), 7.57 (s, 1 H), 7.16 - 7.24 (m, 3 H), 7.07 (s, 1 H), 6.90 (s, 1 H), 6.47 (d, / = 8.39 Hz, 2 H), 5.70 - 5.85 (m, 2 H), 5.62 (br. s, 1 H), 5.23 (d, / = 17.09 Hz, 1 H), 5.12 (d, / = 10.38 Hz, 1 H), 4.99 (d, / = 17.09 Hz, 1 H), 4.93 (d, / = 10.22 Hz, 1 H), 4.81 (d, / = 9.31 Hz, 1 H), 4.47 (t, / = 8.39 Hz, 1 H), 4.23 (d, / = 11.75 Hz, 1 H), 4.12 - 4.20 (m, 1 H), 4.06 (dd, / = 11.75, 2.59 Hz, 1 H), 3.99 (s, 3 H), 3.21 (spt, / = 6.79 Hz, 1 H), 2.89 - 2.99 (m, 1 H), 2.72 (s, 3 H), 2.57 - 2.67 (m, 2 H), 1.99 - 2.08 (m, 4 H), 1.75 - 1.84 (m, 2 H), 1.51 - 1.61 (m, 1 H), 1.43 - 1.50 (m, 2 H), 1.39 - 1.42 (m, 7 H), 1.28 - 1.38 (m, 5 H), 1.06 (dd, / = 8.24, 2.90 Hz, 2 H). LC-MS: purity 100% (UV), tR 2.71 min, m/z [M+H]+ 937.30.
Figure imgf000295_0001
230
[0769] Compound 230 was prepared in a manner analogous to General Procedure OO, to afford 13.4 mg (38%), brown solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.10 (s, 1 H), 8.02 (d, / = 8.24 Hz, 1 H), 8.00 (d, / = 5.95 Hz, 1 H), 7.77 (d, / = 8.09 Hz, 1 H), 7.65 - 7.72 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.29 (d, / = 5.95 Hz, 1 H), 6.97 (br. s, 1 H), 6.66 - 6.79 (m, 2 H), 6.49 (d, / = 7.48 Hz, 1 H), 5.97 (br. s, 1 H), 5.68 - 5.77 (m, 1 H), 5.01 (t, / = 9.61 Hz, 1 H), 4.69 (t, / = 7.86 Hz, 1 H), 4.52 (d, / = 8.85 Hz, 1 H), 4.24 - 4.28 (m, 1 H), 4.20 - 4.25 (m, 1 H), 4.12 - 4.20 (m, 1 H), 2.68 - 2.75 (m, 1 H), 2.60 - 2.68 (m, 1 H), 2.42 - 2.55 (m, 1 H), 2.27 (q, / = 8.65 Hz, 1 H), 1.94 - 2.08 (m, 2 H), 1.74 - 1.94 (m, 4 H), 1.41 - 1.57 (m, 7 H), 1.22 - 1.38 (m, 4 H), 0.80 - 0.86 (m, 2 H). LC-MS: purity 85% (UV), tR 5.41 min, m/z [M+H]+ 754.40.
Example 20-23:
Figure imgf000295_0002
221
[0770] Compound 221 was prepared in a manner analogous to General Procedure 00, to afford 15.1 mg (33%), brown solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.19 (s, 1 H), 8.05 (d, / = 8.25 Hz, 1 H), 8.01 (d, / = 5.87 Hz, 1 H), 7.76 (d, / = 8.07 Hz, 1 H), 7.65 (t, (t, / = 7.89 Hz, 2 H), 6.46 (t, / = 7.34 Hz, 1 H), 6.38 (d, / = 7.70 Hz, 2 H), 5.95 (br. s, 1 H), 5.70 - 5.79 (m, 1 H), 5.03 (t, / = 9.54 Hz, 1 H), 4.52 (t, / = 7.70 Hz, 1 H), 4.27 (d, / = 11.74 Hz, 1 H), 4.19 (br. s, 1 H), 4.11 - 4.17 (m, 2 H), 2.52 - 2.62 (m, 2 H), 2.42 - 2.50 (m, 1 H), 2.19 (q, / = 8.56 Hz, 1 H), 1.92 - 1.98 (m, 1 H), 1.89 (dd, / = 5.87, 7.89 Hz, 1 H), 1.74 - 1.86 (m, 3 H), 1.40 - 1.61 (m, 8 H), 1.22 - 1.40 (m, 3 H), 0.82 - 0.86 (m, 2 H). LC-MS: purity 93% (UV), tR 5.16 min, m/z [M+H]+ 686.40.
Example 20-24:
Figure imgf000296_0001
243
[0771] Compound 243 was prepared in a manner analogous to General Procedure OO, to afford 97 mg (53%), grey solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.17 (s, 1 H), 8.04 (d, / = 8.24 Hz, 1 H), 7.98 (d, / = 5.80 Hz, 1 H), 7.74 (d, / = 8.24 Hz, 1 H), 7.64 (t, / = 7.48 Hz, 1 H), 7.47 (t, / = 7.55 Hz, 1 H), 7.32 (s, 1 H), 7.26 (s, 1 H), 6.63 - 6.71 (m, 1 H), 6.12 - 6.23 (m, 3 H), 5.94 (br. s, 1 H), 5.65 - 5.74 (m, 1 H), 4.98 (t, / = 9.61 Hz, 1 H), 4.59 (t, / = 7.71 Hz, 1 H), 4.40 (d, / = 8.54 Hz, 1 H), 4.19 - 4.24 (m, 1 H), 4.12 - 4.19 (m, 2 H), 2.53 - 2.63 (m, 2 H), 2.43 - 2.53 (m, 1 H), 2.21 (q, / = 8.70 Hz, 1 H), 1.91 - 2.01 (m, 1 H), 1.72 - 1.88 (m, 5 H), 1.41 - 1.50 (m, 7 H), 1.22 - 1.41 (m, 3 H), 0.77 - 0.85 (m, 2 H). LC-MS: purity 100% (UV), tR 5.28 min, m/z [M+H]+ 704.45.
Example 20-25:
Figure imgf000297_0001
[0772] Compound 356 was prepared in a manner analogous to General Procedure 00, to afford 24.2 mg (21%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.46 (br. s,
1 H), 7.91 (d, J = 9.11 Hz, 1 H), 7.80 (d, / = 7.34 Hz, 2 H), 7.65 (br. s, 2 H), 7.28 - 7.37 (m,
2 H), 7.22 - 7.27 (m, 1 H), 7.11 (s, 1 H), 6.90 (t, / = 8.71 Hz, 1 H), 6.75 - 6.81 (m, 1 H), 6.69 - 6.75 (m, 1 H), 5.78 (br. s, 1 H), 5.63 - 5.74 (m, 1 H), 4.98 (t, / = 9.63 Hz, 1 H), 4.75 (t, / = 7.34 Hz, 1 H), 4.18 - 4.35 (m, 2 H), 4.06 - 4.19 (m, 1 H), 3.97 (s, 3 H), 2.79 - 2.95 (m, 1 H), 2.57 - 2.76 (m, 2 H), 2.32 - 2.45 (m, 1 H), 2.28 (q, J = 9.11 Hz, 1 H), 1.97 - 2.06 (m, 1 H), 1.68 - 1.97 (m, 2 H), 1.27 - 1.58 (m, 9 H), 1.02 - 1.14 (m, 2 H), 0.80 - 1.00 (m, 2 H). LC-MS: purity 100% (UV), tR 4.40 min, m/z [M+H]+ 864.20.
Example 20-26:
Figure imgf000297_0002
164
[0773] Compound 164 was prepared in a manner analogous to General Procedure 00, to afford 45 mg (31%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.09 (d, / = 7.32 Hz, 2 H), 7.81 (d, / = 9.16 Hz, 1 H), 7.52 - 7.59 (m, 2 H), 7.46 - 7.51 (m, 1 H), 7.45 (d, / = 1.83 Hz, 1 H), 7.29 (br. s, 1 H), 7.04 (dd, / = 2.44, 9.16 Hz, 1 H), 7.01 (s, 1 H), 6.95 (t, / = (br. s, 1 H), 5.01 (t, J = 9.31 Hz, 1 H), 4.51 (t, J = 5.65 Hz, 1 H), 4.10 - 4.29 (m, 4 H), 3.94 (s, 3 H), 2.86 - 2.96 (m, 1 H), 2.43 - 2.65 (m, 3 H), 2.14 - 2.23 (m, 1 H), 1.93 - 2.01 (m, 1 H), 1.91 (dd, / = 6.26, 7.78 Hz, I H), 1.80 - 1.87 (m, 2 H), 1.54 (dd, / = 5.95, 9.31 Hz, 2 H), 1.41 - 1.52 (m, 4 H), 1.24 - 1.39 (m, 2 H), 1.05 - 1.19 (m, 2 H), 0.89 - 0.99 (m, 1 H). LC-MS: purity 100% (UV), tR 4.03 min, m/z [M+H]+ 778.50.
Example 20-27:
Figure imgf000298_0001
229
[0774] Compound 229 was prepared in a manner analogous to General Procedure OO, to afford 23 mg (14%), yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.36 (br. s, 1 H), 7.81 - 7.98 (m, 3 H), 7.76 (br. s, 2 H), 7.36 (br. s, 3 H), 7.14 - 7.24 (m, 2 H), 7.11 (br. s, 1 H), 6.92 (d, / = 7.63 Hz, 1 H), 6.80 (br. s, 1 H), 6.75 (d, / = 7.63 Hz, 1 H), 5.75 (br. s, 1 H), 5.63 - 5.72 (m, 1 H), 4.97 (t, / = 9.69 Hz, 1 H), 4.75 (br. s, 1 H), 4.23 - 4.39 (m, 2 H), 4.17 (d, / = 10.83 Hz, 1 H), 3.97 (s, 3 H), 2.53 - 2.73 (m, 2 H), 2.19 - 2.42 (m, 2 H), 2.04 - 2.11 (m, 1 H), 1.99 - 2.01 (m, 4 H), 1.87 - 1.98 (m, 1 H), 1.76 - 1.85 (m, 2 H), 1.66 - 1.76 (m, 1 H), 1.43 . 1.49 (m, 4 H), 1.28 - 1.41 (m, 4 H), 0.74 - 0.85 (m, 2 H). LC-MS: purity 100% (UV), tR 4.41 min, m/z [M+H]+ 860.45.
Figure imgf000299_0001
242
[0775] Compound 242 was prepared in a manner analogous to General Procedure 00, to afford 54 mg (31%), grey solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.11 (br. s, 1 H), 8.08 (d, / = 7.32 Hz, 2 H), 7.82 (d, J = 9.16 Hz, 1 H), 7.52 - 7.58 (m, 2 H), 7.45 - 7.51 (m, 1 H), 7.44 (d, / = 2.29 Hz, 1 H), 7.12 (s, 1 H), 7.06 (dd, / = 2.44, 9.16 Hz, 1 H), 7.00 (s,
1 H), 6.87 - 6.95 (m, 1 H), 6.34 (td, / = 2.06, 8.35 Hz, 1 H), 6.21 - 6.31 (m, 2 H), 5.67 - 5.77 (m, 1 H), 5.46 (br. s, 1 H), 4.99 (t, / = 9.61 Hz, 1 H), 4.60 (t, / = 7.55 Hz, 1 H), 4.41 (d, / = 9.00 Hz, 1 H), 4.18 - 4.25 (m, 1 H), 4.11 - 4.18 (m, 1 H), 3.95 (s, 3 H), 2.59 - 2.70 (m,
2 H), 2.40 - 2.53 (m, 1 H), 2.22 (q, / = 8.85 Hz, 1 H), 1.93 - 2.02 (m, 1 H), 1.76 - 1.91 (m, 4 H), 1.39 - 1.51 (m, 9 H), 1.25 - 1.37 (m, 3 H), 0.78 - 0.86 (m, 2 H). LC-MS: purity 100% (UV), tR 4.18 min, m/z [M+H]+ 810.40.
Example 20-29:
Figure imgf000299_0002
357 00, to afford 72 mg (49%), brown solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.10 (br. s, 1 H), 8.06 (d, / = 7.48 Hz, 2 H), 7.83 (d, / = 9.16 Hz, 1 H), 7.51 - 7.57 (m, 2 H), 7.45 - 7.50 (m, 1 H), 7.44 (d, / = 2.14 Hz, 1 H), 7.12 (s, 1 H), 7.06 (dd, J = 2.29, 9.00 Hz, 1 H), 7.00 (s, 1 H), 6.58 - 6.68 (m, 2 H), 6.38 (d, / = 10.83 Hz, 1 H), 5.64 - 5.74 (m, 1 H), 5.47 (br. s, 1 H), 4.96 (t, / = 9.69 Hz, 1 H), 4.81 (d, / = 8.54 Hz, 1 H), 4.67 (t, / = 7.55 Hz, 1 H), 4.26 (td, / = 2.44, 8.16 Hz, 1 H), 4.13 - 4.20 (m, 2 H), 3.95 (s, 3 H), 2.59 - 2.73 (m, 2 H), 2.30 - 2.42 (m, 1 H), 2.25 (q, / = 8.90 Hz, 1 H), 1.99 - 2.09 (m, 1 H), 1.83 - 1.93 (m, 2 H), 1.76 - 1.82 (m, 2 H), 1.71 - 1.74 (m, 1 H), 1.49 - 1.57 (m, 1 H), 1.48 (s, 3 H), 1.37 - 1.46 (m, 4 H), 1.25 - 1.34 (m, 2 H), 0.81 (s, 2 H) LC-MS: purity 97% (UV), tR 3.48 min, m/z [M+H]+ 878.57.
Example 20-30:
Figure imgf000300_0001
392
[0777] Compound 392 was prepared in a manner analogous to General Procedure NN, to afford 59 mg (48%), pale yellow glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.93 (br. s, 1 H), 8.06 (d, / = 7.63 Hz, 2 H), 7.81 (d, / = 9.00 Hz, 1 H), 7.50 - 7.58 (m, 2 H), 7.48 (d, / = 7.17 Hz, 1 H), 7.44 (d, / = 2.14 Hz, 1 H), 7.05 (dd, / = 9.08, 2.37 Hz, 1 H), 6.99 (s, 1 H), 6.93 (t, / = 8.09 Hz, 1 H), 6.50 (d, / = 8.09 Hz, 1 H), 6.43 (s, 1 H), 6.39 (d, / = 8.24 Hz, 1 H), 5.68 (q, / = 8.70 Hz, 1 H), 5.45 (br. s, 1 H), 4.95 (t, / = 9.77 Hz, 1 H), 4.63 (t, / = 7.55 Hz, 1 H), 4.54 (d, / = 8.85 Hz, 1 H), 4.19 - 4.26 (m, 1 H), 4.11 - 4.19 (m, 2 H), 3.95 (s, 3 H), 2.55 - 2.70 (m, 2 H), 2.35 - 2.47 (m, 1 H), 2.23 (q, / = 8.80 Hz, 1 H), 1.92 - 2.03 (m, 1 H), 1.79 - 1.92 (m, 3 H), 1.70 - 1.79 (m, 2 H), 1.47 - 1.52 (m, 1 H), 1.46 (s, 3 H), 1.39 - 1.45 (m, 5 H), 1.22 - 1.35 (m, 2 H), 0.73 - 0.84 (m, 2 H). LC-MS: purity 96% (UV), tR 4.62 min, m/z [M+H]+ 876.30. Example 20-31:
General Procedure TT
Figure imgf000301_0001
358
[0778] Compound 45 (552 mg, 0.541 mmol., 1.0 eq.) and toluene (83 mL, previously degassed by bubbling nitrogen through the solvent for 30 min) were charged in a 250 mL round bottom flask previously flushed with nitrogen gas and the reaction mixture heated to 650C (it is important to keep the reaction mixture under a protective nitrogen atmosphere). Zhan catalyst (1.8 mg, 0.5 mol%) was added and the reaction mixture heated at 650C for a further 20 minutes with constant nitrogen gas bubbling through the reaction mixture (via needle). During this time the reaction mixture color turned from pale yellow to pale orange. LCMS analysis showed 35% conversion of starting material to product, so further catalyst (1.8 mg, 0.5 mol%) was added and stirring continued for a further 25 minutes. LCMS analysis showed 80% conversion of starting material to product, so further catalyst (1.8 mg, 0.5 mol%) was added and stirring continued for a further 25 minutes. LCMS analysis showed 96% conversion of starting material to product so the reaction so the heating was stopped and the reaction mixture left to cool down to ambient temperature. The solvent was removed under vacuum. The residue was purified by flash column chromatography, using a methanol :dichloromethane gradient (from neat dichloromethane to 0.5% methanol in dichloromethane). After combining the relevant fractions and solvent removal, 308 mg (60%) of the title compound was isolated as a beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.14 (s, I H), 7.76 (d, / = 9.16 Hz, 1 H), 7.49 (s, 1 H), 7.24 - 7.35 (m, I H), 7.11 (d, / = 9.46 Hz, 1 H), 7.03 (s, 1 H), 6.61 (s, 1 H), 6.58 (d, / = 8.24 Hz, 1 H), 6.33 (d, / = 10.99 Hz, 1 H), 5.57 - 5.67 (m, 1 H), 5.52 (br. s, 1 H), 4.83 - 4.93 (m, 2 H), 4.66 (t, / = 7.78 Hz, 1 H), 4.18 - 4.25 H), 2.67 (s, 3 H), 2.57 - 2.65 (m, 1 H), 2.29 - 2.41 (m, 1 H), 2.21 (q, / = 8.95 Hz, 1 H), 2.16 (br. s, 1 H), 1.92 - 2.03 (m, 1 H), 1.79 - 1.90 (m, 1 H), 1.65 - 1.79 (m, 3 H), 1.43 - 1.51 (m, 3 H), 1.37 - 1.42 (m, 6 H), 1.33 - 1.51 (m, 4 H), 1.17 - 1.33 (m, 3 H), 0.70 - 0.81 (m, 2 H). LC-MS: purity 100% (UV), tR 5.45 min, m/z [M+H]+ 941.08.
Example 20-32:
Figure imgf000302_0001
359
[0779] Compound 359 was prepared in a manner analogous to General Procedure TT, to afford 644 mg (73%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.14 (br. s, 1 H), 7.72 (d, / = 9.14 Hz, 1 H), 7.52 (s, 1 H), 7.21 (br. s, 1 H), 7.08 (d, / = 9.30 Hz, 1 H), 7.06 (s, 1 H), 6.90 (t, 2 H), 6.61 (t, / = 7.25 Hz, 1 H), 6.46 (d, / = 7.72 Hz, 2 H), 5.76 (q, 1 H), 5.55 (br. s, 1 H), 5.04 (t, 1 H), 4.55 (t, / = 7.72 Hz, 1 H), 4.26 (d, / = 11.51 Hz, 1 H), 4.20 (dd, / = 12.45, 5.83 Hz, 2 H), 4.14 (dd, / = 11.66, 3.63 Hz, 1 H), 3.92 (s, 3 H), 3.23 (spt, 1 H), 2.69 (s, 3 H), 2.66 (dd, / = 8.20, 5.52 Hz, 1 H), 2.51 - 2.60 (m, 2 H), 2.19 (q, / = 8.62 Hz, 1 H), 1.94 - 2.00 (m, 1 H), 1.92 (dd, / = 8.04, 5.99 Hz, 1 H), 1.86 (dt, / = 6.66, 3.21 Hz, 1 H), 1.78 - 1.85 (m, 3 H), 1.62 (s, 3 H), 1.53 - 1.57 (m, 2 H), 1.52 (s, 3 H), 1.49 (d, / = 8.99 Hz, 2 H), 1.41 (d, / = 6.94 Hz, 6 H), 0.82 - 0.87 (m, 2 H). LC-MS: purity 100% (UV), tR 5.15 min, m/z [M+H]+ 855.29.
Figure imgf000303_0001
407
[0780] Compound 407 was prepared in a manner analogous to General Procedure TT, to afford 342 mg (42%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.19 (br. s, 1 H), 7.76 (d, / = 9.31 Hz, 1 H), 7.54 (s, 1 H), 7.13 (d, / = 9.00 Hz, 1 H), 7.06 (s, 1 H), 6.83 - 6.90 (m, 1 H), 6.55 - 6.61 (m, 1 H), 6.48 (d, / = 8.09 Hz, 1 H), 5.72 - 5.83 (m, 1 H), 5.58 (br. s, 1 H), 5.02 (t, J = 9.61 Hz, 1 H), 4.64 (t, / = 8.24 Hz, 1 H), 4.29 (s, 1 H), 4.21 (br. s, 1 H), 4.14 (dd, / = 11.75, 3.97 Hz, 1 H), 3.97 (s, 3 H), 3.23 (quin, / = 6.79 Hz, 1 H), 2.89 - 2.97 (m, 1 H), 2.73 - 2.82 (m, 1 H), 2.69 - 2.73 (m, 3 H), 2.62 - 2.69 (m, 1 H), 2.50 - 2.63 (m, 1 H), 2.22 (q, / = 8.49 Hz, 1 H), 1.90 - 2.01 (m, 2 H), 1.83 (d, J = 9.31 Hz, 2 H), 1.58 (s, 3 H), 1.46 - 1.54 (m, 7 H), 1.41 (d, / = 6.87 Hz, 6 H), 1.29 - 1.38 (m, 3 H), 1.26 (s, 4 H), 1.06 - 1.21 (m, 3 H), 0.91 - 1.01 (m, 2 H), 0.89 (t, / = 6.87 Hz, 1 H). LC-MS: purity 99% (UV), tR 5.04 min, m/z [M+H]+ 841.30.
Figure imgf000304_0001
360
General Procedure TTLS
[0781] Compound 49 as a solution in toluene (3.08 g, 3.24 mmol, 1.0 eq.) and toluene (162 mL, previously degassed by bubbling nitrogen through the solvent for 30 min) were charged in a 500 mL round bottom flask previously flushed with nitrogen gas and the reaction mixture heated to 650C to give a clear yellow solution (it is important to keep the reaction mixture under a protective nitrogen atmosphere). Zhan catalyst (10.7 mg, 0.5 mol%) was added and the reaction mixture heated at 650C for a further 20 min with constant nitrogen gas bubbling through the reaction mixture (via needle). During this time the reaction mixture color turned from pale yellow to pale orange (56% conversion by LCMS-UV). Another catalyst aliquot (10.7 mg, 0.5 mol%) was added and the reaction mixture stirred for a further 20 min. As LCMS analysis showed some residual starting material (97% conversion by LCMS-UV) a third catalyst aliquot was added (10.7 mg, 0.5 mol%) and the reaction mixture was stirred for a further 20 min. LCMS-UV analysis showed full consumption of the starting material. The solvent was removed under vacuum. The residue was purified by flash column chromatography, using a methanol :dichloromethane gradient (from neat dichloromethane to 0.65% methanol in dichloromethane). After combining the relevant fractions and solvent removal, 1.44 mg (48%) of compound 360 was isolated as a beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.08 (s, 1 H) 7.73 (d, J = 9.16 Hz, 1 H) 7.54 (s, 1 H) 7.11 (d, / = 9.31 Hz, 1 H) 7.01 - 7.07 (m, 2 H) 6.76 - 6.87 (m, 3 H) 6.53 (d, / = 7.48 Hz, 1 H) 5.72 (q, 1 H) 5.58 (br. s, 1 H) 5.00 (t, / = 9.61 Hz, 1 H) 4.67 (t, / = 7.78 Hz, 1 H) 4.54 (d, / = 9.16 Hz, 1 H) 4.25 - 4.29 (m, 1 H) 4.13 - 4.25 (m, 2 H) 3.96 (s, 3 H) 3.22 (spt, / = 6.87 1.93 - 2.04 (m, 1 H) 1.83 - 1.92 (m, 2 H) 1.73 - 1.83 (m, 2 H) 1.50 (s, 3 H) 1.43 - 1.54 (m, 6 H) 1.41 (d, / = 6.87 Hz, 6 H) 1.31 (dd, / = 13.12, 6.71 Hz, 2 H) 0.78 - 0.87 (m, 2 H). LC- MS: purity 100% (UV), tR 5.38 min, m/z [M+H]+ 923.28.
Example 20-35:
Figure imgf000305_0001
361
[0782] Compound 361 was prepared in a manner analogous to General Procedure TT, to afford 136 mg (44%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.18 (br. s,
1 H), 7.70 (d, / = 9.00 Hz, 1 H), 7.50 (s, 1 H), 7.45 (s, 1 H), 7.01 - 7.08 (m, 2 H), 6.79 - 6.89 (m, 1 H), 6.33 (td, / = 1.83, 8.32 Hz, 1 H), 6.23 (dd, / = 1.45, 8.16 Hz, 1 H), 6.17 (d, J = 11.14 Hz, 1 H), 5.64 - 5.78 (m, 1 H), 5.52 (br. s, 1 H), 4.99 (t, / = 9.61 Hz, 1 H), 4.55 (t, / = 7.78 Hz, 1 H), 4.39 (d, / = 8.70 Hz, 1 H), 4.07 - 4.22 (m, 3 H), 3.88 (s, 3 H), 3.23 (spt, / = 6.82 Hz, 1 H), 2.66 (s, 3 H), 2.54 - 2.64 (m, 2 H), 2.41 - 2.52 (m, 1 H), 2.17 (q, / = 8.75 Hz, 1 H), 1.91 - 2.03 (m, 1 H), 1.85 (dd, / = 6.10, 7.63 Hz, 3 H), 1.79 (dd, / = 6.79, 10.76 Hz,
2 H), 1.50 - 1.55 (m, 2 H), 1.50 (s, 3 H), 1.42 - 1.47 (m, 2 H), 1.41 (d, J = 7.02 Hz, 6 H), 1.37 - 1.40 (m, 1 H), 1.25 - 1.37 (m, 2 H), 0.82 (br. s, 2 H). LC-MS: purity 100% (UV), tR 5.19 min, m/z [M+H]+ 873.71.
Figure imgf000306_0001
362
[0783] Compound 362 was prepared in a manner analogous to General Procedure TT, to afford 413 mg (59%), pale brown glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.15 (s, 1 H), 7.65 (d, / = 9.00 Hz, 1 H), 7.52 (s, 1 H), 7.28 (s, 1 H), 7.09 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 6.54 (t, / = 8.62 Hz, 2 H), 6.38 (dd, / = 8.85, 4.27 Hz, 2 H), 5.68 - 5.78 (m, 1 H), 5.55 (br. s, 1 H), 5.30 (s, 1 H), 5.02 (t, / = 9.54 Hz, 1 H), 4.57 (t, / = 7.93 Hz, 1 H), 4.23 (d, / = 11.60 Hz, 1 H), 4.02 - 4.18 (m, 3 H), 3.92 (s, 3 H), 3.23 (spt, / = 6.87 Hz, 1 H), 2.70 - 2.73 (m, 1 H), 2.68 (s, 3 H), 2.57 - 2.64 (m, 1 H), 2.51 - 2.58 (m, 1 H), 2.17 (q, / = 8.70 Hz, 1 H), 1.97 - 2.09 (m, 1 H), 1.93 (br. s, 1 H), 1.87 - 1.91 (m, 1 H), 1.73 - 1.82 (m, 5 H), 1.51 - 1.56 (m, 2 H), 1.50 (s, 3 H), 1.41 (d, / = 6.87 Hz, 6 H), 1.27 - 1.36 (m, 2 H), 0.78 - 0.86 (m, 2 H). LC-MS: purity 98% (UV), tR 5.12 min, m/z [M+H]+ 873.29.
Example 20-37:
Figure imgf000306_0002
409 TT, to afford 320 mg (58%), white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.24 (s, 1 H), 7.67 (d, / = 9.16 Hz, 1 H), 7.52 (s, 1 H), 7.13 (s, 1 H), 7.06 (d, / = 0.76 Hz, 1 H), 6.49 - 6.56 (m, 2 H), 6.40 (dd, / = 8.85, 4.27 Hz, 2 H), 5.70 - 5.79 (m, 1 H), 5.59 (dd, / = 6.03, 1.91 Hz, 1 H), 5.56 (br. s, 1 H), 4.96 - 5.03 (m, 1 H), 4.61 (t, / = 7.86 Hz, 1 H), 4.35 (t, / = 7.02 Hz, 1 H), 4.25 (d, / = 11.60 Hz, 1 H), 4.12 - 4.16 (m, 1 H), 4.10 (dd, / = 11.60, 3.36 Hz, 1 H), 3.96 - 4.02 (m, 1 H), 3.95 (s, 3 H), 3.90 - 3.94 (m, 1 H), 3.17 - 3.28 (m, 1 H), 2.91 (s, 1 H), 2.70 - 2.75 (m, 1 H), 2.70 (s, 3 H), 2.61 - 2.68 (m, 1 H), 2.52 - 2.60 (m, 1 H), 2.47 - 2.52 (m, 1 H), 2.22 - 2.30 (m, 1 H), 2.00 - 2.10 (m, 1 H), 1.92 (dd, / = 7.93, 6.10 Hz, 2 H), 1.50 - 1.55 (m, 3 H), 1.45 - 1.48 (m, 1 H), 1.38 - 1.43 (m, 7 H), 1.30 - 1.34 (m, 2 H), 1.12 - 1.19 (m, 1 H), 1.05 - 1.12 (m, 1 H). LC-MS: purity 95% (UV), tR 2.51 min, m/z [M+H]+ 859.40.
Example 20-38:
Figure imgf000307_0001
[0785] Compound 363 was prepared in a manner analogous to General Procedure TT, to afford 100 mg (40%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.09 (s, 1 H), 7.79 (d, / = 9.16 Hz, 1 H), 7.51 (s, 1 H), 7.14 (d, / = 9.16 Hz, 1 H), 7.06 (br. s, 1 H), 7.04 (s, 1 H), 6.07 - 6.13 (m, 1 H), 6.04 (d, / = 7.63 Hz, 2 H), 5.64 - 5.75 (m, 1 H), 5.55 (br. s, 1 H) 4.97 (t, / = 9.61 Hz, 1 H), 4.60 - 4.69 (m, 2 H), 4.12 - 4.22 (m, 3 H), 3.95 (s, 3 H), 3.22 (spt, / = 6.87 Hz, 1 H), 2.69 - 2.78 (m, 2 H), 2.68 (s, 3 H), 2.35 - 2.48 (m, 1 H), 2.23 (q, / = 8.90 Hz, 1 H), 1.95 - 2.07 (m, 1 H), 1.81 - 1.88 (m, 2 H), 1.71 - 1.81 (m, 2 H), 1.50 - 1.56 (m, 1 H), 1.48 (s, 3 H), 1.44 (dd, / = 9.38, 6.03 Hz, 4 H), 1.40 (d, / = 6.87 Hz, 6 H), 1.23 - 1.36 (m, 3 H), 0.76 - 0.85 (m, 2 H). LC-MS: purity 100% (UV), tR 5.28 min, m/z [M+H]+ 891.60.
Figure imgf000308_0001
378
[0786] Compound 378 was prepared in a manner analogous to General Procedure
TT, to afford 103 mg (40%), beige solid. 1H NMR (500 MHz, CDCl3) δ 10.09 (s, 1 H), 7.76 (d, J = 9.16 Hz, 1 H), 7.52 (s, 1 H), 7.12 (d, J = 9.16 Hz, 1 H), 7.05 (s, 2 H), 6.76 (t, / = 8.16 Hz, 1 H), 6.43 (d, / = 8.39 Hz, 1 H), 6.40 (s, 1 H), 6.31 (dd, / = 1.83, 8.24 Hz, 1 H), 5.67 - 5.76 (m, 1 H), 5.57 (d, / = 2.90 Hz, 1 H), 4.99 (t, / = 9.61 Hz, 1 H), 4.66 (t, / = 7.86 Hz, 1 H),
4.48 (d, / = 8.85 Hz, 1 H), 4.13 - 4.26 (m, 3 H), 3.95 (s, 3 H), 3.22 (spt, 1 H), 2.71 - 2.74 (m, 1 H), 2.70 (s, 3 H), 2.66 - 2.69 (m, 1 H), 2.41 - 2.53 (m, 1 H), 2.23 (q, / = 8.75 Hz, 1 H), 1.93 - 2.04 (m, 1 H), 1.88 (dd, / = 6.26, 7.93 Hz, 1 H), 1.70 - 1.87 (m, 4 H), 1.51 - 1.56 (m, 1 H),
1.49 (s, 3 H), 1.46 (dd, J = 5.65, 9.46 Hz, 3 H), 1.41 (d, / = 7.02 Hz, 6 H), 1.23 - 1.36 (m, 3 H), 0.77 - 0.86 (m, 2 H). LC-MS: purity 100% (UV), tR 5.39 min, m/z [M+H]+ 939.33.
Example 20-40:
Figure imgf000308_0002
[0787] Compound 379 was prepared in a manner analogous to General Procedure TT, to afford 670 mg (72%), beige glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.38 (br. s, 1 H), 7.58 (d, / = 9.00 Hz, 1 H), 7.54 (s, 1 H), 7.08 (d, / = 7.93 Hz, 1 H), 7.06 (d, (d, J = 9.16 Hz, 1 H), 5.69 - 5.79 (m, 1 H), 5.59 (br. s, 1 H), 4.99 - 5.05 (m, 1 H), 4.88 - 4.99 (m, 1 H), 4.75 (td, / = 8.93, 2.90 Hz, 1 H), 4.45 - 4.64 (m, 1 H), 4.26 (dd, / = 11.37, 3.43 Hz, 1 H), 3.72 - 3.79 (m, 5 H), 3.24 (spt, 1 H), 2.71 - 2.85 (m, 2 H), 2.62 (s, 3 H), 2.53 - 2.61 (m, 1 H), 2.34 (q, / = 8.75 Hz, 1 H), 2.04 - 2.14 (m, 1 H), 1.92 - 2.01 (m, 1 H), 1.86 (dt, / = 6.75, 3.26 Hz, 3 H), 1.77 - 1.83 (m, 2 H), 1.75 (br. s, 1 H), 1.55 - 1.64 (m, 1 H), 1.52 (s, 3 H), 1.46 (dd, / = 9.54, 5.87 Hz, 2 H), 1.42 (d, /=6.87 Hz, 6 H), 1.31 - 1.39 (m, 2 H), 0.83 (dd, / = 3.74, 2.52 Hz, 2 H). LC-MS: purity 100% (UV), tR 5.09 min, m/z [M+H]+ 896.31.
Example 20-41:
Figure imgf000309_0001
380
[0788] Compound 380 was prepared in a manner analogous to General Procedure
OO, to afford 30.8 mg (16%), beige solid. 1H NMR (500 MHz, CDCl3) δ 10.36 (br. s, 1 H), 8.00 (d, / = 6.10 Hz, 1 H), 7.93 (d, / = 8.54 Hz, 1 H), 7.69 (d, / = 7.93 Hz, 1 H), 7.56 (t, / = 7.32 Hz, 1 H), 7.20 - 7.29 (m, 2 H), 6.98 - 7.12 (m, 3 H), 6.90 - 6.97 (m, 1 H), 6.00 (br. s, 1 H), 5.67 - 5.77 (m, 1 H), 5.01 (t, / = 9.61 Hz, 1 H), 4.90 - 4.98 (m, 1 H), 4.68 - 4.78 (m, 1 H), 4.39 - 4.51 (m, 1 H), 4.26 (dd, / = 4.42, 11.44 Hz, 1 H), 2.71 - 2.81 (m, 1 H), 2.63 - 2.71 (m, 1 H), 2.47 - 2.62 (m, 1 H), 2.36 (q, / = 8.75 Hz, 1 H), 1.93 - 2.14 (m, 2 H), 1.76 - 1.89 (m, 3 H), 1.71 (br. s, 2 H), 1.41 - 1.62 (m, 9 H), 1.28 - 1.41 (m, 3 H), 0.77 - 0.94 (m, 1 H). LC-MS: purity 100% (UV), tR 2.05 min, m/z [M+H]+ 727.25.
Figure imgf000310_0001
381
[0789] Compound 381 was prepared in a manner analogous to General Procedure
00, to afford 103 mg (48%), white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.05 (s, 1 H),
8.00 - 8.01 (m, 1 H), 7.99 (s, 1 H), 7.79 (d, / = 8.09 Hz, 1 H), 7.70 (t, / = 7.48 Hz, 1 H), 7.52 (t, / = 7.63 Hz, 1 H), 7.30 (d, / = 5.80 Hz, 1 H), 6.79 (s, 1 H), 6.28 - 6.37 (m, 2 H), 6.01 (d, / = 9.31 Hz, 1 H), 5.96 (br. s, 1 H), 5.75 (q, 1 H), 5.03 (t, / = 9.61 Hz, 1 H), 4.68 (t, / = 8.01 Hz, 1 H), 4.26 (d, / = 11.60 Hz, 1 H), 4.14 - 4.19 (m, 1 H), 4.11 (dd, / = 11.52, 3.74 Hz, 2 H), 2.70 - 2.77 (m, 1 H), 2.63 - 2.70 (m, 1 H), 2.48 - 2.57 (m, 1 H), 2.21 - 2.28 (m, 1 H), 1.92 -
2.01 (m, 2 H), 1.76 - 1.84 (m, 3 H), 1.52 - 1.56 (m, 2 H), 1.51 (s, 3 H), 1.47 - 1.50 (m, 3 H), 1.32 (d, / = 7.32 Hz, 2 H), 1.26 (s, 1 H), 0.83 - 0.85 (m, 2 H). LC-MS: purity 98% (UV), tR 5.31 min, m/z [M+H]+ 722.0.
Example 20-43:
Figure imgf000310_0002
444
[0790] Compound 444 was prepared in a manner analogous to General Procedure 00, to afford 216 mg (44%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.18 (br. s, 1 H), 8.05 (d, / = 7.93 Hz, 1 H), 8.00 (d, / = 4.43 Hz, 1 H), 7.78 (d, / = 8.09 Hz, 1 H), 7.71 (t, 1 H), 6.30 - 6.36 (m, 2 H), 6.03 (br. s, 1 H), 5.71 (q, / = 8.75 Hz, 1 H), 5.00 (t, J = 9.61 Hz, 1 H), 4.71 (t, J = 7.17 Hz, 1 H), 4.21 (br. s, 3 H), 2.65 - 2.70 (m, 2 H), 2.42 - 2.52 (m, 1 H), 2.26 (q, / = 8.80 Hz, 1 H), 1.95 - 2.04 (m, 1 H), 1.81 - 1.91 (m, 3 H), 1.78 (d, / = 10.68 Hz, 1 H), 1.52 - 1.56 (m, 1 H), 1.38 - 1.57 (m, 10 H), 1.28 - 1.35 (m, 3 H), 0.77 - 0.93 (m, 1 H). LC-MS: purity 99% (UV), tR 5.55 min, m/z [M+H]+ 770.3.
Example 20-44:
Figure imgf000311_0001
382
[0791] Compound 382 was prepared in a manner analogous to General Procedure TT, to afford 34 mg (40%), off white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.01 (br. s,
1 H), 7.77 (d, / = 9.16 Hz, 1 H), 7.53 (s, 1 H), 7.16 (d, / = 9.16 Hz, 1 H), 7.05 (s, 1 H), 6.74 (d, / = 5.49 Hz, 1 H), 6.61 (s, 1 H), 6.41 (d, / = 1.53 Hz, 2 H), 5.75 (q, 1 H), 5.60 (br. s, 1 H), 5.01 (t, / = 9.69 Hz, 1 H), 4.67 (t, / = 7.86 Hz, 1 H), 4.54 (d, / = 9.00 Hz, 1 H), 4.21 (td, / = 8.54, 3.20 Hz, 1 H), 4.18 (br. s, 2 H), 3.97 (s, 3 H), 3.22 (quin, / = 6.75 Hz, 1 H), 2.75 (dd, / = 7.78, 2.14 Hz, 2 H), 2.70 (s, 3 H), 2.40 -2.49 (m, 1 H), 2.26 (q, / = 8.95 Hz, 1 H), 1.98 - 2.07 (m, 1 H), 1.93 (t, / = 6.94 Hz, 1 H), 1.83 - 1.91 (m, 1 H), 1.80 (d, / = 10.99 Hz,
2 H), 1.54 (br. s, 1 H), 1.51(s, 4 H), 1.48 (dd, / = 9.69, 6.03 Hz, 2 H), 1.44 (d, / = 6.41 Hz, 2 H), 1.41 (d, J = 6.87 Hz, 6 H), 1.28 - 1.37 (m, 2 H), 0.84 (t, / = 2.82 Hz, 2 H). LC-MS: purity 100% (UV), tR 5.60 min, m/z [M+H]+ 923.31.
Figure imgf000312_0001
374
[0792] Compound 374 was prepared in a manner analogous to General Procedure TT, to afford 276 mg (33%), pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.03 (br. s, 1 H), 7.69 (d, / = 9.16 Hz, 1 H), 7.53 (s, 1 H), 7.15 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 6.81 - 6.85 (m, 1 H), 6.76 (dd, / = 5.49, 2.59 Hz, 1 H), 6.35 - 6.43 (m, 2 H), 5.74 (q, 1 H), 5.59 (br. s, 1 H), 5.02 (t, / = 9.54 Hz, 1 H), 4.67 (t, / = 7.93 Hz, 1 H), 4.35 (d, / = 9.77 Hz, 1 H), 4.23 (d, 1 H), 4.12 - 4.20 (m, 2 H), 3.98 (s, 3 H), 3.22 (spt, / = 6.84 Hz, 1 H), 2.73 - 2.81 (m, 2 H) 2.71 (s, 3 H), 2.50 (br. s, 1 H), 2.21 (quin, 1 H), 1.90 - 2.02 (m, 2 H), 1.77 - 1.84 (m, 3 H), 1.63 (s, 2 H), 1.52 - 1.56 (m, 1 H), 1.50 (s, 3 H), 1.44 - 1.49 (m, 3 H), 1.41 (d, / = 6.87 Hz, 6 H), 1.26 - 1.36 (m, 2 H), 0.80 - 0.87 (m, 2 H). LC-MS: purity 100% (UV), tR 5.38 min, m/z [M+H]+ 941.30.
Example 20-46:
Figure imgf000312_0002
445 TT, to afford 253 mg (57%), cream solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.12 (s, 1 H), 7.77 (d, / = 9.16 Hz, 1 H), 7.55 (s, 1 H), 7.22 (s, 1 H), 7.09 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 7.03 (d, / = 8.24 Hz, 2 H), 6.36 (d, / = 8.54 Hz, 2 H), 5.71 - 5.80 (m, 1 H), 5.56 - 5.62 (m, 1 H), 5.03 (t, / = 9.61 Hz, 1 H), 4.63 (t, / = 7.93 Hz, 1 H), 4.51 (d, / = 7.93 Hz, 1 H), 4.34 (d, / = 11.90 Hz, 1 H), 4.16 - 4.24 (m, 1 H), 4.12 (dd, / = 11.60, 3.05 Hz, 1 H), 3.90 (s, 3 H), 3.23 (spt, / = 7.02 Hz, 1 H), 2.69 - 2.77 (m, 1 H), 2.68 (s, 3 H), 2.60 - 2.67 (m, 1 H), 2.48 - 2.59 (m, 1 H), 2.15 (q, / = 8.75 Hz, 1 H), 1.93 - 2.02 (m, 1 H), 1.90 (dd, / = 7.93, 6.10 Hz, 1 H), 1.76 - 1.87 (m, 3 H), 1.51 (s, 3 H), 1.44 - 1.60 (m, 6 H), 1.41 (d, / = 7.02 Hz, 6 H), 1.21 - 1.38 (m, 2 H), 0.74 - 0.87 (m, 2 H). LC-MS: purity 100% (UV), tR 5.34 min, m/z [M+H]+ 923.30.
Example 20-47:
Figure imgf000313_0001
369
[0794] Compound 369 was prepared in a manner analogous to General Procedure TT, to afford 297 mg (84%), off-white glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.16 (s, 1 H), 7.73 (d, / = 9.00 Hz, 1 H), 7.54 (s, 1 H), 7.12 (d, / = 9.31 Hz, 1 H), 7.06 (s, 1 H), 6.82 (s, 1 H), 6.77 - 6.82 (m, 3 H), 6.48 - 6.56 (m, 1 H), 5.74 (q, 1 H), 5.59 (br. s, 1 H), 5.00 (t, / = 9.54 Hz, 1 H), 4.66 (t, / = 7.78 Hz, 1 H), 4.50 (br. s, 1 H), 4.20 - 4.29 (m, 2 H), 4.10 - 4.20 (m, 1 H), 3.96 (s, 3 H), 3.22 (spt, 1 H), 2.87 - 2.96 (m, 1 H), 2.72 - 2.78 (m, 1 H), 2.71 (s, 3 H), 2.44 - 2.56 (m, 1 H), 2.20 - 2.29 (m, 1 H), 1.96 - 2.05 (m, 1 H), 1.93 (t, 1 H), 1.74 - 1.91 (m, 2 H), 1.43 - 1.57 (m, 6 H), 1.41 (d, / = 6.87 Hz, 6 H), 1.28 - 1.37 (m, 2 H), 1.06 - 1.20 (m, 2 H), 0.92 - 0.99 (m, 1 H), 0.80 - 0.92 (m, 1 H). LC-MS: purity 100% (UV), tR 5.37 min, m/z [M+H]+ 909.24. Example 20-48:
Figure imgf000314_0001
439
[0795] Compound 439 was prepared in a manner analogous to General Procedure TT, to afford 151 mg (47%), off-white glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.12 (br. s, 1 H), 7.78 (d, / = 9.16 Hz, 1 H), 7.54 (s, 1 H), 7.15 (d, / = 9.31 Hz, 1 H), 7.05 (s, 1 H), 6.81 (s, 1 H), 6.56 - 6.63 (m, 2 H), 6.35 (d, / = 10.68 Hz, 1 H), 5.70 - 5.79 (m, 1 H), 5.60 (br. s, 1 H), 4.98 (t, / = 9.54 Hz, 1 H), 4.76 (d, / = 8.54 Hz, 1 H), 4.67 (t, / = 7.71 Hz, 1 H), 4.26 (td, / = 8.43, 2.37 Hz, 1 H), 4.19 (s, 1 H), 3.96 (s, 2 H), 3.22 (spt, / = 6.87 Hz, 1 H), 2.87 - 2.95 (m, 1 H), 2.74 (dd, / = 7.55, 2.37 Hz, 1 H), 2.69 (s, 3 H), 2.38 - 2.49 (m, 1 H), 2.25 (q, / = 8.85 Hz, 1 H), 2.03 (dd, / = 15.03, 6.18 Hz, 1 H), 1.84 - 1.96 (m, 2 H), 1.80 (br. s, 1 H), 1.52 - 1.59 (m, 1 H), 1.23 - 1.52 (m, 16 H), 1.06 - 1.21 (m, 2 H), 0.91 - 1.00 (m, 1 H). LC-MS: purity 100% (UV), tR 5.37 min, m/z [M+H]+ 927.23.
Example 20-48A:
Figure imgf000314_0002
439 Procedure D, to afford 112 mg, 21%. MS (ESI) m / z (M+H)+ 927.6.
Example 20-49:
Figure imgf000315_0001
446
[0797] Compound 446 was prepared in a manner analogous to General Procedure TT, to afford 148 mg (67%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.24 (s, 1 H), 7.77 (d, / = 9.16 Hz, 1 H), 7.54 (s, 1 H), 7.15 (br. s, 1 H), 7.09 (d, / = 9.16 Hz, 1 H), 7.06 (s, 1 H), 7.04 (d, / = 8.24 Hz, 2 H), 6.36 (d, / = 8.54 Hz, 2 H), 5.69 - 5.82 (m, 1 H), 5.59 (br. s, 1 H) 5.00 (t, / = 9.46 Hz, 1 H), 4.61 (t, / = 7.93 Hz, 1 H), 4.50 (d, / = 8.54 Hz, 1 H), 4.33 (d, / = 11.90 Hz, 1 H), 4.15 - 4.22 (m, 1 H), 4.10 (dd, / = 11.60, 3.05 Hz, 1 H), 3.89 (s, 3 H), 3.16 - 3.28 (m, 1 H), 2.86 - 2.95 (m, 1 H), 2.69 - 2.75 (m, 1 H), 2.68 (s, 3 H), 2.59 - 2.67 (m, 1 H), 2.49 - 2.60 (m, 1 H), 2.14 (q, / = 8.65 Hz, 1 H), 1.93 - 2.01 (m, 1 H), 1.89 - 1.93 (m,
1 H), 1.75 - 1.88 (m, 2 H), 1.44 - 1.60 (m, 6 H), 1.41 (d, / = 6.71 Hz, 6 H), 1.24 - 1.38 (m,
2 H), 1.12 - 1.19 (m, 1 H), 1.05 - 1.12 (m, 1 H), 0.88 - 0.99 (m, 1 H). LC-MS: purity 100% (UV), tR 5.21 min, m/z [M+H]+ 909.25.
Example 20-50:
Figure imgf000316_0001
377
[0798] Compound 377 was prepared in a manner analogous to General Procedure TT, to afford 137 mg (58%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.15 (br. s, 1 H), 7.76 (d, / = 9.16 Hz, 1 H), 7.53 (s, 1 H), 7.14 (d, / = 9.16 Hz, 1 H), 7.05 (s, 1 H), 6.80 (s, 1 H), 6.75 (t, / = 8.09 Hz, 1 H), 6.43 (d, / = 8.24 Hz, 1 H), 6.40 (s, 1 H), 6.30 (dd, / = 8.24, 1.83 Hz, 1 H), 5.70 - 5.79 (m, 1 H), 5.59 (br. s, 1 H), 5.00 (t, / = 9.46 Hz, 1 H), 4.66 (t, / = 7.63 Hz, 1 H), 4.43 (d, / = 8.85 Hz, 1 H), 4.18 - 4.26 (m, 2 H), 4.12 - 4.18 (m, 1 H), 3.96 (s, 3 H), 3.16 - 3.27 (m, 1 H), 2.88 - 2.95 (m, 1 H), 2.72 - 2.78 (m, 1 H), 2.70 (s, 3 H), 2.45 - 2.56 (m, 1 H), 2.24 (q, / = 8.54 Hz, 1 H), 1.96 - 2.03 (m, 1 H), 1.94 (dd, / = 7.93, 6.10 Hz, 1 H), 1.75 - 1.89 (m, 2 H), 1.43 - 1.57 (m, 6 H), 1.41 (d, / = 7.02 Hz, 6 H), 1.24 - 1.37 (m, 3 H), 1.04 - 1.21 (m, 2 H), 0.90 - 1.00 (m, 1 H). LC-MS: purity 100% (UV), tR 5.31 min, m/z [M+H]+ 925.32.
Example 20-51:
Figure imgf000316_0002
447 TT, to afford 145 mg (52%), beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.22 (s, 1 H), 7.68 (d, / = 9.00 Hz, 1 H), 7.51 (s, 1 H), 7.13 (d, J = 9.31 Hz, 1 H), 7.08 (s, 1 H), 7.05 (s, 1 H), 6.77 (d, / = 4.12 Hz, 1 H), 6.36 - 6.42 (m, 2 H), 5.69 (q, / = 8.75 Hz, 1 H), 5.55 (br. s, 1 H), 4.95 (t, / = 9.46 Hz, 1 H), 4.66 (t, / = 7.86 Hz, 1 H), 4.41 - 4.46 (m, 1 H), 4.21 (d, 1 H), 4.10 - 4.17 (m, 2 H), 3.96 (s, 3 H), 3.22 (spt, 1 H), 2.85 - 2.91 (m, 1 H), 2.71 - 2.76 (m, 1 H), 2.70 (s, 3 H), 2.44 - 2.53 (m, 1 H), 2.20 (q, / = 8.65 Hz, 1 H), 1.90 - 1.99 (m, 1 H), 1.85 (t,
1 H), 1.74 - 1.82 (m, 3 H), 1.42 - 1.53 (m, 6 H), 1.40 (d, / = 6.87 Hz, 6 H), 1.25 - 1.32 (m,
2 H), 1.09 - 1.15 (m, 1 H), 1.03 - 1.08 (m, 1 H), 0.88 - 0.95 (m, 1 H). LC-MS: purity 100% (UV), tR 5.29 min, m/z [M+H]+ 927.25.
Example 20-52:
Figure imgf000317_0001
75
[0800] Compound 75 was prepared in a manner analogous to General Procedure SS to afford 370 mg (52%). 1H NMR (500 MHz, CDCl3) δ ppm 10.14 (s, 1 H) 7.82 (d, /=9.00 Hz, 1 H) 7.57 (br. s., 1 H) 7.15 - 7.22 (m, 2 H) 7.06 (s, 1 H) 6.93 (s, 1 H) 6.79 - 6.86 (m, 1 H) 6.70 (d, /=15.87 Hz, 2 H) 5.73 - 5.85 (m, 2 H) 5.63 (br. s., 1 H) 5.22 (d, /=17.24 Hz,
1 H) 5.06 - 5.15 (m, 2 H) 4.91 - 5.03 (m, 2 H) 4.45 (t, /=8.24 Hz, 1 H) 4.15 - 4.23 (m, 2 H) 4.09 - 4.16 (m, 1 H) 3.99 (s, 3 H) 3.21 (spt, /=7.02 Hz, 1 H) 2.68 - 2.73 (m, 3 H) 2.60 - 2.68 (m, 2 H) 1.97 - 2.04 (m, 2 H) 1.77 - 1.89 (m, 2 H) 1.66 - 1.77 (m, 2 H) 1.53 (br. s., 2 H) 1.51 (s, 3 H) 1.44 (dd, /=9.00, 5.19 Hz, 2 H) 1.40 (d, /=6.87 Hz, 6 H) 1.31 - 1.38 (m, 2 H) 1.26 (s,
2 H) 0.90 - 0.96 (m, 1 H) 0.83 - 0.90 (m, 1 H). LC-MS: purity 96% (UV), tR 5.73 min, m/z [M+H]+ 965.00.
Figure imgf000318_0001
76 [0801] Compound 76 was prepared in a manner analogous to General Procedure
SS to afford 300 mg. 1H NMR (500 MHz, CDCl3) δ ppm 10.16 (br. s, 1 H) 7.80 (d, / = 9.16 Hz, 1 H) 7.57 (br. s, 1 H) 7.17 (d, J = 9.31 Hz, 1 H) 7.07 (s, 1 H) 6.89 (br. s, 1 H) 6.77 (s,
1 H) 6.60 (s, 1 H) 6.55 (s, 1 H) 5.73 - 5.84 (m, 2 H) 5.61 (br. s, 1 H) 5.22 (dd, / = 17.09, 0.92 Hz, 1 H) 5.12 (dd, / = 10.38, 1.22 Hz, 1 H) 4.99 (dq, / = 17.09, 1.63 Hz, 1 H) 4.93 (dt, / = 10.15, 0.95 Hz, 1 H) 4.77 - 4.83 (m, 1 H) 4.45 (t, J = 8.32 Hz, 1 H) 4.18 - 4.23 (m, 2 H) 4.14 (br. s, 1 H) 3.99 (s, 3 H) 3.17 - 3.25 (m, 1 H) 2.80 (s, 3 H) 2.70 (s, 3 H) 2.64 (dd, / = 8.16, 1.91 Hz, 2 H) 2.20 (s, 3 H) 1.97 - 2.07 (m, 4 H) 1.77 - 1.87 (m, 2 H) 1.71 - 1.73 (m,
2 H) 1.51 (s, 3 H) 1.41 - 1.45 (m, 2 H) 1.40 (d, / = 6.87 Hz, 6 H) 1.35 - 1.39 (m, 2 H) 0.82 - 0.95 (m, 2 H). LC-MS: purity 97% (UV), tR 5.66 min, m/z [M+H]+ 965.34.
Example 20-54:
Figure imgf000318_0002
77 [0802] Compound 77 was prepared in a manner analogous to General Procedure
SS to afford 252 mg (39%). 1H NMR (500 MHz, CDCl3) δ ppm 10.13 (s, 1 H) 7.83 (d, / = 9.16 Hz, 1 H) 7.55 (s, 1 H) 7.21 (d, / = 9.16 Hz, 1 H) 7.06 (s, 1 H) 6.91 (s, 1 H) 6.22 - 6.28 (m, 1 H) 6.16 - 6.34 (m, 2 H) 5.72 - 5.84 (m, 2 H) 5.60 (br. s, 1 H) 5.23 (d, / = 17.09 Hz, 3.99 (s, 3 H) 3.20 (spt, / = 6.79 Hz, 1 H) 2.71 (s, 3 H) 2.58 - 2.69 (m, 2 H) 1.98 - 2.08 (m, 5 H) 1.75 - 1.87 (m, 3 H) 1.66 - 1.74 (m, 2 H) 1.56 (dd, / = 14.34, 8.85 Hz, 1 H) 1.42 - 1.48 (m, 2 H) 1.40 (d, / = 6.87 Hz, 6 H) 1.31 - 1.34 (m, 1 H) 1.29 - 1.38 (m, 3 H) 0.80 - 0.94 (m, 3 H). LC-MS: purity 100% (UV), tR 2.74 min, m/z [M+H]+ 985.15.
Example 20-55:
Figure imgf000319_0001
487 [0803] Compound 487 was prepared in a manner analogous to General Procedure
TT to afford 185 mg (54%). 1H NMR (500 MHz, CDCl3) δ ppm 10.00 (s, 1 H) 7.76 (d, / = 9.00 Hz, 1 H) 7.54 (s, 1 H) 7.15 (d, / = 9.31 Hz, 1 H) 7.05 (s, 1 H) 6.87 (s, 1 H) 6.77 (s, 1 H) 6.66 (d, / = 19.53 Hz, 2 H) 5.70 - 5.80 (m, 1 H) 5.61 (br. s, 1 H) 5.01 (t, / = 9.61 Hz,
1 H) 4.75 (d, / = 8.70 Hz, 1 H) 4.68 (t, / = 7.86 Hz, 1 H) 4.24 - 4.32 (m, 1 H) 4.14 - 4.24 (m,
2 H) 3.96 (s, 3 H) 3.22 (spt, / = 6.71 Hz, 1 H) 2.75 (dd, / = 7.71, 2.37 Hz, 2 H) 2.69 (s, 3 H) 2.36 - 2.49 (m, 1 H) 2.26 (q, / = 8.65 Hz, 1 H) 1.98 - 2.11 (m, 1 H) 1.85 - 1.97 (m, 2 H) 1.74 - 1.85 (m, 2 H) 1.50 - 1.53 (m, 3 H) 1.40 (d, 6 H) 1.37 - 1.58 (m, 6 H) 1.28 - 1.37 (m, 2 H) 0.84 (br. s, 2 H). LC-MS: purity 100% (UV), tR 5.60 min, m/z [M+H]+ 957.25.
Example 20-56:
Figure imgf000319_0002
[0804] Compound 488 was prepared in a manner analogous to General Procedure TT to afford 185 mg (67%). 1H NMR (500 MHz, CDCl3) δ ppm 10.05 (br. s., 1 H) 7.69 (d, / = 9.16 Hz, 1 H) 7.54 (br. s, 1 H) 7.11 (d, / = 9.16 Hz, 1 H) 7.05 (s, 1 H) 6.85 (br. s, 1 H) 6.70 (s, 1 H) 6.62 (s, 1 H) 6.49 (s, 1 H) 5.70 - 5.77 (m, 1 H) 5.60 (br. s, 1 H) 5.01 (t, 1 H) 4.66 (t, / = 7.78 Hz, 1 H) 4.51 (d, / = 6.26 Hz, 1 H) 4.30 (br. s, 1 H) 4.20 (br. s, 2 H) 3.95 (s, 3 H) 3.18 - 3.27 (m, 1 H) 2.70 - 2.77 (m, 2 H) 2.69 (s, 3 H) 2.41 - 2.51 (m, 1 H) 2.27 (q, / = 8.80 Hz, 1 H) 2.10 (s, 3 H) 1.97 - 2.06 (m, 1 H) 1.74 - 1.95 (m, 4 H) 1.51 - 1.58 (m, 2 H) 1.50 (s, 3 H) 1.43 - 1.49 (m, 3 H) 1.41 (d, /=6.87 Hz, 6 H) 1.24 - 1.38 (m, 3 H) 0.80 - 0.86 (m, 2 H). LC-MS: purity 100% (UV), tR 5.50 min, m/z [M+H]+ 937.31.
Example 20-57:
Figure imgf000320_0001
489
[0805] Compound 489 was prepared in a manner analogous to General Procedure
TT to afford 53 mg (23%). 1H NMR (500 MHz, CDCl3) δ ppm 10.02 (s, 1 H) 7.80 (d, / = 9.16 Hz, 1 H) 7.54 (s, 1 H) 7.16 (d, / = 9.31 Hz, 1 H) 7.05 (s, 1 H) 6.81 (s, 1 H) 6.25 (d, / = 8.85 Hz, 1 H) 6.21 (s, 1 H) 6.15 (d, / = 10.53 Hz, 1 H) 5.69 - 5.80 (m, 1 H) 5.60 (br. s,
1 H) 5.01 (t, / = 9.61 Hz, 1 H) 4.62 - 4.74 (m, 2 H) 4.22 (td, / = 8.47, 2.90 Hz, 1 H) 4.19 (s,
2 H) 3.97 (s, 3 H) 3.22 (spt, / = 6.94 Hz, 1 H) 2.75 (dd, / = 7.86, 2.37 Hz, 2 H) 2.69 (s, 3 H) 2.38 - 2.51 (m, 1 H) 2.25 (q, / = 8.90 Hz, 1 H) 1.97 - 2.08 (m, 1 H) 1.93 (dd, / = 7.93, 6.10 Hz, 1 H) 1.84 - 1.91 (m, 1 H) 1.74 - 1.84 (m, 2 H) 1.53 - 1.59 (m, 2 H) 1.51 (s, 3 H) 1.42 - 1.50 (m, 4 H) 1.40 (d, / = 6.87 Hz, 6 H) 1.28 - 1.37 (m, 2 H) 0.84 (dd, / = 3.59, 2.52 Hz, 2 H). LC-MS: purity 100% (UV), tR 5.60 min, m/z [M+H]+ 951.31.
Figure imgf000321_0001
80 [0806] Compound 80 was prepared in a manner analogous to General Procedure
SS to afford 340 mg (49%). 1H NMR (500 MHz, CDCl3) δ ppm 10.15 (s, 1 H) 7.81 (d, / = 9.16 Hz, 1 H) 7.56 (s, 1 H) 7.18 (d, / = 9.16 Hz, 1 H) 7.06 (s, 1 H) 6.99 (t, / = 8.09 Hz, 1 H) 6.87 (br. s, 1 H) 6.54 (d, / = 8.09 Hz, 1 H) 6.40 - 6.44 (m, 2 H) 5.70 - 5.83 (m, 5 H) 5.60 (d, / = 2.14 Hz, 1 H) 5.23 (dd, / = 17.09, 0.92 Hz, 1 H) 5.12 - 5.15 (m, 1 H) 4.99 (dd, / = 17.09, 1.68 Hz, 1 H) 4.93 (dd, / = 10.15, 0.84 Hz, 1 H) 4.79 (d, / = 9.46 Hz, 1 H) 4.46 (t, / = 8.32 Hz, 1 H) 3.99 (br. s, 3 H) 3.20 (spt, / = 6.87 Hz, 1 H) 2.93 (s, 6 H) 2.71 (s, 3 H) 2.62 - 2.65 (m, 2 H) 1.96 - 2.06 (m, 5 H) 1.73 - 1.86 (m, 2 H) 1.51 - 1.60 (m, 1 H) 1.44 - 1.51 (m, 1 H) 1.41 - 1.44 (m, 1 H) 1.40 (d, /=6.87 Hz, 6 H) 1.29 - 1.38 (m, 3 H). LC-MS: purity 100% (UV), tR 2.72 min, m/z [M+H]+ 956.35.
Example 20-59
Figure imgf000321_0002
490
[0807] Compound 490 was prepared in a manner analogous to General Procedure
TT to afford 82 mg (28%). 1H NMR (500 MHz, CDCl3) δ ppm 10.15 (s, 1 H) 7.81 (d, / = 9.16 Hz, 1 H) 7.56 (s, 1 H) 7.18 (d, / = 9.16 Hz, 1 H) 7.06 (s, 1 H) 6.99 (t, / = 8.09 Hz, (d, / = 2.14 Hz, 1 H) 5.23 (dd, / = 17.09, 0.92 Hz, 1 H) 5.12 - 5.15 (m, 1 H) 4.99 (dd, / = 17.09, 1.68 Hz, 1 H) 4.93 (dd, / = 10.15, 0.84 Hz, 1 H) 4.79 (d, / = 9.46 Hz, 1 H) 4.46 (t, / = 8.32 Hz, 1 H) 3.99 (br. s, 3 H) 3.20 (spt, / = 6.87 Hz, 1 H) 2.93 (s, 6 H) 2.71 (s, 3 H) 2.62 - 2.65 (m, 2 H) 1.96 - 2.06 (m, 5 H) 1.73 - 1.86 (m, 2 H) 1.51 - 1.60 (m, 1 H) 1.44 - 1.51 (m, 1 H) 1.41 - 1.44 (m, 1 H) 1.40 (d, / = 6.87 Hz, 6 H) 1.29 - 1.38 (m, 3 H). LC-MS: purity 100% (UV), tR 2.72 mm, m/z [M+H]+ 956.35.
Example 21
Scheme XVIII: General Route for the Preparation of Macrocyclic Acylsulfonamides and Acylsulfamides
Figure imgf000322_0001
XVIII-D XVIII-C XVIII-B
[0808] Macrocyclic protease inhibitors of general structures XXVIII-C and XXVIII-D were synthesized as shown on Scheme XVIII from synthetic precursor 16 ("RCM Ester). Compound 16 was treated under acidic conditions, for example with HCl-dioxane, to generate free amino derivative 17. Next, this compound was arylated with an optionally substituted boronic acids under Cu """-catalyzed conditions to yield N-aryl intermediates of general structure XXVIII-A. Simultaneous basic hydrolysis of carbamate and ester functions, for example aqueous sodium hydroxide in ethanol, afforded hydroxy carboxylic acids of general structure XXVIII-B, which were then reacted with a heteroaryl chloride, such as 2-(4- isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinohne and the like, under basic XXVIII-C. Finally, these acids were coupled with sulfonamides or sulfamides, for example using CDI in the presence of DBU, to give the target compounds of general structure XXVIII-D.
Example 21-1:
General ProcedureUU
Figure imgf000323_0001
[0809] To a solution of N-Boc compound 16 (13.2 g, 20 mmol.) in DCM (80 niL) was added 4N HCl-dioxane solution (50 mL, 200 mmol.) and the reaction was allowed to proceed overnight at room temperature. After evaporation in vacuo the residue was re- dissolved in DCM and the solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, evaporated, and dried under high vacuum to afford amino intermediate 17 as off-white foam which was used in the next step without further purification. Yield 12.42 g (-100%), -90% purity. 1H-NMR (CDCl3), δ: 7.22-7.32 (m, 1 H), 6.95-7.08 (m, 3 H), 5.46-5.54 (m, 1 H), 5.30-5.36 (m, 1 H), 5.23 (dd, 1 H), 4.87-4.90 (m,
1 H), 4.71-4.78 (m, 2 H), 4.70 (d, 2 H), 4.07-4.20 (m, 2 H), 3.90-3.97 (m, 1 H), 3.69-3.80 (m,
2 H), 2.85-2.95 (m, 1 H), 2.00-2.30 (m, 4 H), 1.60 (dd, 1 H), 1.70-1.85 (m, 1 H), 1.45-1.68 (m, 5 H), 1.35-1.42 (m, 5 H), 1.24 (t, 3 H). General Procedure VV
Figure imgf000324_0001
63
[0810] To a solution of amino compound 17 (3.8 g, -6.1 mmol. based on -90% purity) in DCM (60 mL) were added 3-fluorophenyl boronic acid (1.29 g, 9.2 mmol.), pyridine (1.7 mL, 21 mmol.), copper(II) acetate (0.4 g, 2.2 mmol.) and molecular sieves 4A (-8 g). The mixture was stirred opened to the air for 2 days and then quenched by addition of 10% ammonium hydroxide (150 mL). Solids were filtered off and washed with DCM. Organic layer was separated, additionally washed with 10% aqueous ammonium hydroxide, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography in 40 to 70% ethyl acetate-hexane to give the target compound 63 as white foam. Yield 2.18 g (55%). 1H-NMR (DMSO-d6), δ: 8.75 (s, 1 H), 7.37 (dd, 1 H), 7. 21 (d, 1 H), 6.88-6.69 (m, 1 H), 6.41-6.49 (m, 2 H), 6.05-6.18 (dt, 1 H), 5.88 (d, 1 H), 5.53 (dd, 1 H), 5.40 (br. s, 1 H), 5.31 (dd, 1 H), 4.31-4.70 (m, 6 H), 4.07 (m, 4 H), 3.81-3.87 (m, 1 H), 2.12-2.40 (m, 4 H), 1.90-2.00 (m, 1 H), 1.69-1.82 (m, 1 H), 1.55-1.65 (m, 1 H), 1.18-1.53 (m, 9 H), 1.13 (t, 2 H).
Example 21-3:
Figure imgf000324_0002
64
[0811] Compound 64 was prepared in a manner analogous to General Procedure
VV, and the yield is 49.7%; white foam.
Figure imgf000325_0001
[0812] Compound 65 was prepared in a manner analogous to General Procedure VV, and the yield is 62%; white foam. 1H-NMR (CDCl3), δ: 7.23-7.27 (m, 1 H), 6.95-7.08 (m, 3 H), 6.78-6.83 (m, 2 H), 6.53-6.58 (m, 2 H), 5.52 (dt, 1 H), 5.35 (m, 1 H), 5.25 (dd, 1 H), 4.85 (m, 1 H), 4.75 (m, 2 H), 4.52-4.68 (m, 2 H), 4.32-4.41 (m, 2 H), 4.10-4.21 (m, 3 H), 3.95 (m, 1 H), 3.85 (dd, 1 H), 2.83 (m, 1 H), 2.07-2.26m, 4 H), 1.93 (m, 1 H), 1.88 (dd, 1 H), 1.73 (dd, 1 H), 1.57 (m, 2 H), 1.42 (m, 3 H), 1.22-1.28 (m, 6 H).
Example 21-5:
Figure imgf000325_0002
[0813] Compound 66 was prepared in a manner analogous to General Procedure VV, and the yield is 65%. White foam. 1H-NMR (CDCl3), δ: 7.23-7.28 (m, 1 H), 6.93-7.09 (m, 2 H), 6.87-6.92 (m, 2 H), 6.80 (br. s, 1 H), 6.73 (d, 1 H), 5.51 (dt, 1 H), 5.39 (m, 1 H), 5.26 (dd, 1 H), 4.87 (m, 1 H), 4.75-4.80 (m, 3 H), 4.63 (m, 2 H), 4.42 (m, 1 H), 4.13-4.20 (m, 2 H), 4.04 (m, 1 H), 3.84 (dd, 1 H), 2.87 (m, 1 H), 1.96-2.28 (m, 5 H), 1.88 (dd, 1 H), 1.75 (dd, 1 H), 1.54-1.60 (m, 2 H), 1.38-1.47 (m, 3 H), 1.22-1.36 (m, 6 H).
Figure imgf000326_0001
[0814] Compound 67 was prepared in a manner analogous to General Procedure VV, and the yield is 70%. White foam. 1H-NMR (CDCl3), δ: 7.34 (d, 2 H), 7.29 (m, 1 H), 6.96-7.06 (m, 2 H), 6.90 (d, 1 H), 6.60 (d, 2 H), 5.52 (dt, 1 H), 5.38 (m, 1 H), 5.26 (dd, 1 H), 4.87-4.93 (m, 2 H), 4.73-4.77 (m, 2 H), 4.68 (m, 2 H), 4.43 (m, 1 H), 4.11-4.20 (m, 2 H), 4.15 (dd, 1 H), 3.87 (dd, 1 H), 2.88 (m, 1 H), 1.95-2.27 (m, 5 H), 1.88 (dd, 1 H), 1.75 (dd, 1 H), 1.56 (dd, 1 H), 1.35-1.47 (m, 3 H), 1.20-1.35 (m, 6 H).
Example 21-7:
Figure imgf000326_0002
[0815] Compound 68 was prepared in a manner analogous to General Procedure VV, and the yield is 67%. White foam. 1H-NMR (CDCl3), δ: 7.28 (m, 1 H), 6.87-7.08 (m, 4 H), 6.75 (m, 1 H), 6.71 (m, 1 H), 5.52 (dt, 1 H), 5.38 (m, 1 H), 5.26 (dd, 1 H), 4.86 (m, 1 H), 4.76 (m, 2 H), 4.61-4.71 (m, 3 H), 4.34 (m, 1 H), 4.10-4.20 (m, 2 H), 4.05 (dd, 1 H), 3.81 (dd, 1 H), 2.85 (m, 1 H), 2.05-2.26 (m, 4 H), 1.95-2.03 (m, 1 H), 1.88 (dd, 1 H), 1.75 (dd, 1 H), 1.56 (dd, 1 H), 1.35-1.50 (m, 3 H), 1.18-1.28 (m, 6 H).
Figure imgf000327_0001
69
[0816] Compound 69 was prepared in a manner analogous to General Procedure
VV, and the yield is 69.6%. White foam. 1H-NMR (CDCl3), δ: 7.28 (m, 1 H), 6.92-7.06 (m, 2 H), 6.84 (d, 1 H), 6.56-6.61 (m, 2 H), 6.39 (dd, 1 H), 5.52 (dt, 1 H), 5.40 (m, 1 H), 5.27 (dd, 1 H), 4.87 (m, 1 H), 4.76 (d, 2 H), 4.60-4.71 (m, 2 H), 4.36 dd, 1 H), 4.10-4.20 (m, 2 H), 4.01-4.07 (m, 1 H), 3.83-3.86 (m, 1 H), 2.84-2.88 (m, 1 H), 2.06-2.30 (m, 4 H), 1.95-2.00 (m, 1 H), 1.87 (dd, 1 H), 1.71-1.80 (m, 1 H), 1.57 (dd, 1 H), 1.35-1.50 (m, 3 H), 1.20-1.31 (m, 6 H).
Scheme XIX: General Route for Synthesis of 411
Figure imgf000328_0001
448 411
[0817] Compound 63 can be treated under basic conditions, for example aqueous sodium hydroxide in ethanol, can simultaneous hydrolyze the carbamate and ethyl ester functions thereby providing hydroxy carboxylic acids, for example compound 70. The hydroxy carboxylic acids, for example compound 70, can then reacted with a heteroaryl chloride, such as 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinoline and the like, under basic conditions, for example sodium hydride in DMF, to furnish acids, such as compound 448. Finally, these acids can be coupled, for example using CDI in the presence of DBU, with sulfonamides (e.g. cyclopropylsulfonamide) or sulfamides to provide macrocycles such as compound 411. General Procedure WW
Figure imgf000329_0001
448 [0818] To a mixture of compound 63 (2.18 g, 3.35 mmol.) and ethanol (20 mL) was added aqueous sodium hydroxide (2N, 10 mL, 20 mmol.) and reaction mixture was stirred overnight at 700C. Solvent was removed in vacuo and the residue was dissolved in water. The aqueous solution was acidified with 2N hydrochloric acid to pH ~3 and then extracted with ethyl acetate. Organic phase was dried over magnesium sulfate and evaporated to give crude intermediate 70 as a beige foam (-1.7 g), used on the next step without any further purification.
[0819] Crude compound 70 from the previous step (1.7 g) was co-evaporated twice with DMF and then dissolved in anhydrous DMF (10 mL). This solution was cooled down to 00C and sodium hydride (60% dispersion in mineral oil, 536 mg, 13.4 mmol.) was added in one portion. The reaction was stirred at room temperature until hydrogen evolution subsided (30-40 min), then 4-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxy-8- methylquinoline (1.12 g, 3.35 mmol.) was added to the stirring mixture. The reaction was allowed to proceed overnight at 400C. After addition of water and 2N hydrochloric acid the reaction mixture was extracted with ethyl acetate. Organic phase was washed with water, dried over magnesium sulfate, and evaporated. The desired acid (448) was isolated by flash chromatography in 2-4% methanol in DCM to afford 1.88 g (74% over two steps), pale yellow foam. . 1H-NMR (DMSO-d6), δ: 12.3 (br. s, 1 H), 8.68 (s, 1 H), 7.88 (d, 1 H), 7.58 (s, 1 H), 7.48 (s, 1 H), 6.68 (dd, 1 H), 6.44 (d, 1 H), 6.33 (d, 1 H), 6.21 (dd, 1 H), 5.88 (d, 1 H), 5.73 (m, 1 H), 5.52 (m, 1 H), 5.33 dd, 1 H), 4.51 (dd, 1 H), 4.34-4.40 (m, 2 H), 3.98-4.05 (m, 1.99 (m, 1 H), 1.75 (m, 1 H), 1.65 (m, 1 H), 1.15-1.49 (m, 13 H).
Example 22-2:
Figure imgf000330_0001
449
[0820] Compound 449 was prepared in a manner analogous to General Procedure
WW, and the yield is 58.5% (two steps). Beige foam. 1H-NMR (CDCl3), δ: 7.80 (d, 1 H), 7.50 (s, 1 H), 6.85-7.16 (m, 5 H), 6.69 (dd, 1 H), 6.59 (d, 2 H), 5.50-5.60 (m, 1 H), 5.48 (m, 1 H), 5.35 (dd, 1 H), 4.70 (dd, 1 H), 4.38 (d, 1 H), 4.29 (m, 1 H), 4.09 (d, 1 H), 3.95 (s, 3 H), 3.26 (m, 1 H), 2.87 (m, 1 H), 2.67 (s, 3 H), 2.47 (m, 1 H), 2.28 (m, 2 H), 2.17 (m, 1 H), 1.96 (m, 1 H), 1.82 (m, 2 H), 1.65 (dd, 1 H), 1.26-1.53 (m, 13 H).
Example 22-3:
Figure imgf000330_0002
450
[0821] Compound 450 was prepared in a manner analogous to General Procedure
WW, and the yield is 61.9% (two steps). Tan foam. 1H-NMR (CDCl3), δ: 7.71 (d, 1 H), 7.48 (s, 1 H), 7.15 (d, 1 H), 7.08 (br. s, 1 H), 7.03 (s, 1 H), 6.75 (m, 2 H), 6.52 (m, 2 H), 5.53 (m, 3.97 (s, 3 H), 3.23 (m, 1 H), 2.87 (m, 1 H), 2.67 (s, 3 H), 2.49 (dd, 1 H), 2.28 (m, 2 H), 2.13 (m, 1 H), 1.93 (m, 1 H), 1.80 (m, 2 H), 1.62 (dd, 1 H), 1.25-1.55 (13 H).
Example 22-4:
Figure imgf000331_0001
451
[0822] Compound 451 was prepared in a manner analogous to General Procedure
WW, and the yield is 71% (two steps). Yellow foam. 1H-NMR (CDCl3), δ: 7.79 (d, 1 H), 7.51 (s, 1 H), 7.13-7.17 (m, 2 H), 7.04 (s, 1 H), 6.92 (d, 1 H), 6.84 (m, 2 H), 6.70 (d, 1 H), 5.45- 5.60 (m, 2 H), 5.38 (dd, 1 H), 4.80 (m, 1 H), 4.72 (dd, 1 H), 4.43 (m, 1 H), 4.35 (dd, 1 H), 4.06 (d, 1 H), 3.96 (s, 3 H), 3.29 (m, 1 H), 2.88 (m, 1 H), 2.67 (s, 3 H), 2.49 (m, 1 H), 2.31 (dd, 1 H), 2.21 (m, 2 H), 2.05 (m, 1 H), 1.80-1.93 (m, 2 H), 1.65 (dd, 1 H), 1.26-1.59 (m, 13 H).
Example 22-5:
Figure imgf000331_0002
452 WW, and the yield is 38% (two steps). Brown foam. 1H-NMR (CDCl3), δ: 7.83 (d, 1 H), 7.50 (s, 1 H), 7.29 (d, 2 H), 7.16 (d, 1 H), 6.97-7.07 (m, 2 H), 6.56 (d, 2 H), 5.34 (m, 1 H), 5.49 (m, 1 H), 5.34 (dd, 1 H), 4.85 (m, 1 H), 4.71 (dd, 1 H), 4.39 (m, 1 H), 4.28 (m, 1 H), 3.95 (s, 3 H), 3.23 (m, 1 H), 2.88 (m, 1 H), 2.67 (s, 3 H), 2.52 (dd, 1 H), 2.28 (m, 2 H), 2.15 (m, 1 H), 1.97 (m, 1 H), 1.85 (m, 1 H), 1.79 (dd, 1 H), 1.61 (dd, 1 H), 1.48 (m, 3 H), 1.25-1.39 (m, 10 H).
Example 22-6:
Figure imgf000332_0001
[0824] Compound 453 was prepared in a manner analogous to General Procedure WW, and the yield is 51.1% (two steps). Tan foam. 1H-NMR (CDCl3), δ: 7.73 (d, 1 H), 7.49 (s, 1 H), 7.15 (d, 1 H), 7.04 (s, 1 H), 6.88 (br. s, 1 H), 6.81 (m, 2 H), 6.63 (m, 1 H), 5.54 (m, 1 H), 5.48 (m, 1 H), 5.37 (dd, 1 H), 4.70 (m, 1 H), 4.55-4.65 (m, 1 H), 4.28-4.34 (m, 2 H), 4.05 (d, 1 H), 3.97 (s, 3 H), 3.27 (m, 1 H), 2.86 (m, 1 H), 2.67 (s, 3 H), 2.49 (m, 1 H), 2.15- 2.25 (m, 3 H), 1.95 (m, 1 H), 1.79-1.85 (m, 2 H), 1.64 (dd, 1 H), 1.25-1.55 (m, 13 H).
Example 22-7:
Figure imgf000333_0001
[0825] Compound 454 was prepared in a manner analogous to General Procedure WW, and the yield is 37.8% (two steps). Pale-yellow foam. 1H-NMR (CDCl3), δ: 7.84 (d, 1 H), 7.50 (s, 1 H), 7.18 (d, 1 H), 7.04 (s, 1 H), 6.72 (br. s, 1 H), 6.66 (s, 1 H), 6.65 (d, 1 H), 6.42 (d, 1 H), 5.54 (m, 1 H), 5.50 (m, 1 H), 5.41 (dd, 1 H), 4.99 (d, 1 H), 4.68 (dd, 1 H), 4.39 (m, 2 H), 4.02 (d, 1 H), 3.96 (s, 3 H), 3.29 (m, 1 H), 2.85 (m, 1 H), 2.67 (s, 3 H), 2.50 (m, 1 H), 2.32 (dd, 1 H), 2.20 (m, 2 H), 2.05 (m, 1 H),1.87 (m, 1 H), 1.81 (dd, 1 H), 1.65 (dd, 1 H), 1.25-1.55 (m, 13 H).
Example 22-8:
General Procedure XX
Figure imgf000333_0002
411
[0826] To a solution of carboxylic acid 448 (151 mg, 0.2 mmol.) in anhydrous dichloroethane (5 mL) was added carbonyldiimidazole (49 mg, 0.3 mmol.). After stirring for 3 h at room temperature cyclopropylsulfonamide (39 mg, 0.32 mmol.) was added, followed by DBU (48 μL, 0.32 mmol.). The reaction was stirred overnight at 400C. Water and 2N Organic phase was washed with water, dried over magnesium sulfate, and evaporated. Compound 411 was isolated by column chromatography in 40-50% ethyl acetate-hexane to afford 120 mg (70%). Pale yellow foam, m/z [M+l]+ 859.2.1H-NMR (CDCl3), δ: 10.31 (br. s, 1 H), 7.70 (d, 1 H), 7.57 (br. s, 1 H), 7.48 (s, 1 H), 7.05 (d, 1 H), 7.03 (s, 1 H), 6.81 (dd, 1 H), 6.31 (dd, 1 H), 6.14-6.22 (m, 2 H), 5.64-5.71 (m, 1 H), 5.48 (br. d, 1 H), 4.90-4.96 (m, 2 H), 4.55 (dd, 1 H), 4.06-4.15- (m, 3 H), 3.87 (s, 3 H), 3.21 (m, 1 H), 2.88 (m, 1 H), 2.65 (s, 3 H), 2.56-2.58 (m, 2 H), 2.40-2.55 (m, 1 H), 2.15 (dd, 1 H), 1.90-2.02 (m, 1 H), 1.68-1.84 (m, 3 H), 1.36-1.55 (m, 11 H), 1.20-1.35 (m, 2 H), 1.00-1.18 (m, 2 H), 0.85-1.00 (m, 2 H).
Example 22-9:
Figure imgf000334_0001
[0827] 417
[0828] Compound 417 was prepared in a manner analogous to General Procedure XX, and the yield is 79%. Pale yellow foam, m/z [M+l]+ 862.6.1H-NMR (DMSO-d6), δ: 10.76 (s, 1 H), 8.91 (s, 1 H), 7.81 (d, 1 H), 7.59 (s, 1 H), 7.48 (s, 1 H), 7.32 (d, 1 H), 6.67 (dd, 1 H), 6.47 (ddd, 1 H), 6.35 (dd, 1 H), 6.24 (dd, 1 H), 6.01 (d, 1 H), 5.75 (m, 1 H), 5.63 (m, 1 H), 5.10 (dd, 1 H), 4.35-4.45 (m, 3 H), 4.02 (dd, 1 H), 3.96 (s, 3 H), 3.18 (m, 1 H), 3.741 (s, 6 H), 2.55-2.70 (m, 5 H), 2.40-2.49 (m, 1 H), 2.28 (dd, 1 H), 1.70-1.85 (m, 2 H), 1.40-1.65 (m, 7 H), 1.36 (d, 3 H), 1.34 (d, 3 H), 1.20-1.30 (m, 2 H).
Example 22-10:
Figure imgf000335_0001
412
[0829] Compound 412 was prepared in a manner analogous to General Procedure
XX, and the yield is 79%. Yellow foam, m/z [M+l]+ 844.3.1H-NMR (DMSO-d6), δ: 10.76 (s, 1 H), 8.90 (s, 1 H), 7.82 (d, 1 H), 7.60 (s, 1 H), 7.48 (s, 1 H), 7.34 (d, 1 H), 6.71 (dd, 2 H), 6.52 (d, 2 H), 6.42 (dd, 1 H), 5.74 (m, 1 H), 5.59-5.70 (m, 2 H), 5.09 (dd, 1 H), 4.41-4.60 (m,
2 H), 4.31 (dd, 1 H), 4.01 (dd, 1 H), 3.97 (s, 3 H), 3.18 (m, 1 H), 2.74 (s, 6 H), 2.52-2.68 (m, 5 H), 2.40-2.48 (m, 1 H), 2.27 (dd, 1 H), 1.72-1.85 (m, 2 H), 1.39-1.65 (m, 7 H), 1.36 (d,
3 H), 1.34 (d, 3 H), 1.15-1.30 (m, 2 H).
Example 22-11:
Figure imgf000335_0002
[0830] 455
[0831] Compound 455 was prepared in a manner analogous to General Procedure XX, and the yield is 54%. Yellow foam, m/z [M+l]+ 870.1.1H-NMR (CDCl3), δ: 9.97 (br. s, 1 H), 7.72 (d, 1 H), 7.50 (s, 1 H), 7.48 (br. s, 1 H), 7.06 (d, 1 H), 7.04 (s, 1 H), 6.88 (dd, 2 H), 6.56 (t, 1 H), 6.43 (d, 2 H), 5.71 (dt, 1 H), 5.51 (m, 1 H), 5.02 (dd, 1 H), 4.52 (m, 1 H), 4.10- (m, 2 H), 2.13 (dd, 1 H), 1.72-1.92 (m, 11 H), 1.20-1.60 (m, 12 H).
Example 22-12:
Figure imgf000336_0001
[0832] Compound 456 was prepared in a manner analogous to General Procedure XX, and the yield is 35%. Yellow foam, m/z [M+l]+ 884.2.1H-NMR (CDCl3), δ: 9.95 (br. s, 1 H), 7.70 (d, 1 H), 7.50 (s, 1 H), 7.32 (br. s, 1 H), 7.06 (d, 1 H), 7.05 (s, 1 H), 6.90 (dd, 2 H), 6.60 (t, 1 H), 6.44 (d, 2 H), 5.76 (dt, 1 H), 5.51 (m, 1 H), 5.06 (dd, 1 H), 4.48 (dd, 1 H), 4.09- 4.25 (m, 3 H), 3.90 (s, 3 H), 3.20-3.35 (m, 4 H), 2.67 (s, 3 H), 2.40-2.65 (m, 2 H), 2.12 (dd, 1 H), 1.75-1.95 (m, 4 H), 1.25-1.68 (22 H).
Example 22-13:
Figure imgf000336_0002
415
[0833] Compound 415 was prepared in a manner analogous to General Procedure
XX, and the yield is 74.8%. Pale yellow foam, m/z [M+l]+ 862.3.1H-NMR (DMSO-d6), δ: 10.78 (s, 1 H), 8.95 (s, 1 H), 7.75 (d, 1 H), 7.59 (s, 1 H), 7.48 (s, 1 H), 7.34 (d, 1 H), 6.48- 4.38-4.49 (m, 2 H), 4.30 (dd, 1 H), 4.00 (m, 1 H), 3.96 (s, 3 H), 3.18 (m, 1 H), 2.74 (s, 6 H), 2.65 (m, 2 H), 2.61 (s, 3 H), 2.45 (m, 1 H), 2.27 (dd, 1 H), 1.65-1.82 (m, 2 H), 1.40-1.60 (m, 7 H), 1.36 (d, 3 H), 1.34 (d, 3 H), 1.15-1.30 (m, 2 H).
Example 22-14:
Figure imgf000337_0001
457 [0834] Compound 457 was prepared in a manner analogous to General Procedure
XX, and the yield is 79%. Pale yellow foam, m/z [M+l]+ 912.3.1H-NMR (DMSO-d6), δ: 10.76 (s, 1 H), 8.92 (s, 1 H), 7.74 (d, 1 H), 7.60 (s, 1 H), 7.48 (s, 1 H), 7.32 (d, 1 H), 7.04 (s, 1 H), 6.67-6.75 (m, 3 H), 6.16 (d, 1 H), 5.75 (s, 1 H), 5.63 (dt, 1 H), 5.10 (dd, 1 H), 4.40 - 4.50 (m, 3 H), 4.04 (dd, 1 H), 3.96 (s, 3 H), 3.17 (m, 1 H), 2.74 (s, 6 H), 2.63 (m, 2 H), 2.60 (s, 3 H), 2.44 (m, 1 H), 2.27 (dd, 1 H), 1.75-1.85 (m, 2 H), 1.37-1.60 (m, 7 H), 1.36 (d, 3 H), 1.34 (d, 3 H), 1.18-1.27 (m, 2 H).
Example 22-15:
Figure imgf000337_0002
458 XX, and the yield is 85%. Pale yellow foam, m/z [M+l]+ 912.3.1H-NMR (DMSO-d6), δ: 10.78 (s, 1 H), 8.96 (s, 1 H), 7.88 (d, 1 H), 7.62 (s, 1 H), 7.49 (s, 1 H), 7.34 (d, 1 H), 6.72 (d, 2 H), 6.50 (d, 1 H), 6.42 (d, 2 H), 5.78 (m, 1 H), 5.64 (dt, 1 H), 5.10 (dd, 1 H), 4.52-5.70 (m,
2 H), 4.34 (m, 1 H), 3.97 (dd, 1 H), 3.94 (s, 3 H), 3.18 (m, 1 H), 2.75 (s, 6 H), 2.63 (m, 2 H), 2.61 (s, 3 H), 2.38 (dd, 1 H) 1.72-1.84 (m, 2 H), 1.39-1.62 (m, 7 H), 1.36 (d, 3 H), 1.34 (d,
3 H), 1.23 (m, 2 H).
Example 22-16:
Figure imgf000338_0001
[0836] Compound 459 was prepared in a manner analogous to General Procedure XX, and the yield is 83%. Pale yellow foam, m/z [M+l]+ 930.3.1H-NMR (DMSO-d6), δ: 10.78 (s, 1 H), 8.95 (s, 1 H), 7.69 (d, 1 H), 7.59 (s, 1 H), 7.48 (s, 1 H), 7.30 (d, 1 H), 7.04 (m, 1 H), 6.70 (m, 1 H), 6.42 (dd, 1 H), 6.05 (d, 1 H), 5.76 (m, 1 H), 5.64 (dt, 1 H), 5.09 (dd, 1 H), 4.37-4.49 (m, 3 H), 4.03 (dd, 1 H), 3.94 (s, 3 H), 3.36 (m, 1 H), 2.74 (s, 6 H), 2.60-2.64 (m, 1 H), 2.60 (s, 3 H), 2.40-2.49 (m, 1 H), 2.25 (dd, 1 H), 1.70-1.86 (m, 2 H), 1.38-1.60 (m, 7 H), 1.36 (d, 3 H), 1.34 (d, 3 H), 1.18-1.28 (m, 2 H).
Figure imgf000339_0001
[0837] 460
[0838] Compound 460 was prepared in a manner analogous to General Procedure XX, and the yield is 83.8%. Pale yellow foam, m/z [M+l]+ 930.3.1H-NMR (DMSO-d6), δ: 10.77 (s, 1 H), 8.97 (s, 1 H), 7.75 (d, 1 H), 7.59 (s, 1 H), 7.48 (s, 1 H), 7.27 (d, 1 H), 6.95 (s, 1 H), 6.74 (d, 1 H), 6.60 (d, 1 H), 6.54 (d, 1 H), 5.76 (s, 1 H), 5.64 (dt, 1 H), 5.11 (dd, 1 H), 4.55 (m, 1 H), 4.38-4.46 (m, 2 H), 4.05 (dd, 1 H), 3.83 (s, 3 H), 3.17 (m, 1 H), 2.74 (s, 6 H), 2.58-2.68 (m, 2 H), 2.58 (s, 3 H), 2.40-2.49 (m, 1 H), 2.28 (dd, 1 H), 1.74-1.83 (m, 2 H), 1.40-1.63 (m, 7 H), 1.35 (d, 3 H), 1.34 (d, 3 H), 1.16-1.30 (m, 2 H).
Example 22-18:
Figure imgf000339_0002
[0839] Compound 391 was prepared in a manner analogous to General Procedure R, to afford 39.7 mg (23.9%). MS (ESI) m / z (M+H)+ 792.3. Scheme XX: General Route for synthesis of Acylsulfonamides
Figure imgf000340_0001
XX-C
[0840] N-aryl amines having a general structure XX-C, can be synthesized as shown in Scheme XX. The isoindoline carbamate 6 can be treated with acid, for example TFA in DCM, to remove the Boc protecting group thereby providing compound 71. Compound 71 can be treated with optionally substituted aryl boronic acids under Cu2+- catalyzed conditions thereby providing isoindoline carbamates having general structure XX-A. The isoindoline carbamate having general structure XX-A can be treated under basic conditions, for example aqueos sodium hydroxide in methanol, to hydrolyse the isoindoline carbamate thereby providing alcohols having general structure XX-B. The alcohol having general structure XX-B can be treated with a heteroaryl chloride, such as 2-chloro-l -ethyl - benzoimidazole, 2-chloro-l-isobutyl-benzoimidazole, 2-chloro-l-isopropyl-6-methyl- benzoimidazole, 2-chloro-l-isopropyl-6-methyl-benzoimidazole, and the like, under basic conditions to afford a compound of general structure XX-C.
Figure imgf000341_0001
[0841] Compound 71 can be prepared in a manner analogous to General Procedure S.
Example 23-2:
Figure imgf000341_0002
XX-A
[0842] Compounds of general structure XX-A can be prepared in a manner analogous to General Procedure O.
Example 23-2:
Figure imgf000341_0003
XX-B
[0843] Compounds of general structure XX-B can be prepared in a manner analogous to General Procedure P.
Figure imgf000342_0001
XX-C
[0844] Compounds of general structure XX-C can be prepared in a manner analogous to General Procedure F.
Example 23-4:
Figure imgf000342_0002
402
[0845] Compound 402 was prepared in a manner analogous to General Procedure F, to afford 5.1mg (9.8%). MS (ESI) m / z (M+H)+ 817.4.
Example 23-5:
Figure imgf000342_0003
401
[0846] Compound 401 was prepared in a manner analogous to General Procedure F, to afford 5.1 mg (3.6%). MS (ESI) m / z (M+Na)+ 853.3.
Figure imgf000343_0001
365
[0847] Compound 365 was prepared in a manner analogous to General Procedure
F, to afford 50.7 mg, 28.3%. MS (ESI) m / z (M+H)+ 717.3.
Example 23-7:
Figure imgf000343_0002
[0848] Compound 461 was prepared in a manner analogous to General Procedure F, to afford 40 mg, 28%. MS (ESI) m / z (M+H)+ 735.4.
Example 23-8:
Figure imgf000343_0003
[0849] Compound 462 was prepared in a manner analogous to General Procedure F, to afford 32.6 mg, 15%. MS (ESI) m / z (M+H)+ 731.4.
Example 23-9:
Figure imgf000344_0001
[0850] To a solution of 2-chloro-benzoimidazole (1.0 eq.) in DMF was added
K2CO3 (2.0 eq.) and isobutyl iodide (1.5 eq.). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was poured into ice- water. The mixture was extracted with ethyl acetate (3 x 100 mL), washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by column chromatography to afford 4 g (96%) of 2-chloro-l -isobutyl -benzoimidazole.
Example 23-10:
[0851] 2-Chloro-l-neopenty il-bXenzotimidaazole was prepared in a manner analogous to Example 23-9, to afford 1.1 g, 75.3%.
Example 23-11:
Scheme XXI: Synthesis of substituted 2-chloro-Λ^-(2-propyl)-benzoimidazoles:
Figure imgf000344_0002
XXI-A XXI-B
Figure imgf000344_0003
XXl-C XXI-D
Figure imgf000344_0004
XXI-B in 15 mL of pyridine was added methyl chloroformate (1.5 eq.) at 00C. The reaction mixture was stirred at 00C for 2h. The resulting solution was filtered and concentrated. The residue was dissolved in ethyl acetate, washed with HCl (IM) and brine. The organic was dried over Na2SO4, concentrated and purified by column chromatography on silica gel using petroleum ether/ethyl acetate (10:1) to afford a compound having the general structure XXI-B.
Example 23-12:
Figure imgf000345_0001
XXI-C
[0853] A schlenk tube was charged with a compound having the general structure
XXI-B (1 eq.), CuI (0.2 eq.), trans-4-hydroxy-L-proline (0.4 eq.) and K3PO4 (2.0 eq.), evacuated and backfilled with argon, isopropylamine (2.0 eq.) and DMSO were added successively. The reaction mixture was stirred at 700C for 12h and then at 1300C for 6h .The reaction mixture was poured into saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic was dried over Na2SO4, concentrated and purified by column chromatography on silica gel using DCM/MeOH (80:1) to afford a compound having the general structure XXI-C.
Example 23-13:
Figure imgf000345_0002
XXI-D
[0854] A mixture of a compound having the general structure XXI-C in POCI3 was refluxed for 6h. Most of the POCI3 was removed in vacuo and the residue was quenched with ice water and treated with aq. NaOH (5M) until pH=7-8. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to afford crude product. Crude product was purified by column chromatography on silica gel using DCM/MeOH (40:1) to afford a compound having the general structure XXI-D.
Example 23-14:
Figure imgf000346_0001
[0855] 2-Chloro-6-fluoro-l-isopropyl-benzoimidazole was prepared in a manner analogous to Example 23-13, to afford 0.76 g (63%). 1H NMR (400 MHz, OMS0-d6) δ 7.79 (m, 1 H), 7.42 (m, 1 H), 7.13 (m, IH), 4.95 (m, 1 H), 1.52 (d, / = 6.8 Hz, 6 H).
Example 23-15:
Figure imgf000346_0002
[0856] 2-chloro-l-isopropyl-6-methyl-benzoimidazole was prepared in a manner analogous to Example 23-13, to afford 0.87 g (53%).
Example 23-16:
Figure imgf000346_0003
[0857] 2-chloro-l-isopropyl-7-methyl-benzoimidazole was prepared in a manner analogous to Example 23-13.
Example 23-17:
Figure imgf000346_0004
[0858] 2-chloro-l-isopropyl-5-methyl-benzoimidazole was prepared in a manner analogous to Example 23-13. Example 23-18:
Figure imgf000346_0005
[0859] 2-chloro-l-isopropyl-4-methyl-benzoimidazole was prepared in a manner analogous to Example 23-13.
Figure imgf000347_0001
[0860] 2-chloro-l-isopropyl-7-fluoro-benzoimidazole was prepared in a manner analogous to Example 23-13. 1H NMR (400 MHz, DMSOd6) δ 7.5 (d, / = 8.0 Hz, 1 H), 7.15-7.27 (m, 2 H), 5.0 (m, 1 H), 1.52 (d, / = 13.6 Hz, 6 H).
Example 23-19:
Figure imgf000347_0002
[0861] 2-chloro-l-isopropyl-5-fluoro-benzoimidazole was prepared in a manner analogous to Example 23-13.
Example 23-20:
Figure imgf000347_0003
[0862] 2-chloro-l-isopropyl-4-fluoro-benzoimidazole was prepared in a manner analogous to Example 23-13. 1H NMR (400 MHz, DMSOd6) δ 7.71 (m, 1 H), 7.16 (m, 1 H), 7.08 (m, 1 H), 4.90 (m, IH), 1.57 (d, / = 8.0 Hz, 6 H).
Example 23-20:
Figure imgf000347_0004
[0863] Compound 467 was prepared in a manner analogous to General Procedure F, to afford 60.9 mg (30.9%). MS (ESI) m / z (M+H)+ 735.3. Example 23-21:
Figure imgf000348_0001
468 [0864] Compound 468 was prepared in a manner analogous to General Procedure
F, to afford 45 mg (22.8%). MS (ESI) m / z (M+H)+ 735.3.
Example 23-22:
Figure imgf000348_0002
469
[0865] Compound 469 was prepared in a manner analogous to General Procedure
F, to afford 25.5 mg (12.9%). MS (ESI) m / z (M+H)+ 735.3.
Example 23-23:
General Procedure DDD
[0866] To a solution of general compound XX-B (leq) in 3 ml of DMSO was added t-BuOK (6 eq) with ice water bath. The resulting mixture was stirred at this temperature for 0.5h before the addition of compound 5 (l.leq), and it was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by water (10 mL), extracted with ethyl acetate, washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by prep-HPLC to give target general compound XX-C.
Figure imgf000349_0001
470 [0867] Compound 470 was prepared in a manner analogous to General Procedure
DDD, to afford 5.9 mg (3.0%). MS (ESI) m / z (M+H)+ 731.4.
Example 23-25:
Figure imgf000349_0002
[0868] Compound 471 was prepared in a manner analogous to General Procedure DDD, to afford 25.2 mg (10%). MS (ESI) m / z (M+H)+ MS: 731.3.
Example 23-26:
Figure imgf000349_0003
364
[0869] Compound 364 was prepared in a manner analogous to General Procedure DDD, to afford 25.2 mg (10%). MS (ESI) m / z (M+H)+ MS: 731.3.
Figure imgf000350_0001
General Method DDDA
[0870] To a solution of compound 78 (150 mg, 0.27 mmol) in 3 mL of DMSO was added /-BuOK (182 mg, 1.62 mmol.) with ice water bath. The resulting mixture was stirred at this temperature for 0.5 h before the addition of 2-chloro-3-isopropyl-3H- imidazo[4,5-c]pyridine (59 mg, 0.30 mmol.), and it was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by water (10 mL), extracted with ethyl acetate, washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by Prep-ΗPLC to afford compound 491 (56.5 mg, 29%). MS (ESI) m / z (M+Η)+ 718.2.
Example 24:
Scheme XXII: Synthesis of Compound 396
Figure imgf000350_0002
396
[0871] Compound 17 can be treated with a heteroaryl chloride, such as 2-chloro-
4-phenylthiazole and the like, under basic conditions, for example sodium hydride in DMF, to shown) to provide macrocycles, such compound 396.
Example 24-1:
Figure imgf000351_0001
[0872] Compound 463 was prepared in a manner analogous to General Procedure B, to afford the desired product in 13.9% yield.
Example 24-2:
Figure imgf000351_0002
396
[0873] Compound 396 was prepared in a manner analogous to General Procedure F, to afford 5.6 mg (12.6%). MS (ESI) m / z (M+H)+ 804.3.
Figure imgf000352_0001
XXIII-C
[0874] Macrocyclics of general structures XXIII-B and XXIII-C can be synthesized as shown in Scheme XXIII. The isoindoline carbamate 10 can be treated under basic conditions to hydrolyse the isoindoline carbamate thereby providing alcohol 11. The alcohol 11 can be treated with a heteroaryl chloride, such as 4-chloro-7-methoxy-2- DMSO, to afford an heteroaryl ether, such as compound 72. The heteroaryl ether, such as compound 72 can be treated with acid in methanol to remove the Boc protecting group and form a methyl ester thereby providing an amino ester, such as compound 73. The an amino ester, such as compound 73, can be treated with optionally substituted aryl boronic acids under Cu2+-catalyzed conditions thereby providing N-aryl compounds of general structure XXIII-A. The compounds of general structure XXIII-A can be treated under basic conditions, for example lithium hydroxide in methanol and water, to hydrolyse the methyl ester thereby providing carboxylic acids of general structure XXIII-B. Finally, acids of general structure XXIII-B can be coupled with sulfonamides (or sulfamides, not shown) thereby providing compounds general structure XXIII-C.
Example 25-1:
General Procedure YY
OH
Figure imgf000353_0001
11
[0875] To a solution of compound 10 (10 g, 15.9 mmol.) in 100 mL of methanol was added aq. NaOH (5 M, 95 mL), the resulting mixture was heated to 50 0C and stirred overnight, The reaction was monitored by LCMS. After completion of the reaction, the mixture was cooled by ice water, acidified by aq. HCl (2 M) to pH=3-4, then the mixture was extracted by ethyl acetate (3 X 200 mL), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the crude compound 11 was used directly in the next step (7.5 g, 83%). General Procedure ZZ
Figure imgf000354_0001
[0876] To a solution of compound 11 (4.0 g, 7 mmol.) in 4 mL of DMSO was added J-BuOK (6.0 g, 42 mmol.) in portions at ambient temperature, then the mixture was stirred for 2 h at ambient temperature. After that, 4-chloro-7-methoxy-2-phenylquinoline (2.8 g, 10.5 mmol.) was added, the resulting mixture was stirred at ambient temperature for 12 h, the reaction was monitored by LCMS. After completion of the reaction, the mixture was cooled by ice water, acidified by aq.HCl (2 M) to pH=8, then the mixture was extracted by ethyl acetate (3 x 100 mL), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure, the crude product was purified by column chromatography to afford compound 72 (3.0 g , 54%).
Example 25-3:
General Procedure AAA
Figure imgf000354_0002
[0877] Compound 72 (1.2 g, 1.5 mmol.) was dissolved in a solution of HCl (gas) in MeOH (4 moL/L, 100 mL), the resulting mixture was stirred at room temperature for 12h. After that, the solvent was evaporated, the mixture was basified by saturated aqueous
NaHCO3, then extract with ethyl acetate (3 x 50 mL), the organic layer was dried over 73 (910 mg, 99%) was used directly in the next step.
Example 25-4:
Figure imgf000355_0001
[0878] Aryl amines of general structure XXIII-A can be prepared, by coupling an optionally substituted arylboronic acid with compound 73 using a copper catalyst, as depicted in Scheme XXIII.
Example 25-5:
Figure imgf000355_0002
[0879] Carbocyclic acids of general structure XXIII-B can be prepared, by base catalyzed hydrolysis of the methyl ester of general structure XXIII-A, as depicted in Scheme XXIII.
Example 25-6:
Figure imgf000356_0001
[0880] Acyl sulfonamides of general structure XXIII-C can be prepared, by coupling 1-methylcyclopropane-l- sulfonamide with carbocyclic acids of general structure XXIII-B as depicted in Scheme XXIII.
Example 25-7:
Figure imgf000356_0002
229
[0881] Compound 229 was prepared in a manner analogous to General Procedure
F, to afford 58 mg (45%) of the desired compound. MS (ESI) m / z (M+H)+ 860.2.
Example 25-8:
Figure imgf000356_0003
355 F, to afford 127 mg (45%) of the desired compound. MS (ESI) m / z (M+H)+ 878.2.
Example 26
Scheme XXIV: General Route for synthesis of Acylsulfonamides
Figure imgf000357_0001
XXIV-A XXIV-B
Figure imgf000357_0002
XXIV-C XXIV-D
[0883] Macrocyclics of general structures XXIV-C and XXIV-D can be synthesized as shown in Scheme XXIV. The isoindoline carbamate 6 can be treated with under acidic conditions, for example hydrochloric acid in methanol, to remove the Boc protecting group and form a methyl ester thereby providing compound 12. Compound 12 can be treated with optionally substituted aryl boronic acids under Cu2+-catalyzed conditions thereby providing N- aryl compounds, such as compound having general structure XXIV-A. Compounds having general structure XXIV-A can be treated under basic conditions, for example aqueous sodium hydroxide in methanol, to hydrolyse the methyl ester and the isoindoline carbamate thereby providing a hydroxy acid having general structure XXIV-B. such as 1-chloro-isoquinoline and the like, under basic conditions, such as sodium hydride in DMF, to afford carboxylic acids having general structure XXIV-C. Finally, carboxylic acids having general structure XXIV-C can be coupled with sulfonamides (or sulf amides, not shown) thereby providing compounds general structure XXIV-D.
Example 26-1:
General Procedure BBB
Figure imgf000358_0001
12
[0884] Compound 6 (3 g) was dissolved in a solution HCl in MeOH (4 M, 100 mL), the resulting mixture was stirred at 25 0C, the reaction was monitored by LCMS, after completion of the reaction, the solvent was removed, the HCl salt of amino ester 12 was obtained.
Example 26-2:
Figure imgf000358_0002
XXIV-A
[0885] Aryl amines of general structure XXIV-A can be prepared, by coupling an optionally substituted arylboronic acid with compound 12 using a copper catalyst, as depicted in Scheme XXIV.
Figure imgf000359_0001
XXIV-B
[0886] Carboxylic acid alcohols of general structure XXIV-B can be prepared, by base catalyzed hydrolysis of both the isoindoline carbamate and methyl ester of general structure XXIV-A, as depicted in Scheme XXIV.
Example 26-4:
Figure imgf000359_0002
XXIV-C
[0887] Carboxylic acids of general structure XXIV-C can be prepared, by base catalyzed coupling of carboxylic acid alcohols of general structure XXIV-B with 1- chloroisoquinoline, as depicted in Scheme XXIV.
Example 26-5:
Figure imgf000359_0003
XXIV-D coupling 1-methylcyclopropane-l- sulfonamide with carbocyclic acids of general structure XXIV-C, as depicted in Scheme XXIV.
Example 26-6:
Figure imgf000360_0001
346
[0889] Compound 346 was prepared in a manner analogous to General Procedure
F, to afford 45 mg (26%) of the desired compound. MS (ESI) m / z (M+H)+ 772.2.
Example 26-7:
Figure imgf000360_0002
444 [0890] Compound 444 was prepared in a manner analogous to General Procedure
F, to afford 28.1 mg (16%) of the desired compound. MS (ESI) m / z (M+H)+ 770.1.
Figure imgf000361_0001
76 XXV-A
[0891] Macrocyclics of general structures XXV-A can be synthesized as shown in
Scheme XXV. Alcohol 11 can be treated with a heteroaryl chloride, such as 4-chloro-2-(4- isopropylthiazol-2-yl)-7-methoxy-8-methylquinoline and the like, under basic conditions, for example sodium fert-butoxide in DMSO, to afford a heteroaryl ether, such as compound 75. The heteroaryl ether, such as compound 75, can be treated under acidic conditions, for example TFA in DCM, to remove the Boc protecting group thereby providing an amino acylsulfonamide, such as compound 76. The amino acylsulfonamide, such as compound 76, can be treated with optionally substituted aryl boronic acids under Cu2+-catalyzed conditions thereby providing macrocycles of general structure XXV-A.
General Procedure CCC
Figure imgf000362_0001
75
[0892] To a solution of compound 11 (570 mg, 1 mmol.) in 4 mL of DMSO was added t-BuOK (732 mg, 6 mmol.) portionwise at ambient temperature, then the mixture was stirred for 2 h at ambient temperature, after that, compound 4-chloro-2-(4-isopropylthiazol-2- yl)-7-methoxy-8-methylquinoline (400 mg, 1.2 mmol.) was added, the resulting mixture was stirred at ambient temperature for 12 h. The reaction was monitored by LCMS, after completion of the reaction, The mixture was cooled by ice water, acidified by aq. HCl (2 M) to pH=8, then the mixture was extracted by ethyl acetate (3 x 50 mL), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure, the crude product was purified by column chromatography, 430 mg (85% purity) of compound 75 was obtained (yield 42%).
Example 27-2:
Figure imgf000362_0002
[0893] Compound 76 is prepared in a manner analogous to General Procedure S.
Example 27-3:
Figure imgf000363_0001
464 [0894] Compound 464 was prepared in a manner analogous to General Procedure
D, to afford 154 mg (32%). MS (ESI) m / z (M+H)+ 866.4.
Example 28
Scheme XXVI: Synthesis of N-aryl & P4 Quinoline Analogs
General Procedure EEE
Figure imgf000363_0002
9 XXVI-A
[0895] A mixture of compound 9 (1 eq.), boronic acid (3 eq.), Cu(OAc)2 (2 eq.), pyridine (10 eq.), pyridine N-Oxide (2 eq.) and molecular sieves 4A in dichloromethane (5 mL) was stirred for 12 h at room temperature under an atmosphere of oxygen. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by prep-HPLC to give general compound XXVI-A.
Figure imgf000364_0001
472 [0896] Compound 472 was prepared in a manner analogous to General Procedure
EEE, to afford 5.5 mg (9.8%). MS (ESI) m / z (M+H)+ 869.3.
Example 28-2
Figure imgf000364_0002
473 [0897] Compound 473 was prepared in a manner analogous to General Procedure
EEE, to afford 8.0 mg (14%). MS (ESI) m / z (M+H)+ 891.3.
Example 28-3
Figure imgf000364_0003
474 [0898] Compound 474 was prepared in a manner analogous to General Procedure
EEE, to afford 5.5 mg (9.4%). MS (ESI) m / z (M+H)+ 912.3.
Figure imgf000365_0001
475 [0899] Compound 475 was prepared in a manner analogous to General Procedure
EEE, to afford 5.6 mg (9.6%). MS (ESI) m / z (M+H)+ 912.3.
Example 28-5
Figure imgf000365_0002
476 [0900] Compound 476 was prepared in a manner analogous to General Procedure
EEE, to afford 5.6 mg (6.4 %). MS (ESI) m / z (M+H)+ 880.1.
Example 28-6
Figure imgf000365_0003
477 [0901] Compound 477 was prepared in a manner analogous to General Procedure
EEE, to afford 5.4 mg (9.7%). MS (ESI) m / z (M+H)+ 869.2.
Figure imgf000366_0001
478 [0902] Compound 478 was prepared in a manner analogous to General Procedure
EEE, to afford 5.5 mg (9.7%). MS (ESI) m / z (M+H)+ 885.3.
Example 28-8
Figure imgf000366_0002
479 [0903] Compound 479 was prepared in a manner analogous to General Procedure
EEE, to afford 22 mg (37%). MS (ESI) m / z (M+H)+ 926.3.
Example 28-9
Figure imgf000366_0003
[0904] Compound 480 was prepared in a manner analogous to General Procedure EEE, to afford 14.6 mg (17 %). MS (ESI) m / z (M+H)+ 908.9.
Figure imgf000367_0001
[0905] Compound 481 was prepared in a manner analogous to General Procedure EEE, to afford 19.7 mg (23 %). MS (ESI) m / z (M+H)+ 879.9.
Example 28-11
Figure imgf000367_0002
482 [0906] Compound 482 was prepared in a manner analogous to General Procedure
EEE, to afford 17.6 mg, 22 %. MS (ESI) m / z (M+H)+ 887.
Example 28-12
Figure imgf000367_0003
[0907] Compound 483 was prepared in a manner analogous to General Procedure EEE, to afford 9 mg (15 %). MS (ESI) m / z (M+H)+ 898.4.
Figure imgf000368_0001
[0908] Compound 484 was prepared in a manner analogous to General Procedure EEE, to afford 29.1 mg (48 %). MS (ESI) m / z (M+H)+ 947.9.
Example 28-14
Figure imgf000368_0002
[0909] Compound 485 was prepared in a manner analogous to General Procedure EEE, to afford 20.1 mg, (34 %). MS (ESI) m / z (M+H)+ 912.
Example 28-15:
Figure imgf000368_0003
492
[0910] Compound 492 was prepared in a manner analogous to General Procedure EEE, to afford 12.9 mg (15% yield). MS (ESI) m / z (M+H)+ 873.4. Example 28-16 :
Figure imgf000369_0001
[0911] Compound 493 was prepared in a manner analogous to General Procedure EEE, to afford 5.8 mg (6.4% yield). MS (ESI) m / z (M+H)+ 939.3.
Example 29
Scheme XXVII: Synthesis Quinoxalene Analogs
Example 29-1
Figure imgf000369_0002
[0912] A mixture of o-phenylenediamine (2.16 g, 20 mmol) and ethyl thiophene- 2-glyoxylate (3.68 g, 20 mmol.) in anhydrous methanol (60 mL) was stirred at room temperature for 12 hours under nitrogen atmosphere. The precipitate formed during this time was collected and washed with methanol to give a crude yellow solid, which was recrystallized from ethanol to give pure 3-(2-thienyl)quinoxalin-2(l/7)-une (3.2 g, 70%). 1H NMR (400MHz, DMSOd6) δ 12.7 (s, 1 H), 8.39 (d, / = 4.4 Hz, 1 H), 7.83 (d, / = 5.2 Hz, 1 H), 7.77 (d, / = 8.0 Hz, IH), 7.50 (t, / = 7.6 Hz, IH), 7.35-7.29 (m, 1 H), 7.22 (t, / = 4.8 Hz, 1 H).
Example 29-2
Figure imgf000369_0003
[0913] A mixture of 3-(2-thienyl)quinoxalin-2(l/f}-one (500 mg, 2.19 mmol.) and POCI3 (6 mL) was heated to reflux at 1200C. After the material was consumed, the reaction 2-chloro-3-f2-thienyl)quinoxaline (400 mg, 74%). 1H NMR (400MHz, CDCl3) δ 8.22 (d, / = 4.8 Hz, 1 H), 8.00 (d, / = 10.4 Hz, 1 H), 7.91 (d, / = 10.4 Hz, 1 H), 7.72-7.61 (m, 2 H), 7.52 (d, / = 6.8 Hz, 1 H), 7.13 (t, /= 6.0 Hz, I H).
Example 29-4
Figure imgf000370_0001
XX-A 74
[0914] Compound 74 can be formed in a manner analogous to the procedure for forming general compound XX-B.
Figure imgf000370_0002
74 486
[0915] To a solution of intermediate 74 (140 mg, 0.25 mmol) in 3ml of dry DMF was added Cs2CO3 (407 mg, 1.25 mmol) and 2-chloro-3-(2-thienyl)quinoxaline (74 mg, 0.3 mmol). The resulting mixture was stirred at 700C overnight. The reaction was quenched by water (10ml),extract by ethyl acetate, washed with brine 700C, dried over Na2SO4, concentrated to get a residue, which was purified by prep-HPLC to give compound 486 (56.4 mg, 27.4%). 1H NMR (400 MHz, CDCl3 + D2O) δ 10.84 (d, / = 8.8Hz , 2 H), 7.71 (d, / = 12.0 Hz, 1 H ), 7.56 (m, 2 H), 7.34 (d, / = 8.2 Hz, 2 H), 7.0 (m,l H), 6.76 (t, / = 10.6 Hz, 2 H), 6.42 (m,3 H), 5.98 (s,l H), 5.68 (m, 1 H), 4.95 (t, / = 12.6 Hz, 1 H), 4.55 (d, / = 12 Hz, 5 H), 1.18-1.51 (m,ll H). MS (ESI) m / z (M+H)+ 768.9.
Table 1: Examples of compounds that can be prepared according to Examples 1-29
Figure imgf000371_0001
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
-All-
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0001
-All-
Figure imgf000473_0001
PREPARATION OF NS3 INHIBITORS: SECTION VII
Example 31-1: Synthesis of Compound 1001 Scheme XXIX
Figure imgf000473_0002
General Method XA
[0916] To a solution of compound 2 (1 g, 2.2 mmol.) in 10 mL of dry DMF was added sodium hydride (0.53 g, 13.2 mmol.) at 0 0C. The resulting mixture was stirred at this temperature for 1 h before the addition of 2-chloro-benzothiazole, the mixture was then allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched by careful addition of methanol (10 mL) and water (30 mL). The resulting solution and concentrated under reduced pressure to afford a residue. The residue was purified by Prep-HPLC to afford compound 1001 as a white solid 0.78 g (yield 60.5 %). 1H NMR (400 MHz, DMSOd6) δ 12.22 (bra, 1 H), 8.61 (s, 2 H), 7.83 (d, / = 7.6 Hz, 1 H), 7.67 (d, / = 7.6 Hz, 1 H), 7.36 (t, / = 7.2 Hz, 1 H), 7.24 (t, / = 7.2 Hz, 1 H), 6.94 (d, / = 6.8 Hz, 1 H), 5.74 (s, 1 H), 5.46 (q, / = 8 Hz, 1 H), 5.25 (t, / = 9.2 Hz, 1 H), 4.51 (d, / = 12.8 Hz, 1 H), 4.41 (t, / = 8 Hz, 1 H), 4.00 (t, / = 10 Hz, 1 H), 3.87 (d, / = 9.6 Hz, 1 H), 2.29-2.30 (m, 1 H), 2.14- 2.16 (m, 1 H), 1.43-1.47 (m, 2 H), 1.29-1.14 (m, 16H). MS (ESI) m/e (M+H+) 598.7.
Example 31-2: Synthesis of Compound 1002:
Figure imgf000474_0001
1002
[0917] The acid 1002 was prepared following General Method XA, and the yield was 65%. MS (ESI) m/e (M+H+) 617.2.
Example 31-3: Synthesis of Compound 1003:
Figure imgf000474_0002
1003
[0918] The acid 1003 was prepared following General Method XA, and the yield was 65%. MS (ESI) m/e (M+H+) 677.6. Example 31-4: Synthesis of Compound 1004:
Figure imgf000475_0001
1004
[0919] The acid 1004 was prepared following General Method XA, and the yield was 50%. MS (ESI) m/e (M+H+) 613.3.
Example 31-5: Synthesis of Compound 1005:
Figure imgf000475_0002
1005
[0920] The acid 1005 was prepared following General Method XA, and the yield was 51%, MS (ESI) m/e (M+H+) 629.3.
Figure imgf000476_0001
1006
[0921] The acid 1006 was prepared following General Method XA, and the yield was 41%, MS (ESI) m/e (M+H+) 633.
Scheme XXX
Figure imgf000477_0001
701 702
Figure imgf000477_0002
1079
[0922] Compound 1079 can be synthesized by the method of Scheme XXX. The benzimidazole can be introduced by use of a SEM protected benzimidazole, l-((2- (trimethylsilyl)ethoxy)methyl)-2-chloro-lH-benzo[ύ0imidazole. The SEM protecting group can be introduced by treatment of 2-chloro-lH-benzo[ύf|imidazole with a base, such as sodium hydride, potassium hydride and the like, followed by addition of 2- (trimethylsilyl)ethoxymethyl chloride (SEMCl) thereby providing l-((2- (trimethylsilyl)ethoxy)methyl)-2-chloro-lH-benzo[rf]imidazole (1.13 g, 60.8%). The alcohol, compound 7, can be treated with a base, such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium terf-butoxide, and the like, then reacted with l-((2-(trimethylsilyl)ethoxy)methyl)-2-chloro-lH- benzo [d] imidazole to afford compound 701. The SEM and Boc groups can be removed under acidic conditions to afford compound 702. For example, the acid can be trifluoroacetic of compound 702 with (Boc)2O in the presence of a base, such as cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, to afford compound compound 1079.
Example 32-2: Synthesis of Compound 701:
Figure imgf000478_0001
701
General Method XB
[0923] To a solution of compound 7 (300 mg, 0.515 mmol.) in 3mL of dry DMF was added sodium hydride (60%, 204 mg, 5.1 mmol.) at 00C. The resulting mixture was stirred at this temperature for Ih, then l-((2-(trimethylsilyl)ethoxy)methyl)-2-chloro-lH- benzo [d] imidazole (175 mg, 0.618 mmol.) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate (50 mLx3), washed with brine, dried over Na2SO4, concentrated to give a residue, which was purified by prep-TLC to give compound 701 as white solid (150 mg, yield 35.2%). MS (ESI) m / z (M+Η)+ 829.4.
Example 32-3: Synthesis of Compound 702:
Figure imgf000478_0002
701 702
General Method XC was added TFA (1 mL). The reaction mixture was stirred at room temperature for 3 h. LCMS analysis showed the reaction complete. The reaction mixture was concentrated to give crude compound 702 (40 mg, 93%), which was used without further purification.
Example 32-4: Synthesis of Compound 1079:
Figure imgf000479_0001
General Method XD
[0925] To a solution of compound 702 (40 mg, 0.067 mmol.) in dry THF (2 mL) was added NaHCU3 (16.9 mg, 0.261 mmol.) and followed by adding di-tert-butyl dicarbonate (34.6 mg, 0.201 mmol.). The reaction mixture was stirred at room temperature overnight. LCMS analysis showed the reaction complete. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mLx3). The organic layer was dried over Na2SO4, concentrated and purified by prep-TLC to give compound 1079 (14.2 mg, 15%). MS (ESI) m/z (M+H)+ 699.3.
Example 32-5: Synthesis of l-((2-(trimethylsilyl)ethoxy)methyl)-2-chloro-lH- benzo [d] imidazole :
Figure imgf000479_0002
General Method XE
[0926] To a solution of 2-chloro-lH-benzo[rf]imidazole (1 g, 6.6 mmol.) in dry DMF (10 mL) was added sodium hydride (60%, 0.26 g, 6.5 mmol.) at room temperature under nitrogen atmosphere. 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 1.14 g, 6.8 mmol.) was added dropwise after the solution stirred for 1.5 h. The resulting mixture stirred combined organic layers was washed with water, dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography to give l-((2- (trimethylsilyl)ethoxy)methyl)-2-chloro-lH-benzo[rf]imidazole (1.13 g, 60.8%).
Example 32-6: Synthesis of Compound 1077:
Figure imgf000480_0001
General Method XF
[0927] To a suspension of NaH (60%, 62 mg, 1.54 mmol.) in 2 mL DMF was added compound 7 (150 mg, 0.257 mmol.) at 0 0C. After the mixture was stirred for 2 h at 0-5 0C, 2-chloro-l-isopropyl-benzimidazole (60 mg, 0.31 mmol.) was added, the resulting mixture was warmed to room temperature and stirred for 12 h. After completion of the reaction, the mixture was cooled by ice water, acidified by aq HCl (IN) to ~pH=5-6, then the mixture was extracted by ethyl acetate (30 mLx3), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the residue was purified by prep-HPLC to afford compound 1077 (20 mg, 10.5%). MS (ESI) m/z (M+H)+ 741.4.
Example 32-7: Synthesis of Compound 1007:
Figure imgf000481_0001
11 1007
[0928] The acylsulfonamide 1007 was prepared following General Method XF, and the yield was 45%, MS (ESI) m/e (M+H+) 713.
Example 33-1: Synthesis of Compound 1008:
Figure imgf000481_0002
1001 1008
General Method B
[0929] To a solution of compound 1001 (100 mg, 0.17 mmol.) in 5 mL of dry DMF was added HATU (226 mg,, 0.6 mmol.) and DIEA (0.1 mL, 0.6 mmol.) at 20 0C. The resulting mixture was stirred 1 h at the same temperature then treated with methylcyclopropanyl sulfonamide (45.9 mg, 0.34 mmol.), DMAP (104 mg, 0.85 mmol.), and DBU (0.1 mL, 0.85 mmol.). Subsequently, the resulting mixture was stirred overnight at 20 0C. The reaction was quenched by adding EtOAc (20 mL), and washed with aqueous NaOAc buffer (pH 4, 2 x 15 mL), 5% aqueous NaHCO3 (15 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to get a residue, which was m/e (M+H+) 716.3.
Example 33-2: Synthesis of Compound 1009:
Figure imgf000482_0001
1001 1009
[0930] The acylsulfonamide 1009 was prepared following General Method B, the pure product was isolated as a white solid. Yield = 45.3%. MS (ESI) m/e (M+H+) 702.3.
Example 33-3: Synthesis of Compound 1010:
Figure imgf000482_0002
1002 1010
[0931] The acylsulfonamide 1010 was prepared following General Method B, the pure product was isolated as a white solid. Yield= 36%. MS (ESI) m/e (M+H+) 720.3.
Figure imgf000483_0001
1002 1011
[0932] The acylsulfonamide 1011 was prepared following General Method B, the pure product was isolated as a white solid. Yield =43% MS (ESI) m/e (M+H+) 734.3.
Example 33-5: Synthesis of Compound 1012:
Figure imgf000483_0002
1003 1012
[0933] The acylsulfonamide 1012 was prepared following General Method B, the pure product was isolated as a white solid. Yield = 40%. MS (ESI) m/e (M+H+) 780.8.
Figure imgf000484_0001
1003 1013
[0934] The acylsulfonamide 1013 was prepared following General Method B, the pure product was isolated as a white solid. Yield= 36%. MS (ESI) m/e (M+H+) 794.8.
Example 33-7: Synthesis of Compound 1014:
Figure imgf000484_0002
1004 1014
[0935] The acylsulfonamide 1014 was prepared following General Method B, the pure product was isolated as a white solid. Yield =37%. MS (ESI) m/e (M+H+) 730.3.
Figure imgf000485_0001
1004 1015
[0936] The acylsulfonamide 1015 was prepared following General Method B, the pure product was isolated as a white solid. Yield =41%. MS (ESI) m/e (M+H+) 716.3.
Example 33-9: Synthesis of Compound 1016:
Figure imgf000485_0002
1005 1016
[0937] The acylsulfonamide 1016 was prepared following General Method B, the pure product was isolated as a white solid. Yield =33%. MS (ESI) m/e (M+H+) 746.3.
Figure imgf000486_0001
1005 1017
[0938] The acylsulfonamide 1017 was prepared following General Method B, the pure product was isolated as a white solid. Yield=39%. MS (ESI) m/e (M+H+) 742.3.
Example 33-11: Synthesis of Compound 1018:
Figure imgf000486_0002
1006 1018
[0939] The acylsulfonamide 1018 was prepared following General Method B, the pure product was isolated as a white solid. Yield=42%. MS (ESI) m/e (M+H+) 736.
Figure imgf000487_0001
1006 1019
[0940] The acylsulfonamide 1019 was prepared following General Method B, the pure product was isolated as a white solid. Yield=40%. MS (ESI) m/e (M+H+) 742.3.
Example 34-1: Synthesis of Compound 7-E:
Figure imgf000487_0002
1001 1020
General Method C
[0941] To a solution of compound 1001 (100 mg, 0.17 mmol.) in 5 mL of dry DMF was added PyBOP (177 mg, 0.34 mmol.) and HOBT (46 mg, 0.34 mmol.) at room temperature, the resulting mixture was stirred 2 h at the same temperature. Subsequently, the stirring mixture was treated with O-phenylhydroxylamine hydrochloride (26.9 mg, 0.19 mmol.) and DIEA (88 mg, 0.68 mmol.), the resulting mixture was stirred overnight at rt. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to get a residue, which was purified by Prep-HPLC to give compound 1020 as white solid 50 mg (yield 32.5%). MS (ESI) m/e (M+H+) 690.3.
Figure imgf000488_0001
1002 1021
[0942] The hydroxamate 1021 was prepared following General Method C, the pure product was isolated as a white solid. Yield = 45.3% MS (ESI) m/e (M+H+) 708.3.
Example 34-3: Synthesis of Compound 1022:
Figure imgf000488_0002
1003 1022
[0943] The hydroxamate 1022 was prepared following General Method C, the pure product was isolated as a white solid. Yield = 45.5% MS (ESI) m/e (M+H+) 768.7.
Figure imgf000489_0001
1006 1023
[0944] The hydroxamate 1023 was prepared following General Method C, the pure product was isolated as a white solid. Yield = 43.5% MS (ESI) m/e (M+H+) 724.
Figure imgf000489_0002
1004 1024
[0945] The hydroxamate 1024 was prepared following General Method C, the pure product was isolated as a white solid. Yield =43.5% MS (ESI) m/e (M+H+) 704.3.
Figure imgf000490_0001
1005 1025
[0946] The hydroxamate 1025 was prepared following General Method C, the pure product was isolated as a white solid. Yield= 45.3% MS (ESI) m/e (M+H+) 720.3.
Example 35-1: Synthesis of Compound 1026:
Figure imgf000490_0002
1026
[0947] The acid 1026 was prepared following General Method A, oxazole chloride was used in place of thiazole chloride. The isolated yield of the acid 1026 was 16%, MS (ESI) m/e (M+H+) 583.3.
Figure imgf000491_0001
1026 1027
[0948] The hydroxamate 1027 was prepared following General Method C, the pure product was isolated as a white solid. Yield = 44.3% MS (ESI) m/e (M+H+) 674.3.
Example 36-1: Synthesis of Compound 1028:
Figure imgf000491_0002
1026 1028 General Method D
[0949] To a solution of compound 1026 (100 mg, 0.17 mmol.) in dry DCM (3 mL) was added CDI (55 mg, 0.34 mmol.) at 25 0C, the mixture was stirred 1 h at the same temperature. Subsequently, the stirring mixture was treated with methylcyclopropanyl sulfonamide (46 mg, 0.34 mmol.) and DBU (0.1 mL, 0.85 mmol.), the resulting mixture was stirred overnight at 25 0C. The solvent was removed to afford a residue which was purified by Prep-HPLC to afford 1028 as white solid 50 mg (yield 43%). MS (ESI) m/e (M+H+) 700.3.
Example 36-2: Synthesis of Compound 1029:
Figure imgf000492_0001
1026 1029
[0950] The acylsulfonamide 1029 was prepared following General Method D, the pure product was isolated as a white solid. Yield is 17.3%. MS (ESI) m/e (M+H+) 686.3.
Example 37-1: Synthesis of Compound 2:
Figure imgf000492_0002
1 2
General Method E
[0951] To a solution of compound 1 (10 g, 15.9 mmol.) in methanol (100 mL) was added 100 mL of aqueous solution of NaOH (20%). The resulted mixture was stirred at 70 0C for 3 h. Concentrated hydrochloric acid was then added slowly at 5-10 0C until the pH was adjusted to 3-4. Methanol was removed under vacuum, and the resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford compound 2, as a brown solid 6.5 g (yield 88%), which was used without further purification. Example 39-1: Procedure for the Synthesis of 2-chloro benzoxazoles or 2-chloro benzothiazoles:
Scheme
Figure imgf000493_0001
[0952] The synthetic intermediate 2-chloro-5-methylbenzo[rf]oxazole can be prepared by the method shown in Scheme XXXI. 2-Amino-4-methyl-phenol can be treated with potassium ethyl xanthate in a solvent, such as ethanol, methanol and the like, to afford 5- methylbenzo[ύT|oxazole-2-thiol. 5-methylbenzo[rf]oxazole-2-thiol can be treated with a chlorinating agent, such as P(O)Cl3, P(O)Cl3 with PCI5, and the like, to afford 2-chloro-5- methylbenzo [d] oxazole.
General Procedure for preparing 2-thiol benzoxazole or benzothiazole intermediates:
[0953] Potassium ethyl xanthate (4.4 g, 27.5 mmol.) was added to solution of 2- amino-4-methyl -phenol (2 g, 16.2 mmol.) in ethanol (40 mL). The reaction mixture was heated at reflux for 4 h then allowed to cool to rt. Upon cooling to rt the mixture was concentrated and the resulting residue was dissolved in water. Acetic acid was added until ~pH=5 and a white solid precipitated from the solution. The solid was collected by filteration, washed with water and dried to afford 5-methylbenzo[ύf|oxazole-2-thiol as a powder (2.4 g, 92.3%) which was used without further purification. MS (ESI) m/e (M+H+) 166. General Procedure for preparing 2-chloro benzoxazole or benzothiazole intermediates:
[0954] To a suspension of 5-methylbenzo[rf]oxazole-2-thiol (1.0 g, 6.1 mmol.) in POCl3 (11.7 g, 76.4 mmol.) at room temperature was added PCI5 (1.9 g, 9.15 mmol.) along with CH2CI2 (10 mL). After 4 h of stirring at room temperature, the reaction mixture was concentrated to remove excess POCl3 , and the residue was treated with Na2CO3 solution until ~pH 8 was reached. The aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 2-chloro-5- methylbenzo [d] oxazole (1.1 g crude product) which was used without further purification. MS (ESI) m/e (M+H+) 168. intermediates were prepared following the same experimental procedure for making 2-chloro- 5 -methylbenzo [d] oxazole.
Example 40-1: Synthesis of Compound 1030:
Figure imgf000494_0001
11 1030
General Method O
[0956] To a solution of compound 11 (100 mg , 0.176 mmol.) in 3 mL of dry DMF was added sodium hydride (42 mg, 10.3 mmol.) at 0 °C.The resulting mixture was stirred at this temperature for 1 h before the addition of 2-chloro-5-methylbenzooxazole, and it was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by careful addition of water (15 mL), extracted by ethyl acetate, backwashed with water, dried over Na2SO4, concentrated to afford a residue, which was purified by Prep-HPLC to give compound 1030 as white solid 5.3 mg (yield 4.3%). 1H NMR (400 MHz, CDCl3) δ 10.23 (bra, 1 H), 7.31 (s, 1 H), 7.20 (d, / = 8.4 Hz, 1 H), 7.67 (d, / = 7.6 Hz, 1 H), 6.85 (s, 1 H), 5.72 (m, 2 H), 5.67 (s, 1 H), 5.30 (t, / = 9.4 Hz, 2 H), 4.65 (d, / = 8 Hz, 1 H), 4.23 (t, / = 9.2 Hz, 1 H), 4.51 (d, / = 12.8 Hz, 1 H), 4.41 (t, / = 8 Hz, 1 H), 4.23 (t, / = 7.2 Hz, 1 H), 3.60 (d, / = 11.6 Hz, 1 H), 2.90-2.95 (m, 1 H), 2.43 (s, 1 H), 1.70 (m, 1 H), 1.18-1.87 (m, 26 H), 1.0 (m, IH ). MS (ESI) m/e (M+H+) 700.
Figure imgf000495_0001
11 1031
[0957] Compound 1031 was prepared following General Method O, and the yield was 2%. MS (ESI) m/e (M+H+) 700.
Example 40-3: Synthesis of Compound 1032:
Figure imgf000495_0002
11 1032
[0958] Compound 1032 was prepared following General Method O. The pure product was purified by TLC to give white solid, and the yield was 18%. MS (ESI) m/e (M+H+) 720.
Example 40-4: Synthesis of Compound 1033:
Figure imgf000495_0003
product was isolated as a white solid, and the yield was 14%. MS (ESI) m/e (M+H+) 700.
Example 40-5: Synthesis of Compound 1034:
Figure imgf000496_0001
11 1034
[0960] Compound 1034 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 6%. MS (ESI) m/e (M+H+) 704.
Example 40-6: Synthesis of Compound 1035:
Figure imgf000496_0002
11 1035
[0961] Compound 1035 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 22%. MS (ESI) m/e (M+H+) 716.
Figure imgf000497_0001
11 1036
[0962] Compound 1036 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 4%. MS (ESI) m/e (M+H+) 720.
Example 40-8: Synthesis of Compound 1037:
Figure imgf000497_0002
11 1037
[0963] Compound 1037 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 15%. MS (ESI) m/e (M+H+) 704.
Example 40-9: Synthesis of Compound 1038:
Figure imgf000497_0003
product was isolated as a white solid, and the yield was 7%. MS (ESI) m/e (M+H+) 704.
Example 40-10: Synthesis of Compound 1039:
Figure imgf000498_0001
11 1039
[0965] Compound 1039 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 7%. MS (ESI) m/e (M+H+) 716.
Example 40-11: Synthesis of Compound 1040:
Figure imgf000498_0002
11 1040
[0966] Compound 1040 was prepared following General Method O. The pure product was isolated as a white solid, and the yield was 3%. MS (ESI) m/e (M+H+) 716.
Figure imgf000499_0001
1041
General Method P
[0967] To a solution of compound 2 (200 mg , 0.35 mmol.) in 3 mL of dry DMF was added sodium hydride (84.5 mg, 2.11 mmol.) at 0 °C.The resulting mixture was stirred at this temperature for Ih before the addition of 2,6-Dichloro-benzoxazole, and it was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by careful addition of water (20 mL). The aqueous layer was extracted by ethyl acetate, backwashed with water, dried over Na2SO4, concentrated to get a residue, which was purified by Prep-HPLC to give compound 1041 as white solid 12.8 mg(yield 6.0%), MS (ESI) m/e (M+H+) 617.
Example 41-2: Synthesis of Compound 1042:
Figure imgf000499_0002
2 1042
[0968] Compound 1042 was prepared following General Method P. The pure product was isolated as a white solid, and the yield was 7%. MS (ESI) m/e (M+H+) 601.
Figure imgf000500_0001
1043
[0969] Compound 1043 was prepared following General Method P, and the yield was 6%. MS (ESI) m/e (M+H+) 601.
Example 41-4: Synthesis of Compound 1044:
Figure imgf000500_0002
2 1044
[0970] Compound 1044 was prepared following General Method P, and the yield was 8%. MS (ESI) m/e (M+H+) 597.
Example 41-5: Synthesis of Compound 1045:
Figure imgf000500_0003
1045 product was used in the next step without further purification.
Example 42-1: Synthesis of Compound 1046:
Figure imgf000501_0001
1045 1046
General Method Q
[0972] To a solution of compound 1045 (120 mg, 0.08 mmol.) which was used without further purification in dry DCM (3 mL) was added CDI (20 mg, 0.16 mmol.) at 25 0C. The resulting mixture was stirred at same temperature for 1 h before the addition of methylcyclopropanyl sulfonamide (21.6 mg, 0.16 mmol.) and DBU (0.12 mL, 0.8 mmol.). The resulting mixture was stirred overnight at 25 0C then concentrated to get a residue, which was purified by Prep-HPLC to afford compound 1046 as white solid 7 mg (yield 3%). MS (ESI) m/e (M+H+) 734.2.
Example 43-1: Synthesis of Compound 1047:
Figure imgf000501_0002
2 1047
General Method R
[0973] To a solution of compound 2 (300 mg, 0.65 mmol.) in 10 mL of dry DMF was added sodium hydride (155 mg 3.87 mmol.) at 0 0C. The resulting mixture was stirred at 13 mmol.), and it was allowed to warm to room temperature slowly with ice bath and stir overnight. The reaction was quenched by adding methanol (10 mL) and water (30 mL). The resulting solution was stirred for 15 min, extract by ethyl acetate, washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by Prep-TLC to give compound 1047 as white solid 130 mg (yield 33%). MS (ESI) m/e (M+H+) 609.3.
Example 43-2: Synthesis of Compound 1048:
Figure imgf000502_0001
1047 1048
General Method S
[0974] To a solution of compound 1047 (100 mg, 0.16 mmol.) in 3 mL of dry DCM was added CDI (54 mg, 0.32 mmol.) at 25 0C. The resulting mixture was stirred at the same temperature for 1 h before the addition of methylcyclopropanyl sulfonamide (43 mg, 0.32 mmol.) and DBU (0.1 mL, 0.85 mmol.). The resulting mixture was stirred overnight at 25 0C. The solvent was removed to afford residue. The residue was dissolved in ethyl acetate (20 mL), washed with IN HCl, then aq. sat. NaHCθ3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford a residue. The crude residue was purified by Prep-TLC to afford 1048 as white solid 40 mg (yield 35%). MS (ESI) m/e (M+H+) 726.9.
Figure imgf000503_0001
2 1049
[0975] Compound 1049 was prepared following General Method R, and the yield is 53%. MS (ESI) m/e (M+H+) 671.3.
Example 43-4: Synthesis of Compound 1050:
Figure imgf000503_0002
1049 1050
[0976] Compound 1050 was prepared following General Method S, and the yield is 53%. MS (ESI) m/e (M+H+) 789.0.
Figure imgf000504_0001
1049 1051
[0977] Compound 1051 was prepared following General Method S, and the yield is 53%. MS (ESI) m/e (M+H+) 774.3.
Example 43-6: Synthesis of 1080:
Figure imgf000504_0002
1080
General Method XAX
[0978] To a solution of compound 1048 in ethyl acetate was added 5% Rh/Al2θ3
(10 mol%). The reaction mixture was stirred at room temperature under 1 atm H2 for 16h. The reaction mixture was filtered, concentrated and purified by prep-HPLC to afford compound 1080 36 mg, (26% yield). MS (ESI) m / z (M+H)+ 729.3.
Figure imgf000505_0001
1081
[0979] Compound 1081 was prepared in a manner analogous to General Method XAX to afford 170 mg (33% yield). MS (ESI) m / z (M+H)+ 748.3.
PREPARATION OF NS3 INHIBITORS: SECTION IX Example 44-1:
Figure imgf000505_0002
1082
[0980] Compound 1082 was prepared in a manner analogous to General Method S, to afford 43.9 mg, 42%. MS (ESI) m / z (M+H)+ 847.
Figure imgf000506_0001
1083
[0981] Compound 1083 was prepared in a manner analogous to General Method S, to afford 20 mg, 13%. MS (ESI) m / z (M+H)+ 841.1.
Example 44-3:
Figure imgf000506_0002
1084
[0982] Compound 1084 was prepared in a manner analogous to General Method S, to afford 14.7 mg, 16%. MS (ESI) m / z (M+H)+ 855.2.
Example 44-5:
Figure imgf000506_0003
1 1086
General Method XBX
[0983] A solution of compound 1 (200 mg, 0.32 mmol.), HATU (182 mg, 0.48 mmol.) and DIEA (0.22 mL, 1.28 mmol.) in dry DMF was stirred for 1 h before the addition DBU (0.19 mL, 1.28 mmol.) in dry DMF (1.5 mL). The mixture was stirred overnight. Then the mixture was diluted with brine and Ethyl acetate, the organic layers was separated, dried over anhydrous sodium sulfate, the residue was purified by prep-TLC to give compound 1086 (35.1 mg, 14%). MS (ESI) m / z (M+H)+ 782.
Example 44-6:
Scheme XXXII: Synthesis of Benzimidazole-dimethylsulfonamide Compounds
Figure imgf000507_0001
XVlIl-A
[0984] Macrocycles of general structures XVIII-A can be synthesized according to the method of Scheme XXXII. Compound 1 can be coupled with dimethylsulfamide to afford compound 75. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like. Subsequently, compound 75 can be treated under basic conditions to hydrolyse the isoindoline carbamate thereby providing alcohol 76. The alcohol, compound 76, can be compound of general structure XVIII-A. For example, the base can be sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium ferf-butoxide, and the like.
Example 44-7
Figure imgf000508_0001
1 75
[0985] To a solution of compound 1 (1.5 g, 2.38 mmol.) in anhydrous dichloromethane was added CDI (1.56 g, 9.5 mmol.) under nitrogen protection. The resulting mixture was stirred at 35°C for 2 h, then dimethylsulfamide (0.44 g, 3.57 mmol.) and DBU (2.89 g, 19.04 mmol.) was added, the resulting mixture was stirred at room temperature for another 12 h and the reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed under reduced pressure. Then the residue was diluted with brine and Ethyl acetate, the organic layers was separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford compound 75 (0.94 g, 55%).
Example 44-8
Figure imgf000508_0002
75 76
[0986] To a solution of compound 75 (1.4 g, 1.9 mmol) in 100 mL of methanol was added aq. NaOH (5 M, 11 mL), the resulting mixture was heated to 500C and stirred overnight, The reaction was monitored by LCMS. After completion of the reaction, the mixture was cooled by ice water, acidified by aq. HCl (2 M) to pH=4-5, then the mixture was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the crude compound 76 was used directly in the next step (0.89 g, 82%).
Example 44-9 General Procedure FFF
Figure imgf000509_0001
76 XVIII-A
[0987] To a solution of compound 76 (1.0 eq.) in 2 mL of DMSO was added t-
BuOK (5 eq.) in portions at ambient temperature, then the mixture was stirred for 2 h at ambient temperature. After that, substituted 2-chlorobenzimidazole (1.2 eq.) was added, the resulting mixture was stirred at ambient temperature for 12 h, the reaction was monitored by LC-MS. After completion of the reaction, the mixture was cooled by ice water, acidified by aq. HCl (2 M) to pH = ~8, then the mixture was extracted by ethyl acetate, the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure, the crude product was purified by prep-HPLC to afford general compound XVIII-A.
Example 44-10
Figure imgf000509_0002
1129
[0988] Compound 1129 was prepared in a manner analogous to General
Procedure FFF, to afford 5.2 mg (8 %). MS (ESI) m / z (M+H)+ 744.4. Example 44-11
Figure imgf000510_0001
1130
[0989] Compound 1130 was prepared in a manner analogous to General
Procedure FFF, to afford 57.1 mg (23.3%). MS (ESI) m / z (M+H)+ 701.9.
Example 44-12
Figure imgf000510_0002
1131
[0990] Compound 1131 was prepared in a manner analogous to General Procedure FFF, to afford 52.8 mg (20.7%). MS (ESI) m / z (M+H)+ 730.5.
Example 44-13
Figure imgf000510_0003
1132 [0991] Compound 1132 was prepared in a manner analogous to General
Procedure FFF, to afford 52.3 mg (38.0%). MS (ESI) m / z (M+H)+ 716.5.
Figure imgf000511_0001
1133
[0992] Compound 1133 was prepared in a manner analogous to General
Procedure FFF, and the yield is 8%. MS (ESI) m / z (M+H)+ 748.4.
Example 44-15
Figure imgf000511_0002
1134
[0993] Compound 1134 was prepared in a manner analogous to General
Procedure FFF, and the yield is 13.4%. 1H NMR (400 MHz, DMSO-^6) δ 10.84 (s, IH), 9.06 (s, 1 H), 7.37 (d, / = 8 Hz, 1 H), 7.21 (s, 1 H), 7.12 (m, 1 H), 6.98 (t, / = 8.2 Hz, 1 H), 5.80 (s, 1 H), 5.69 (m, 1 H), 5.14 (t, J =9 Hz, 1 H), 4.71 (m, 1 H), 4.33 (d, / = 12 Hz,l H), 4.48 (t, / = 4 Hz, 2 H), 4.08 (m, 1 H), 3.96 (d, / = 4 Hz, 1 H), 2.79 (s, 6 H), 2.73 (s, 1 H), 2.33-2.47 (m, 2 H), 1.78 (m, 2 H), 1.25-1.62 (m, 26 H). MS (ESI) m / z (M+H)+ 748.5.
Example 44-16
Figure imgf000511_0003
1135 Procedure FFF, and the yield is 8%. 1H NMR (400 MHz, OMSO-d6) δ 10.84 (s, 1 H), 9.06 (s,
1 H), 7.37 (d, / = 8 Hz, 1 H), 7.21 (s, 1 H), 7.12 (m, 1 H), 6.98 (t, / = 8.2 Hz, 1 H), 5.80 (s, 1
H), 5.69 (m, 1 H), 5.14 (t, / = 9 Hz, 1 H), 4.71 (m, 1 H) , 4.33 (d, J = 12 Hz, 1 H), 4.48 (t, J =
4 Hz, 2 H), 4.08 (m, 1 H), 3.96 (d, J = 4 Hz, 1 H), 2.79 (s, 6 H), 2.73 (s,l H), 2.33 - 2.47 (m,
2 H), 1.78 (m, 2 H), 1.25 - 1.62 (m, 26 H). MS (ESI) m / z (M+H)+ 748.5.
Example 44-17
Figure imgf000512_0001
1136
[0995] Compound 1136 was prepared in a manner analogous to General
Procedure FFF, and the yield is 10 %. MS (ESI) m / z (M+H)+ 748.3.
Example 44-18
Figure imgf000512_0002
1137
[0996] Compound 1137 was prepared in a manner analogous to General Procedure FFF, and the yield is 8.6%. MS (ESI) m / z (M+H)+ 744.3.
Example 44-19
Figure imgf000513_0001
1138
[0997] Compound 1138 was prepared in a manner analogous to General
Procedure FFF, and the yield is 4.6%. 1H NMR (400 MHz, DMSOd6) δ 10.80 (s, 1 H), 9.01 (s, 1 H), 7.24 (t, J = 1.2 Hz, 1 H), 7.15 (m, 1 H), 6.97 (m, 1 H), 6.83 (d, / = 7.2 Hz, 1 H), 5.70 (s, 1 H), 5.60 (m, 1 H), 5.08 (m, 1 H), 5.00 (m, 1 H), 4.51 (d, / = 12 Hz, 1 H), 4.01 (m, 1 H), 3.90 (d, / = 8 Hz, 1 H), 2.72 (s, 6 H), 2.67 (s, 1 H), 2.58 (s, 1 H), 1.00-1.72 (m, 32 H). MS (ESI) m / z (M+H)+ 744.3.
Example 44-20
Figure imgf000513_0002
1139
[0998] Compound 1139 was prepared in a manner analogous to General
Procedure FFF, to afford 20 mg, 26.8%. MS (ESI) m / z (M+H)+ 744.3.
Example 44-21
Figure imgf000513_0003
1140 Procedure FFF, to afford 20 mg, 27.5%. MS (ESI) m / z (M+H)+ 744.3.
Example 44-22:
Figure imgf000514_0001
76 1141
[1000] Compound 1141 was prepared in a manner analogous to General Procedure FFF, to afford 64.8 mg, 21%. MS (ESI) m / z (M+H)+ 755.9.
Example 44-23:
Figure imgf000514_0002
1142
[1001] Compound 1142was prepared in a manner analogous to General Procedure FFF, to afford 60 mg, 21.8%. MS (ESI) m / z (M+H)+ 727.2
Scheme XXXIII
Figure imgf000515_0001
720 1144
[1002] Compound 1144 can be synthesized by the method of Scheme XXXIII.
The alcohol, compound 76, can be treated with a base, such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium terf-butoxide, and the like, then reacted with l-((2-(trimethylsilyl)ethoxy)methyl)- 2-chloro-lH-benzo[ύf|imidazole to afford compound 1143. The SEM and Boc groups can be removed under acidic conditions to afford compound 720. For example, the acid can be trifluoroacetic acid, hydrochloric acid, and the like. The Boc group can then be re-introduced by treatment of compound 720 with (Boc)2O in the presence of a base, such as cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, to afford compound compound 1144.
Figure imgf000516_0001
1143
General Method XCX
[1003] To a solution of compound 76 (300 mg, 0.515 mmol.) in 3 mL of dry DMF was added sodium hydride (60%, 204 mg, 5.1 mmol.) at 00C. The resulting mixture was stirred at this temperature for Ih. Then compound 7 (175 mg, 0.618 mmol.) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate (50 mLx3), washed with brine, dried over Na2SO4, concentrated to give a residue, which was purified by prep-TLC to give compound 1143 as white solid (150 mg, yield 35.2%). MS (ESI) m/z (M+H)+ 818.
Example Example 44-26: Synthesis of Compound 720:
Figure imgf000516_0002
[1004] To a solution of compound 1143 (60 mg, 0.072 mmol.) in dry DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 3 h. LCMS analysis showed the reaction complete. The reaction mixture was concentrated to give crude compound 720 (40 mg, 93%), which was used directly without further purification.
Example 44-27: Synthesis of Compound 1144:
Figure imgf000517_0001
720 1144
[1005] To a solution of compound 720 (40 mg, 0.067 mmol.) in dry THF (2 niL) was added NaHCC>3 (16.9 mg, 0.261 mmol.) and followed by adding di-tert-butyl dicarbonate (34.6 mg, 0.201 mmol.). The reaction mixture was stirred at room temperature overnight. LCMS analysis showed the reaction complete. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mLx3). The organic layer was dried over Na2SO4, concentrated and purified by prep-TLC to give compound 1144 (14.2 mg, 15%). MS (ESI) m/z (M+H)+688.4.
Example 44-28: Synthesis of Compound 1145:
Figure imgf000517_0002
1145
[1006] To a solution of compound 76 (120 mg, 0.21 mmol.) in 2 mL of DMSO was added J-BuOK (118 mg, 1.05 mmol.). The resulting mixture was stirred at room temperature for 1.5 h before the addition of 2-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (82 mg, 0.42 mmol.), and it was stirred overnight. The reaction was quenched with water (10 mL), extracted with ethyl acetate, washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by prep-ΗPLC to afford compound 1145 (55.1 mg, 36.0 %). MS (ESI) m / z (M+Η)+ 731.1.
Example 44-29: Synthesis of 2-chloro-l-cyclopentyl-lH-benzo[rf]imidazole:
Figure imgf000518_0001
[1007] To a solution of 2-chloro-lH-benzo[rf]imidazole (152 mg, 1.0 mmol.) in DMF was added K2CO3 (277 mg, 2.0 mmol.) and iodocyclopentane (295 mg, 1.5 mmol.). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate (30 mL x 3), washed with brine, dried over Na2SO4, concentrated to give a residue, which was purified by column chromatography to afford 2-chloro-l-cyclopentyl-lH-benzo[d]imidazole (130 mg, 59%). 1H NMR (400MHz, CDCl3) δ 7.68-7.60 (m, 1 H), 7.39-7.30 (m, 1 H), 7.20-7.15 (m, 2 H), 5.04-4.90 (m, 1 H), 2.25-1.92 (m, 6 H), 1.85-1.70 (m, 2 H).
Example 44-30: Synthesis of 2-chloro-l-cyclopentyl-lH-benzo[rf]imidazole:
Figure imgf000518_0002
[1008] To a solution of compound 3-bromopyridin-4-amine (3 g, 17.4 mmol.) in 20 mL of anhydrous THF was added a solution of LiHMDS (IM in THF, 36.4 mL, 36.4 mmol) at 00C. After stirring for 30 min, methyl chloroformate (2 g, 20.8 mmol) was added at 00C. The reaction mixture was stirred at 00C for 2 hrs and then at r.t. overnight. The reaction was quenched with saturated aqueous ammonium chloride. The organic solvent was evaporated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over Na2SO4, concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 1 : 2) to afford methyl 3-bromopyridin-4- ylcarbamate (2.34 g, 59%).
Example 44-31: Synthesis of 3-isopropyl-lH-imidazo[4,5-c]pyridin-2(3H)-one:
Figure imgf000519_0001
then 1300C, 12h
[1009] A sealed tube was charged with methyl 3-bromopyridin-4-ylcarbamate (1.76 g, 7.6 mmol.), CuI (290 mg, 1.52 mmol.), trans-4-hydroxy-L-proline (400 mg, 3.04 mmol.) and K3PO4 (3.2 g, 15.2 mmol.), evacuated and backfilled with argon. Isopropylamine (674 mg, 11.4 mmol.) and DMSO (15 mL) were added successively. The reaction mixture was stirred at 700C for 12h and then at 1300C for 12h .The reaction mixture filtered and the filtrate was concentrated and purified by prep-HPLC to afford 3-isopropyl-lH-imidazo[4,5- c]pyridin-2(3Η)-one (765 mg, 57%).
Example 44-32: Synthesis of 2-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine:
Figure imgf000519_0002
[1010] A mixture of 3-isopropyl-lH-imidazo[4,5-c]pyridin-2(3H)-one (0.5 g, 2.82 mmol.) in POCI3 (5 mL) was refluxed for 16 hrs. Then the reaction mixture was poured into ice water and basified with NH4OH to pH=7~8. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to afford crude 2-chloro-3- isopropyl-3H-imidazo[4,5-c]pyridine which was used directly for the next step (150 mg, 27%).
Example 45-1: Synthesis of Compound 1052:
Figure imgf000519_0003
HATU, Et3N, DCM 1052 [1011] Compound 1 (100 mg, 0.16 mmol.), 3-amino-N-benzylpropionamide hydrochloride (34 mg, 0.16 mmol.), and HATU (63 mg, 0.16 mmol.) were dissolved in DCM (5 mL). The stirring mixture was treated with Et3N (145 mg, 1.4 mmol.) and then stirred overnight. The organic solution was partitioned with water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on prep-TLC (DCM: MeOH 20:1) to afford compound 1052, as white solid (76 mg, yield 61%).
Example 45-2:
Figure imgf000520_0001
[1012] Compound 1053 was prepared following General Method T, and the yield was 30 %. MS (ESI) m/e (M+H+) 775.
Example 45-3:
Figure imgf000520_0002
1 1054
[1013] Compound 1054 was prepared following General Method T, and the yield was 10%. MS (ESI) m/e (M+H+) 815. HO HO
Figure imgf000521_0001
2 1055
[1014] Compound 1055 was prepared following General Method T, and the yield was 53.3%. MS (ESI) m/e (M+H+) 612.
Example 45-5:
Figure imgf000521_0002
2 1056
[1015] Compound 1056 was prepared following General Method T, and the yield was 50%. MS (ESI) m/e (M+H+) 652.
Example 45-6:
Figure imgf000521_0003
1 1057
[1016] Compound 1057 was prepared following General Method T, and the yield was 30%. MS (ESI) m/e (M+H+) 815.41. hydrochloride: Scheme XXXIV
BocH
Figure imgf000522_0001
[1017] 3-Amino-N-benzylpropionamide hydrochloride can be prepared by the method shown in Scheme XXXIV. 3-ferf-Butoxycarbonylaminopropanoic acid can be coupled with benzylamine to provide 3-ferf-butoxycarbonylamino-N-benzylpropionamide. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like. The Boc group can then be removed under acidic conditions to afford 3-amino-Ν-benzylpropionamide hydrochloride. For example, the acid can be trifluoroacidic acid, hydrochloric acid, and the like.
[1018] A solution of 3-ferf-butoxycarbonylaminopropanoic acid (2 g, 10.6 mmol.) and HOSu (1.22 g, 10.6 mmol.) in 40 mL DCM/Dioxane (2: 1) was cooled in an ice bath. To this solution was added DCC (2.4 g, 11.6 mmol.), and the mixture was stirred at room temperature for 1 h. To the resulting mixture was added benzylamine (1.7 g, 15.8 mmol.), the mixture was stirred for 4 h at room temperature. The solid that formed in the mixture was removed by filtration and washed with EtOAc. The filtrate and washings were combined and washed with IN HCl and saturated aqueous NaHCθ3. The organic layer was dried over Na2SO4, filtered and concentrated to afford 3-ferf-butoxycarbonylamino-N- benzylpropionamide (2.4 g, 82%). 3-ferf-Butoxycarbonylamino-N-benzylpropionamide was dissolved in cooled HCl/MeOH (20 mL) and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed to afford 3-amino-N-benzylpropionamide hydrochloride (1.8 g, 100%).
[1019] Similar N-benzylamide amine hydrochlorides were prepared following the same experimental procedure of making 3-amino-N-benzylpropionamide hydrochloride.
Figure imgf000523_0001
1052 1058
General Method U
[1020] To a solution of compound 1052 (76 mg, 0.1 mmol.) in 2 mL MeOH, was added 5N NaOH (1 mL). The mixture was heated at 50 0C overnight. After cooling to room temperature, the pH was adjusted to ~4 with 2N HCl, and then extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on prep-TLC (DCM:MeOH 20: 1) to afford compound 1058 , as a white solid (28 mg, yield 47%).
Example 46-2: Synthesis of Compound 1059:
Figure imgf000523_0002
1058 1059 General Method V
[1021] To a solution of compound 1058 (46 mg, 0.07 mmol.) in DCM (2 mL) were added Ac2O (15 mg, 0.14 mmol.) and Et3N (22 mg, 0.22 mmol.), the mixture was stirred at room temperature overnight. The organic solution was partitioned with water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on prep-TLC to afford compound 1059 as a white solid (27 mg, 56%). MS (ESI) m/e (M+H+) 668.2. Example 46-3:
Figure imgf000524_0001
1055 1060
[1022] Compound 1060 was prepared following General Method V, and the yield was 40%. MS (ESI) m/e (M+H+) 654.
Example 46-4:
Figure imgf000524_0002
1056 1061
[1023] Compound 1061 was prepared following General Method V, and the yield was 37.7%. MS (ESI) m/e (M+H+) 694.
Example 46-5:
Figure imgf000524_0003
2 1087
[1024] Compound 1087 was prepared following General Method T, to afford 46 mg (43% yield). MS (ESI) m / z (M+H)+ 652.3.
Figure imgf000525_0001
1087 1088
[1025] Compound 1088 was prepared following General Method V, to afford 30 mg (28% yield). MS (ESI) m / z (M+H)+ 694.1.
Example 47-1: Synthesis of Compound 1062:
Figure imgf000525_0002
1058 1062 General Method W
[1026] Compound 1058 was dissolved in DMF (1 mL), the resulting solution was treated with CH3I (18.5 mg, 0.13 mmol.) and the mixture cooled to 0 0C. Subsequently, the mixture was treated with NaH (4.3 mg, 0.108 mmol.) and the mixture was stirred at room temperature overnight. The organic solution was partitioned with water and the aqueous layer was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on Prep-TLC (DCM:MeOH 20:1) to afford compound 1062, as white solid (20 mg, 28%). MS (ESI) m/e (M+H+) 640.4.
Figure imgf000526_0001
1055 1063
[1027] Compound 1063 was prepared following General Method W, and the yield was 30%.MS (ESI) m/e (M+H+) 626.
Figure imgf000526_0002
1056 1064
[1028] Compound 1064 was prepared following General Method W, and the yield was 15%. MS (ESI) m/e (M+H+) 666.
Example 47-4:
Figure imgf000526_0003
1087 1089
[1029] Compound 1089 was prepared in a manner analogous to General Method W, to afford 8 mg (8% yield). MS (ESI) m / z (M+H)+ 666.3.
Figure imgf000527_0001
1065
General Method X
[1030] To a solution of compound 7 (50 mg, 0.08 mmol.) in THF (1 niL) at -10 0C was added NaH (6.4 mg, 0.16 mmol.). Subsequently, the stirring mixture was treated with dimethylcarbamic chloride (9 mg, 0.08 mmol.). The resultant mixture was stirred at room temperature overnight. The organic solution was partitioned with water and the aqueous layer was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on prep-TLC (DCM:MeOH 20: 1) to afford compound 1065, as a white solid (21 mg, 37%). MS (ESI) m/e (M+H+) 654.3.
Example 48-2:
Figure imgf000527_0002
7 1072
[1031] Compound 1072 was prepared following General Method X, and the yield was 60%. MS (ESI) m/e (M+H+) 680.3.
Figure imgf000528_0001
1055 1066
[1032] Compound 1066 was prepared following General Method X, and the yield was 70%. MS (ESI) m/e (M+H+) 683.
Example 48-4: Synthesis of Compound 1067:
Figure imgf000528_0002
1058 1067
[1033] Compound 1067 was prepared following General Method X, and the yield was 60%. MS (ESI) m/e (M+H+) 697.4.
Example 48-5: Synthesis of Compound 1068:
Figure imgf000528_0003
1056 1068
[1034] Compound 1068 was prepared following General Method X, and the yield was 60%. MS(ESI) m/e (M+H+) 723. Example 48-6:
Figure imgf000529_0001
1087 1090
[1035] Compound 1090 was prepared following General Method X, to afford 35 mg (32%). MS (ESI) m / z (M+H)+ 723.2.
Example 49-1: Procedure for the Synthesis of Compound 1069: Scheme XXXV
Figure imgf000529_0002
1069
[1036] Compound 1069 can be prepared according to the method of Scheme XXXV. Compound 6 can be treated with a base, such as sodium hydroxide, to afford compound 7. Compound 7 can be treated with an acylating agent, such as acetyl chloride, acetic anhydride and the like, to afford compound 1069.
Figure imgf000530_0001
General Method Y
[1037] To a solution of compound 6 (1.0 g, 1.37 mmol.) in 20 mL of methanol was added 8.6 mL of 5M NaOH . The resulting mixture was stirred at 50 0C for 20 h. The solution was cooled down below 5 0C and acidified using diluted HCl and extracted. The crude material was purified by column chromatography to afford 0.58 g of 7 was obtained and the yield was 73%.
Example 49-3:
Figure imgf000530_0002
7 1069
[1038] Compound 1069 was prepared following General Method V, and the yield was 77%. MS (ESI) m/e (M+H+) 583.2.
Figure imgf000531_0001
10 11
[1039] Compound 11 was prepared following General Method Y, and the yield was 70%. MS (ESI) m/e (M+H+) 569.2.
Example 49-5:
Figure imgf000531_0002
11 1071
[1040] Compound 1071 was prepared following General Method V, and the yield was 93%. MS (ESI) m/e (M+H+) 611.2.
Example 49-6: Synthesis of Compound 1081:
Figure imgf000531_0003
705 7
General Method VW
[1041] To a solution of compound 705 (2 g, 2.6 mmol.) in 100 mL methanol was added 15 mL of aq. NaOH solution (5 M), the resulting mixture was heated to 50 0C and The mixture was cooled by ice water, acidified by 2 M HCl to pH = -3-4, then the mixture was extracted by ethyl acetate (100 mLx3), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the crude product compound 7 (1.5 g, 99%) was used directly in the next step. MS (ESI) m / z (M+H)+ 583.1.
Example 49-7: Synthesis of Compound 1091:
OH O
Figure imgf000532_0001
7 1091
General Method VX
[1042] To a solution of compound 7 (100 mg, 0.17 mmol.) and DIEA (0.1 niL) in 1 mL of CH2CI2 was added a (trimethylsilyl)diazomethane solution (2.0 M in hexanes, 0.17 mL, 0.34 mmol.) at 00C. After stirring for 3 h at 00C, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford 1091 (4.2 mg, 4.1%). MS (ESI) m / z (M+Na)+ 619.2.
Example 49-8:
Figure imgf000532_0002
1092
[1043] Compound 1092 was prepared in a manner analogous to General Method D, to afford 33.7 mg, 14%. MS (ESI) m / z (M+H)+ 662.1. OH
Figure imgf000533_0001
1093
[1044] Compound 1093 was prepared in a manner analogous to General Method D, to afford 91.7 mg, 19.1%. MS (ESI) m / z (M+H)+ 678.3.
Example 49-10:
OH
Figure imgf000533_0002
1094
[1045] Compound 1094 was prepared in a manner analogous to General Method D, to afford 86.5 mg, 19.6%. MS (ESI) m / z (M+H)+ 692.1.
Example 49-11: General Procedure for Preparation of Carbamates:
Figure imgf000533_0003
M-A M-B
General Procedure VA
[1046] To a solution of a compound having the general structure H-A (1.0 eq.) in dry THF was added to NaH (10 eq.). The reaction mixture was stirred for 10 minutes, dimethylcarbamic chloride (1.1 eq.) was injected into flask at 0-5 0C. The resulting solution was stirred overnight at room temperature. TLC analysis showed the reaction complete. The reaction mixture was poured into ice- water, and extracted with ethyl acetate (x3). The prep-HPLC to afford a compound having the general structure H-B.
Example 49-12:
Figure imgf000534_0001
1095
[1047] Compound 1095 was prepared in a manner analogous to General Procedure VA, to afford 20.9 mg, 31%. MS (ESI) m / z (M+Na)+ 755.2.
Example 49-13:
Figure imgf000534_0002
1096
[1048] Compound 1096 was prepared in a manner analogous to General Procedure VA, to afford 41 mg, 46 %. MS (ESI) m / z (M+H)+ 749.2.
Example 49-14:
Figure imgf000534_0003
1097 Procedure VA, to afford 42 mg, 50%. MS (ESI) m / z (M+H)+ 763.2.
Example 49-15: General Procedure for Preparation of Esters: o
OH O^
Figure imgf000535_0001
M-A M-C
General Procedure VB
[1050] To a stirred solution of compound H-A (1 eq.) in CH2Cl2 was added triethylamine (6 eq.) and Ac2O (4 eq.). The mixture was stirred at room temperature overnight. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (x3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by prep-HPLC to afford compound H-C.
Example 49-16: o o
Figure imgf000535_0002
1098
[1051] Compound 1098 was prepared in a manner analogous to General Procedure VB, to afford 26.2 mg, 41%. MS (ESI) m / z (M+H)+ 704.1. Scheme XXXVI:
OH O^
Figure imgf000536_0001
1099
[1052] Compound 1099 can be prepared according to Scheme XXXVI.
Compound 2 can be treated with a methylating agent, such as methyl iodide, methyl triflate, dimethylsulfate, and the like, under basic condition to afford compound 721. For example, the base can be sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, and the like. Compound 721 can be coupled with 2- (sulfamoyl)-N-phenylacetamide to afford compound 1099. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like.
Example 49-18:
OH O
Figure imgf000536_0002
2 721
General Method VY
[1053] To a solution of compound 2 (200 mg, 0.21mmol.) and MeI (28 μL, 0.5 mmol.) in 2 mL of DMF was added to NaH (60%, 34 mg, 0.84 mmol.) at -200C. The reaction mixture was stirred for 30 minutes at -200C. The resulting solution was allowed to warm to was extracted with EtOAc (20 mLx3) and dried over Na2SO4, concentrated. The residue was purified with prep-HPLC to afford compound 721 (33 mg, 32%).
Example 49-19:
Figure imgf000537_0001
721 1099
[1054] Compound 1099 was was prepared in a manner analogous to General Method VY, to afford 14.6 mg (29% yield) as white solid. MS (ESI) m / z (M+Na)+ 698.3.
Example 50-1: Synthesis of (Λ^-phenylaminocarbonyl)methanesulfonamide: Scheme XXXVII
Figure imgf000537_0002
[1055] 2-(Sulfamoyl)-N-phenylacetamide can be prepared according to the method of Scheme XXXVII. Ethyl 2-chloroacetate can be treated with Na2S O3 to afford (ethoxycarbonyl)methanesulfonic acid. The acid can be converted to an acid chloride by treating (ethoxycarbonyl)methanesulfonic acid with a chlorinationg agent, such as phosphorus oxychloride and the like, thereby affording (ethoxycarbonyl)methanesulfonyl chloride. The acid chloride can be converted to a sulfonamide by treating (ethoxycarbonyl)methanesulfonyl chloride with ferz-butylamine, therby affording ethyl-2-(N-tert-butylsulfamoyl) acetate. The ester can be hydrolyzed under basic conditions, such as sodium hydroxide in ethanol and Butylsulfamoyl)acetic acid can be coupled with aniline to afford 2-(N-tert-butylsulfamoyl)-N- phenylacetamide. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, EDCI, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like. The tert-buty\ can be removed under acidic conditions to afford 2-(sulfamoyl)-N- phenylacetamide. For example, the acid can be trifluoroacetic acid, hydrochloric acid, and the like.
Example 50-2: Preparation of (EthoxycarbonyOmethanesulfonic Acid:
Figure imgf000538_0001
[1056] To a solution of Na2SO3 (10 g, 79 mmol.) in 50 mL of H2O was added a solution of ethyl 2-chloroacetate (12.7 mL, 119 mmol.) in 55 mL of EtOH. The mixture was heated at reflux for 6 h, after which time all the volatiles were removed by evaporation under reduced pressure. The concentrated materials were dried to afford crude (ethoxycarbonyl)methanesulfonic acid (13.3 g, 100%) used directly without purification.
Example 50-2: Preparation of (Ethoxycarbonyl)methanesulfonyl Chloride:
Figure imgf000538_0002
[1057] A mixture of (ethoxycarbonyl)methanesulfonic acid (10 g, 60 mmol.) and POCI3 (45 mL) was heated at 125°C for 5 h. The mixture was cooled and filtered, and excess POCI3 was removed to give crude (ethoxycarbonyl)methanesulfonyl chloride (8.1 g, 80%) used directly without purification.
Example 50-3: Preparation of ethyl-2-(iV-tert-butylsulfamoyl) acetate:
Figure imgf000538_0003
[1058] terf-Butylamine (7.9 mL, 75 mmol.) was dissolved in 50 mL of THF. The solution was cooled to -200C and (ethoxycarbonyl)methanesulfonyl chloride dissolved in 10 mL of THF was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in 2-(N-tert-butylsulfamoyl) acetate (4.1 g, 43%).
Example 50-4: Preparation of 2-(Λ^-tert-butylsulfamoyl)acetic acid:
Figure imgf000539_0001
[1059] To a solution of ethyl-2-(N-tert-butylsulfamoyl) acetate (4 g, 17.9 mmol.) in 65 mL of EtOH and 13mL of H2O at 00C was slowly added ΝaOH (3.6 g, 89.5 mmol.). The reaction was allowed to room temperature and stirred overnight. TLC analysis showed the reaction complete. The mixture was acidified to pH=5 with aq. HCl (IM). The resulting mixture was extracted with EtOAc (30 ml_x3). The combined organic layer was dried over
Na2SO4, concentrated to afford crude 2-(N-tert-butylsulfamoyl)acetic acid (2.4 g, 69%), which was used directly without purification.
Example 50-5: Preparation of 2-(N-tert-butylsulfamoyl)-jV-phenylacetamide:
Figure imgf000539_0002
[1060] To a solution of compound 2-(N-tert-butylsulfamoyl)acetic acid (5 g, 25.6 mmol.) in dry THF (20 mL) was added HOBt (13.8 g, 102.4 mmol.) and EDCI (18.3 g, 102.4 mmol.). Then aniline (3.6 g, 38.4 mmol.) was added successively. The reaction mixture was stirred overnight at room temperature. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (30ml_x3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by column chromatography (PE : EtOAc = 2 : 1) to afford 2-(N-ferz-butylsulfamoyl)-N-phenylacetamide
(3.5 g, 51%).
Example 50-5: Preparation of 2-(sulfamoyl)-jV-phenylacetamide:
Figure imgf000539_0003
(2.5 g, 9.2 mmol.) in 40 mL of TFA was stirred at room temperature overnight. TLC analysis showed the reaction complete. Excess TFA was removed in vacuo. The value of pH was adjusted to 7-8 with NaHCU3. The mixture was extracted with EtOAc (30 ml_x3). The combined organic layer was over Na2SO4, concentrated to afford compound 2-(sulfamoyl)-N- phenylacetamide (1.9 g, 96%), which was used directly without purification.
Example 50-6: Synthesis of 2-(2-sulfamoylphenoxy)acetamide: Scheme XXXVIII
Figure imgf000540_0001
[1062] 2-(2-Sulfamoylphenoxy)acetamide can be prepared according to the method of Scheme XXXVIII. 2-Sulfamoyl fluorobenzene can be reacted with benzyl alcohol under basic conditions to afford l-(phenoxymethyl)-2-sulfamoylbenzene. For example, the base can be sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, and the like. The benzyl group of l-(phenoxymethyl)-2- sulfamoylbenzene can be cleaved by hydrogenolysis to afford l-(hydroxy)-2- sulfamoylbenzene. For example, the hydrogenolysis can be catalyzed using a catalyst, such as Pd/C in the presence of hydrogen or a hydrogen source. The hydrogen source can be formic acid, hydrazine, and the like. The phenoxy group of l-(hydroxy)-2-sulfamoylbenzene can be alkylated with 2-bromoacetamide in the presence of a base, such as cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, to afford 2-(2-sulfamoylphenoxy)acetamide.
Example 50-7: Preparation of l-(phenoxymethyl)-2-sulfamoylbenzene:
Figure imgf000540_0002
added to NaH (0.7 g, 17.1 mmol.) at 00C. The reaction mixture was stirred at 00C for 30 min under N2. To the resulting mixture was added 2-sulfamoyl fluorobenzene (1 g, 5.7 mmol.) in 20 mL of dry DMF. The reaction mixture was stirred at 80-900C for 3 hours . After cooling to r.t, the reaction mixture was poured into ice-water and neutralized with aq. HCl (2 M) to pH 7. The mixture was extracted with ethyl acetate (3x50 mL). The combined organic layer was over Na2SO4, filtered and concentrated to afford crude l-(phenoxymethyl)-2- sulfamoylbenzene (1 g, 66.7%), which was used directly without further purification.
Example 50-8: Preparati
Figure imgf000541_0001
[1064] To a solution of crude l-(phenoxymethyl)-2-sulfamoylbenzene (1.6 g, 6 mmol.) in 200 mL of methanol was added Pd/C (0.64 g). The reaction mixture was stirred at room temperature for 5 hours under H2 with a pressure of 30 psi. After the material was consumed, the reaction mixture was filtered .The solvent was evaporated to give crude 1- (hydroxy)-2-sulfamoylbenzene (800 mg, 80%) which was used directly without purification.
Example 50-9: Preparation of 2-(2-sulfamoylphenoxy)acetamide:
Figure imgf000541_0002
[1065] To a solution of crude l-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromoacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)acetamide (260 mg, 47%).
Example 50-10: Synthesis of 2-(2-Sulfamoylphenoxy)-Λ^-methylacetamide: Scheme XXXIX
Figure imgf000541_0003
the method of Scheme XXXIX. Bromoacetyl bromide can be reacted methylamine hydrochloride in the presence of a base, such as sodium hydroxide to afford 2-bromo-N- methylacetamide. The phenoxy group of l-(hydroxy)-2-sulfamoylbenzene can be alkylated with 2-bromo-N-methylacetamide in the presence of a base, such as cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, to afford 2-(2-sulfamoylphenoxy)-N-methylacetamide.
Example 50-11: Synthesis
Figure imgf000542_0001
[1067] To a solution of NaOH (0.64 g, 16 mmol.) in 3 mL of water and 3 mL of DCM was added methylamine hydrochloride (0.51 g, 7.5 mmol.). To the mixture was added bromoacetyl bromide (1 g, 5 mmol.) in 3 mL of DCM at -100C. The reaction mixture was stirred at -100C for 30 min, then at room temperature for 2 h. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was evaporated to give crude 2-bromo-N-methylacetamide (400 mg, 54%), which was used directly without purification.
Example 50-12: Synthesis of 2-(2-Sulfamoylphenoxy)-N-methylacetamide:
H2
Figure imgf000542_0002
[1068] To a solution of crude l-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromo-N-methylacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)-N-methylacetamide (260 mg, 47%).
PREPARATION OF NS3 INHIBITORS: SECTION X Example 51-1: Synthesis of compound 707:
Figure imgf000543_0001
General Method Z
[1069] Deprotected heteroaryl ether intermediate 706 (HCl salt, 500 mg, 1.03 mmol., 1.0 eq.) and N,N-dimethylformamide (9 mL) were charged into a 25 mL round bottom flask under nitrogen. HATU (505 mg, 1.33 mmol., 1.3 eq.) and diisopropylethylamine (665 mg, 5.15 mmol., 5.0 eq.) were added and the reaction mixture stirred at ambient temperature for a further 15 minutes. (S)-2-(3-fluoro-5-(trifluoromethyl)phenylamino)non-8- enoic acid (376 mg, 1.13 mmol., 1.1 eq.) was added as a single portion and stirring was continued at ambient temperature for a further 15 hours. Monitoring the reaction extent by LCMS showed full consumption of the starting material. The solvent was removed under vacuum and the residue partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried over Νa2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography, using a heptanes: ethyl acetate gradient (from 95:5 to 50:50). After combining the relevant fractions and solvent removal, 531 mg (65%) of compound 707 was isolated as a yellow glassy solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.21 (br. s, 1 H) 8.06 (d, / = 8.24 Hz, 1 H) 7.99 (d, / = 5.95 Hz, 1 H) 7.78 (d, / = 8.24 Hz, 1 H) 7.66 - 7.73 (m, 1 H) 7.54 (t, / = 7.55 Hz, 1 H) 7.30 (d, / = 5.80 Hz, 1 H) 6.87 (s, 1 H) 6.61 (d, / = 8.39 Hz,
1 H) 6.58 (s, 1 H) 6.38 (d, / = 10.83 Hz, 1 H) 6.04 (br. s, 1 H) 5.73 - 5.85 (m, 2 H) 5.24 (dd, / = 17.17, 0.99 Hz, 1 H) 5.13 (dd, / = 10.38, 1.22 Hz, 1 H) 5.08 (d, / = 9.77 Hz, 1 H) 4.99 (dd, / = 17.17, 1.75 Hz, 1 H) 4.94 (dt, / = 10.19, 0.93 Hz, 1 H) 4.50 (t, / = 8.39 Hz, 1 H) 4.05 - 4.17 (m, 3 H) 2.53 - 2.65 (m, 2 H) 2.02 - 2.09 (m, 4 H) 1.77 - 1.87 (m, 2 H) 1.68 - 1.75 (m,
2 H) 1.51 (s, 3 H) 1.44 - 1.49 (m, 2 H) 1.32 - 1.43 (m, 4 H) 0.82 - 0.96 (m, 3 H). LC-MS: purity 92% (UV), tR 2.79 min, m/z [M+H]+ 800.35. Scheme XXXX
Figure imgf000544_0001
710 1074
[1070] Compound 1074 can be prepared according to the method of Scheme XXXX. Compound 708 can be coupled with (S)-2-(7e?t-butoxycarbonyl)aminonon-8-enoic acid to afford compound 709. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like. Compound 709 can be cyclized using an olefin metathesis catalyst, such as a Schrock catalyst, a Grubb's catalyst, a Zhan catalyst, a Hoveyda catalyst, a Nolan catalyst, and the like. The ester of compound 709 can be hydrolyzed under basic conditions, such as sodium hydroxide in ethanol and optionally water, and the like, to afford compound 710. Compound 708 can be coupled with 1-methylcyclopropane-l- sulfonamide to afford compound 1074. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like.
Figure imgf000545_0001
709
[1071] Compound 709 was prepared following General Method Z, and the yield is 78%. MS (ESI) m/e (M+H+) 693.3.
Example 51-3: Synthesis of compound 1073:
Figure imgf000545_0002
1073
General Method AA
[1072] To a solution of compound 709 (200 mg, 0.288 mmol.) in 2 mL of anhydrous toluene was added Zhan catalyst (30 mg, 0.044 mmol.), this solution was stirred at 50 0C overnight. The reaction mixture was concentrated to give a residue, the crude product was purified by Prep-TLC to afford compound 1073 (70 mg, 37%) as white solid. MS (ESI) m/e (M+H+) 665.3.
Figure imgf000546_0001
1074
[1073] Compound 1074 was prepared following General Method S, and the yield is 18%. MS (ESI) m/e (M+H+) 754.3.
Example 52-1: Synthesis of 2-phenyl-4-chloro-7-methoxy-quinoline: Scheme XXXXI
Figure imgf000546_0002
[1074] 2-Phenyl-4-chloro-7-methoxy-quinoline can be prepared according to Scheme XXXXI. Ethyl benzoylacetate and m-anisidine can reacted together under thermal conditions to afford 2-phenyl-4-hydroxy-7-methoxy-quinoline in the presence of an acid, such as hydrochloric acid and the like. 2-Phenyl-4-hydroxy-7-methoxy-quinoline can be converted to 2-phenyl-4-chloro-7-methoxy-quinoline using a chlorinating agent. For example, the chlorinating can be P(O)Cl3, P(O)Cl3 with PCl5, and the like.
Figure imgf000547_0001
General Method BB:
[1075] To a solution of ethyl benzoylacetate (10.00 g, 52.0 mmol., 1 eq) and m- anisidine (7.05 g, 57.2 mmol., 1.1 eq) in toluene (85 mL) was added 4M HCl in dioxane (0.520 mL, 2.08 mmol., 0.04 eq) drop wise. The reaction mixture was refluxed over night while ethanol and water were collected in a Dean and Stark's apparatus. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was suspended in diphenyl ether (28 mL) and the mixture was heated for 2 h at 2400C. The reaction mixture was then left to cool to ambient temperature and dichloromethane (55 mL) was added, leading to the precipitation of a yellow solid. Stirring was continued at ambient temperature for a further 30 min and the solid collected by filtration, rinsing the cake with a small amount of dichloromethane. The solid was transferred to a 100 ml round bottom flask and stirred with dichloromethane (50 mL) for another 45 min at ambient temperature. After filtration and drying under high vacuum, the title compound, 2-phenyl-4-hydroxy-7-methoxy- quinoline, was isolated as a pale yellow solid. Yield: 2.85 g (22%). 1H NMR (250 MHz, DMSOd6) δ 11.54 (s, 1 H), 7.99 (d, / = 8.91 Hz, 1 H), 7.73 - 7.90 (m, 2 H), 7.48 - 7.64 (m, 3 H), 7.20 (d, / = 2.32 Hz, 1 H), 6.94 (dd, / = 2.34, 8.97 Hz, 1 H), 6.26 (s, 1 H), 3.86 (s, 3 H). LC-MS: purity 97% (ELS) 98% (UV), tR 1.52 min, m/z [M+l]+ 252.10.
Example 52-2: Synthesis of 2-Phenyl-4-chloro-7-methoxy-quinoline:
Figure imgf000547_0002
General Method CC:
[1076] 2-Phenyl-4-hydroxy-7-methoxy-quinoline (2.73 g, 10.9 mmol., 1 eq) was suspended in neat phosphorus oxychloride (30 mL). The reaction mixture was heated under reflux. After 2 h, LCMS analysis showed full conversion of the starting material. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The solution (80 mL). The mixture was stirred at ambient temperature for a further 10 min, and then the two layers were separated. The organic phase was washed with water (2 x 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The obtained solid, 2-phenyl-4-chloro-7-methoxy- quinoline, was further dried under high vacuum for 2 h. Yield: 2.66 g (91%). 1H NMR (250 MHz, DMSOd6) δ 8.25 - 8.35 (m, 2 H), 8.21 (s, 1 H), 8.09 (d, / = 9.14 Hz, 1 H), 7.47 - 7.61 (m, 4 H), 7.38 (dd, / = 2.55, 9.18 Hz, 1 H), 3.97 (s, 3 H). LC-MS: purity 100% (ELS) 100% (UV), tR 2.58 min, m/z [M+l]+ 270.00
Example 53-1: Synthesis of compound 1075:
Figure imgf000548_0001
Figure imgf000548_0002
tert-Butyl-OK, DMSO, rt
Figure imgf000548_0003
Scheme XXXXII 1075
[1077] Compound 1075 can be prepared according to Scheme XXXXII.
Compound 10 can be treated with a base, such as sodium hydroxide, to hydrolyze the isoindoline carbamate, thereby affording compound 11. The alcohol, compound 11, can be treated with a base, such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium ferz-butoxide, and the like, then reacted with 2-phenyl-4-chloro-7-methoxy-quinoline to afford compound 1075. HO
Figure imgf000549_0001
11 General Method DD:
[1078] To a solution of the carbamate 10 (3.00 g, 4.10 mmol.) in 26 mL of methanol was added 26 mL of 5M aqueous sodium hydroxide. Precipitated material was not re-dissolved at 500C so further methanol (10 mL) was added. The resulting clear solution was stirred at 500C for 17h when LCMS showed the reaction to be complete. The solution was cooled below 100C and 2M aqueous hydrochloric acid solution was added slowly until ~pH 4, much product had precipitated at this stage. The resulting gum and aqueous solution were stirred with ethyl acetate (30 mL) until all was in solution. The aqueous layer was further extracted with of ethyl acetate (3 x 3OmL). The combined organic layers were washed twice with brine, dried over Na2SO4, filtered and the solvent removed under vacuum to give beige solid (2.50 g) which was purified by flash column chromatography using a methanol/dichloromethane gradient (neat DCM to 5%MeOH in DCM). The relevant fractions were combined and the solvent removed under vacuum to afford compound 11 as a beige solid. Yield 1.98 g (85%). 1H NMR (250 MHz, CDCl3) δ 10.60 (br. s, 0.2 H), 10.46 (s, 0.8 H), 8.48 (br. s, 0.2 H), 7.74 (s, 0.8 H), 6.60 (br. s, 0.2 H), 5.56 - 5.81 (m, 1 H), 5.34 (m, 0.8 H), 4.85 - 5.03 (m, 1 H), 4.41 - 4.73 (m, 2 H), 4.28 (br. s, 1 H), 3.39 - 4.10 (m, 3 H), 2.73 - 2.98 (m, 1 H), 2.06 - 2.63 (m, 4H), 1.68 - 2.05 (m, 3 H), 1.20 - 1.67 (m, 17 H), 0.65 - 1.13 (m, 4 H). LC-MS: purity 100% (ELS) 99% (UV), tR 1.89 min, m/z [M+Na]+ 591.
Example 53-3: Synthesis of 1075:
Figure imgf000550_0001
1075 General Method EE:
[1079] To a solution of compound 11 (1.00 g, 1.76 mmol., 1 eq) and 2-phenyl-4- chloro-7-methoxy-quinoline (0.520 g, 1.934 mmol., 1.1 eq) in dimethyl sulfoxide (20 mL) was added potassium fert-butoxide (0.790 g, 7.04 mmol., 4 eq) portionwise. Stirring was continued at ambient temperature for 17 h. The reaction was monitored by LCMS showing complete disappearance of the starting material as well as partial N-butoxycarbonyl cleavage. The reaction mixture was cooled to 00C and quenched with water (10 mL). The resulting mixture was partitioned between ethyl acetate (40 mL) and water (30 mL). The organic phase was collected and the aqueous phase was further extracted with ethyl acetate (2 x 40 mL). The organic extracts were combined, washed with brine (50 mL), dried over sodium sulphate, filtered and the solvent was removed under vacuum. The residue was purified by flash column chromatography using a methanol/dichloromethane gradient (neat DCM to 2%MeOH in DCM). The relevant fractions were combined and the solvent removed under vacuum to afford compound 1075 as an off-white glassy solid. Yield 0.468 g (33%). 1H NMR (500 MHz, CDCl3) δ 10.25 (br. s, 1 H), 7.98 - 8.10 (m, 3 H), 7.51 - 7.58 (m, 2 H), 7.45 - 7.50 (m, 1 H), 7.43 (d, / = 2.02 Hz, 1 H), 7.03 (dd, / = 2.50, 9.10 Hz, 1 H), 6.99 (s, 1 H), 6.94 (s, 1 H), 5.68 (q, / = 8.83 Hz, 1 H), 5.37 (br. s, IH), 5.13 (d, / = 7.66 Hz, 1 H), 4.96 (t, / = 9.38 Hz, 1 H), 4.77 (d, / = 11.37 Hz, 1 H), 4.59 (t, / = 7.93 Hz, 1 H), 4.52 - 4.64 (m, 1 H), 4.32 (ddd, / = 3.07, 7.93, 10.73 Hz, 1 H), 4.04 (dd, / = 3.30, 11.05 Hz, 1 H), 3.96 (s, 3 H), 2.82 - 2.94 (m, 1 H), 2.68 - 2.77 (m, 1 H), 2.62 - 2.68 (m, 1 H), 2.50 - 2.60 (m, 1 H), 2.33 (q, / = 8.48 Hz, 1 H), 1.77 - 1.94 (m, 3 H), 1.54 - 1.70 (m, 2 H), 1.42 - 1.49 (m, 4 H), 1.36 (s, 9 H), 1.26 - 1.32 (m, 2 H), 1.01 - 1.16 (m, 2 H), 0.84 - 0.96 (m, 1 H). LC-MS: purity 96% (ELS) 99% (UV), tR 1.88 min, m/z [M+l]+ 802. [1080] Compoundl078 can be synthesized by one of the preceding methods:
Figure imgf000551_0001
1078
Example 55-1: Synthesis of N-aryl amines: Scheme XXXXIII
Figure imgf000551_0002
VII-C
[1081] Compounds having having the general structure VII-C can be synthesized as shown in Scheme XXXXIII. The isoindoline carbamate 16 can be treated with acid, for Compound 17 can be treated with an optionally substituted aryl boronic acids under Cu +- catalyzed conditions thereby providing a compound having the general structure VII-A. A compound having the general structure VII-A can be treated under basic conditions to hydrolyse the ethyl ester and the isoindoline carbamate thereby providing an acid having the general structure VII-B. The acid having the general structure VII-B can be coupled with 1- methylcyclopropane-1 -sulfonamide to afford a compound having the general structure VII-C. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like.
Example 55-2 Preparation of compound 17
Figure imgf000552_0001
16 17
General Method XCX
[1082] To a solution of compound 16 (2 g, 3.0 mmol.) in dichloromethane (20 mL) was added 10 mL of trifluoroacetic acid, the resulting mixture was stirred at room temperature for 2 h, after that, the solvent was removed, the mixture was basified by aqueous NaHCO3, extracted by ethyl acetate (3 x 100 mL), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the crude compound 17 (1.6 g) was used directly in the next step.
Example 55-3 General procedure for preparation of compounds of general structure VII-A:
Figure imgf000552_0002
[1083] A mixture of compound 17 (350 mg, 0.50 mmol.), optionally substituted phenylboronic acid (1.5 mmol.), Cu(OAc)2 (188 mg,1.0 mmol.), pyridine (316 mg, 4 mmol.), pyridine N-Oxide(47.5 mg, 0.5 mmol.) and molecular sieves 4A in dichloromethane (10 mL) was stirred for 12 h at room temperature opening to the air. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate
(100 mL) and filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by prep-TLC (eluted with PE/EtOAc = 1/1) to afford a compound of general structure VII-A. (yield 40-60%).
Example 55-4 General procedure for preparation of compounds of general structure VII-B:
Figure imgf000553_0001
VII-A VII-B
General Procedue XB
[1084] To a solution of a compound of general structure VII-A (1 eq.) in methanol (10 mL) is added LiOH (30 eq.) and some water, the resulting mixture was stirred at room temperature overnight, after completion of the reaction, The mixture was cooled by ice water, acidified by aq. HCl (2 M) to pH=3-4, then the mixture was extracted by ethyl acetate (50 mLx3), the organic layers were combined, washed by brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the crude was purified by prep-TLC to provide a compound of general structure VII-B (EtOAc/Methanol = 10: 1) (yield 80-90%).
Example 55-5 General procedure for preparation of compounds of general structure VII-C:
Figure imgf000554_0001
VII-B VII-C
General Procedue XC
[1085] To a solution of a compound of genereal structure VII-B (1 eq.) in anhydrous dichloromethane was added CDI (4 eq.) under nitrogen protection. The resulting mixture was stirred at 35°C for 2 h, then 1-methylcyclopropane-l -sulfonamide (4 eq.) and DBU (8 eq.) was added, the resulting mixture was stirred at room temperature for another 12 h and the reaction was monitored by LCMS. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the final compound of genereal structure VII-C (yield 6-40%).
Example 55-6: Synthesis of compound 1100:
Figure imgf000554_0002
1100
[1086] Compound 1100 was prepared in a manner analogous to General Procedure XC, to afford 140 mg (40% yield). MS (ESI) m / z (M+H)+ 808.
Example 55-7: Synthesis of compound 1101:
Figure imgf000554_0003
[1087] Compound 1101 was prepared in a manner analogous to General Procedure XC, to afford 5.4 mg (9% yield). MS (ESI) m / z (M+H)+ 765.2.
Example 55-8: Synthesis of compound 1102:
Figure imgf000555_0001
1102
[1088] Compound 1102 was prepared in a manner analogous to General Procedure XC, to afford 26.4 mg (28% yield). MS (ESI) m / z (M+H)+ 722.1.
Example 55-9: Synthesis of compound 1103:
Figure imgf000555_0002
1103
[1089] Compound 1103 was prepared in a manner analogous to General Procedure XC, to afford 36.1 mg (38% yield). MS (ESI) m / z (M+H)+ 736.1.
Example 55-10: Synthesis of compound 1104:
Figure imgf000555_0003
1104 Procedure XC, to afford 22.7 mg (19% yield). MS (ESI) m / z (M+H)+ 752.2.
Example 55-11: Synthesis of compound 1105:
Figure imgf000556_0001
1105
[1091] Compound 1105 was prepared in a manner analogous to General Procedure XC, to afford 22.5 mg (yield 19%). MS (ESI) m/z (M+H)+ 754.2.
Example 55-12: Synthesis of compound 1106 by General Procedue XC:
Figure imgf000556_0002
1106
[1092] Compound 1106 was prepared in a manner analogous to General Procedure XC, to afford 5.5 mg (6% yield). MS (ESI) m/z (M+H)+ 793.4.
Example 55-13: Synthesis of compound 1107:
Figure imgf000556_0003
1107 Procedure XC, to afford 5.2 mg (6% yield). MS (ESI) m / z (M+H)+ 758.2.
Example 55-14: Synthesis of compound 1108:
Figure imgf000557_0001
1108
[1094] Compound 1108 was prepared in a manner analogous to General Procedure XC, to afford 5.6 mg (6% yield). MS (ESI) m / z (M+Na)+ 798.2
Example 55-15: Synthesis of compound 1109:
Figure imgf000557_0002
1109
[1095] Compound 1109 was prepared in a manner analogous to General Procedure XC, to afford 20 mg (21% yield). MS (ESI) m/z (M+H)+ 747.4.
Example 55-16: Synthesis of compound 1110:
Figure imgf000557_0003
1110 Procedure XC, to afford 41.3 mg (35% yield). MS (ESI) m / z (M+Na)+ 801.5.
Example 55-17: Synthesis of compound 1111:
Figure imgf000558_0001
1111
[1097] Compound 1111 was prepared in a manner analogous to General Procedure XC, to afford 5.4 mg (6% yield). MS (ESI) m / z (M+H)+ 740.3.
Example 55-18: Synthesis of compound 1112:
Figure imgf000558_0002
1112
[1098] Compound 1112 was prepared in a manner analogous to General Procedure XC, to afford 5.4 mg (7% yield). MS (ESI) m / z (M+H)+ 779.5.
Example 55-19: Synthesis of compound 1113:
Figure imgf000558_0003
1113 Procedure XC, to afford 6.5 mg, (11% yield). MS (ESI) m/z (M+H)+ 747.3.
Example 55-20: Synthesis of compound 1114:
Figure imgf000559_0001
1114
[1100] Compound 1114 was prepared in a manner analogous to General Procedure XC, to afford 30.1 mg (yield 36 %). MS (ESI) m / z (M+H)+ 736.
Example 55-21: Synthesis of compound 1115:
Figure imgf000559_0002
1115
[1101] Compound 1115 was prepared in a manner analogous to General Procedure XC, to afford 5.6 mg (8 % yield). MS (ESI) m / z (M+H)+ 806.1.
Example 55-22: Synthesis of compound 1116:
Figure imgf000559_0003
1116 Procedure XC, to afford 5 mg (8.6% yield). MS (ESI) m / z (M+H)+ 790.1.
Example 55-23: Synthesis of compound 1117:
Figure imgf000560_0001
1117
[1103] Compound 1117 was prepared in a manner analogous to General Procedure XC, to afford 5.1 mg (6% yield). MS (ESI) m / z (M+H)+ 740.1.
Example 56-1: Synthesis of compound 1128: Scheme XXXXIV
Figure imgf000560_0002
1070 1128
[1104] Compound 1128 can be synthesized as shown in Scheme XXXXIV.
Compound 17 can be treated with 3-fluoro-5-(trifluoromethyl)phenylboronic acid under Cu2+- catalyzed conditions thereby providing compound 722. Compound 722 can be treated under basic conditions to hydrolyse the ethyl ester thereby providing compound 1070. For example, the base can be lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like.
Example 56-2:
Figure imgf000561_0001
722 [1105] Copper (II) acetate (457 mg, 2.5 mmol, 1.4 eq.), pyridine (0.726 mL,
9.0 mmol, 5 eq.), pyridine-N-oxide (170 mg, 1.8 mmol, 1 eq.), 4A molecular sieves (700 mg) and dichloromethane (100 mL, previously saturated with air) were charged into reaction flask. Compound 17 (Ig, 1.8 mmol, 1 eq.) was added as a single portion and the reaction mixture was stirred for a further 5 min by when the initial light blue solution had turned dark blue. 3- fluoro-5-(trifluoromethyl)phenylboronic acid (370 mg, 1.8 mmol, 1 eq.) was added portion wise. The reaction mixture was stirred under an air atmosphere, at ambient temperature, for 72 hours. Water was added to the reaction mixture and the aqueous phase acidified to pH 5 with 1 M hydrochloric acid. The aqueous phase was further extracted with dichloromethane (100 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and the solvent removed under vacuum to give 882 mg (68%) of the desired product as a brown foamy solid, which was used in the next step without further purification. LC-MS: 73% (UV), tR 2.61 min, m/z [M +I]+ 719.35. 1H NMR (250 MHz, CDCl3) δ 6.82 - 7.16 (m, 3 H), 6.51 - 6.68 (m, 2 H), 6.40 (d, / = 10.96 Hz, 1 H), 5.46 - 5.70 (m, 1 H), 5.34 - 5.47 (m, 1 H), 5.15 - 5.34 (m, 1 H), 5.01 (dd, / = 4.26, 8.22 Hz, 1 H), 4.81 - 4.91 (m, 1 H), 4.76 (d, / = 4.87 Hz, 2 H), 4.55 - 4.71 (m, 2 H), 4.37 (t, / = 7.31 Hz, 1 H), 3.96 - 4.27 (m, 4 H), 3.86 (d, / = 10.66 Hz, 1 H), 2.69 - 2.96 (m, 1 H), 2.08 - 2.39 (m, 4 H), 1.86 (dd, / = 5.48, 8.22 Hz, 3 H), 1.56 (dd, / = 5.48, 9.75 Hz, 2 H), 1.33 - 1.48 (m, 3 H), 1.10 - 1.33 (m, 5 H).
Example 56-3:
Figure imgf000562_0001
1070
[1106] Compound 1070 (882 mg, 1.2 mmol., 1 eq.) and tetrahydrofuran (26 mL) were charged into reaction flask and the reaction mixture cooled on top of an ice bath for 5 minutes. Lithium hydroxide (128 mg, 3.06 mmol., 2.5 eq.) was dissolved in a mixture of water (26 mL) and methanol (13 mL) and the resulting solution was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for a further 15 hours. LCMS analysis of a sample showed limited hydrolysis of the ester, so extra Lithium hydroxide (103 mg, 2 eq.) was added and the reaction mixture stirred for a further 24 hours. LCMS analysis showed good conversion of the ester to the acid (86%) but also formation of the 4-hydroxy-proline derivative by-product so the reaction was stopped. The reaction mixture volume was reduced by half in vacuo and acidified to pH 1 with IM hydrochloric acid. The reaction mixture was then extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and the solvent removed under vacuum to give 688 mg (82%) of the desired product as brown solid. LC-MS: 46% (UV), 88% ELS, tR 2.37 min m/z [M +1]+ 691.30. 1H NMR (500 MHz, CDCl3) δ ppm 7.11 - 7.21 (m, 1 H) 6.87 - 7.00 (m, 2 H) 6.59 - 6.66 (m, 1 H) 6.52 - 6.60 (m, 1 H) 6.34 - 6.45 (m, 1 H) 5.52 - 5.65 (m, 1 H) 5.36 - 5.49 (m, 1 H) 5.16 - 5.31 (m, 1 H) 4.79 - 4.89 (m, 1 H) 4.57 - 4.80 (m, 5 H)
4.32 - 4.43 (m, 1 H) 3.98 - 4.05 (m, 1 H) 3.85 - 3.97 (m, 2 H) 2.73 - 2.89 (m, 1 H) 2.21 - 2.36 (m, 2 H) 1.88 - 2.03 (m, 1 H) 1.81 - 1.89 (m, 1 H) 1.69 - 1.79 (m, 1 H) 1.54 - 1.64 (m, 1 H)
1.33 - 1.52 (m, 2 H) 1.13 - 1.34 (m, 7 H).
Example 56-4:
Figure imgf000563_0001
1128
[1107] Compound 1070 (276 mg, 0.40 mmol., 1 eq.) and dichloromethane (8 niL) were charged into the reaction flask. EDC (159 mg, 0.83 mmol., 2.1 eq.) was added portion wise and the reaction mixture stirred at ambient temperature for 15 hours. The reaction mixture was diluted with dichloromethane (10 mL) washed with water (2 x 10 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was dissolved in dichloromethane (4 mL) and cyclopropylsulfonamide (111 mg, 0.92 mmol, 2.3 eq) and DBU (152 mg, 1.0 mmol, 2.5 eq.) were added. The reaction mixture was stirred at ambient temperature for a further 15 hours. LCMS analysis of a sample showed full consumption of the starting material. The reaction mixture was diluted with dichloromethane (10 mL) and then washed with 10% aqueous citric acid solution (2 x 10 mL) and brine (10 mL). The organic phase was dried over sodium sulfate, filtered and the solvent removed under vacuum to give 150 mg (48% crude, 68% pure by LCMS-UV) of product isolated as a brown solid. The solid was purified by preparative HPLC to give 5 mg (1.6% overall yield) of the desired product as a beige solid. LC-MS: purity 100% (UV), tR 5.21 min, m/z [M-H]" 792.20. 1H NMR (500 MHz, CDCl3) δ 10.19 - 10.41 (m, 1 H), 7.31 - 7.43 (m, 1 H), 7.20 - 7.31 (m, 1 H), 6.87 - 7.10 (m, 2 H), 6.55 - 6.62 (m, 1 H), 6.47 - 6.55 (m, 1 H), 6.26 - 6.38 (m, 1 H), 5.63 - 5.80 (m, 1 H), 5.44 - 5.56 (m, 1 H), 4.95 (t, / = 9.54 Hz, 1 H), 4.77 (d, / = 10.27 Hz, 2 H), 4.51 - 4.70 (m, 3 H), 4.16 - 4.26 (m, 1 H), 3.95 - 4.09 (m, 2 H), 2.84 - 2.96 (m, 1 H), 2.35 - 2.58 (m, 3 H), 2.21 - 2.33 (m, 1 H), 1.94 - 2.08 (m, 1 H), 1.79 - 1.93 (m, 2 H), 1.66 - 1.79 (m, 1 H), 1.36 - 1.61 (m, 6 H), 1.19 - 1.36 (m, 3 H), 1.01 - 1.17 (m, 2 H), 0.84 - 0.99 (m, 1 H). Scheme XXXXV
Figure imgf000564_0001
VIII-A
[1108] Compounds having having the general structure VIII-A can be synthesized as shown in Scheme XXXXV. Compound 705 can be treated with acid, for example TFA in DCM, to remove the Boc protecting group thereby providing compound 71. Compound 71 can be treated with an optionally substituted aryl boronic acid under Cu2+-catalyzed conditions thereby providing a compound having the general structure VIII-A.
Example 57-2:
Figure imgf000564_0002
705 71
General Method XDX
[1109] To a solution of compound 705 (1 g, 1.34 mmol.) in dichloromethane (2 mL) was added 1 mL of trifluoroacetic acid, the resulting mixture was stirred at room temperature for 2h, after that, the solvent was removed, the mixture was basified by aqueous
NaHCU3, extracted by ethyl acetate (50 ml_x3), the organic layers were combined, washed by the crude compound 71 (0.86 g, 100%) was used directly in the next step.
Example 57-3:
Figure imgf000565_0001
71 VIII-A
General Procedue XD
[1110] A mixture of compound 71 (1 eq.), optionally substituted phenyl boronic acid (3 eq), Cu(0Ac)2 (2 eq.), pyridine (10 eq.), pyridine N-Oxide (1 eq.) and molecular sieves 4A in dichloromethane (4 mL) was stirred at room temperature under oxygen atmosphere. The reaction was monitored by LC-MS. After completion of the reaction, the solid was removed by filteration, the solvent was removed and the crude mixture was purified by prep-TLC or prep-HPLC to give final compound VIII-A.
Example 57-4:
Figure imgf000565_0002
1118
[1111] Compound 1118 was prepared in a manner analogous to General Procedure XD, to afford 22.7 mg (18.6 % yield). MS (ESI) m/z (M+H)+ 790.3.
Figure imgf000566_0001
1119
[1112] Compound 1119 was prepared in a manner analogous to General Procedure XD, to afford 12 mg (10 % yield). MS (ESI) m / z (M+H)+ 806.2.
Example 57-6:
Figure imgf000566_0002
1120
[1113] Compound 1120 was prepared in a manner analogous to General Procedure XD, to afford 12.5 mg (10 % yield). MS (ESI) m / z (M+H)+ 808.2.
Example 57-7:
Figure imgf000566_0003
1121
[1114] Compound 1121 was prepared in a manner analogous to General Procedure XD, to afford 21.2 mg (17 % yield). MS (ESI) m/z (M+H)+ 779.3.
Figure imgf000567_0001
1122
[1115] Compound 1122 was prepared in a manner analogous to General Procedure XD, to afford 11.1 mg (9 % yield). MS (ESI) m / z (M+H)+ 815.1.
Example 57-9:
Figure imgf000567_0002
1123
[1116] Compound 1123 was prepared in a manner analogous to General Procedure XD, to afford 11.2 mg (10 % yield). MS (ESI) m / z (M+H)+ 808.4.
Example 57-10:
Figure imgf000567_0003
1124
[1117] Compound 1124 was prepared in a manner analogous to General Procedure XD, to afford 2.7 mg (2.3 % yield). MS (ESI) m / z (M+H)+ 739.9.
Figure imgf000568_0001
85
[1118] Compound 85 was prepared in a manner analogous to General Procedure XD, to afford 33 mg (25% yield).
Example 57-11:
Figure imgf000568_0002
[1119] Compound 86 was prepared in a manner analogous to General Procedure XD, to afford 29 mg (15% yield).
Example 57-12:
Scheme XXXXVI
Figure imgf000568_0003
XXXXVl-A XXXXVI-B General Procedure XXD fresh HCl/Et2O (5 mL) was stirred at 0 0C protected by nitrogen for 1.5h. The resulting mixture was dried by vacuum to give a compound having the general structure XXXXVI-B.
Example 57-12: Preparation of Compound 1146:
Figure imgf000569_0001
1146
[1121] Compound 1146 was prepared in a manner analogous to General Procedure XXD, to afford 7.9 mg (45% yield). MS (ESI) m / z (M+H)+ 736.7.
Example 57-13: Preparation of Compound 1147:
Figure imgf000569_0002
1147
[1122] Compound 1147 was prepared in a manner analogous to General Procedure XXD, to afford 5.1 mg (49% yield). MS (ESI) m / z (M+H)+ 736.8.
Scheme XXXXVII:
1125 1126
[1123] Compound 1126 can be synthesized as shown in Scheme XXXXVII.
Compound 17 can be treated with l-teτt-butyl-3-iodobenzene under copper catalyzed conditions, for example copper iodide and L-proline, thereby providing compound 714. Compound 714 can be treated under basic conditions to hydrolyse the ethyl ester thereby providing acid 1125. For example, the base can be lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. Finally, acid 1125 of can be coupled with 1- methylcyclopropane-1 -sulfonamide to afford compound 1126. For example, the coupling reagents can be CDI, DCC, DIC, EDAC, HOSu, HOBt, HOAt, PyBOP, PyBrOP, HBTU, HATU, TBTU, combinations thereof, and the like.
Figure imgf000571_0001
17 714
General Method XEX
[1124] A schlenk tube was charged with compound 17 (200 mg, 0.36mmol.), CuI
(13.7 mg, 0.072 mmol.), L-proline (16.6 mg, 0.144 mmol.) and K2CO3 (298.5 mg, 2.16 mmol.), evacuated and backfilled with argon. DMSO (2 mL) and l-ferf-butyl-3-iodobenzene (94 mg, 0.36 mmol.) were added successively. The resulting mixture was heated at 500C for 12 hours. LCMS monitored the reaction, after material was consumed, the reaction mixture was cooled to r.t. and diluted with ethyl acetate (100 mL), filtered. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with prep-TLC (petroleum ether: ethyl acetate = 1:1 ) to afford compound 714 (30 mg, 12% yield).
Example 58-3:
Figure imgf000571_0002
714 1125
General Method XFX
[1125] To a solution of compound 714 (30 mg, 0.043 mmol.) in methanol (5 mL) was added LiOH ( 30 mg, 1.29 mmol.) and water (0.5 mL), the resulting mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, the residue was acidified by aq. HCl (1 N) to pH=5-6, then the mixture was extracted by Ethyl acetate, the organic layers were combined, washed by brine, dried over anhydrous sodium acetate/methanol = 10:1) to afford compound 1125 (25 mg, 88%).
Example 58-3:
Figure imgf000572_0001
1125 1126
[1126] Compound 1126 was prepared in a manner analogous to General Procedure XC, to afford 7 mg (24% yield). MS (ESI) m / z (M+H)+ 778.4.
Figure imgf000572_0002
71 1127
General Method XGX
[1127] To a solution of compound 71 (86.5 mg, 0.13 mmol.) in ethanol (2 mL) was added triethylamine (39 mg,0.39 mmol.) and 2-chlorobenzoxazole (24 mg, 0.15mmol.), the resulting mixture was stirred at ambient temperature overnight, the reaction was monitored by LCMS. After completion of the reaction, the solvent was removed and the residue was purified by prep-TLC to afford compound 1127 (28.1 mg, 28%). MS (ESI) m / z (M+H)+ 763.3. Scheme XXXXVIII
Figure imgf000573_0001
1085
Example 59-2: Preparation of bicyclo[3.1.0]hexan-3-ol:
Figure imgf000573_0002
[1128] To a dry, nitrogen purged Schlenk tube were added anhydrous dichloromethane and Et2Zn solution in hexane (1.0 M, 10.2mL, 10.2 mmol) at O0C. Cyclopent-3-enol (0.25 mL, 2.97 mmol) was added dropwise. After the addition completion, the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (0.48 mL, 5.94 mmol) was then added dropwise slowly. The reaction was allowed to warm to room temperature and continued to stir overnight. The reaction was then diluted with CH2CI2 and quenched with 2M HCl. The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 1 mL directly for the next step.
Example 59-3: Preparation of bicyclo[3.1.0]hexan-3-yl succinimidylcarbonate:
Figure imgf000574_0001
[1129] Anhydrous dichloromethane (1 mL) was added to the solution of crude bicyclo[3.1.0]hexan-3-ol (2.97 mmol.) from previous step followed by the dropwise addition of Et3N (0.88 mL, 6.11 mmol.). The reaction continued to stir at room temperature under nitrogen. Disuccinimidylcarbonate (988 mg, 3.86 mmol.) was added to the flask portionwise. The reaction was allowed to stir for 2 days. The reaction mixture was quenched with IM HCl and washed with water. The desired material was extracted with CH2Cl2, and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude material was purified using prep-TLC (PE: EtOAc = 3: 1) to provide crude bicyclo[3.1.0]hexan-3-yl succinimidylcarbonate (210 mg, purity 50%).
Example 59-4: Preparation of Compound 1085:
Figure imgf000574_0002
[1130] Crude compound 77 (0.27 mmol.) was dissolved in EtOAc (2 mL) and saturated aqueous NaHCO3 (3 mL). It was stirred vigorously. After 10 min, bicyclo[3.1.0]hexan-3-yl succinimidylcarbonate (78 mg, 0.33 mmol.) was added in one portion. After the resulting mixture was stirred for another 30 min, the organic layer was collected and washed with brine (5 mL), dried over NaSO4, and concentrated. The residue was purified by prep-HPLC to afford compound 1085: 51.3 mg, yield 25%. MS (ESI) m / z (M+H)+ 756.0. PREPARATION OF NS3 INHIBITORS: SECTION XI Example 60-1: Preparation of Phosphinates Scheme XXXXIX (Stage 1)
Figure imgf000575_0001
[1131] The dipeptide intermediate (product of Stage 1) may be prepared according to Scheme XXXXIX using the following reagents and conditions:
(a) N2H4, EtOH, rt;
(b) PhCHO, toluene, reflux;
(c) trans- 1 ,4-dibromo-butene, CsOH, rt, DCM;
(d) HCl (aq), rt;
(e) CbzCl, Na2CO3, DCM, rt;
(f) NaI, Py, 1100C; protection with a suitable phosphinate protecting group R (e.g., Me)
(g) (COCl)2, DMF, O0C; then MeLi, -78°C, DCM;
(h) protection with a suitable phosphinate protecting group R (h1) TMSI, DCM, O0C
Figure imgf000576_0001
RCM carboxylic acid
[1132] The macrocycle product may be prepared from the dipepide intermediate of Stage 1 according to Scheme L. Example 60-2: Preparation of Phosphonates XXXXIX and L with the modification that intermediate A is deprotected to give the free amine and coupled to the proline to give a Boc-dipeptide diethyl phosphonate. The diethyl phosphonate can be carried through the remaining synthesis as the protected diethyl phosphonate then deprotected to give the final compound.
Example 61 - Examples of NS3-NS4 activity
[1134] NS3-NS4 inhibition activity can be determined using known assay methods. For example, NS3/NS4 complexes may be formed and inhibitory concentrations of test compounds determined as described in U.S. Patent Application Publication Number 2007/0054842 paragraph numbers 1497-1509, which is incorporated herein by reference in its entirety. Similarly, hepatitis C replicon EC50 may be determined using known assay methods such as described in U.S. Patent Application Publication Number 2007/0054842 paragraph numbers 1510-1515. Assays may be conducted at ambient temperature (23 0C) in assay buffer containing 50 mM Tris-HCl, pH 7.5, 15% glycerol, 0.6 mM Lauryldimethylamine Oxide (LDAO), 25 μM NS4A peptide, and 10 mM Dithiothreitol (DTT).
[1135] Inhibition of NS3/NS4 activity was determined for several compounds exemplified herein and is presented in Tables 2 and 3.
Table 2: Examples NS3-NS4 activity.
Figure imgf000577_0001
Figure imgf000578_0001
Figure imgf000579_0001
Figure imgf000580_0001
A indicates an EC50 or IC50 > 500 nM
B indicates an EC50 or IC50 between 75 and 500 nM
C indicates an EC50 or IC50 between 10 and 75 nM NA means the data is not available
Table 3: Examples NS3-NS4 activity.
Figure imgf000581_0001
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000584_0002
A indicates an EC50 or IC50 > 100 nM B indicates an EC50 or IC50 between 10 and 100 nM C indicates an EC50 or IC50 of less than 10 nM NA means the data is not available
Example 62-1 - ITMN- 191 Treatment Effect on HCV viral load (Comparative) Monotherapy:
Figure imgf000584_0001
ITMN- 191
[1136] The study was designed to provide the plasma pharmacokinetics (PK) of multiple ascending daily oral doses of ITMN- 191 monotherapy and to evaluate the viral kinetics (VK) of multiple ascending daily oral doses of ITMN- 191 monotherapy in patients, as measured by changes from Baseline in hepatitis C virus ribonucleic acid (HCV RNA) levels. The ITMN-191 was administered in the form of its sodium salt. Proposed Dose Escalation:
[1137] In Part A and Part B, up to six cohorts (treatment arms) of 10 patients each were planned. In Part A, up to five cohorts of 10 treatment-naϊve patients per cohort were planned to receive multiple ascending doses of study drug. Patients within each of the five cohorts were randomly assigned 8:2 to receive either ITMN-191 or placebo for 14 days. In Part B, one cohort of non-responder (NR) patients (Cohort 6) was planned to receive a single dose level of study drug for 14 days. Patients in Cohort 6 were randomly assigned 8:2 to cohorts and doses.
Figure imgf000585_0001
Number of Patients:
[1138] Planned enrollment: 60 patients (10 per cohort). Actual enrollment: 50 patients.
[1139] In Part A, there were 32 males and 8 females, ranging in age from 26 to 65 years old
[1140] Patients who met all of the following criteria were eligible to participate in the study:
Between 18 and 65 years of age, inclusive, at the time of dosing; History of chronic hepatitis C genotype 1, documented with HCV genotype and detectable HCV RNA levels at the Screening Visit; HCV treatment history:
Part A: Treatment- naϊve (i.e., had never received IFN-based monotherapy or combination therapy for their condition)
Part B: NR (nonresponders), defined as:
Previously treated with the combination of PEG-IFNα plus RBV; and Failed to achieve a >2 logio reduction in HCV RNA at Week 12, or detectable HCV RNA levels at Week 24 or beyond while on therapy; Liver biopsy or noninvasive (e.g., fibroscan) procedure in the past 2 years showing absence of cirrhosis; and on assessment with both protocol-specified cardiac troponin immunoassays.
[1141] The treatment period consisted of 14 days of blinded study drug. In Part A, optional Standard of Care (SOC) consisting of PEG-IFN-α plus ribivarin (RBV) therapy was provided to treatment- naϊve patients 24 hours after the last dose on Day 14. In Part B, NR patients were not permitted to start any additional HCV therapy before Day 44.
Part A (Treatment-Naive Patients):
[1142] Overall age ranged from 25 years to 65 years. Most of the treatment-naϊve patients were male (80%) and European (90%). Median BMI ranged from 23.6 kg/m2 to 26.9 kg/m2, with an overall range of 19 kg/m2 to 31 kg/m2. The median duration since HCV diagnosis ranged from 2 years to 7.5 years, with an overall range of 1 year to 34 years. Median HCV RNA log10 levels ranged from 5.73 log10 IU/mL to 6.46 log10 IU/mL. Median ALT levels ranged from 56 U/L to 74 U/L with an overall range of 26 U/L to 241 U/L.
Part B (NR Patients):
[1143] Overall age ranged from 25 years to 62 years. Of the 10 NR patients, 8 were male (ITMN-191), 2 were female (placebo), and 100% were European. Median BMI ranged from 23.5 kg/m2 to 25.1 kg/m2, with an overall range of 19 kg/m2 to 30 kg/m2. The median duration since HCV diagnosis ranged from 1 year to 9.5 years, with an overall range of 1 to 16 years. Median HCV RNA levels ranged from 6.47 log10 IU/mL to 6.64 log10 IU/mL, with an overall range of 5.98 logio IU/mL to 7.63 logio IU/mL. Median ALT levels ranged from 62.5 U/L to 75.5 U/L, with an overall range of 26 U/L to 152 U/L.
Patient Disposition
[1144] All patients completed 14 days of treatment (40 on ITMN-191 and 10 on placebo). During the 14-day dosing period, 3 treatment-naϊve patients in the 200 mg ql2h treatment arm received less than the assigned daily dose of blinded study drug dose (2 patients received 100 mg ql2h of ITMN-191 during the entire 14 days, and 1 patient received 100 mg ql2h of ITMN-191 during Day 1 through the first dose of Day 5 of the dosing period). Of the 50 enrolled patients, 49 completed through Day 44 (1 patient was lost to follow-up after Day 21), and 48 patients completed through Day 90. Among treatment-naϊve patients, 31/40 initiated optional SOC treatment on Day 15, and among NR patients, 7/10 initiated optional SOC treatment on Day 44. reductions in ALT values using the Efficacy-Evaluable Population, defined as those patients who received at least 90% of prescribed doses of assigned blinded study drug. Three patients in the treatment-naive 200 mg ql2h cohort received less than the assigned randomized dose and were excluded from all efficacy analyses. The HCV RNA levels were determained by Roche COBAS Taqman HCV/HPS test, v2.0. This is a reverse transcriptase PCR method.
Viral Kinetics (VK)
Part A (Treatment-Naive Patients)
[1146] In the treatment-naϊve patients, ITMN- 191 treatment resulted in generally rapid, sustained (over the 14-day treatment period), dose-dependent reductions in HCV RNA levels, with median reductions of -3.12 log10 IU/mL in the 200 mg ql2h cohort and -3.76 logio IU/mL for the 200 mg q8h cohort at end of treatment (EOT) (Day 14). Similarly, median maximum reductions in HCV RNA levels in the 200 mg ql2h and 200 mg q8h cohorts were -3.17 log10 IU/mL and -3.90-log10 IU/mL, respectively. Median ALT values declined from elevated Baseline levels in all ITMN-191 cohorts during study treatment, with the largest median EOT reduction of -37.5 U/L observed in the 200 mg q8h cohort.
Part B (NR Patients)
[1147] In the NR patients, 300 mg q8h of ITMN-191 treatment resulted in a median reduction of -2.46 logio IU/mL at EOT. The median maximum reduction in HCV RNA levels was -2.93 log10 IU/mL. The median ALT value declined from an elevated Baseline level by -34.5 U/L at EOT.
Viral Resistance
[1148] In Parts A and B, rebound, plateau, and continuous decline of virologic response profiles were defined based on the HCV RNA level at end of treatment (EOT) relative to the nadir HCV RNA level. In general, patients experiencing virologic rebound (14/40 patients) and plateau (12/40 patients) were observed in the lower dose treatment arms, while the majority of patients (14/40 patients) experiencing a continual decline in HCV RNA level were observed in the upper dose treatment arms. The frequency of rebound for treatment-naϊve patients (Part A) was higher in the 100 mg q2h treatment arm (4 patients) than in the higher dose treatment arms (2 to 3 patients). The frequency of rebound for NR q8h treatment arm. However, there were no statistically significant differences in ITMN-191 AUC, Cmax, or Cτ between rebound, plateau, and continual decline groups. At EOT, every patient classified as experiencing virologic rebound carried NS3 variants in which arginine at amino acid position 155 was replaced, at least in part, by lysine. Arginine substitution was observed 21 and 90 days following cessation of ITMN-191 administration in the majority of patients with amplifiable NS3 at those time points, indicating that NS3 bearing this substitution were genetically fit.
Conclusions:
[1149] ITMN-191 treatment provides a dose-dependent reduction in HCV RNA levels in treatment-naϊve patients, with a daily dose of 200 mg q8h for 14 days providing the highest median reduction of HCV RNA levels of all the treatment arms. In the treatment- naϊve cohorts (Part A) the median maximum post-Baseline log10 reduction in HCV RNA in the 200 mg ql2h and the 200 mg q8h cohorts are -3.17 log10 IU/mL and -3.90 log10 IU/mL, respectively during study drug treatment. In the single NR cohort (Part B), the 300 mg ql2h dose results in a more modest median maximum post-Baseline change in HCV RNA of - 2.93 logio IU/mL during study drug treatment. Virologic rebound occurred in 14 (35%) of the 40 ITMN-191 treated patients and was primarily associated with an R155K substitution in the NS3 protein coding sequence at end of treatment. ITMN-191 administration resulted in reductions in elevated Baseline ALT levels during 14 days of treatment in all cohorts.
Table 4: Viral Kinetic Assessments of Monotherapy Following 14 Days of Treatment.
Figure imgf000588_0001
(200 mg q8h) that 13% of the patients in each group had HCV RNA lowered to levels below 43 IU/mL.
Example 62-2 - ITMN-191 Treatment Effect on HCV viral load - Combination therapy
Study Design:
[1151] This is a double-blind, placebo-controlled, multicenter study in treatment- naϊve patients with chronic hepatitis C genotype 1 infection. All patients receive standard of care (SOC) treatment with PEG-IFN alfa-2a and weight-based ribavirin in accordance with the product labeling. In addition to this standard of care treatment, patients are randomized to receive either ITMN-191 or matching placebo, administered in the fed state, for 14 complete days, and a single dose on Day 15. PEG-IFN alfa-2a and ribavirin is provided from Day 0 and following the completion of study drug treatment on Day 15 through Day 44. No other HCV therapies are permitted prior to Day 44. All patients receive SOC and then are administered a pill containing either ITMN-191 or placebo. The ITMN-191 was administered in the form of its sodium salt.
[1152] Patients are admitted to a research facility and initiate PEG-IFN alfa-2a and ribavirin on Day 0. Study drug (ITMN-191 or placebo) administration begins on Day 1 and continues to the morning of Day 15, and patients are discharged from the research facility on Day 16. Meals and activity levels are standardized across research facilities. Patients are contacted by telephone on Day 21 and return to the research facility for the Safety Follow-up Visit on Day 28 and the End of Study Visit on Day 44.
[1153] The initial ITMN-191 dose levels administered in this study resulted in exposures generally similar to those studied a completed multiple ascending dose study of ITMN-191 monotherapy (see Comparative Example 21-1 above).
[1154] Over the course of the study, blood samples are obtained for clinical laboratory analysis and for PK (pharmokinetics) and VK (viral kinetics). In addition, blood samples to assess VR (viral rebound) are obtained. To monitor potential cardiac toxicity, cardiac troponin are assessed every day during the treatment period. Methods:
[1155] End of treatment (EOT) and nadir HCV RNA levels were used to define virologic rebound, continual decline, and plateau response patterns. NS 3 protease domain was amplified and population sequenced by nested reverse transcription polymerase chain reaction used for clonal sequencing. The HCV RNA levels were determained by Roche COBAS
Taqman HCV/HPS test, v2.0. This is a reverse transcriptase PCR method.
Results:
[1156] After 14 days of triple combination therapy, the median change in HCV RNA from baseline exceeded 5 logs in five of the six cohorts and was -5.5 log and -5.7 log in the best performing ql2h and q8h cohorts, respectively. At the end of only 14 days of treatment, HCV RNA was below the limit of quantification (<25 IU/mL) in nearly three- quarters (71%, or 32 of 45) of patients at all doses and intervals who received treatment with ITMN-191 as summarized in Table 5. In all ql2h and q8h cohorts of ITMN- 191 in combination with SOC, reductions in HCV RNA occurred rapidly and there was no evidence of the viral rebound seen during during ITMN-191 monotherapy treatment (see Comparative Example 62-1 above).
Table 5: Viral Kinetic Assessments of Combination Therapy Following 14 Days of Treatment.
Figure imgf000590_0001
[1157] The combination of ITMN-191 with SOC provides a much greater reduction in HCV RNA levels as compared to SOC alone, as evidenced by the median change of HCV RNA levels shown in Table 5. Further, the combination protocol prevents a viral rebound in all treatment groups, in contrast to patients treated with ITMN-191 alone where seen in patients under SOC and placebo treatment. It was observed that at least 57% of the patients treated with the combination therapy obtained HCV RNA levels below 25 IU/mL. Further, it was observed that at least 13% of the patients treated with the combination therapy obtained HCV RNA levels below 9.3 IU/mL (detection limit of analysis method). Additionally, there was no viral rebound observed for any patients in the combination treatment groups.
[1158] Various trends are observed by comparing the earlier ITMN-191 monotherapy study (see Example 62-1) with the more recent combination study, as summarized in Table 5. The combination treatment provides (group 4 and group 6, Table 6) reduction of HCV RNA levels below 43 IU/mL in a significant percentage of the patients in each study group. This reduction is observed in the combination study where 100 mg of ITMN-191 was administered every 8 hours or 200 mg of ITMN-191 was administered every 8 hours. The baseline comparison can be seen in the placebo group (placebo alone) and the SOC treatment group (placebo with peginterferon alfa-2a and ribavirin) which did not show any patients with an HCV RNA level below 43 IU/mL after 14 days of treatment.
[1159] The superior virologic response of the combination therapy is evident by comparing the monotherapy cohorts to their corresponding combination therapy cohorts. The monotherapy cohort (group 3) where 100 mg of ITMN-191 was administered every 8 hours provided a reduction of HCV RNA levels below 43 IU/mL in 13% of patients after 14 days of treatment. In contrast, the corresponding cohort from the combination study where 100 mg of ITMN-191 was administered every 8 hours in combination with pegylated interferon-alfa and ribavirin provided a reduction of HCV RNA levels below 43 IU/mL in 75% of patients (group 4) after 14 days of treatment. The cohort from the monotherapy study where the amount of ITMN-191 was increased to 200 mg, again administered every 8 hours, provided a similar reduction of HCV RNA levels below 43 IU/mL in 13% of patients (group 5) after 14 days of treatment. Similar to the previous comparison, the corresponding cohort (group 6) where 200 mg of ITMN-191 was administered every 8 hours in combination with pegylated interferon-alfa and ribavirin provided a reduction of HCV RNA levels below 43 IU/mL in 88% of patients after 14 days of treatment. Thus, the combination cohorts provide a superior reduction in HCV RNA levels in comparison to the monotherapy cohorts, as evidenced by the much greater percentage of patients with a reduction of HCV RNA levels in the blood. Table 6: Comparison of Viral Kinetic Assessments Among Placebo, SOC, ITMN-191 Monotherapy and Combination Therapy Following 14 Days of Treatment.
Figure imgf000592_0001
Conclusion
[1160] The combination of ITMN-191 with SOC provides, on average, reduction of HCV RNA in all patient cohorts that is greater than SOC alone. The reduction of HCV RNA is observed without viral rebound.
[1161] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

1. A compound having the structure of Formula I:
Figure imgf000593_0001
or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and Ci_6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(d) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, -S(O)2NRlaRlb, -NHC(O)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(O)R2a, -NHC(O)OR2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(e) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) each R2a is separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(g) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(h) each R4a is separately imidazolyl or pyrazolyl;
(i) each m is separately 0, 1 or 2;
(j) each p is separately an integer selected from 1-6;
(k) each q is separately 0, 1 or 2;
(1) each r is separately an integer selected from 1-6;
(m) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, -(CH2)qC6 or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy- Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3_6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(CO)NHR1'1, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and -(CH2)qC3-7cycloalkyl; (o) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3-7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro;
(p) each u is separately 0, 1 or 2;
(q) Z is selected from the group consisting of
Figure imgf000596_0001
Figure imgf000596_0002
(r) R19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
(s) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(t) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond; with the proviso that the compound of formula I is not
Figure imgf000597_0001
2. The compound of Claim 1 having the structure:
Figure imgf000597_0002
3. The compound of any of Claims 1 to 2, wherein R20 is selected from the group consisting of hydrogen, -SOmR2a, and -C(0)R2a.
4. The compound of any one of the preceeding claims, wherein:
R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and
R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl.
5. The compound of any one of Claims 1-3, wherein R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro.
6. The compound of any one of Claims 1-3, wherein R4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro. or more substituents each independently selected from the group consisting of fluorine and CF3.
8. The compound of Claim 1 or 2, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen, -C(O)CH3, or -SO2CH3.
9. The compound of Claim 1 or 2, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
10. The compound of Claim 1 or 2, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
11. The compound of Claim 1 or 2, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and
12. The compound of any one of the preceeding claims, wherein R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and Ci_6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, Ci-6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
13. The compound of any one of the preceeding claims, wherein R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkoxy, -(CH2)qC3_7cycloalkyl, aryl and heteroaryl; wherein said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of Ci_6 alkyl, and -NRlaRlb, wherein q is 0 and Rla and Rlb are each separately a hydrogen atom or Q-6 alkyl.
14. The compound of any one of the preceeding claims, wherein R2 is selected from the group consisting of thiazole, oxazole, imidazole, benzothiazole, benzoxazole, benzoimidazole, quinoline, isoquinoline, quinazoline, quinoxaline, imidazopyridine, and imidazopyrazine, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkoxy, -(CH2)qC3_7cycloalkyl, phenyl, thiazole, oxazole, thiophene, and pyridine; wherein said thiazole and oxazole as an optional substituent are each further optionally substituted with one or more substituents each and Rla and Rlb are each separately a hydrogen atom or Ci_6 alkyl.
15. The compound of any one of the preceeding claims, wherein Z is propyl.
16. The compound of any one of the preceeding claims, wherein R3 is carboxylic acid.
17. The compound of any one of Claims 1-15, wherein R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy.
18. The compound of any one of Claims 1-15, wherein R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3 m is 0 or 1 ; and q is 0 or 1.
19. The compound of any one of Claims 1-15, wherein R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci-6 alkyl or -NR9aR9b is a pyrrolidine or piperidine.
20. A compound having the structure of Formula II:
Figure imgf000600_0001
II or i i pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-C^ alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or io aryl> each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy- C1-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl;
(d) each m is separately 0, 1 or 2;
(e) each q is separately 0, 1 or 2; (g) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(h) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(i) each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(j) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(k) each R4a is separately imidazolyl or pyrazolyl;
(1) each p is separately an integer selected from 1-6; (n) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro;
(0) R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkoxy, C2_6 alkenyl, C2-6 alkynyl, -(CH2)qC3-7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)PNR14R15], -S[(CH2)pNR14R15], -(CH2)pNR14R15, -(CH2)pR16, -O(CH2)pR16, and C1-6 alkyl optionally substituted with up to 5 fluoro;
(p) R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3_7 cycloalkyl, C4-Io alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(q) R13 is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(r) R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(s) each R16 is separately imidazolyl or pyrazolyl;
(t) V is selected from the group consisting of -O-, -S-, and -NR15-;
(u) W is -N- or -CR15-; wherein R15 is H, or selected from the group consisting of Ci-6 alkyl,
(CH2)qC3-7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl;
(v) each u is separately 0, 1 or 2;
(w) Z is selected from the group consisting of
Figure imgf000604_0001
Figure imgf000604_0002
(x) R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
(y) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(z) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(aa) the dashed line represents an optional double bond. 21. The compound of Claim 20 having the structure:
Figure imgf000605_0001
22. The compound of any of Claims 20 to 21, wherein R20 is selected from the group consisting of hydrogen, -SOmR2a, and -C(0)R2a.
23. The compound of any of Claims 20 to 22, wherein:
R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and
R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with CL6 alkyl.
24. The compound of Claim 23, wherein R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro.
25. The compound of Claim 24, wherein R4 is aryl substituted with one or more substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro.
26. The compound of Claim 25, wherein R4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF3.
27. The compound of Claim 20 or 21, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen;
R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen, -C(O)CH3, or -SO2CH3.
28. The compound of Claim 20 or 21, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
29. The compound of Claim 20 or 21, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
30. The compound of Claim 20 or 21, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and
R20 is hydrogen.
31. The compound of any one of Claims 20-30, wherein R11 and R12 are each separately selected from the group consisting of hydrogen, halo, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy, and -(CH2)qC3_7cycloalkyl where q is 0.
32. The compound of any one of Claims 20-31, wherein Z is propyl.
33. The compound of any one of Claims 20-32, wherein R3 is carboxylic acid.
34. The compound of any one of Claims 20-32, wherein R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl or Ci_6 alkoxy. where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3 m is 0 or 1; and q is 0 or 1.
36. The compound of any one of Claims 20-32, wherein R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine.
37. A compound having the structure of Formula III or Formula IV:
Figure imgf000607_0001
III IV or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci-6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Q-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each hydroxy, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy- C1-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci-6 alkoxy, and phenyl; or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, C3_6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and (CH2)qC3-7cycloalkyl;
(d) each m is separately 0, 1 or 2;
(e) each q is separately 0, 1 or 2;
(f) each t is separately 0, 1 or 2;
(g) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3-7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -C(O)R2a, -C(O)OR2a, -NHC(O)R23, -NHC(O)OR23, -SO1nR23, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(h) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, Cj,.η cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(i) R2a is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(j) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(k) each R4a is separately imidazolyl or pyrazolyl;
(1) each p is separately an integer selected from 1-6;
(m) each r is separately an integer selected from 1-6;
(n) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro;
(0) R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl, Ci-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3-7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)pNR14R15], -S[(CH2)pNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
(p) R7 and R8 are each separately a hydrogen, or separately selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C3_7 cycloalkyl, C4-Io alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(q) R13 is selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(r) R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(s) each R16 is separately imidazolyl or pyrazolyl; -(CH2)qC3-7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, phenyl, and -NRlaRlb;
(u) E and F are independently -N- or -CR -; when E is -CR18-, F is -N-; when F is -CR18-, E is -N-;
(v) each R18 is separately a hydrogen, or selected from the group consisting of Ci-6 alkyl, (CH2)qC3_7cycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl;
(w) each u is independently 0, 1 or 2;
(x) Z is selected from the group consisting of
Figure imgf000611_0001
Figure imgf000611_0002
Figure imgf000611_0003
(y) R19 is hydrogen, Ci_6 alkyl optionally substituted with up to 5 fluoro, or
-SOmR2a;
(z) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(aa) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(bb) the dashed line represents an optional double bond. 38. The compound of Claim 37 having the structure:
Figure imgf000612_0001
39. The compound of Claim 37 having the structure:
Figure imgf000612_0002
40. The compound of any of Claims 37 to 39, wherein R20 is selected from the group consisting of hydrogen, -SOmR2a, and -C(0)R2a.
41. The compound of any of Claims 37 to 40, wherein:
R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; n is 0; and
R3 is -C(O)NHS(O)2R9 where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl.
42. The compound of Claim 41, wherein R4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents each independently selected from the group consisting of halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro. substituents each independently selected from the group consisting of halo, Ci-6 alkyl optionally substituted with up to 5 fluoro.
44. The compound of Claim 43, wherein R4 is aryl substituted with one or more substituents each independently selected from the group consisting of fluorine and CF3.
45. The compound of any of Claims 37 to 39, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen;
R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen, -C(O)CH3, or -SO2CH3.
46. The compound of any of Claims 37 to 39, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
47. The compound of any of Claims 37 to 39, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
48. The compound of any of Claims 37 to 39, wherein: n is 0 or 1 ;
R5 and R6 are each hydrogen; with CF3; and
R20 is hydrogen.
49. The compound of any of Claims 37 to 48, wherein R11 and R12 are each separately selected from the group consisting of hydrogen, Ci-6 alkyl, and Ci-6 alkoxy.
50. The compound of any of Claims 37 to 48, wherein R11 and R12 are each separately selected from the group consisting of hydrogen, methyl and methoxy.
51. The compound of any of Claims 37 to 50, wherein R17 is a hydrogen, or selected from the group consisting of phenyl, thiazole, thiophene, oxazole and pyridine, each optionally substituted with one or more substituents each independently selected from the group consisting Ci_6 alkyl and -NRlaRlb, wherein Rla and Rlb are each separately a hydrogen atom or Ci-6 alkyl.
52. The compound of any of Claims 37 to 51, wherein Z is propyl.
53. The compound of any of Claims 37 to 52, wherein R3 is carboxylic acid.
54. The compound of any of Claims 37 to 52, wherein R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy.
55. The compound of any of Claims 37 to 52, wherein R3 is a -CONHO(CH2)mR10 where R10 is Ci-6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3 m is 0 or 1; and q is 0 or 1.
56. The compound of any of Claims 37 to 52, wherein R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine.
57. A compound having the structure of Formula V or VI:
Figure imgf000615_0001
or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is (CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, C1-6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(d) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; cycloalkyl, and Ce or 10 aiyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(f) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(g) each R4a is separately imidazolyl or pyrazolyl; (h) each m is separately 0, 1 or 2;
(i) each p is separately an integer selected from 1-6; (j) each q is separately 0, 1 or 2; (k) each r is separately an integer selected from 1-6;
(1) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a carboxylic acid; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3-7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy- Ci_6 alkyl, phenyl, alkyl substituted with up to 5 fluoro, and
Figure imgf000616_0001
alkoxy substituted with up to 5 fluoro, of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or -NR9aR9b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, Ci-6 alkyl, Ci-6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ci_6 alkoxy, C3_6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(CO)NHR1'1, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci-6 alkyl, and -(CH2)qC3_7cycloalkyl; (m) each t is separately 0, 1 or 2;
(n) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)uC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3-7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3-7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro;
(0) each u is separately 0, 1 or 2; (p) Z is selected from the group consisting of
Figure imgf000618_0001
(q) R19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or -SOmR2a;
(r) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(O)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(s) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(t) the dashed line represents an optional double bond.
58. The compound of Claim 57, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen, -C(O)CH3, or -SO2CH3.
59. The compound of Claim 57, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
60. The compound of Claim 57, wherein: R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more substituents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro; and
R20 is hydrogen.
61. The compound of Claim 57, wherein: n is 0 or 1;
R5 and R6 are each hydrogen;
R4 is phenyl substituted with one or more fluoro and optionally substituted with CF3; and
R20 is hydrogen.
62. The compound of any one of Claims 57-61, wherein Z is propyl.
63. The compound of any one of Claims 57-62, wherein R3 is carboxylic acid.
64. The compound of any one of Claims 57-62, wherein R3 is -C(O)NHS(O)2R9, where R9 is C3_7cycloalkyl optionally substituted with Ci_6 alkyl or Ci_6 alkoxy.
65. The compound of any one of Claims 57-62, wherein R3 is a -CONHO(CH2)mR10 where R10 is Ci_6 alkyl, -(CH2)qC3_7cycloalkyl or phenyl optionally substituted with CF3 m is 0 or 1; and q is 0 or 1.
66. The compound of any one of Claims 57-62, wherein R3 is -C(O)NHS(O)2R9, where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine.
67. A compound selected from the group consisting of the formulas of compounds 101-492 in the specification.
68. A compound selected from the group consisting of the formulas of compounds 101-156, 318, 320-325, 327, 329, 331, 335, 338, 343-344, 354, 448-454, and 463 in the specification.
69. A compound selected from the group consisting of the formulas of compounds 269-314 in the specification.
70. A compound selected from the group consisting of the formulas of compounds 390-391, 415, 417, 440-443, 455-460, and 490 in the specification. 157-163, 166-172, 175-176, 179-185, 188-194, 197-203, 213-219, 222-228, 231-232, 235- 241, 244-250, 253-259, 315-317, 319, 326, 328, 330, 332, 334, 336, 337, 339-342, 345, 348- 353, 364-365, 367-368, 370-373, 376, 387-389, 393-405, 461-462, 465-471, and 491 in the specification.
72. A compound selected from the group consisting of the formulas of compounds 164-165, 173-174, 177-178, 186-187, 195-196, 204-212, 220-221, 229-230, 233-234, 242- 243, 251-252, 260-268, 346-347, 355-363, 366, 369, 374-375, 377-386, 392, 406-411, 413- 414, 416, 418-439, 444-447, 464, 472-489, and 492 in the specification.
73. A compound having the structure of Formula V or VI:
Figure imgf000620_0001
(V) (VI) or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci-6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(b) R2a is selected from the group consisting of Ci_6 alkyl, C?,-η cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(c) each m is separately 0, 1 or 2;
(d) each p is separately an integer selected from 1-6; (e each q is separately 0, 1 or 2;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or 10 aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is -NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)tC3-7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, C\-e alkyl substituted with up to 5 fluoro, and C\-e alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each separately selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or
-(CH2)qC3-7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom,
Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is a carboxylic acid;
(g) each t is separately 0, 1 or 2;
(h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(j) R200a and R200b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; (1) Z is selected from the group consisting of
Figure imgf000623_0001
(m) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(n) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(o) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(p) the dashed line represents an optional double bond. 74. The compound of Claim 73 having the structure:
Figure imgf000623_0002
75. The compound of any of Claims 73-7 '4, wherein R20 is selected from the group consisting of -SOmR2a, and -C(0)R2a.
76. The compound of any of Claims 73-74, wherein R20 is -C(0)0R2a.
77. The compound of Claim 76, wherein R2a is Ci-6 alkyl.
78. The compound of any of Claims 73-77, wherein Z is
Figure imgf000623_0003
7799.. TThhee ccoommppoouunndd ooff aannyy ooff CCllaaiimmss 7733--7788,, wwhheerreeiinn RR33 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl optionally substituted with Ci_6 alkyl.
81. The compound of any of Claims 73-78, wherein R3 is -C(O)NHO(CH2)mR10 where R10 is Ci_6alkyl, -(CH2)qC3_7cycloalkyl, or phenyl optionally substituted with CF3; m is 0 or 1 ; and q is 0 or 1.
82. The compound of any of Claims 73-78, wherein R3 is -C(O)NHS(O)2R9 where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is a pyrrolidine or piperidine.
83. A compound having the structure of Formula I:
Figure imgf000624_0001
I or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is hydrogen;
(b) R2 is hydrogen, -C(O)R4 or selected from the group consisting of Ci_6 alkyl, aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(c) R4 is Ci_6 alkyl or polycyclic moiety optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxyl-C^ alkyl, Ci- substituted with up to 5 fluoro; or R4 is -NR90aR90b or Ci_6 alkyl optionally substituted with up to 5 fluoro; wherein R90a and R90b are each separately a hydrogen atom or Ci-6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(d) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(e) R2a is selected from the group consisting of Ci_6 alkyl, C?,-η cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(f) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci-6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(g) R4a is imidazolyl or pyrazolyl; (h) each m is separately 0, 1 or 2;
(i) each p is separately an integer selected from 1-6;
(j) each q is separately 0, 1 or 2;
(k) each r is separately an integer selected from 1-6; -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONR1003R100";
(m) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(n) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(o) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(p) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(q) Z is selected from the group consisting of
Figure imgf000626_0001
Figure imgf000626_0002
Figure imgf000626_0003
fluoro;
(s) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(t) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond. 84. The compound of Claim 83 having the structure:
Figure imgf000627_0001
85. The compound of any of Claims 83 to 84, wherein R20 is selected from the group consisting of -SOmR2a, and -C(0)R2a.
86. The compound of any of Claims 83 to 84, wherein R20 is -C(0)0R2a.
87. The compound of Claim 86, wherein R2a is Ci_6 alkyl.
88. The compound of any of Claims 83 to 87, wherein Z is
Figure imgf000627_0002
89. The compound of any of Claims 83 to 88, wherein R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl.
90. The compound of any of Claims 83 to 88, wherein R3 is -CONR100aR100b.
91. The compound of Claim 90, wherein R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
92. The compound of Claim 91, wherein:
R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl; v is 0; and p is 1.
93. The compound of Claim 91, wherein R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen, or -(CH2)vCONR200aR200b.
95. The compound of any of Claims 83 to 93, wherein R2 is -C(O)R4 where R4 is a dihydroisoindole optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxyl-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
96. The compound of Claim 95, wherein R4 is a dihydroisoindole optionally substituted with one or more substituents each separately selected from the group consisting of halo, Ci_6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro.
97. The compound of any of Claims 83 to 93, wherein R2 is -C(O)R4 where R4 is CL6 alkyl.
98. The compound of any of Claims 83 to 93, wherein R2 is Ci-6 alkyl.
99. The compound of any of Claims 83 to 93, wherein R2 is -C(O)R4 where R4 is -NR90aR90b; wherein R90a and R90b are each separately a hydrogen atom or Ci_6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring.
100. The compound of Claim 99, wherein R90a and R90b are each separately a hydrogen atom or Ci_6 alkyl.
101. A compound having the structure of Formula I:
Figure imgf000628_0001
or a pharmaceutically acceptable salt or prodrug thereof wherein: (a) R1 is hydrogen; fluoro;
(c) R4 is -NR90aR90b, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(d) R90a and R90b are each separately a hydrogen atom, or Ci_6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring;
(e) R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3-7cycloalkyl substituted with methyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of C\-e alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b;
(f) each m is separately 0, 1 or 2;
(g) each q is separately 0, 1 or 2; (h) each t is separately 0, 1 or 2;
(i) each r is separately an integer selected from 1-6;
(J) R100a is hydrogen, and R100b is a hydrogen, or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b; (1) R200a and R200b are each separately hydrogen or -(CH2)PC6 or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(m) each p is separately an integer selected from 1-6;
(n) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(o) Z is selected from the group consisting of
Figure imgf000630_0001
Figure imgf000630_0002
Figure imgf000630_0003
(p) R19 is hydrogen, -SOmR2a, or Ci_6 alkyl optionally substituted with up to 5 fluoro;
(q) R20 is selected from the group consisting of -SOmR2a, -C(O)OR2a, -C(O)R2a, -C(O)NRlaRlb, and -C(S)NRlaRlb;
(r) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(s) the dashed line represents an optional double bond. 102. The compound of Claim 101 having the structure:
Figure imgf000630_0004
104. The compound of Claim 103, wherein R2a is Ci_6 alkyl.
105. The compound of any one of Claims 101-104, wherein Z is
Figure imgf000631_0001
106. The compound of any one of Claims 101-105, wherein R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl.
107. The compound of any one of Claims 101-105, wherein R3 is -CONR100aR100b.
108. The compound of Claim 107, wherein R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
109. The compound of Claim 108, wherein:
R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl; v is 0; and p is 1.
110. The compound of Claim 107, wherein R100a is hydrogen, and R100b is a hydrogen or -(CH2)vCONR200aR200b.
111. The compound of any one of Claims 101-110, wherein R2 is Ci-6 alkyl.
112. The compound of any one of Claims 101-110, wherein: R2 is -C(O)R4;
R4 is -NR90aR90b or Ci_6 alkyl; and
R90a and R90b are each separately a hydrogen atom, or Ci-6 alkyl; or R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle.
113. The compound of Claim 112, wherein R90a and R90b are each separately a hydrogen atom or Ci_6 alkyl.
114. The compound of Claim 112, wherein R90a and R90b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle.
115. A compound having the structure of Formula II:
Figure imgf000632_0001
II or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is hydrogen;
(b) each m is separately 0, 1 or 2;
(c) each p is separately an integer selected from 1-6;
(d) each q is separately 0, 1 or 2;
(e) each r is separately an integer selected from 1-6;
(f) R3 is -C(O)NHS(O)2R9, where R9 is selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, Ce or io aryl, and a heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci-6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro, or R9 is
-NR9aR9b; wherein R9a and R9b are each separately a hydrogen atom, or separately selected from the group consisting of Q-6 alkyl, -(CH2)qC3_7cycloalkyl, and Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2_6 alkenyl, Ci-6 alkoxy, hydroxy-C^ alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heterocycle, which is a five-, six-, or seven- membered, saturated or unsaturated heterocyclic group, containing from one to sulfur, or R9a and R9b are each separately selected from the group consisting of a hydrogen atom and a heteroaryl group; or R9a and R9b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, C\-e alkyl, C\-e alkoxy, and phenyl, or R9a and R9b are taken together with the nitrogen to which they are attached to form a heteroaryl, optionally substituted with one or more substituents each separately selected from the group consisting of a halogen, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, -NH(C0)0Rle, wherein Rle is Ci_6 alkyl, or -(CH2)qC3_7cycloalkyl, -N(Rld)2, -NH(C0)Rld, and -NH(C0)NHRld, wherein each Rld is separately selected from the group consisting of a hydrogen atom, Ci_6 alkyl, and -(CH2)qC3-7cycloalkyl; or R9 is selected from the group consisting of -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR1003R100"; or R3 is a carboxylic acid; (h) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(i) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(j) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(k) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(1) R11 and R12 are each separately selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR7R8, -NHC(O)NR7R8, -NHC(S)NR7R8, -C(O)NR7R8, -NR7R8, -C(O)R13, -C(O)OR13, -NHC(O)R13, -NHC(O)OR13, -SO1nR13, -NHS(O)2R13, -NR13[(CH2)POH], -O[(CH2)PNR14R15], -S[(CH2)PNR14R15], -(CH2)PNR14R15, -(CH2)PR16 and -O(CH2)PR16;
(m) R and R are each separately a hydrogen, or separately selected from the group consisting of Ci_6 alkyl, -(CH2)qC3_7cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C3-7 cycloalkyl, C4- 10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or R7 and R8 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; Ce or io aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2-6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R13 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R13 is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
(0) R14 and R15 are each separately selected from hydrogen and Ci_6 alkyl; or R14 and R15 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(p) R16 is imidazolyl or pyrazolyl;
(q) V is selected from the group consisting of -O-, -S-, and -NR23-;
(r) R23 is H, or selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl; wherein said phenyl as an optional substituent is further optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(s) W is -N- or -CR30-;
(t) R30 is H, or selected from the group consisting of Ci-6 alkyl, -(CH2)qC3-7cycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, Ci_6 alkyl, Ci_6 alkoxy, or phenyl;
(u) Z is selected from the group consisting of
Figure imgf000635_0001
Figure imgf000635_0002
fluoro;
(w) R20 is selected from the group consisting of -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(x) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl;
(y) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2-6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(z) R2a is selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-6 alkenyl, -(CH2)qC3-7cycloalkyl, Ci_6 alkoxy, phenyl, and hydroxy-Ci_6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R2a is a tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring; and
(aa) the dashed line represents an optional double bond. 116. The compound of Claim 115 having the structure:
Figure imgf000636_0001
group consisting of -SOmR2a, and -C(0)R2a.
118. The compound of any of Claims 115 to 116, wherein R20 is -C(0)0R2a.
119. The compound of Claim 118, wherein R2a is Ci-6 alkyl.
120. The compound of any of Claims 115 to 119, wherein Z is
Figure imgf000637_0001
121. The compound of any of Claims 115 to 120, wherein R3 is an acylsulfonamide of the formula -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl optionally substituted with Ci-6 alkyl.
122. The compound of any of Claims 115 to 120, wherein R3 is a -CONHO(CH2)mR10 where R10 is optionally substituted aryl and m is 0.
123. The compound of any of Claims 115 to 120, wherein R3 is -C(O)NHS(O)2R9 where R9 is -NR9aR9b and R9a and R9b are each independently a hydrogen atom or Ci_6 alkyl or -NR9aR9b is pyrrolidine or piperidine.
124. The compound of any of Claims 115 to 123, wherein:
V is selected from the group consisting of -O- and -S-; and W is -N-.
125. The compound of any of Claims 115 to 123, wherein:
V is -NR21-;
R21 is H, Ci_6 alkyl, or arylalkyl; and W is -N-.
126. The compound of any of Claims 115 to 125, wherein R11 and R12 are each separately selected from the group consisting of hydrogen, halo, Ci_6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy, and -(CH2)qC3_7cycloalkyl where q is 0.
127. A compound having the structure:
Figure imgf000638_0001
128. A compound having the structure of Formula VII:
Figure imgf000638_0002
VII or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R »i i •s hydrogen;
(b) R2 is selected from the group consisting of:
Figure imgf000638_0003
and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci_6 alkyl, Ci_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3_6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NR I1a3 nRIb -NHC(0)NRlaRlb,
-NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a,
-NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH],
-0[(CH2)pNRJaRJb], -S[(CH2)pNRJaRJb], -(CH2)pNRJaRJb, -(CH2)pR4a and
-0(CH2)pR 4'lad; from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(d) each R2a is separately selected from the group consisting of Q-6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl, C2-β alkenyl, -(CH2)qC3_7cycloalkyl, Q-6 alkoxy, phenyl, and hydroxy-C^ alkyl;
(e) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R4a is imidazolyl or pyrazolyl;
(g) each m is separately 0, 1 or 2;
(h) each p is separately an integer selected from 1-6;
(i) each q is separately 0, 1 or 2;
(j) each r is separately an integer selected from 1-6;
(k) R20 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, C2-6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)p0H][(CH2)r0H], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(O)R2a, -C(O)OR2a, -NHC(0)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a; -(CH2)rC(O)NHR9c, -(CH2)rC(O)OR9c, and -(CH2)qR9d; wherein R9c is Ce or 10 aryl optionally substituted with one or more substituents each separately selected from the group consisting of
-O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9d is Ce or 10 aryl substituted with one or more substituents each separately selected from the group consisting of -O(CH2)qC(O)NHR9e and -NH(CH2)qC(O)NHR9e; wherein R9e is selected from the group consisting of hydrogen, Ce or 10 aryl, and Ci-6 alkyl optionally substituted with up to 5 fluoro; or R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3-7cycloalkyl substituted with methyl; or R3 is a -CONHO(CH2)mR10 where R10 is selected from the group consisting of Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3 is a -CONR100aR100b; or R3 is carboxylic acid;
(m) each t is separately 0, 1 or 2;
(n) R100a is -(CH2)vCONR200aR200b, and R100b is a hydrogen or -(CH2)vCONR200aR200b; or R100a and R100b are optionally taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle, which optionally has one to three additional hetero atoms incorporated in the ring, and which is optionally substituted with -(CH2)vCONR300aR300b;
(o) each v is separately 0, 1, 2, 3, 4, 5, or 6;
(p) R200a and R200b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(q) R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl optionally substituted with one or more substituents each separately selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; (r) Z is selected from the group consisting of
Figure imgf000641_0001
(s) R19 is hydrogen, -SOmR2a, or Ci-6 alkyl optionally substituted with up to 5 fluoro;
(t) R21 and R21 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(u) the dashed line represents an optional double bond. 129. The compound of Claim 128, wherein R2 is selected from the group consisting
Figure imgf000641_0002
and , each optionally substituted with one or more substituents each separately selected from the group consisting of halo, hydroxy, Ci_6 alkyl, and Ci-6 alkoxy.
130. The compound of Claim 128 or 129, wherein R3 is -C(O)NHS(O)2R9, where R9 is -(CH2)qC3_7cycloalkyl substituted with methyl.
131. The compound of Claim 128 or 129, wherein R3 is -CONR100aR100b.
132. The compound of Claim 131, wherein R100a and R100b are taken together with the nitrogen to which they are attached to form a three- to six- membered heterocycle substituted with -(CH2)vCONR300aR300b.
133. The compound of Claim 132, wherein:
R300a and R300b are each separately hydrogen or -(CH2)PC6 or io aryl; v is 0; and p is 1.
134. The compound of Claim 131, wherein R100a is hydrogen, and R100b is a hydrogen or -(CH2)vCONR200aR200b.
135. The compound of any one of Claims 128 to 134, wherein R20 is selected from the group consisting of phenyl, thiazole, oxazole, benzoxazole, benzothiazole, pyridine, or naphthyl, each optionally substituted with one or more substitutents each independently 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
136. The compound of any one of Claims 128 to 134, wherein R20 is phenyl optionally substituted with one or more substitutents each independently selected from the group consisting of halo, cyano, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci-6 alkoxy optionally substituted with up to 5 fluoro, and phenyl.
137. The compound of any one of Claims 128 to 134, wherein R20 is phenyl substituted with one or more substitutents each independently selected from the group consisting of halo and Ci_6 alkyl optionally substituted with up to 5 fluoro.
138. The compound of any one of Claims 128 to 134, wherein R20 is phenyl substituted with one or more fluoro and optionally substituted with CF3.
139. The compound of any one of Claims 128-138, wherein Z is
Figure imgf000642_0001
140. A compound selected from the group consisting of compounds having the compound numbers 1001-1147 as identified in the specification.
141. A compound having the structure of Formula I:
Figure imgf000642_0002
(I) or a pharmaceutically acceptable salt or prodrug thereof wherein:
(a) R1 is-(CR5R6)nR4;
(b) n is 0, 1 or 2;
(c) R2 is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(O)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(O)NRlaRlb, -NRlaRlb, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a, -O(CH2)pR4a, and Ci_6 alkyl optionally substituted with up to 5 fluoro; said aryl and heteroaryl as an optional substituent are each further optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, aryl, heteroaryl, -NRlaRlb, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro;
(d) R4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, cyanoamino, -SH, Ci-6 alkyl optionally substituted with up to 5 fluoro, Ci_6 alkoxy optionally substituted with up to 5 fluoro, C2_6 alkenyl, C2_6 alkynyl, -(CH2)qC3_7cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aryloxy, arylthio, Ci_6 alkylthio, -N[(CH2)pOH][(CH2)rOH], -S(0)2NRlaRlb, -NHC(0)NRlaRlb, -NHC(S)NRlaRlb, -C(0)NRlaRlb, -NRlaRlb, -C(0)R2a, -C(0)0R2a, -NHC(O)R2a, -NHC(0)0R2a, -SOmR2a, -NHS(O)2R23, -NR2a[(CH2)pOH], -O[(CH2)pNR3aR3b], -S[(CH2)pNR3aR3b], -(CH2)pNR3aR3b, -(CH2)pR4a and -O(CH2)pR4a;
(e) Rla and Rlb are each separately a hydrogen atom, or separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)qC3_7cycloalkyl, C2_6 alkenyl, hydroxy-Ci-6 alkyl, Ci-6 alkyl optionally substituted with up to 5 fluoro, and Ci-6 alkoxy optionally substituted with up to 5 fluoro; or Rla and Rlb are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) each R2a is separately selected from the group consisting of Ci_6 alkyl, C3_7 cycloalkyl, and Ce or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C2_6 alkenyl, -(CH2)qC3_7cycloalkyl, Ci-6 alkoxy, phenyl, and hydroxy-Ci-6 alkyl; or R2a is a tetrahydrofuran ring linked through the C3 or C4 position of the the tetrahydropyran ring;
(g) R3a and R3b are each separately selected from the group consisting of hydrogen and Ci_6 alkyl; or R3a and R3b are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(h) each R4a is separately imidazolyl or pyrazolyl;
(i) each m is separately 0, 1 or 2;
(j) each p is separately an integer selected from 1-6;
(k) each q is separately 0, 1 or 2;
(1) each r is separately an integer selected from 1-6;
(m) R3 is -P(O)R10aR10b, wherein R1Oa and R1Ob are each separately selected from the group consisting of hydroxy, -(O)v-Ci_6 alkyl, -(O)v-(CH2)qC3_7cycloalkyl, -(O)v-aryl, and -(O)v-heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, -COOH, Ci_6 alkyl, -(CH2)tC3_7cycloalkyl, C2-6 alkenyl, Ci_6 alkoxy, hydroxy-Ci_6 alkyl, Ci_6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy optionally substituted with up to 5 fluoro;
(n) wherein each v is separately 0 or 1 ;
(0) each t is separately 0, 1 or 2;
(p) R5 and R6 are each separately a hydrogen, or separately selected from the group consisting of alkyl and arylalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-6 alkenyl, Ci-6 alkoxy, hydroxyl-Ci_6 alkyl, phenyl, Ci_6 alkyl substituted with up to 5 fluoro, and Ci_6 alkoxy substituted with up to 5 fluoro; or R5 and R6 are taken together with the carbon to which they are attached to form a C3_7 cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, -(CH2)uC3_7cycloalkyl, C2-β alkenyl, Q-6 alkoxy, hydroxy-Ci-6 alkyl, phenyl, Ci-6 alkyl substituted with up to 5 fluoro, and Ci-6 alkoxy substituted with up to 5 fluoro;
(q) each u is separately 0, 1 or 2; (r) Z is selected from the group consisting of
Figure imgf000645_0001
(s) R ,19 is hydrogen, Ci-6 alkyl optionally substituted with up to 5 fluoro, or
-SOmR2a;
(t) R20 is selected from the group consisting of hydrogen, -SOmR2a, -C(0)0R2a, -C(0)R2a, -C(0)NRlaRlb, and -C(S)NRlaRlb;
(u) R21 and R22 are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and
(v) the dashed line represents an optional double bond.
142. The compound of Claim 141, wherein R1Oa is hydroxy.
143. The compound of Claim 141 or 142, wherein R1Ob is -0-Ci-6 alkyl.
144. The compound of Claim 143, wherein R1Ob is -0-methyl or -O-ethyl.
145. The compound of Claim 141 or 142, wherein R1Ob is -Ci-6 alkyl.
146. The compound of Claim 145, wherein R1Ob is methyl or ethyl.
147. The compound of Claim 141, wherein R ,10a is hydroxy or -0-Ci-6 alkyl and
R1Ob is C Cii__66 aallkkyyll..
148. A compound of the formula (X):
Figure imgf000645_0002
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
(a) Y is a moiety having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y is within 4 A or less of at least one moiety selected from NS3 protease His57 imidazole moiety and NS3 protease GIy 137 nitrogen atom;
(b) Pi' is a moiety, different from Y, having a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Pi' is within 6 A or less of at least one NS3 protease Sl' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43;
(c) L is a moiety consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
(d) P2 is a moiety selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic;
(e) the dashed line represents an optional double bond;
(f) P2 is positioned by L such that, upon binding of the compound to NS 3 protease, at least one atom of P2 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Tyr56, His57, Val78, Asp79, Gln80, Asp81, Argl55 and Alal56;
(g) R50 is H and R60 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; or R50 and R60 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
(h) R50 and R60 are positioned such that, upon binding of the compound to NS3 protease, at least one atom of R50 or R60 is within 5 A or less of any backbone or side chain atom of at least one NS 3 protease residue selected from the group consisting of Argl23, Alal56, Alal57, Vall58, Cysl59, and Aspl68.
149. The compound of Claim 148, wherein Y is -NH-SO2- and Pi' is selected from the group consisting of C3_7 cycloalkyl, C4-Io alkylcycloalkyl and di(Ci_4 alkyl)amine.
150. The compound of Claim 149, wherein Y-Pi' is -NH-SC^-methylcyclopropyl.
152. The compound of Claim 148, wherein Y has a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y forms a hydrogen bond with at least one moiety selected from a NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom.
153. The compound of Claim 148, wherein P1' has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of P1' forms a non- polar interaction with at least one NS 3 protease Sl' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43.
154. The compound of Claim 148 of the formula (Xa):
Figure imgf000647_0001
(XA) or a pharmaceutically acceptable salt, prodrug, or ester thereof.
155. The compound of Claim 154, wherein Y is -NH-SO2- and P1' is selected from the group consisting of C3-7 cycloalkyl, C4-io alkylcycloalkyl and di(Ci_4 alkyl)amine.
156. The compound of Claim 155, wherein Y-P1' is -NH-SCVmethylcyclopropyl.
157. The compound of Claim 155, wherein Y-P1' is -NH-SO2-N(CH3)2.
158. The compound of Claim 154, wherein Y has a size and configuration such that, upon binding of the compound to NS3 protease, at least one atom of Y forms a hydrogen protease Glyl37 nitrogen atom.
159. The compound of Claim 154, wherein Pi' has a size and configuration such that, upon binding of the compound to NS 3 protease, at least one atom of Pi' forms a non- polar interaction with at least one NS 3 protease Sl' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43.
160. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any of the preceding claims.
161. A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with the compound of any of Claims 1-159 or with the composition of Claim 160.
162. The method of Claim 161 in which the contacting is conducted in vivo.
163. The method of Claim 162, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection.
164. The method of Claim 163, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
165. The method of Claim 164, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
166. The method of Claim 163, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
167. The method of Claim 166, wherein the protease inhibitor is ritonavir.
168. The method of Claim 163, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
169. The method of Claim 163, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
170. The method of Claim 169, wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
171. The method of Claim 163, wherein the method further comprises administering to the individual an effective amount of interferon- alpha (IFN-α). IFN-α administered at a dosing interval of every 8 days to every 14 days.
173. The method of Claim 171, wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
174. The method of Claim 171, wherein the IFN-α is INFERGEN consensus IFN- α.
175. The method of Claim 163, further comprising administering an effective amount of an agent selected from 3 ' -azidothymidine, 2',3'-dideoxyinosine, 2',3'- dideoxycytidine, 2',3'-didehydro-2',3'-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
176. The method of Claim 163, wherein a sustained viral response is achieved.
177. The method of Claim 161, in which the contacting is conducted ex vivo.
178. A method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a compound of any of Claims 1-159 or with the composition of Claim 160.
179. The method of Claim 178, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
180. The method of Claim 179, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
181. The method of Claim 178, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
182. The method of Claim 181, wherein the protease inhibitor is ritonavir.
183. The method of Claim 178, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
184. The method of Claim 178, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
185. The method of Claim 184, wherein the IFN-γ is administered subcutaneous Iy in an amount of from about 10 μg to about 300 μg.
186. The method of Claim 178, wherein the method further comprises administering to the individual an effective amount of interferon- alpha (IFN-α). IFN-α administered at a dosing interval of every 8 days to every 14 days.
188. The method of Claim 186, wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
189. The method of Claim 186, wherein the IFN-α is INFERGEN consensus IFN- α.
190. The method of Claim 178, further comprising administering an effective amount of an agent selected from 3 ' -azidothymidine, 2',3'-dideoxyinosine, 2',3'- dideoxycytidine, 2',3'-didehydro-2',3'-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
191. A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a compound of any of Claims 1-159 or with the composition of Claim 160.
192. The method of Claim 191, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
193. The method of Claim 192, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
194. The method of Claim 191, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
195. The method of Claim 194, wherein the protease inhibitor is ritonavir.
196. The method of Claim 191, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
197. The method of Claim 196, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
198. The method of Claim 197, wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
199. The method of Claim 191, wherein the method further comprises administering to the individual an effective amount of interferon- alpha (IFN-α).
200. The method of Claim 199, wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days. IFN-α administered at a dosing interval of once every 7 days.
202. The method of Claim 199, wherein the IFN-α is INFERGEN consensus IFN- α.
203. The method of Claim 191, further comprising administering an effective amount of an agent selected from 3 ' -azidothymidine, 2',3'-dideoxyinosine, 2',3'- dideoxycytidine, 2',3'-didehydro-2',3'-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
204. A method of treating a hepatitis C virus infection in a population of humans, the method comprising: administering to each human in the population dosages of peginterferon alfa- 2a, ribavirin and a compound having the formula XIX:
Figure imgf000651_0001
XIX or a pharmaceutically acceptable salt thereof; wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the population of humans to an average level of below about 43 IU/mL.
205. The method of Claim 204, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 50 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
206. The method of Claim 204, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 100 mg about every 6 or about every 48 hours.
207. The method of Claim 204, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 150 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or every about 48 hours.
208. The method of Claim 204, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 200 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
209. The method of any one of Claims 204 to 208, wherein the period of time is about 14 days or less.
210. The method of Claim 209, wherein the period of time is greater than 7 days.
211. The method of Claim 204, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 43 IU/mL.
212. The method of Claim 211, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 25 IU/mL.
213. The method of Claim 211 to 212, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 75% of the population of humans to an average level of below about 25 IU/mL.
214. The method of any one of Claims 211 to 213, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 88% of the population of humans to an average level of below about 25 IU/mL. compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the individuals to a level of below 9.3 IU/mL.
216. The method of Claim 215, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 20% of the individuals to a level of below 9.3 IU/mL.
217. The method of any one of Claims 215 to 216, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 30% of the individuals to a level of below 9.3 IU/mL.
218. The method of any one of Claims 215 to 217, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 40% of the individuals to a level of below 9.3 IU/mL.
219. The method of any one of Claims 215 to 218, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 50% of the individuals to a level of below 9.3 IU/mL.
220. The method of Claim 219, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 57% of the individuals to a level of below 9.3 IU/mL.
221. The method of Claim 204, wherein the dosage of the compound having the formula XIX or a pharmaceutically acceptable salt thereof is administered one time every day, one time every two days, one time every three days, one time every four days, one time every five days, one time every six days, or one time every seven days.
222. A method of treating liver fibrosis in a population of humans, the method comprising: administering to each human in the population dosages of peginterferon alfa- 2a, ribavirin and a compound having the formula XIX:
Figure imgf000654_0001
XIX or a pharmaceutically acceptable salt thereof; wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the population of humans to an average level of below about 43 IU/mL.
223. The method of Claim 222, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 50 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
224. The method of Claim 222, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 100 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
225. The method of Claim 222, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 150 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or every about 48 hours.
226. The method of Claim 222, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 200 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
227. The method of any one of Claims 222 to 226, wherein the period of time is about 14 days or less.
228. The method of Claim 227, wherein the period of time is greater than 7 days. compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 43 IU/mL.
230. The method of Claim 229, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 25 IU/mL.
231. The method of any one of Claims 229 to 230, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 75% of the population of humans to an average level of below about 25 IU/mL.
232. The method of any one of Claims 229 to 231, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 88% of the population of humans to an average level of below about 25 IU/mL.
233. The method of Claim 222, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the individuals to a level of below 9.3 IU/mL.
234. The method of Claim 233, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 20% of the individuals to a level of below 9.3 IU/mL.
235. The method of any one of Claims 233 to 234, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 30% of the individuals to a level of below 9.3 IU/mL. 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 40% of the individuals to a level of below 9.3 IU/mL.
237. The method of any one of Claims 233 to 236, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 50% of the individuals to a level of below 9.3 IU/mL.
238. The method of any one of Claims 233 to 237, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 57% of the individuals to a level of below 9.3 IU/mL.
239. The method of Claim 222, wherein the dosage of the compound having the formula XIX or a pharmaceutically acceptable salt thereof is administered one time every day, one time every two days, one time every three days, one time every four days, one time every five days, one time every six days, or one time every seven days.
240. A method of increasing liver function in a population of humans, the method comprising: administering to each human in the population dosages of peginterferon alfa- 2a, ribavirin and a compound having the formula XIX:
Figure imgf000656_0001
XIX or a pharmaceutically acceptable salt thereof; wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the population of humans to an average level of below about 43 IU/mL. formula XIX, or a pharmaceutically acceptable salt thereof, is about 50 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
242. The method of Claim 240, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 100 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
243. The method of Claim 240, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 150 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or every about 48 hours.
244. The method of Claim 240, wherein the dosage of the compound having the formula XIX, or a pharmaceutically acceptable salt thereof, is about 200 mg about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours or about every 48 hours.
245. The method of any one of Claims 240 to 244, wherein the period of time is about 14 days or less.
246. The method of Claim 245, wherein the period of time is greater than 7 days.
247. The method of Claim 240, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 43 IU/mL.
248. The method of Claim 247, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 57% of the population of humans to an average level of below about 25 IU/mL.
249. The method of any one of Claims 247 to 248, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to average level of below about 25 IU/mL.
250. The method of any one of Claims 247 to 249, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 88% of the population of humans to an average level of below about 25 IU/mL.
251. The method of Claim 240, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 14% of the individuals to a level of below 9.3 IU/mL.
252. The method of Claim 251, wherein the peginterferon alfa-2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 20% of the individuals to a level of below 9.3 IU/mL.
253. The method of any one of Claims 251 to 252, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 30% of the individuals to a level of below 9.3 IU/mL.
254. The method of any one of Claims 251 to 253, wherein the peginterferon alfa- 2a, ribavirin and compound having the formula XIX, or a pharmaceutically acceptable salt thereof, are administered in combination for a period of time and in amounts effective to reduce HCV RNA levels in the blood of at least 40% of the individuals to a level of below 9.3 IU/mL.
255. The method of any one of Claims 251 to 254, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 50% of the individuals to a level of below 9.3 IU/mL.
256. The method of any one of Claims 251 to 255, wherein the amount of peginterferon alfa-2a, ribavirin and compound having the formula XIX are effective to reduce HCV RNA in at least 57% of the individuals to a level of below 9.3 IU/mL.
257. The method of Claim 240, wherein the dosage of the compound having the formula XIX or a pharmaceutically acceptable salt thereof is administered one time every every five days, one time every six days, or one time every seven days.
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