WO2007146695A1 - Acyclic oximyl hepatitis c protease inhibitors - Google Patents

Acyclic oximyl hepatitis c protease inhibitors Download PDF

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Publication number
WO2007146695A1
WO2007146695A1 PCT/US2007/070481 US2007070481W WO2007146695A1 WO 2007146695 A1 WO2007146695 A1 WO 2007146695A1 US 2007070481 W US2007070481 W US 2007070481W WO 2007146695 A1 WO2007146695 A1 WO 2007146695A1
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Prior art keywords
substituted
cycloalkyl
cycloalkenyl
heteroaryl
aryl
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PCT/US2007/070481
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French (fr)
Inventor
Yat Sun Or
Ying Sun
Zhe Wang
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Enanta Pharmaceuticals, Inc.
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Publication of WO2007146695A1 publication Critical patent/WO2007146695A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel acyclic oximyl HCV protease inhibitor compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • HIV human immunodeficiency virus
  • anti-HC V therapeutics There are considerable barriers to the development of anti-HC V therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non-structural protein-3
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins.
  • NS2 is a zinc- dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3-NS4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin- like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881
  • HCV protease inhibitors More relevant patent disclosures describing the synthesis of HCV protease inhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); US5861297 (1999); US publications 20050153877, 20050261200 and 20050065073.
  • the present invention relates to novel HCV protease inhibitor compounds, and pharmaceutically acceptable salts, esters, or prodrugs thereof, which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3- NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention further relates to pharmaceutical compositions comprising the aforementioned compounds, salts, esters or prodrugs for administration to a subject suffering from HCV infection.
  • the present invention further features pharmaceutical compositions comprising a compound of the present invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and another anti-HCV agent, such as alpha-interferon, beta-interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
  • a pharmaceutical composition of the present invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition of the present invention.
  • Ri and R 2 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl; e) substituted heteroaryl; f) heterocyclic or substituted heterocyclic; g) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, or substituted -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -Ci 2 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -
  • R 3 and R 4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl;
  • G is -E-R 3 , where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO 2 )NH or NHSO 2 ;
  • A is selected from the group consisting of R 5 , (CO)R 5 , (CO)OR 5 , (CO)NHR 5 , SO 2 R 5 , (SO 2 )OR 5 and SO 2 NHR 5 ;
  • R 5 is selected from the group consisting of: a) aryl; b) substituted aryl; c) heteroaryl; d) substituted heteroaryl; e) heterocyclic; f) substituted heterocyclic; g) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, or substituted -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -C 12 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2
  • B is H or CH 3 ;
  • L and Z are independently selected from the group consisting of:
  • the present invention features pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • methods of treating a hepatitis C infection in a subject in need of such treatment with said pharmaceutical compositions are disclosed.
  • the present invention is a compound of formula I as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • the present invention relates to a compound of formula II, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Ri is not hydrogen .
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, and substituted -C 3 -C 12 cycloalkenyl.
  • A is selected from the group consisting of -C(O)-R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • L and Z can be independently selected from Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)-R 3 , -NH-SO 2 -NH- R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 - Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO2-R3, where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -C 1 -C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula III, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • A, G, L, R 1 , R 2 and Z are as previously defined in the first embodiment.
  • Ri and R 2 are not both hydrogen.
  • Ri and R 2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 - Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl; or Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A can be selected from the group consisting of -C(O)-R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 - C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)- R 3 , -NH-SO 2 -NH-R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 2 - Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 - Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-O-Rs, where Rs is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from Ci-Cg alkyl, substituted -Ci-C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • A is -C(O)-O-Rs, where R5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • Ri and R 2 taken together with the
  • each group is independently selected from halogen, hydroxy, nitro, cyano, amino, formyl, -Ci-Cgalkyl or -C 2 -Cgalkenyl, or -C 2 - Cgalkynyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-R 5 , where R 5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R 5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, - C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is - NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -C r C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • V is absent, or V is CO, O, S, SO, SO 2 , NH, NCH 3 , or (CH 2 ) q ; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of: aryl; substituted aryl; heteroaryl; substituted heteroaryl; heterocyclic; substituted heterocyclic; and where A, G, L and Z are as previously defined in the first embodiment.
  • Xi-Xg are independently selected from CH and N and Xi-Xg can be further substituted when it is a CH
  • Y 1 -Y 3 are independently selected from CH, N, NH, S and O and Yi-Y 3 can be further substituted when it is CH or NH
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A can be selected from the group consisting of -C(O)-R 5 , - C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -Cs-Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)-R 3 , -NH-SO 2 -NH-R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • CH and N and Xi-X 8 can be further substituted when it is a CH
  • Yi-Y 3 are independently selected from CH, N, NH, S and O and Yi-Y 3 can be further substituted when it is CH or NH
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • +&* ⁇ is selected from
  • W l I e I eIn X 1 -X 8 are independently selected from CH and N and X 1 -X 8 can be further substituted when it is a CH, and Y 1 -Y 3 are independently selected from CH, N, NH, S and O and Y 1 -Y 3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -C 1 -C 8 alkyl or substituted -C 1 -C 8 alkyl.
  • Z is selected from C 1 -C 8 alkyl, substituted -C 1 -C 8 alkyl,- C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • R 1 and R 2 taken together with the carbon atom to
  • X 1 -X 8 are independently selected from CH and N and X 1 -X 8 can be further substituted when it is a CH;
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O- R 5 , where R 5 is -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -C 1 -C 8 alkyl or substituted -C 1 -C 8 alkyl.
  • Z is selected from C 1 -C 8 alkyl, substituted -C 1 -C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is - NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl. In a most preferred example, R 1 and R 2 taken together with the carbon atom
  • A is -C(O)-O-R 5 , where R 5 is - C3-C12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from Ci-Cg alkyl, substituted -Ci-Cg alkyl, -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO2-R3, where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula
  • X 1 -X 4 are independently selected from CO, CH, NH, O and N; where X 1 -X 4 can be further substituted when any one of X 1 -X 4 is a CH or NH; where R 6 and R 7 are independently R 3 , where R 3 is independently selected from the group consisting of:
  • R ⁇ and R 7 can be independently selected from halogen, oxo, thioxo, nitro, cyano, -OR 3 , -SR 3 , -NR 3 R 4 , -SOR 3 , -SO 2 R 3 , -NHSO 2 R 3 , -SO 2 NHR 3 , -COR 3 , -CO 2 R 3 , (CO)NHR 3 , -OCOR 3 , OCONHR 3 , NHCO 2 R 3 , - NH(CO)R 3 , -NH(CO)NHR 3 , and -NH(SO 2 )NHR 3 .
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is selected from the group consisting of -C(O)- R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 ', -NH-C(O)-R 3 ', -NH-SO 2 -NH-R 3 ' or -NHSO 2 - R 3 ', where R 3 ' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Re and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is - Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -C 1 -C 8 alkyl, substituted - C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 - Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-Rs, where R 5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - C 12 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, and substituted -C 3 -C 12 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cs alkyl, -C 2 -Cs alkenyl, substituted -Ci-Cs alkyl, or substituted -C 2 -Cs alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 - Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula VI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Yi-Y 3 are independently selected from CO, CH, NH, N, S and O; and Y 1 -Y 3 can be further substituted when any one OfYi-Y 3 is CH or NH; Y 4 is selected from C, CH and N; and where A, G, L, R 6 , R 7 , V and Z are as previously defined in the embodiment immediately above.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is selected from the group consisting of -C(O)- R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 ', -NH-C(O)-R 3 ', -NH-SO 2 -NH-R 3 ' or -NHSO 2 - R 3 ', where R 3 ' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is - Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted - C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 - Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-Rs, where R5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-NH-R 5 , where R5 is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-R 5 , where R 5 is substituted -Ci-C 8 alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R 5 is substituted -Ci-C 8 alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 - C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Mi is selected from the group consisting of: wherein R 31 and R 32 are independently selected from the group consisting of: a) hydrogen; b) aryl; substituted aryl; c) heteroaryl; substituted heteroaryl; d) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; e) -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkyl; -C 3 -C 12 cycloalkenyl, or substituted -C 3 -C 12 cycloalkenyl; heterocyclic or substituted heterocyclic; f) -A-R 30 , where A is (CO), (
  • V is absent, or V is O, S, SO, SO 2 , NR50, or
  • R 50 is selected from H, OH, OCH 3 , -0-Ci-C 8 alkyl, -Ci-C 8 alkyl, -0-C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl, -O- C 3 -C 8 cycloalkenyl; -C 3 -C 8 cycloalkenyl; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of:
  • NR 50 (SO 2 )OR 30 NR 50 (SO 2 )NR 30 R 40 ; where R 30 , R 40 and R 50 are as previously defined; alternatively, for formula (I), R 30 and R 40 are taken together with the nitrogen atom to which they are attached to form the group consisting of: heterocyclic, or substituted heterocyclic; heteroaryl, or substituted heteroaryl; M 2 is selected from the group consisting of:
  • R 60 is selected from H, OH, OCH 3 , -0-Ci-C 8 alkyl, -Ci-C 8 alkyl;
  • J is selected from the group consisting of CO, (CO)O, (CO)NR 50 , SO 2 , (SO 2 )O or SO 2 NR 50 ;
  • Rg 0 is selected from the group consisting of: (1) hydrogen;
  • L is selected from the group consisting of:
  • the present invention relates to compound of formula X, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Yet another embodiment of the present invention relates to compound of formula XI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • the present invention relates to compound of formula XII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Xi and Yi are independently selected from CH and N; R90, R100, Ri 10, and R120 are independently R30; G, J, L, M 2 , R70, and Rso are as previously defined in the embodiment above.
  • the present invention relates to compound of formula XIII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • G, J, L, M 2 , R70, Rso, V, X and Y are as previously defined in the embodiment above.
  • the present invention relates to compound of formula XIV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Xi-X 4 are independently selected from CH and N; Xi-X 4 can be further substituted when it is a CH; where G, J, L, M 2 , R70, Rso, R90, R100 and V are as previously defined in the embodiment above.
  • the present invention relates to compound of formulae XV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Y 1 -Y 3 are independently selected from CH, N, NH, S and O; and Y 1 - Y 3 can be further substituted when it is CH or NH; Y 4 is selected from CH and N; where G, J, L, M 2 , R70, Rso, R90, R100 and V are as previously defined.
  • the present invention relates to compound of formula XVI or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • the present invention relates to compound of formula XVII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • -C 2 -Cg alkynyl each containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -C 12 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl; k) oxo substituted -C 3 -Ci 2 cycloalkyl, or oxo substituted -C 3 -Ci 2 cycloalkenyl; 1) -Q-Ri 03 , where Q is (CO), (CO)O, (CO)NRi 04 , (SO), (SO 2 ),
  • (SO 2 )NRiO 4 ; and Rio 3 and Rio4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl; (iii) substituted aryl;
  • Gi is -E-R 103 , where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO 2 )NH or NHSO 2 ;
  • A is selected from the group consisting of R 105 , (CO)Rios, (CO)ORios, (CO)NHRios,
  • RiO 5 is selected from the group consisting of: a) hydrogen b) substituted aryl; c) heteroaryl fused with O, 1, 2, or 3 more group selected from heteroaryl and aryl; d) substituted heteroaryl fused with O, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; e) heterocyclic; f) substituted heterocyclic; g) oxo substituted heterocyclic; h) -C 1 -C 8 alkyl, -C 2 -Cs alkenyl, or -C 2 -Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; i) substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, or substituted -C 2 -Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; j)
  • Bi is H or CH 3 ;
  • Li and Zi are independently selected from the group consisting of: (1) hydrogen; (2) aryl;
  • n 0, 1, 2 or 3
  • h 0, 1, 2, or 3.
  • the invention provides intermediate compounds useful in the synthesis of compounds of formulas I-XVII, B and C, selected from the group consisting of: Compounds (I)- (2) of the formula A:
  • Rx , G and W are delineated for each example in TABLE 1 :
  • Representative compounds of the invention are those selected from compounds (3)- (109) of the formula B:
  • Ri and R 2 are taken together with the carbon to which they are attached to form RiR 2 , and RiR 2 , Rx, L, Z and G are delineated for each example in TABLE 2:
  • the present invention features pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • a further embodiment of the present invention includes pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • compositions of the present invention are a pharmaceutical composition comprising a combination of two or more compounds of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions of the present invention may further contain other anti-HCV agents.
  • anti-HCV agents include, but are not limited to, alpha-interferon, beta-interferon, ribavirin, and amantadine.
  • the pharmaceutical compositions of the present invention may further contain other HCV protease inhibitors.
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject a therapeutically effective amount of the pharmaceutical compounds or compositions of the present invention.
  • the methods can further include administration of an additional therapeutic agent, including another antiviral agent or an anti-HCV agent.
  • the additional agent can be coadministered, concurrently administered or sequentially administered with a compound or pharmaceutical composition of the present invention.
  • the additional agent and the compound of the present invention can be co-formulated in a single dosage form or composition, or prepared in separate dosage forms or compositions.
  • the methods herein can further include the step of identifying that the subject is in need of treatment for hepatitis C infection.
  • the identification can be by subjective (e.g., health care provider determination) or objective (e.g., diagnostic test) means.
  • the present invention also features the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, for the manufacture of a medicament for the treatment of HCV infection.
  • the medicament can also include one or more other anti-HCV agent, such as alpha-interferon, beta- interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
  • aryl refers to a mono- or polycyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • heteroaryl refers to a mono- or polycyclic (e.g. bi-, or tri-cyclic or more), fused or non-fused, aromatic radical or ring having from five to ten ring atoms of which one or more ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from, for example, S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • Ci-Cs alkyl or “C 1 -C 12 alkyl,” as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing from one to eight, or from one and twelve carbon atoms, respectively.
  • Ci-Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals; and examples of C 1 -C 12 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, decyl, dodecyl radicals.
  • C 2 -Cs alkenyl denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon double bond.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.
  • C 2 -Cs alkynyl denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon triple bond.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • Cs-Cg-cycloalkyl or "C3-Ci2-cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively.
  • C 3 -C 8 -cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-C12- cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • Cs-Cg-cycloalkenyl or "C 3 -Ci 2 -cycloalkenyl” as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has at least one carbon-carbon double bond and contains from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively.
  • Cs-Cs-cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C3-C12- cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • substituted refers to independent replacement of one, two, three or more of hydrogen atoms on a parent moiety with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, - NH 2 , protected amino, -NH -C r C 12 -alkyl, -NH -C 2 -C 12 -alkenyl, -NH -C 2 -C 12 - alkenyl, -NH -C 3 -C 12 -cycloalkyl, -NH -aryl, -NH -heteroaryl, -NH - heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C 2 -Ci2-alkenyl
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from -F, -Cl, -Br, -I, - OH, -NO 2 , -CN, or -NH 2 .
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can be replaced by an aliphatic group, an alicyclic group or a heterocyclic group.
  • An "aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocyclic refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
  • Such heterocyclic groups may be further substituted to give substituted heterocyclic.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be divalent or trivalent.
  • alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency.
  • halo or halogen,” as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, /?-nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-propenyl, 3 -methyl- 3 -butenyl, allyl, benzyl, para-methoxy
  • Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or -C(O)C 6 H 5 ), and trimethylsilyl (TMS or- Si(CHs) 3 ).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T. H. Greene and P. G. M.
  • amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • alkylamino refers to a group having the structure -NH(Ci-Ci 2 alkyl) where C1-C12 alkyl is as previously defined.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • protogenic organic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • General synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
  • subject refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. Likewise, unless the text states otherwise, a carbon-carbon double bond or carbon-heteroatom double bond depicted herein as cis may be cis, trans, or a mixture of the two in any proportion.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means or by hydrolysis to a compound of Formula I.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxyysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; algin
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • viral infections are treated or prevented in a subject, such as a human, by administering to the subject a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention means a sufficient amount of the compound so as to decrease the viral load in a subject and/or decrease the subject's HCV symptoms.
  • a therapeutically effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of the present invention in such amounts and for such time as is necessary to inhibit viral replication and/or reduce viral load.
  • the term “inhibitory amount” means a sufficient amount to inhibit viral replication and/or decrease the hepatitis C viral load in a biological sample.
  • biological sample(s) as used herein means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • Another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • Boc for te/t-butoxycarbonyl
  • Bz for benzoyl
  • CDI for carbonyldiimidazole
  • dba for dibenzylidene acetone
  • DMSO dimethyl sulfoxide
  • dppb diphenylphosphino butane
  • EtOAc ethyl acetate
  • HATU 2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate; iPrOH for isopropanol;
  • NaHMDS for sodium bis(trimethylsilyl)amide
  • NMO for N-methylmorpholine N-oxide
  • POPd for dihydrogen dichlorobis(di-tert-butylphosphino)palladium(II); TBAHS for tetrabutyl ammonium hydrogen sulfate;
  • TPP for triphenylphosphine
  • Tris for Tris(hydroxymethyl)aminomethane
  • DIBAL-H for diisobutylaluminum hydride
  • DIEA for diisopropyl ethylamine
  • KHMDS is potassium bis(trimethylsilyl) amide
  • RT-PCR for reverse transcription-polymerase chain reaction
  • TEA for triethyl amine
  • Scheme 1 describes the synthesis of intermediate (1-6).
  • the acyclic peptide precursor (1-6) was synthesized from Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • Scheme 1 describes the synthesis of intermediate (1-6).
  • the acyclic peptide precursor (1-6) was synthesized from Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • intermediate (2-2) can also be made by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide; followed with the deprotection of the phthalimide moiety with ammonia or hydrazine.
  • Oximes (2-3) can be prepared by treating hydroxy amine with appropriate aldehyde or ketone optionally in the presence of an acid. Subsequent removal of the acid protecting group furnishes compounds of formula (2-4).
  • a thorough discussion of solvents and conditions for protecting the acid group can be found in T. W. Greene and P. GM. Wuts, Protective Groups in Organic Synthesis, 3 rd ed., John Wiley & Son, Inc, 1999.
  • the Scheme 3 describes the alternative methods to synthesize formula (3-2).
  • the intermediates (3-1) can be made directly through (1-6) and oximes using Mitsunobu conditions. Or, intermediate (3-1) can also be made through SN2 replacement of activated hydroxyl group by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide. Subsequent removal of the acid protecting group furnishes compounds of formula (3-2).
  • Scheme 4 [
  • Scheme 4 illustrates the modification of the N-terminal and C-terminal of the acyclic peptide (4-1).
  • Deprotection of the Boc moiety with an acid yields compounds of formula (4-2).
  • the amino moiety of formula (4-2) can be alkylated or acylated with appropriate alkyl halide or acyl groups to give compounds of formula (4-3).
  • Compounds of formula (4-3) can be hydrolyzed with base such as lithium hydroxide to free up the acid moiety of formula (4-4). Subsequent activation of the acid moiety followed by treatment with appropriate acyl or sulfonyl groups to provide compounds of formula (4-5).
  • step Ib To a solution of the free acid obtained from step Ib (1.5g) in 5 ml DMF, D- ⁇ -vinyl cyclopropane amino acid ethyl ester (1.Og), DIEA (3.8ml) and HATU (2.15g) were added. The coupling was carried out at 0 0 C over a period of 5 hours. The reaction mixture was diluted with 200 mL EtOAc, and followed by washing with 5% citric acid 2x 20 ml, water 2x20 ml, IM NaHCO 3 4x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na 2 SO 4 and then evaporated.
  • Step If To a solution of the compound from step Ie (1.22mmol) in DCM was added DIEA (2.2ml) and cyclopentylchloroformate (3eq) at O 0 C. The mixture was stirred for 1.5h at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by silica gel chromatography to give 850mg of desired product.
  • Step 3a is attached to Step 3a.
  • Step 3b To a solution of the compound from step 3a in THF/MeOH was added INLiOH. The reaction mixture was stirred overnight at room temperature. After acidified with INHCl, the resulting mixture was extracted with EtOAc. The organic extracts were washed with water and concentrated. The residue was purified by preparative HPLC to give desired product 1 and product 2.
  • 13C (CD 3 OD): 5174.0, 172.0, 169.5, 157.4, 153.6, 141.8, 140.5, 135.2, 133.1, 131.3, 130.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 117.4, 82.8, 77.8, 59.8, 59.4, 54.1, 53.6, 41.3, 35.1, 34.8, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.5, 5.6, 5.3.
  • 13C (CD3OD): 5174.0, 171.9, 170.4, 157.5, 153.6, 141.8, 140.5, 135.2, 131.3, 130.2, 129.2, 128.2, 127.9, 121.6, 119.9, 82.8, 77.8, 59.8, 59.4, 54.1, 39.1, 35.1, 34.5, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 19.6, 12.7, 5.5, 5.1.
  • Step 12a is cyclopropyl
  • 13C(CDCB) 5172.9, 172.3, 168.5, 156.1, 153.6, 141.5, 140.3, 135.2, 132.5, 131.2, 130.2, 129.4, 128.4, 128.0, 121.9, 119.8, 118.5, 82.2, 73.6, 59.8, 59.1, 53.8, 41.8, 35.6, 35.4, 34.0, 31.9, 31.8, 31.2, 26.4, 26.3, 25.3, 23.9, 23.6, 22.5, 6.3, 6.2, 6.1.
  • Example 20 to Example 109 are made following the procedures described in Examples 1, 3, 4 or 12.
  • step HOd The compound from step HOd was hydro lyzed with LiOH in THF/MeOH/H 2 O (2:1 :1) overnight.
  • the reaction mixture was acidified with IN HCl, extracted with 3 mL EtOAc, and washed with brine 2x1 ml.
  • the organic phase was dried over anhydrous Na 2 SO 4 and then evaporated to give desired acid (660mg) without further purification.
  • 13C (CD3OD): 5174.1, 172.9, 170.5, 156.7, 153.5, 141.8, 140.5, 135.2, 130.2, 129.1, 128.3, 127.9, 121.6, 119.9, 119.8, 82.9, 79.1, 60.0, 58.2, 53.3, 39.1, 34.2, 30.8, 30.5, 27.3, 23.0, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
  • Step 112b To the solution of the compound from step 112a in 2ml DCM was added DIEA
  • 13C (CD3OD): 5174.1, 172.9, 170.5, 157.4, 153.6, 141.7, 140.5, 135.3, 131.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.8, 82.9, 77.7, 59.9, 58.6, 53.3, 39.1, 34.2, 32.4, 32.3, 30.8, 30.4, 23.2, 22.9, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
  • Step 116a
  • Step 118a
  • Step 122a
  • 13C(CDCB) ⁇ 173.0, 172.5, 167.9, 156.7, 153.7, 141.5, 140.3, 139.0, 135.1, 135.0, 133.5, 132.1, 131.3, 130.2, 129.4, 128.3, 128.0, 126.8, 121.8, 119.8, 118.4, 82.1, 77.2, 61.2, 59.9, 59.3, 58.6, 53.9, 50.7, 41.6, 35.6, 34.1, 16.5, 22.6, 18.1, 14.3.
  • Example 129 Compound of formula C, wherein Rx .OrV .w.
  • Example 126 The title compound was prepared with compound from Example 126 with 4- morpholinecarbonyl chloride via the similar conditions described in Example 127.
  • Example 133b To a flask containing the compound from Example 133b (200mg) was added 4N HCl/dioxane (8ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification.
  • step 133d The compound from step 133d was hydro lyzed with LiOH in THF/MeOH/H 2 O (2:1 :1) overnight.
  • the reaction mixture was acidified with IN HCl, extracted with 5 mL EtOAc, and washed with brine 2x1 ml.
  • the organic phase was dried over anhydrous Na 2 SO 4 and then evaporated to give desired acid without further purification.
  • MS (ESI): m/z 522.15 [M+H].
  • Example 136 Compound of formula C, wherein Rx .W-
  • Step 136a To a solution of D- ⁇ -vinyl cyclopropane amino acid (2.8g) in DCM (30ml) was added CDI (2.8g). The reaction mixture was stirred at 4O 0 C for Ih and then added cyclopropylsulfonamide 2.98g and DBU 3.69ml. The reaction mixture was stirred overnight at 4O 0 C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was added 4N HCl/dioxne. The reaction mixture was stirred at room temperature for Ih. The mixture was then concentrated to give desired product without further purification.
  • Example 137 Compound of formula C, wherein Rx ⁇ OJy
  • Example 139 Compound of formula C, wherein Rx ⁇ OJy
  • Example 142 The title compound was prepared with compound from Example 126 with 3,3- dimethylbutyraldehyde via the similar conditions described in Example 142.
  • Example 146 Compound of formula C, wherein Rx -Cr-Yi . w-
  • Example 127 The title compound was prepared with compound from Example 126 with cyclobutanemethylchloroformate via the similar conditions described in Example 127.
  • Example 142 The title compound was prepared with compound from Example 126 with phenylacetaldehyde via the similar conditions described in Example 142.
  • Example 142 The title compound was prepared with compound from Example 126 with glyoxylic acid via the similar conditions described in Example 142.
  • Example 142 The title compound was prepared with compound from Example 126 with cyclohexanone via the similar conditions described in Example 142.
  • Example 165 Compound of formula C, wherein Rx - ⁇ i .l .w-
  • Example 142 The title compound was prepared with compound from Example 126 with 1- adamantane-ethylaldehyde via the similar conditions described in Example 142.
  • Example 166 Compound of formula C, wherein Rx -l&y. .w-
  • Example 137 The title compound was prepared with compound from Example 136 with T- methoxybiphenyl-2-aldehyde via the similar conditions described in Example 137.
  • Example 184 Compound of formula C, wherein Rx ⁇ /. .W
  • Example 185 Compound of formula C, wherein Rx . . >
  • Example 184 The title compound was prepared with compound of Example 184 with via the similar conditions described in Example 114.
  • 13C (CDC13): 5172.9, 172.2, 169.2, 156.6, 153.9, 141.8, 140.5, 135.3, 132.6, 131.5, 130.5, 129.6, 128.7, 128.2, 122.1, 120.1, 118.9, 82.3, 78.5, 69.7, 60.3, 56.4, 53.5, 41.1, 36.0, 34.7, 33.0, 32.7, 31.4, 24.5, 23.8, 23.7, 20.2, 6.5, 6.3.
  • 13C (CDC13): 5172.4, 169.3, 157.1, 153.9, 148.5, 141.7, 140.5, 135.4, 132.6, 131.4, 130.5, 130.4, 129.7, 128.9, 128.2, 122.1, 120.1, 120.0, 118.8, 83.8, 82.4, 78.2, 72.1, 60.0, 57.7, 53.5, 41.0, 36.1, 34.9, 33.1, 32.6, 32.5, 31.4, 27.2, 26.5, 24.6, 23.8, 23.7, 23.6, 6.4, 6.3.
  • Example 196 The title compound was prepared with compound of Example 196 with bezoic acid via the similar conditions described in Example 144.
  • Example 126 The title compound was prepared with compound of Example 126 with cyclohexylisocynate via the similar conditions described in Example 127.
  • Example 216 Compound of formula C, wherein Rx ⁇ OJy
  • Example 137 The title compound was prepared with compound from Example 136 with benzaldehyde via the similar conditions described in Example 137.
  • the compound was prepared using (2S,4S)-l-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid and (lR,2S)-ethyl l-amino-2- vinylcyclopropanecarboxylate via conditions similar to those described in step Ic of Example 1.
  • the compound was prepared using the compound from step 226a of example 226 and 2,7-dibromo-9H-fluoren-9-one oxime via conditions similar to those described in step 10b of Example 10.
  • the compound was prepared with the compound from step 226b of example 226 via conditions similar to those described in step Ie of Example 1.
  • reaction mixture was stirred at 40 0 C for 1 h and then cyclopropylsulfonamide and DBU were added.
  • the reaction mixture was stirred at 40 0 C for 2 h.
  • the reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO 4 , filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product.
  • a DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.
  • the assay is run in Corning white half-area 96-well plates (VWR 29444-312 [Corning 3693]) with full-length NS3 HCV protease Ib tethered with NS4A co factor (final enzyme concentration 1 to 15 nM).
  • the assay buffer is complemented with 10 ⁇ M NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8).
  • RET Sl (Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser- LyS-(DABCYL)-NH 2 , AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate.
  • the assay buffer contains 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME. The enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
  • HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu- Met-Glu-Glu-Cys-OH, [-20 0 C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac- Asp-Glu-Dif-Cha-Cys-OH, are used as reference compounds.
  • HCV Cell Based Assay Quantification of HCV replicon RNA (HCV Cell Based Assay) is accomplished using the Huh 11-7 cell line (Lohmann, et al Science 285:110-113, 1999). Cells are seeded at 4x10 3 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non-essential amino acids. Cells are incubated in a 7.5% CO 2 incubator at 37 0 C. At the end of the incubation period, total RNA is extracted and purified from cells using Ambion RNAqueous 96 Kit (Catalog No. AMI 812).
  • primers specific for HCV mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).
  • PCR polymerase chain reaction
  • the nucleotide sequences of the RT-PCR primers, which are located in the NS5B region of the HCV genome, are the following: HCV Forward primer "RBNS5bfor"
  • Detection of the RT-PCR product is accomplished using the Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is degraded during the PCR reaction.
  • SDS Sequence Detection System
  • the increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product.
  • quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997).
  • the data is analyzed using the ABI SDS program version 1.7.
  • the relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
  • the RT reaction is performed at 48 0 C for 30 minutes followed by PCR.
  • Sequence Detection System are: one cycle at 95 0 C, 10 minutes followed by 40 cycles each of which include one incubation at 95 0 C for 15 seconds and a second incubation for 60 0 C for 1 minute.
  • RNA, RT-PCR is performed on the cellular messenger RNA glyceraldehyde-3- phosphate dehydrogenase (GAPDH).
  • GAPDH messenger RNA glyceraldehyde-3- phosphate dehydrogenase
  • the GAPDH copy number is very stable in the cell lines used.
  • GAPDH RT-PCR is performed on the same RNA sample from which the HCV copy number is determined.
  • the GAPDH primers and probes are contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E).
  • the ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication.
  • Activity of compounds as inhibitors of HCV replication (Cell based Assay) in replicon containing Huh-7 cell lines.
  • the effect of a specific anti-viral compound on HCV replicon RNA levels in Huh-1 l-7cells is determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the DMSO vehicle (negative control).
  • cells are seeded at 4x 10 3 cells/well in a 96 well plate and are incubated either with: 1) media containing 1% DMSO (0% inhibition control), or 2) media/1 %DMS0 containing a fixed concentration of compound.
  • Cl the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0% inhibition control (media/1 %DMSO).
  • the dose-response curve of the inhibitor is generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a specific compound at 1.5 uM and ending with the lowest concentration of 0.23 nM. Further dilution series (500 nM to 0.08 nM for example) is performed if the EC50 value is not positioned well on the curve.
  • EC50 is determined with the IDBS Activity Base program "XL Fit" using a 4-paramater, non-linear regression fit (model # 205 in version 4.2.1, build 16).
  • representative compounds of the present invention are found to have HCV replication inhibitory activity and HCV NS3 protease inhibitory activity.
  • representative compounds of formulae III and IV as depicted above, showed significant HCV replication inhibitory activity. These compounds were also effective in inhibiting HCV NS3 proteases of different HCV genotypes including genotypes 1, 2, 3 and 4.
  • representative compounds in the preferred examples of formulae III and IV showed EC50s in the range of from less than 0.2 nM to about 10 nM using cell-based replicon assays.
  • Representative compounds of these preferred examples also inhibited HCV NS3 proteases of different HCV genotypes, such as genotypes Ia, Ib, 2a, and 4a, with IC50s in the range of from less than 0.2 nM to about 50 nM.

Abstract

The present invention discloses compounds of formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

ACYCLIC OXIMYL HEPATITIS C PROTEASE INHIBITORS
Inventors: Ying Sun, Yat Sun Or, Zhe Wang
RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No. 60/811,464, filed on June 6, 2006, and U.S. Provisional Application No. 60/xxxxxx, which was converted from U.S. Application Serial Number 11/503,385 filed August 11, 2006. The entire teachings of the above applications are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel acyclic oximyl HCV protease inhibitor compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world. There are considerable barriers to the development of anti-HC V therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
Only two approved therapies for HCV infection are currently available. The original treatment regimen generally involves a 3-12 month course of intravenous interferon-alpha (IFN-α), while a new approved second-generation treatment involves co-treatment with IFN- α and the general antiviral nucleoside mimics like ribavirin. Both of these treatments suffer from interferon-related side effects as well as low efficacy against HCV infections. There exists a need for the development of effective antiviral agents for treatment of HCV infection due to the poor tolerability and disappointing efficacy of existing therapies.
In a patient population where the majority of individuals are chronically infected and asymptomatic and the prognoses are unknown, an effective drug preferably possesses significantly fewer side effects than the currently available treatments. The hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme required for processing of the viral polyprotein and consequently viral replication. Despite the huge number of viral variants associated with HCV infection, the active site of the NS3 protease remains highly conserved thus making its inhibition an attractive mode of intervention. Recent success in the treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle against HCV.
HCV is a flaviridae type RNA virus. The HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids. The HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, El and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins. NS2 is a zinc- dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus. NS4A is a tightly associated but non-covalent cofactor of the serine protease.
The NS3-NS4A protease is responsible for cleaving four sites on the viral polyprotein. The NS3-NS4A cleavage is autocatalytic, occurring in cis. The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans. NS3 is a serine protease which is structurally classified as a chymotrypsin- like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus. Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881
(2002). More relevant patent disclosures describing the synthesis of HCV protease inhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); US5861297 (1999); US publications 20050153877, 20050261200 and 20050065073.
SUMMARY OF THE INVENTION
The present invention relates to novel HCV protease inhibitor compounds, and pharmaceutically acceptable salts, esters, or prodrugs thereof, which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3- NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds, salts, esters or prodrugs for administration to a subject suffering from HCV infection. The present invention further features pharmaceutical compositions comprising a compound of the present invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and another anti-HCV agent, such as alpha-interferon, beta-interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition of the present invention.
In one embodiment of the present invention, there are disclosed compounds of formula I:
Figure imgf000005_0001
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein: Ri and R2 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl; e) substituted heteroaryl; f) heterocyclic or substituted heterocyclic; g) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; k) -Q-R3, where Q is (CO), (CO)O, (CO)NR4, (SO), (SO2),
(SO2)NR4; and R3 and R4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl;
(iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocyclic; (vii) substituted heterocyclic;
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N;
(ix) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing O, 1 , 2, or 3 heteroatoms selected from O, S or N; (x) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; (xi) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; or Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from: substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic; or substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more R3;
G is -E-R3, where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO2)NH or NHSO2;
A is selected from the group consisting of R5, (CO)R5, (CO)OR5, (CO)NHR5, SO2R5, (SO2)OR5 and SO2NHR5;
R5 is selected from the group consisting of: a) aryl; b) substituted aryl; c) heteroaryl; d) substituted heteroaryl; e) heterocyclic; f) substituted heterocyclic; g) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C3-C12 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; alternatively, R5 can be hydrogen;
B is H or CH3;
L and Z are independently selected from the group consisting of:
(I) hydrogen; (2) aryl;
(3) substituted aryl;
(4) heteroaryl;
(5) substituted heteroaryl;
(6) heterocyclic; (7) substituted heterocyclic;
(8) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(9) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(10) -C3-Ci2 cycloalkyl, Or -C3-Ci2 cycloalkenyl;
II 1) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl;
m = 0, 1, 2 or 3; n = 1 , 2 or 3 and h = 0, 1, 2, or 3. In another embodiment, the present invention features pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof. In still another embodiment of the present invention there are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient. In yet another embodiment of the invention are methods of treating a hepatitis C infection in a subject in need of such treatment with said pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention is a compound of formula I as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
In another embodiment, the present invention relates to a compound of formula II, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000008_0001
where A, G, L, Ri and Z are as previously defined. In a preferred example, Ri is not hydrogen . In another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, and substituted -C3-C12 cycloalkenyl. A is selected from the group consisting of -C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. L and Z can be independently selected from Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. G can be -0-R3, -NH-C(O)-R3, -NH-SO2-NH- R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. In still another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. A is -C(O)-O-R5 or -C(O)-NH-R5, where R5 is -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted - C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl.
In still yet another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. A is -C(O)-O-R5, where R5 is -C3-Ci2 cycloalkyl or substituted -C3- Ci2 cycloalkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. In another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. A is -C(O)-NH-R5, where R5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl.
In yet another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents. L is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3- C12 cycloalkenyl.
In still another example, Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl. L is -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -Ci-C8 alkyl, -C2-C8 alkenyl, substituted -C1-C8 alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In one embodiment, the present invention relates to a compound of formula III, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000010_0001
where A, G, L, R1, R2 and Z are as previously defined in the first embodiment. In one example, Ri and R2 are not both hydrogen.
In another example, Ri and R2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3- Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl; or Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R3, where each R3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. A can be selected from the group consisting of -C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C2-Cs alkenyl, -C2-Cs alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-C8 alkyl, -C2- C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted - C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. G can be -0-R3, -NH-C(O)- R3, -NH-SO2-NH-R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. In a preferred example, Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R3, where each R3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. A is -C(O)-O-R5 or -C(O)-NH-R5, where R5 is -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- C12 cycloalkenyl. L is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from Ci-C8 alkyl, substituted -Ci-C8 alkyl, -C2- Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3- Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
In another preferred example, Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R3, where each R3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. A is -C(O)-O-Rs, where Rs is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from Ci-Cg alkyl, substituted -Ci-C8 alkyl, -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In still another preferred example, Ri and R2 taken together with the carbon
atom to which they are attached form
Figure imgf000012_0001
which is optionally substituted with one or more groups, and each group is independently selected from halogen, hydroxy, nitro, cyano, amino, formyl, -Ci-C8alkyl or -C2-C8alkenyl, or -C2- C8alkynyl. A is -C(O)-O-Rs, where R5 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. L is selected from -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In yet another preferred example, Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R3, where each R3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. A is -C(O)-NH-R5, where R5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. Preferably, Ri and R2 taken together with the
carbon atom to which they are attached form
Figure imgf000013_0001
which is optionally substituted with one or more groups, and each group is independently selected from halogen, hydroxy, nitro, cyano, amino, formyl, -Ci-Cgalkyl or -C2-Cgalkenyl, or -C2- Cgalkynyl. In another preferred example, Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R3, where each R3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. A is -C(O)-R5, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents. L is selected from -Ci-Cg alkyl, - C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted - C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-C8 alkenyl, substituted -Ci-C8 alkyl, or substituted -C2-C8 alkenyl. G is - NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. In yet another preferred example, Ri and R2 taken together with the carbon
atom to which they are attached form
Figure imgf000013_0002
which is optionally substituted with one or more groups, and each group is independently selected from halogen, hydroxy, nitro, cyano, amino, formyl, -Ci-Cgalkyl or -C2-C8alkenyl, or -C2- Cgalkynyl. A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl. L is -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -CrC8 alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In a further embodiment, the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000014_0001
wherein V is absent, or V is CO, O, S, SO, SO2, NH, NCH3, or (CH2)q; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of: aryl; substituted aryl; heteroaryl; substituted heteroaryl; heterocyclic; substituted heterocyclic; and where A, G, L and Z are as previously defined in the first embodiment.
In one example,
Figure imgf000014_0003
is selected from
Figure imgf000014_0002
Figure imgf000014_0004
, wherein Xi-Xg are independently selected from CH and N and Xi-Xg can be further substituted when it is a CH, and Y1-Y3 are independently selected from CH, N, NH, S and O and Yi-Y3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A can be selected from the group consisting of -C(O)-R5, - C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -Cs-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. G can be -0-R3, -NH-C(O)-R3, -NH-SO2-NH-R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
In still another example,
Figure imgf000015_0001
is selected from
Figure imgf000015_0002
selected from CH and N and Xi-X8 can be further substituted when it is a CH, and Yi-Y3 are independently selected from CH, N, NH, S and O and Yi-Y3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A is -C(O)-O-R5, where R5 is -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L is selected from -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from Ci-C8 alkyl, substituted -Ci-C8 alkyl, -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
Figure imgf000016_0001
In still yet another example, +&*^ is selected from
Figure imgf000016_0002
, WlIeIeIn X1-X8 are independently selected from CH and N and X1-X8 can be further substituted when it is a CH, and Y1-Y3 are independently selected from CH, N, NH, S and O and Y1-Y3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A is -C(O)-O-R5, where R5 is -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. L is selected from -C1-C8 alkyl or substituted -C1-C8 alkyl. Z is selected from C1-C8 alkyl, substituted -C1-C8 alkyl,- C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl.
In a preferred example, R1 and R2 taken together with the carbon atom to
which they are attached form
Figure imgf000016_0003
S wherein X1-X8 are independently selected from CH and N and X1-X8 can be further substituted when it is a CH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A is -C(O)-O- R5, where R5 is -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. L is selected from -C1-C8 alkyl or substituted -C1-C8 alkyl. Z is selected from C1-C8 alkyl, substituted -C1-C8 alkyl, -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is - NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. In a most preferred example, R1 and R2 taken together with the carbon atom
to which they are attached form
Figure imgf000016_0004
, wherein Ra and Rb is independently selected from hydrogen or halogen. A is -C(O)-O-R5, where R5 is - C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from Ci-Cg alkyl, substituted -Ci-Cg alkyl, -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C 12 cycloalkyl or substituted -C3-Ci2 cycloalkyl. In one embodiment, the present invention relates to a compound of formula
V, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000017_0001
Where X1-X4 are independently selected from CO, CH, NH, O and N; where X1-X4 can be further substituted when any one of X1-X4 is a CH or NH; where R6 and R7 are independently R3, where R3 is independently selected from the group consisting of:
(i) hydrogen; (ii) aryl; (iii) substituted aryl; (iv) heteroaryl;
(v) substituted heteroaryl; (vi) heterocyclic; (vii) substituted heterocyclic;
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or
N;
(ix) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (x) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; (xi) substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl; and where A, G, L, V and Z are as previously defined in the embodiment immediately above. Alternatively, R^ and R7 can be independently selected from halogen, oxo, thioxo, nitro, cyano, -OR3, -SR3, -NR3R4, -SOR3, -SO2R3, -NHSO2R3, -SO2NHR3, -COR3, -CO2R3, (CO)NHR3, -OCOR3, OCONHR3, NHCO2R3, - NH(CO)R3, -NH(CO)NHR3, and -NH(SO2)NHR3.
In one example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is selected from the group consisting of -C(O)- R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. G can be -0-R3', -NH-C(O)-R3', -NH-SO2-NH-R3' or -NHSO2- R3', where R3' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
In another example, Re and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-O-R5 or -C(O)-NH-R5, , where R5 is - Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -C1-C8 alkyl, substituted - C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. L is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C2-Cg alkenyl. G is -NHSO2-R3', where R3' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- C12 cycloalkenyl.
In still another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2- Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-O-Rs, where R5 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3', where R3' is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3- C12 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-NH-R5, where R5 is -Ci-C8 alkyl or substituted -Ci-C8 alkyl. L is selected from -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. In yet another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, and substituted -C3-C12 cycloalkenyl. A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents. L is selected from -Ci-Cs alkyl, -C2-Cs alkenyl, -C2-Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, substituted -C2-Cs alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -Ci-Cs alkyl, -C2-Cs alkenyl, substituted -Ci-Cs alkyl, or substituted -C2-Cs alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
In still another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C2-Cs alkenyl, -C2- Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, substituted -C2-Cs alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl. L is -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -Ci-C8 alkyl, -C2-C8 alkenyl, substituted -Ci-C8 alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In another embodiment, the present invention relates to a compound of formula VI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000020_0001
Where Yi-Y3 are independently selected from CO, CH, NH, N, S and O; and Y1-Y3 can be further substituted when any one OfYi-Y3 is CH or NH; Y4 is selected from C, CH and N; and where A, G, L, R6, R7, V and Z are as previously defined in the embodiment immediately above. In one example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C2-Cs alkenyl, -C2-Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, substituted -C2-Cs alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is selected from the group consisting of -C(O)- R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. G can be -0-R3', -NH-C(O)-R3', -NH-SO2-NH-R3' or -NHSO2- R3', where R3' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
In another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-O-R5 or -C(O)-NH-R5, where R5 is - Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted - C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L is selected from -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3', where R3' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl.
In still another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2- Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-O-Rs, where R5 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl. Z is selected from -C2-Cg alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3', where R3' is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-NH-R5, where R5 is -Ci-C8 alkyl or substituted -Ci-C8 alkyl. L is selected from -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In yet another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3- Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-R5, where R5 is substituted -Ci-C8 alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents. L is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -Ci-Cg alkyl, -C2-Cg alkenyl, substituted -Ci-C8 alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. In still another example, R6 and R7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, -C2- C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl. A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl. L is -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -Ci-C8 alkyl, -C2-C8 alkenyl, substituted -Ci-C8 alkyl, or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl.
In one embodiment of the present invention, there are disclosed compounds of formula IX:
Figure imgf000023_0001
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
Mi is selected from the group consisting of:
Figure imgf000023_0002
wherein R31 and R32 are independently selected from the group consisting of: a) hydrogen; b) aryl; substituted aryl; c) heteroaryl; substituted heteroaryl; d) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; e) -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; f) -A-R30, where A is (CO), (CO)O, (CO)NR40, (SO), (SO2), (SO2)NR40; and R30 and R40 are independently selected from the group consisting of:
(i) Hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl
(iii) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic; with added proviso that when A= CO, (CO)O, (SO), (SO2), R30 is not hydrogen; with added proviso that when R31= hydrogen, R32 is not hydrogen; alternatively, R31 and R32 are taken together with the carbon atom to which they are attached to form the group consisting of: a) -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl heterocyclic or substituted heterocyclic; b) -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic fused with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C3-C12 cycloalkyl, substituted -C3-C12 cycloalkyl, - C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic;
c)
Figure imgf000025_0001
wherein V is absent, or V is O, S, SO, SO2, NR50, or
(CH2)q; where R50 is selected from H, OH, OCH3, -0-Ci-C8 alkyl, -Ci-C8 alkyl, -0-C3-C8 cycloalkyl, -C3-C8 cycloalkyl, -O- C3-C8 cycloalkenyl; -C3-C8 cycloalkenyl; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of:
(i) aryl; substituted aryl; (ii) heteroaryl; substituted heteroaryl; (iii) heterocyclic; substituted heterocyclic;
(2) NR30R40; NR5(CO)R30; NR50(CO)OR30; NR50(CO)NR30R40;
NR50(SO2)OR30; NR50(SO2)NR30R40; where R30, R40 and R50 are as previously defined; alternatively, for formula (I), R30 and R40 are taken together with the nitrogen atom to which they are attached to form the group consisting of: heterocyclic, or substituted heterocyclic; heteroaryl, or substituted heteroaryl; M2 is selected from the group consisting of:
(1) oxygen; (2) sulfur;
(3) NR60; where R60 is selected from H, OH, OCH3, -0-Ci-C8 alkyl, -Ci-C8 alkyl;
G is -E-R30; and where E is absent, or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(CNR50)NH, NH(SO2)NH or NHSO2; where R30 and R50 are as previously defined; Z is selected from the group consisting of CH2, O, CO, (CO)O, (CO)NH, S, SO, SO2, CF, CF2, aryl, substituted aryl, heteroaryl and substituted heteroaryl; n = 0, 1, 2, 3 or 4; U is CH, CF or N; R70 is selected from the group consisting of H, OH, OCH3, -O-Ci-Cg alkyl, -Ci-Cs alkyl;
J is selected from the group consisting of CO, (CO)O, (CO)NR50, SO2, (SO2)O or SO2NR50;
Rg0 is selected from the group consisting of: (1) hydrogen;
(2) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(3) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-C12 cycloalkyl, or substituted -
C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; with added proviso that when J= CO, (CO)O, (SO), (SO2), R80 is not hydrogen;
L is selected from the group consisting of:
(1) protected or unprotected side chain of natural amino acid;
(2) Side chain of unnatural amino acid as described in M. G. Natchus and X. Tian, " The asymmetric synthesis of unnatural α-amino acids as building blocks for complex molecule synthesis", Organic Synthesis: Theory and Applications, 5: 89-196 (2001); and R.M. Williams, "
Synthesis of Optically Active α-amino Acids", Pergamon, Oxford (1989).
(3) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; Q is selected from the group consisting of:
(1) hydrogen;
(2) CH=CH2;
(3) CHF2; (4) SH; SR30; where R30 is as previously defined;
(5) -C1-C8 alkyl, -C2-Cs alkenyl, or -C2-Cs alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -Cs-Ci2 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic; m = 0, 1, 2 or 3; and s = 0, 1, 2 or 3.
In another embodiment the present invention relates to compound of formula X, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000027_0001
where G, J, L, M2, R31, R70, and Rso are as previously defined in the embodiment immediately above, with added proviso R31 is not hydrogen.
Yet another embodiment of the present invention relates to compound of formula XI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000028_0001
where G, J, L, M2, R31, R32, R70, and Rso are as previously defined in the embodiment above.
In another embodiment the present invention relates to compound of formula XII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000028_0002
Where Xi and Yi are independently selected from CH and N; R90, R100, Ri 10, and R120 are independently R30; G, J, L, M2, R70, and Rso are as previously defined in the embodiment above.
In one embodiment the present invention relates to compound of formula XIII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000028_0003
where G, J, L, M2, R70, Rso, V, X and Y are as previously defined in the embodiment above.
In another embodiment the present invention relates to compound of formula XIV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000029_0001
Where Xi-X4 are independently selected from CH and N; Xi-X4 can be further substituted when it is a CH; where G, J, L, M2, R70, Rso, R90, R100 and V are as previously defined in the embodiment above.
In another embodiment the present invention relates to compound of formulae XV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000029_0002
Where Y1-Y3 are independently selected from CH, N, NH, S and O; and Y1- Y3 can be further substituted when it is CH or NH; Y4 is selected from CH and N; where G, J, L, M2, R70, Rso, R90, R100 and V are as previously defined.
In one embodiment the present invention relates to compound of formula XVI or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000030_0001
Where Wi is hydrogen, R30, COR30, CONR30R40, SOR30, SO2NR30R40; G, J, L, M2, R70 and Rs0 are as previously defined.
In one embodiment the present invention relates to compound of formula XVII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
Figure imgf000030_0002
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein: Rioi and Ri02 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl fused with O, 1, 2, or 3 more group selected from heteroaryl and aryl; e) substituted heteroaryl fused with 0, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; f) heterocyclic, substituted heterocyclic, oxo substituted heterocyclic; wherein oxo refer to substituted by independent replacement of two of the hydrogen atoms thereon with =0; g) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1,
2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted
-C2-Cg alkynyl each containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N; i) -C3-C12 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; k) oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl; 1) -Q-Ri03, where Q is (CO), (CO)O, (CO)NRi04, (SO), (SO2),
(SO2)NRiO4; and Rio3 and Rio4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl; (iii) substituted aryl;
(iv) heteroaryl fused with O, 1,2, or 3 more group selected from aryl and heteroaryl;
(v) substituted heteroaryl fused with 0, 1,2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl;
(vi) heterocyclic; (vii) substituted heterocyclic; (viii) oxo substituted heterocyclic;
(ix) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or
N;
(x) substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (xi) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl;
(xii) substituted -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkenyl, oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl; or Rioi and R102 taken together with the carbon atom to which they are attached form a cyclic moiety selected from: substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic; substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each substituted an oxo; substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more R103; or oxo substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more
Gi is -E-R103, where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO2)NH or NHSO2;
A is selected from the group consisting of R105, (CO)Rios, (CO)ORios, (CO)NHRios,
SO2Ri05, (SO2)ORi05 and SO2NHRi05;
RiO5 is selected from the group consisting of: a) hydrogen b) substituted aryl; c) heteroaryl fused with O, 1, 2, or 3 more group selected from heteroaryl and aryl; d) substituted heteroaryl fused with O, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; e) heterocyclic; f) substituted heterocyclic; g) oxo substituted heterocyclic; h) -C1-C8 alkyl, -C2-Cs alkenyl, or -C2-Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; i) substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, or substituted -C2-Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; j) -C3-C12 cycloalkyl, or -C3-C12 cycloalkenyl; k) substituted -C3-C12 cycloalkyl, substituted -C3-C12 cycloalkenyl, oxo substituted -C3-C12 cycloalkyl, or oxo substituted -C3-C12 cycloalkenyl; and 1) aryl;
Bi is H or CH3;
Li and Zi are independently selected from the group consisting of: (1) hydrogen; (2) aryl;
(3) substituted aryl;
(4) heteroaryl fused with 0, 1, 2, or 3 more group selected from heteroaryl and aryl; (5) substituted heteroaryl fused with 0, 1, 2, or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl;
(6) heterocyclic;
(7) substituted heterocyclic;
(8) oxo substituted heterocyclic; (9) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(10) substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (11) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl;
(12) substituted -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkenyl, oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl;
m = 0, 1, 2 or 3; n = 1, 2 or 3 and h = 0, 1, 2, or 3.
In another embodiment, the invention provides intermediate compounds useful in the synthesis of compounds of formulas I-XVII, B and C, selected from the group consisting of: Compounds (I)- (2) of the formula A:
Figure imgf000033_0001
Rx , G and W are delineated for each example in TABLE 1 :
TABLE 1
Figure imgf000034_0003
Representative compounds of the invention are those selected from compounds (3)- (109) of the formula B:
Figure imgf000034_0001
Wherein Ri and R2 are taken together with the carbon to which they are attached to form RiR2, and RiR2, Rx, L, Z and G are delineated for each example in TABLE 2:
TABLE 2
Figure imgf000034_0002
Figure imgf000035_0001
V7
V7
V7
V7
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000040_0001
Figure imgf000041_0001
Additional non-limiting examples of the compounds of the invention are those Compounds (110)-(237) of the formula C:
Figure imgf000042_0001
, Rx, L, n, Z and G are delineated for each example in TABLE 3 :
TABLE 3
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
V V7
Figure imgf000054_0001
In one embodiment, the present invention features pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A further embodiment of the present invention includes pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
Yet another embodiment of the present invention is a pharmaceutical composition comprising a combination of two or more compounds of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient. In another embodiment, the pharmaceutical compositions of the present invention may further contain other anti-HCV agents. Examples of anti-HCV agents include, but are not limited to, alpha-interferon, beta-interferon, ribavirin, and amantadine. In another embodiment, the pharmaceutical compositions of the present invention may further contain other HCV protease inhibitors.
According to yet another embodiment, the pharmaceutical compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
According to another embodiment, the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject a therapeutically effective amount of the pharmaceutical compounds or compositions of the present invention. The methods can further include administration of an additional therapeutic agent, including another antiviral agent or an anti-HCV agent. The additional agent can be coadministered, concurrently administered or sequentially administered with a compound or pharmaceutical composition of the present invention. The additional agent and the compound of the present invention can be co-formulated in a single dosage form or composition, or prepared in separate dosage forms or compositions. The methods herein can further include the step of identifying that the subject is in need of treatment for hepatitis C infection. The identification can be by subjective (e.g., health care provider determination) or objective (e.g., diagnostic test) means. The present invention also features the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, for the manufacture of a medicament for the treatment of HCV infection. The medicament can also include one or more other anti-HCV agent, such as alpha-interferon, beta- interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
The term "heteroaryl," as used herein, refers to a mono- or polycyclic (e.g. bi-, or tri-cyclic or more), fused or non-fused, aromatic radical or ring having from five to ten ring atoms of which one or more ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from, for example, S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. The term "Ci-Cs alkyl," or "C1-C12 alkyl," as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing from one to eight, or from one and twelve carbon atoms, respectively. Examples of Ci-Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals; and examples of C1-C12 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, decyl, dodecyl radicals.
The term "C2-Cs alkenyl," as used herein, denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.
The term "C2-Cs alkynyl," as used herein, denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon triple bond. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like. The term "Cs-Cg-cycloalkyl", or "C3-Ci2-cycloalkyl," as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively. Examples of C3-C8-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-C12- cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
The term "Cs-Cg-cycloalkenyl", or "C3-Ci2-cycloalkenyl" as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has at least one carbon-carbon double bond and contains from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively. Examples of Cs-Cs-cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C3-C12- cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
The term "substituted" as used herein, refers to independent replacement of one, two, three or more of hydrogen atoms on a parent moiety with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO2, -CN, - NH2, protected amino, -NH -CrC12-alkyl, -NH -C2-C12-alkenyl, -NH -C2-C12- alkenyl, -NH -C3-C12-cycloalkyl, -NH -aryl, -NH -heteroaryl, -NH - heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C2-Ci2-alkenyl, -O-C2-C12-alkenyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)- CrC12-alkyl, -C(O)- C2-C12-alkenyl, -C(O)- C2-Ci2- alkenyl, -C(O)-C3-C12-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)- heterocycloalkyl, -CONH2, -CONH- Ci-Ci2-alkyl, -CONH- C2-C12-alkenyl, - CONH- C2-Ci2-alkenyl, -CONH-C3-C12-cycloalkyl, -CONH-aryl, -CONH- heteroaryl, -CONH-heterocycloalkyl, -OCO2- d-C^-alkyl, -OCO2- C2-C12-alkenyl, -OCO2- C2-Ci2-alkenyl, -OCO2-C3-C 12-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, - OCO2-heterocycloalkyl, -OCONH2, -OCONH- Ci-Ci2-alkyl, -OCONH- C2-Ci2- alkenyl, -OCONH- C2-C12-alkenyl, -OCONH- C3-C12-cycloalkyl, -OCONH- aryl, - OCONH- heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)- d-C^-alkyl, - NHC(O)-C2-C i2-alkenyl, -NHC(O)-C2-Ci2-alkenyl, -NHC(O)-C3-C i2-cycloalkyl, - NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2- C1-C12- alkyl, -NHCO2- C2-C12-alkenyl, -NHCO2- C2-C12-alkenyl, -NHCO2- C3-Ci2- cycloalkyl, -NHCO2- aryl, -NHCO2- heteroaryl, -NHCO2- heterocycloalkyl, - NHC(O)NH2, -NHC(O)NH- Ci-Ci2-alkyl, -NHC(O)NH-C2-C12-alkenyl, -
NHC(O)NH-C2-Ci2-alkenyl, -NHC(O)NH-C3-C 12-cycloalkyl, -NHC(O)NH-aryl, - NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH- Ci-Ci2-alkyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-C2-C 12-alkenyl, - NHC(S)NH-C3-C 12-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH- Ci-Ci2-alkyl, -
NHC(NH)NH-C2-Ci2-alkenyl, -NHC(NH)NH-C2-Ci2-alkenyl, -NHC(NH)NH-C3- Ci2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH- heterocycloalkyl, -NHC(NH)-Ci-Ci2-alkyl, -NHC(NH)-C2-Ci2-alkenyl, -NHC(NH)- C2-Ci2-alkenyl, -NHC(NH)-C3-C 12-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)- heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-Ci-Ci2-alkyl, -C(NH)NH-C2- Ci2-alkenyl, -C(NH)NH-C2-Ci2-alkenyl, -C(NH)NH-C3-C i2-cycloalkyl, -C(NH)NH- aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-Ci-Ci2-alkyl, - S(O)-C2-Ci2-alkenyl, - S(O)-C2-Ci2-alkenyl, - S(O)-C3-Ci2-cycloalkyl, - S(O)-aryl, - S(O)-heteroaryl, - S(O)-heterocycloalkyl -SO2NH2, -SO2NH- Ci-Ci2-alkyl, - SO2NH- C2-C 12-alkenyl, -SO2NH- C2-Ci2-alkenyl, -SO2NH- C3-Ci2-cycloalkyl, - SO2NH- aryl, -SO2NH- heteroaryl, -SO2NH- heterocycloalkyl, -NHSO2-Ci-Ci2- alkyl, -NHSO2-C2-Ci2-alkenyl, - NHSO2-C2-Ci2-alkenyl, -NHSO2-C3-Ci2- cycloalkyl, -NHS02-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3- Ci2-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, - SH, -S-Ci-Ci2-alkyl, -S-C2-Ci2-alkenyl, -S-C2-Ci2-alkenyl, -S-C3-C i2-cycloalkyl, - S-aryl, -S-heteroaryl, -S-heterocycloalkyl, methylthiomethyl.lt is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted. In some cases, each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from -F, -Cl, -Br, -I, - OH, -NO2, -CN, or -NH2. In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.
It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can be replaced by an aliphatic group, an alicyclic group or a heterocyclic group. An "aliphatic group" is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
The term "alicyclic," as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
The term "heterocyclic" as used herein, refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted to give substituted heterocyclic.
It will be apparent that in various embodiments of the invention, the substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be divalent or trivalent. Thus, alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency. The terms "halo" or "halogen," as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.
The term "hydroxy activating group", as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, /?-nitrobenzoate, phosphonate and the like.
The term "activated hydroxy", as used herein, refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example. The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
The term "hydroxy protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-propenyl, 3 -methyl- 3 -butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH3), benzoyl (Bz or -C(O)C6H5), and trimethylsilyl (TMS or- Si(CHs)3). The term "amino protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
The term "protected amino," as used herein, refers to an amino group protected with an amino protecting group as defined above.
The term "alkylamino" refers to a group having the structure -NH(Ci-Ci2 alkyl) where C1-C12 alkyl is as previously defined.
The term "acyl" includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term "protogenic organic solvent," as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. General synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
The term "subject" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al, Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. Likewise, unless the text states otherwise, a carbon-carbon double bond or carbon-heteroatom double bond depicted herein as cis may be cis, trans, or a mixture of the two in any proportion.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate,/?-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means or by hydrolysis to a compound of Formula I. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).
This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention. For example, compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxyysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
PHARMACEUTICAL COMPOSITIONS The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, viral infections are treated or prevented in a subject, such as a human, by administering to the subject a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the invention, as used herein, means a sufficient amount of the compound so as to decrease the viral load in a subject and/or decrease the subject's HCV symptoms. As is well understood in the medical arts a therapeutically effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of the present invention in such amounts and for such time as is necessary to inhibit viral replication and/or reduce viral load. The term "inhibitory amount" means a sufficient amount to inhibit viral replication and/or decrease the hepatitis C viral load in a biological sample. The term "biological sample(s)" as used herein means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells. Thus another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.
ABBREVIATIONS
Abbreviations which may appear in the following synthetic schemes and examples are:
Ac for acetyl;
Boc for te/t-butoxycarbonyl; Bz for benzoyl;
Bn for benzyl;
CDI for carbonyldiimidazole; dba for dibenzylidene acetone;
DBU for l,8-diazabicyclo[5.4.0]undec-7-ene; DIAD for diisopropylazodicarboxylate;
DMAP for dimethylaminopyridine;
DMF for dimethyl formamide;
DMSO for dimethyl sulfoxide; dppb for diphenylphosphino butane; EtOAc for ethyl acetate;
HATU for 2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate; iPrOH for isopropanol;
NaHMDS for sodium bis(trimethylsilyl)amide; NMO for N-methylmorpholine N-oxide;
MeOH for methanol;
Ph for phenyl;
POPd for dihydrogen dichlorobis(di-tert-butylphosphino)palladium(II); TBAHS for tetrabutyl ammonium hydrogen sulfate;
TEA for triethylamine;
THF for tetrahydrofuran;
TPP for triphenylphosphine; Tris for Tris(hydroxymethyl)aminomethane;
BME for 2-mercaptoethanol;
BOP for benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
COD for cyclooctadiene; DAST for diethylaminosulfur trifluoride;
DABCYL for 6-(N-4'-carboxy-4-(dimethylamino)azobenzene)- aminohexyl- l-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;
DCM for dichloromethane;
DIBAL-H for diisobutylaluminum hydride; DIEA for diisopropyl ethylamine;
DME for ethylene glycol dimethyl ether;
DMEM for Dulbecco's Modified Eagles Media;
EDANS for 5 -(2-Amino-ethylamino)-naphthalene-l -sulfonic acid;
EDCI or EDC for l-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II);
KHMDS is potassium bis(trimethylsilyl) amide;
Ms for mesyl; NMM for N-4-methylmorpholine;
PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;
RCM for ring-closing metathesis;
RT for reverse transcription;
RT-PCR for reverse transcription-polymerase chain reaction; TEA for triethyl amine;
TFA for trifluoroacetic acid;
THF for tetrahydrofuran; and
TLC for thin layer chromatography. SYNTHETIC METHODS
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared.
Scheme 1
Figure imgf000075_0001
(1-6) ( (11 --55)) (1-4)
Scheme 1 describes the synthesis of intermediate (1-6). The acyclic peptide precursor (1-6) was synthesized from Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1. For further details of the synthetic methods employed to produce the acyclic peptide precursor (1-6), see U.S. Pat. No. 10,849,107, which is herein incorporated by reference in its entirety.
Scheme 2
Figure imgf000075_0002
The analogs of the present invention were prepared via several different synthetic routes. The simplest method, shown in Scheme 2, is to condense commercially available hydroxyphthalimide using Mitsunobu conditions followed by deprotection of the phthalimide moiety with ammonia or hydrazine to provide hydroxy amine (2-2). For further details on the Mitsunobu reaction, see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 29, 1-162 (1983); D. L. Hughes, Organic Preparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997). Alternatively, intermediate (2-2) can also be made by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide; followed with the deprotection of the phthalimide moiety with ammonia or hydrazine. Oximes (2-3) can be prepared by treating hydroxy amine with appropriate aldehyde or ketone optionally in the presence of an acid. Subsequent removal of the acid protecting group furnishes compounds of formula (2-4). A thorough discussion of solvents and conditions for protecting the acid group can be found in T. W. Greene and P. GM. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Son, Inc, 1999.
Scheme 3
Figure imgf000076_0001
The Scheme 3 describes the alternative methods to synthesize formula (3-2). The intermediates (3-1) can be made directly through (1-6) and oximes using Mitsunobu conditions. Or, intermediate (3-1) can also be made through SN2 replacement of activated hydroxyl group by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide. Subsequent removal of the acid protecting group furnishes compounds of formula (3-2). Scheme 4 [
Figure imgf000077_0001
Hydrolysis
Figure imgf000077_0002
Scheme 4 illustrates the modification of the N-terminal and C-terminal of the acyclic peptide (4-1). Deprotection of the Boc moiety with an acid, such as, but not limited to hydrochloric acid yields compounds of formula (4-2). The amino moiety of formula (4-2) can be alkylated or acylated with appropriate alkyl halide or acyl groups to give compounds of formula (4-3). Compounds of formula (4-3) can be hydrolyzed with base such as lithium hydroxide to free up the acid moiety of formula (4-4). Subsequent activation of the acid moiety followed by treatment with appropriate acyl or sulfonyl groups to provide compounds of formula (4-5).
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.
EXAMPLES
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.
Example 1. Compound of formula A, wherein Rx = Cyclopentyloxycarbonyl, W= - Q-NH7 and G = OEt. Step Ia.
To a solution of Boc-L-t-butyl glycine (2.78g) and commercially available cis-L- hydroxyproline methyl ester (3.3g) in 15 ml DMF, DIEA (10ml) and HATU (5.9g) were added. The coupling was carried out at RT overnight. The reaction mixture was diluted with 200 mL EtOAc and subsequently the extract was washed with 5% citric acid (2x20 ml), water (2x20 ml), IM NaHCO3 (4x20 ml), and brine (2x10 ml), respectively. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo, affording dipeptide which was directly used in the next step. MS (ESI): m/z = 359.20 [M+Na].
Step Ib.
A solution of dipeptide from step Ia dissolved in 15 mL of dioxane and 15 mL of aqueous 1 N LiOH solution was carried out at room temperature for 4 hours. The reaction mixture was acidified by 5% citric acid and extracted with 200 mL EtOAc, and washed with water (2x20 ml), and brine (2x20 ml), respectively. The organic phase was dried over anhydrous Na2SO4 and then concentrated in vacuo, yielding the free carboxylic acid compound (4.Og), which was used in step Ic in its crude form. MS (ESI): m/z = 345.28[M+Na].
Step Ic.
To a solution of the free acid obtained from step Ib (1.5g) in 5 ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester (1.Og), DIEA (3.8ml) and HATU (2.15g) were added. The coupling was carried out at 0 0C over a period of 5 hours. The reaction mixture was diluted with 200 mL EtOAc, and followed by washing with 5% citric acid 2x 20 ml, water 2x20 ml, IM NaHCO3 4x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2SO4 and then evaporated. The residue was purified by silica gel flash chromatography using different ratios of hexanes :EtOAc as elution phase (5 : 1 — »3 : 1 — > 1 : 1 — > 1 :2). The desired linear tripeptide was isolated as an oil after removal of the elution solvents (1.4g, 66%). MS (ESI): m/z = 482.36 [M+Na].
Step Id.
To a solution of the acyclic precursor from step Ic, N-hydroxylphthalamide and PPh3 in THF was added DIAD at O0C. The reaction mixture was stirred for overnight at room temperature. The mixture was then concentrated and purified by silica gel chromatography to give desired product. MS (ESI): m/z = 627.25 [M+H].
Step Ie.
To a flask containing the compound from step Id (1.6g) was added 4N HCl/dioxane (30ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated. The residue was precipitated with MTBE. The precipitates was filtered and washed with MTBE to give desired product. MS (ESI): m/z = 527.21 [M+H].
Step If. To a solution of the compound from step Ie (1.22mmol) in DCM was added DIEA (2.2ml) and cyclopentylchloroformate (3eq) at O0C. The mixture was stirred for 1.5h at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give 850mg of desired product.
MS (ESI): m/z = 651.21 [M+H].
Step Ig. To a solution of compound from step If (0.41mmol)) in EtOH was added NH2NH2 (80μL)). The reaction mixture was stirred for 45min at room temperature. The mixture was then concentrated and extracted with DCM. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was carried directly for the next step without further purification. MS (ESI): m/z = 509.27 [M+H].
Example 2. Compound of formula I, wherein Rx = Boc, W= -OMs and G = OEt.
To a solution of the acyclic peptide precursor from step Ic of Example 1 (500mg, 1.04 mmol) and DIEA (0.543 ml, 3.12 mmol) in 10.0 ml DCM, mesylate chloride (0.122 ml) was added slowly at 0 0C where the reaction was kept for 3 hours. 100 mL EtOAc was then added and followed by washing with 5% citric acid 2x20 ml, water 1x20 ml, IM NaHCO3 2x20 ml and brine 1x20 ml, respectively. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated, yielding the title compound mesylate (590mg) that was used for next step synthesis without need for further purification. MS (ESI): m/z = 560.32 [M+H].
Example 3. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, R1 and R? taken together with the carbon atom to which they
are attached are
Figure imgf000080_0001
Step 3a.
The mixture of compound from step Ig of Example 1 (0.098mmol), 9-fluorenone (0.1 mmol), HOAc (0.3mmol) and pyridine (0. lmmol) in MeOH was stirred at 4O0C overnight. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by silica gel chromatography to give desired product.
MS (ESI): m/z = 671.24 [M+H].
Step 3b. To a solution of the compound from step 3a in THF/MeOH was added INLiOH. The reaction mixture was stirred overnight at room temperature. After acidified with INHCl, the resulting mixture was extracted with EtOAc. The organic extracts were washed with water and concentrated. The residue was purified by preparative HPLC to give desired product 1 and product 2. product 1 : MS (ESI): m/z = 643.33 [M+H]. product 2: MS (ESI): m/z = 645.22 [M+H].
Example 4. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
are attached are
Figure imgf000081_0001
cyclopropyl.
To a solution of product 1 from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide and DBU. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 746.26 [M+H].
13C (CD3OD): 5174.0, 172.0, 169.5, 157.4, 153.6, 141.8, 140.5, 135.2, 133.1, 131.3, 130.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 117.4, 82.8, 77.8, 59.8, 59.4, 54.1, 53.6, 41.3, 35.1, 34.8, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.5, 5.6, 5.3.
Example 5. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R7 taken together with the carbon atom to which they
are attached are
Figure imgf000081_0002
. Z= CH7CH1 and G = NHSO7- cyclopropyl. To a solution of product 2 (17mg) from step 3b of Example 3 in DMF was added CDI (6mg). The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide (6.3mg) and DBU (7.5 μl) . The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCθ3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product.
MS (ESI): m/z = 748.62 [M+H].
13C (CD3OD): 5174.0, 171.9, 170.4, 157.5, 153.6, 141.8, 140.5, 135.2, 131.3, 130.2, 129.2, 128.2, 127.9, 121.6, 119.9, 82.8, 77.8, 59.8, 59.4, 54.1, 39.1, 35.1, 34.5, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 19.6, 12.7, 5.5, 5.1.
Example 6. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
Figure imgf000082_0001
Step 6a.
The mixture of compound from step Ig of Example l(0.12mmol), 5-Methoxy-2- thiophen-2-yl-benzaldehyde (0.13mmol), HOAc (0.36mmol) and pyridine (0.12mmol) in MeOH was stirred at RT overnight. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give desired product.
MS (ESI): m/z = 709.47 [M+H].
Step 6b.
The title compound was prepared with compound from step 6a via the similar conditions described in step 3b of Example 3.
MS (ESI): m/z = 681.27 [M+H].
Example 7. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
Figure imgf000083_0001
cyclopropyl.
The title compound was prepared with compound from step 6b of Example 6 via the similar conditions described in Example 4. MS (ESI): m/z = 784.37 [M+H].
13C(CD3OD): 5174.1, 171.7, 169.6, 159.7, 157.4, 148.8, 140.4, 133.1, 132.0, 131.2, 127.7, 127.4, 127.3, 126.0, 117.4, 116.8, 110.1, 81.3, 77.8, 60.1, 59.3, 54.9, 54.0, 41.2, 35.3, 34.9, 34.2, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 5.5, 5.3.
Example 8. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
Figure imgf000083_0002
Step 8a.
The mixture of compound from step Ig of Example l(0.12mmol), 6-Fluoro-4- chromanone (0.13mmol), HOAc (0.36mmol) and pyridine (0.12mmol) in MeOH was stirred at RT overnight. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give desired product. MS (ESI): m/z = 657.34 [M+H].
Step 8b. The title compound was prepared with compound from step 8a via the similar conditions described in step 3b of Example 3. MS (ESI): m/z = 629.26 [M+H]. Example 9. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
Figure imgf000084_0001
The title compound was prepared with compound from step 8b of Example 8 via the similar conditions described in Example 4. MS (ESI): m/z = 732.33 [M+H].
13C(CD3OD): 5174.1, 171.8, 169.5, 158.4, 157.4, 156.5, 153.4, 150.0, 133.1, 119.2, 119.0, 118.3, 118.1, 117.4, 109.6, 109.4, 81.5, 77.8, 65.0, 60.1, 59.4, 54.1, 41.3, 35.2, 34.9, 34.3, 32.5, 32.4, 30.9, 25.8, 23.7, 23.3, 22.6, 5.6, 5.3.
Example 10. Compound of formula B, wherein Rx = Boc, L= tButyl, R1 and R? taken together with the carbon atom to which they are attached are
Figure imgf000084_0002
Step 10a.
The mixture of xanthone (1.Og), hydroxylamine hydrochloride (1.77g) and pyridine (12ml) was heated to HO0C for 2days. The reaction mixture was concentrated and the residue was extracted with EtOAc. The organic layer was washed with 1%HC1, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give desired oxime. MS (ESI): m/z = 212.08 [M+H].
Step 10b.
To a solution of the mesylate from Example 2 (lOOmg) in 2 mL DMF, was added 76mg of the oxime from step 10a and anhydrous sodium carbonate (175mg). The resulting reaction mixture was stirred vigorously at 6O0C for 12 hours. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 82mg of desired product. MS (ESI): m/z = 675.26 [M+H]. Step 10c.
The title compound was prepared with compound from step 10b via the similar conditions described in step 3b of Example 3. MS (ESI): m/z = 647.23 [M+H].
Example 11. Compound of formula B, wherein Rx = Boc, L= tButyl, R^ and R? taken together with the carbon atom to which they are attached are
Figure imgf000085_0001
The title compound was prepared with compound from step 10c of Example 10 via the similar conditions described in Example 4. MS (ESI): m/z = 750.22 [M+H].
Example 12. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
are attached are
Figure imgf000085_0002
cyclopropyl. Step 12a.
The solution of the compound from Example 11 in 5ml 4NHC1/Dioxne was stirred at RT for Ih. The reaction mixture was concentrated in vacuum. The residue was evaporated twice with DCM. The desired product was carried out directly to the next step. MS (ESI): m/z = 650.24 [M+H].
Step 12b.
To the solution of the compound from Example 12a in 2ml DCM was added DIEA (1.07mmol) and cyclopentylchloroformate (0.321mmol). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give 62mg of desired product. MS (ESI): m/z = 762.28 [M+H]. 13C(CD3OD): 5174.5, 172.2, 169.9, 157.8, 153.3, 151.8, 141.6, 133.5, 132.4, 131.6, 131.2, 124.9, 124.1, 123.3, 119.3, 117.7, 117.6, 117.3, 117.0, 116.4, 82.7, 78.1, 60.3, 59.8, 54.5, 41.6, 35.6, 35.2, 34.8, 32.9, 32.7, 31.3, 26.2, 23.7, 22.9, 5.9, 5.7.
Example 13. Compound of formula B, wherein Rx = Boc, L= tButyl, R^ and R? taken together with the carbon atom to which they are attached are
Figure imgf000086_0001
Step 13a. To a solution of the mesylate from Example 2 (1.23g) in 10 mL DMF, was added 858mg of 9-Fluorenone oxime and anhydrous sodium carbonate (2.15g). The resulting reaction mixture was stirred vigorously at 6O0C for 12 hours. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 1.29 of desired product. MS (ESI): m/z = 659.41 [M+H].
Step 13b.
The title compound was prepared with compound from step 13a via the similar conditions described in step 3b of Example 3. MS (ESI): m/z = 631.43 [M+H].
Example 14. Compound of formula B, wherein Rx = Boc, L= tButyl, R^ and R? taken together with the carbon atom to which they are attached are
Figure imgf000086_0002
The title compound was prepared with compound from step 13b of Example 13 via the similar conditions described in Example 4. MS (ESI): m/z = 734.53 [M+H]. 13C(CD3OD): 5174.0, 172.1, 169.6, 156.7, 153.5, 141.8, 140.5, 135.2, 133.1, 133.0, 131.3, 130.2, 129.1, 128.3, 127.9, 121.6, 119.9, 117.4, 82.8, 79.2, 59.9, 59.0, 54.1, 41.3, 35.2, 35.1, 34.9,34.5, 31.0,30.9,27.3, 25.8, 22.6, 5.6, 5.4, 5.3.
Example 15. Compound of formula B, wherein Rx = Boc, L= tButyl, R^ and R? taken together with the carbon atom to which they are attached are
Figure imgf000087_0001
The title compound was prepared with compound from step 13b of Example 13 with N, N-Dimethylsulfonamide via the similar conditions described in Example 4. MS (ESI): m/z = 737.33 [M+H].
Example 16. Compound of formula B, wherein Rx = Cyclopentyloxycarbonyl, L= tButyl, Ri and R7 taken together with the carbon atom to which they
are attached are
Figure imgf000087_0002
. Z= CH=CH7 and G = NHSO7-N(CHQ7.
The title compound was prepared with compound from Example 15 via the similar conditions described in Example 12. MS (ESI): m/z = 749.55 [M+H]. 13C(CDCB): 5173.1, 172.7, 168.1, 156.6, 153.8, 141.8, 140.5, 135.4, 133.1, 131.4, 130.5, 130.4, 129.6, 128.6, 128.2, 122.1, 120.0, 118.6, 82.3, 78.0, 59.9, 59.4, 54.0, 41.8, 38.5, 35.7, 35.1, 34.2, 33.0, 32.6, 26.7, 26.6, 26.4, 23.8, 22.2.
Example 17. Compound of formula B, wherein Rx = Cyclobutyloxycarbonyl, L= tButyl, Ri and R7 taken together with the carbon atom to which they
are attached are
Figure imgf000087_0003
. Z= CH=CH7 and G = NHSO7-cvclopropyl. The title compound was prepared with compound from Example 14 with cyclobutyl chloro formate via the similar conditions described in Example 12. MS (ESI): m/z = 732.58 [M+H]. 13C(CD3OD): 5174.0, 171.9, 169.5, 156.8, 153.6, 141.7, 140.5, 135.2, 133.1, 131.3, 130.3, 129.2, 128.3,127.9, 121.6, 119.9, 117.4, 82.8, 69.1, 59.8,59.4, 54.1, 41.3, 35.1, 34.8,34.4, 30.9, 30.2, 29.7, 25.8, 22.5,12.7, 5.5, 5.3.
Example 18. Compound of formula B, wherein Rx = Cyclohexyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
are attached are
Figure imgf000088_0001
The title compound was prepared with compound from Example 14 with cyclohexyl chloro formate via the similar conditions described in Example 12. MS (ESI): m/z = 760.60 [M+H].
13C(CDCB): 5172.9, 172.3, 168.5, 156.1, 153.6, 141.5, 140.3, 135.2, 132.5, 131.2, 130.2, 129.4, 128.4, 128.0, 121.9, 119.8, 118.5, 82.2, 73.6, 59.8, 59.1, 53.8, 41.8, 35.6, 35.4, 34.0, 31.9, 31.8, 31.2, 26.4, 26.3, 25.3, 23.9, 23.6, 22.5, 6.3, 6.2, 6.1.
Example 19. Compound of formula B, wherein Rx = 1-Adamatyloxycarbonyl, L= tButyl, Ri and R? taken together with the carbon atom to which they
are attached are
Figure imgf000088_0002
The title compound was prepared with compound from Example 14 with 1- Adamatyl chloro formate via the similar conditions described in Example 12. MS (ESI): m/z = 812.94 [M+H].
13C(CDCB): 5172.8, 172.4, 168.5, 155.2, 155.1, 153.5, 141.6, 10.2, 135.2, 132.5, 131.2, 130.2, 129.2, 128.4, 128.0, 121.9, 119.8,118.5, 82.1, 79.5, 71.9, 59.9, 58.7, 58.6, 53.8, 45.1, 41.7, 41.6, 41.3, 36.5, 35.8,35.5, 34.0,31.2, 30.8, 30.7,30.5, 29.7, 27.9, 26.5, 26.4, 22.5, 6.3, 6.2.
Example 20 to Example 109 (Formula B) are made following the procedures described in Examples 1, 3, 4 or 12.
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Step HOa.
To a solution of commercially available Boc-trans-L-hydroxyproline (2.Og) and D- β-vinyl cyclopropane amino acid ethyl ester (2.Og) in 15 ml DMF, DIEA (6ml) and HATU (3.95g) were added. The coupling was carried out at O0C for 1.5 hours. The reaction mixture was diluted with 200 mL EtOAc and subsequently the extract was washed with 5% citric acid (2x20 ml), water (2x20 ml), IM NaHCO3 (4x20 ml), and brine (2x10 ml), respectively. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo, affording dipeptide (3.2g) which was directly used in the next step. MS (ESI): m/z = 369.23 [M+H]. Step HOb.
A solution of dipeptide from step HOa (8.65mmol) in 20 mL DCM was cooled down to -780C. 2,6-lutidine (2.3ml) was added and followed by trifluoromethanesulfonyl anhydride (1.6ml) dropwise. The reaction mixture was kept at -780C for 1 hour and then diluted with 300ml ether. The organic phase was washed with 5% citric acid (3xl00ml) and water. The ether layer was concentrated in vacuo. DMSO/H2O (20ml/lml) was poured into the residue. The inversion finished in 30 minutes followed by HPLC. The reaction mixture was extracted with 300 mL EtOAc, and washed with brine (3x100 ml), respectively. The organic phase was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (5:1— »3:1— »1 :1— »1 :2). The desired cis dipeptide was isolated as oil after removal of the elution solvents (2.Og, 65%). MS (ESI): m/z = 369.23 [M+H].
Step HOc.
To a solution of the dipeptide precursor from step 11Ob(LOg, 2.72 mmol) and DIEA (1.42 ml, 8.16 mmol) in 10.0 ml DCM, mesylate chloride (0.318 ml, 4.08mmol) was added slowly at 0 0C where the reaction was kept for 3 hours. 100 mL EtOAc was then added and followed by washing with 5% citric acid 2x20 ml, water 1x20 ml, IM NaHCO3 2x20 ml and brine 1x20 ml, respectively. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated, yielding the title compound mesylate (1.2g) that was used for next step synthesis without need for further purification. MS (ESI): m/z = 447.25 [M+H].
Step HOd.
To a solution of the mesylate from step 110b (800mg) in 5 mL DMF, was added 525mg of 9-Fluorenone oxime and anhydrous cesium carbonate (1.75g). The resulting reaction mixture was stirred vigorously at 5O0C for 12 hours. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 760mg of desired product. MS (ESI): m/z = 546.32 [M+H].
Step HOe.
The compound from step HOd was hydro lyzed with LiOH in THF/MeOH/H2O (2:1 :1) overnight. The reaction mixture was acidified with IN HCl, extracted with 3 mL EtOAc, and washed with brine 2x1 ml. The organic phase was dried over anhydrous Na2SO4 and then evaporated to give desired acid (660mg) without further purification.
MS (ESI): m/z = 518.34 [M+H].
Step HOf.
To a solution of the compound (460mg) from step HOe in DCM was added CDI
(202mg). The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide (269mg) and DBU (267 μl). The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product (570mg).
MS (ESI): m/z = 621.41 [M+H].
Step HOg.
To a flask containing the compound from step 11 Of (200mg) was added 4N
HCl/dioxane (25ml). The resulting mixture was stirred for 1 hr at room temperature.
The mixture was then concentrated to give desired product without further purification.
MS (ESI): m/z = 521.26 [M+H].
StepllOh.
To a solution of the compound from Step HOg (0.08mmol) in acetonitrile (2ml) was added Boc-Val-OH (26mg), HATU (50mg) and DIEA (84μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification.
MS (ESI): m/z = 720.43 [M+H].
Figure imgf000098_0001
To the solution of compound (60mg) from Example 110 in methanol ImI was added 14μl hydrazine. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by HPLC to give desired product. MS (ESI): m/z = 722.47 [M+H]
13C (CD3OD): 5174.1, 172.9, 170.5, 156.7, 153.5, 141.8, 140.5, 135.2, 130.2, 129.1, 128.3, 127.9, 121.6, 119.9, 119.8, 82.9, 79.1, 60.0, 58.2, 53.3, 39.1, 34.2, 30.8, 30.5, 27.3, 23.0, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
Example 112. Compound of formula C, wherein Rx °V 'Y w=
Figure imgf000098_0002
Step 112a
To a flask containing the compound from Example 111 (25mg) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 622.37 [M+H].
Step 112b To the solution of the compound from step 112a in 2ml DCM was added DIEA
(0.175mmol) and isobutylchloroformate (lOμl). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 122 Al [M+H]. 13C(CD3OD): 5174.1, 172.8, 170.5, 157.6, 153.6, 141.7, 140.5, 135.2, 131.3, 130.3, 129.3, 128.2, 127.9, 121.6, 119.9, 82.9, 70.9, 59.9, 58.7, 53.3, 39.1, 34.1, 30.8, 30.4, 27.9, 22.9, 19.4, 18.6, 18.0, 17.8, 12.7, 5.5, 5.0. Λ.>Yw
Figure imgf000099_0001
Step 113a
To a flask containing the compound from step 11Oh of Example 110 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 620.31 [M+H].
Step 113b To the solution of the compound from step 113a in 2ml DCM was added DIEA and cyclopentylchloro formate. The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 732.31 [M+H].
13C(CDCB): 5173.1, 172.6, 168.8, 156.5, 153.6, 141.6, 140.3, 135.2, 132.6, 131.2, 130.3, 130.2, 129.3, 128.3, 128.0, 121.9, 119.9, 119.8, 118.4, 82.4, 77.8, 60.1, 58.1, 53.1, 50.7, 41.4, 35.3, 34.1, 32.7, 32.4, 31.1, 30.7, 23.6, 19.3, 18.0, 6.3, 5.9.
Figure imgf000099_0002
To the solution of compound (20mg) from Example 110 in methanol ImI was added 8μl hydrazine. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by HPLC to give desired product. MS (ESI): m/z = 734.43 [M+H]
13C (CD3OD): 5174.1, 172.9, 170.5, 157.4, 153.6, 141.7, 140.5, 135.3, 131.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.8, 82.9, 77.7, 59.9, 58.6, 53.3, 39.1, 34.2, 32.4, 32.3, 30.8, 30.4, 23.2, 22.9, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
Example 115. Compound of formula C, wherein Rx = Boc, L= I , W=
o,,o -!- . n=l. Z= CH=CH7 and G = H V:
To a solution of the compound from Step HOg (0.08mmol) of Example 110 in acetonitrile (2ml) was added Boc-Ile-OH (29mg), HATU (50mg) and DIEA (84μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 734.44 [M+H].
Figure imgf000100_0001
Step 116a
To a flask containing the compound from Example 115 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 634.34 [M+H].
Step 116b
To the solution of the compound from step 116a in 2ml DCM was added DIEA and cyclopentylchloro formate. The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 746.31 [M+H].
13C(CDCB): 5171.4, 171.0, 166.9, 154.6, 151.7, 139.7, 138.4, 133.3, 130.5, 129.4, 128.4, 128.3, 127.5, 126.5, 126.1, 120.0, 117.9, 116.7, 80.5, 76.1, 58.3, 55.2, 51.3, 39.6, 35.0, 33.4, 32.2, 30.8, 30.5, 29.2, 22.6, 21.7, 21.6, 13.3, 8.9, 4.4, 4.0.
Example 117. Compound of formula C, wherein Rx = Boc, L= v»>, W=
Figure imgf000101_0001
To a solution of the compound from Step HOg (0.08mmol) in acetonitrile (2ml) was added Boc-Chg-OH (31mg), HATU (50mg) and DIEA (84μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 760.47 [M+H].
Figure imgf000101_0002
Step 118a
To a flask containing the compound from Example 117 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 660.26 [M+H].
Step 118b
To the solution of the compound from step 118a in 2ml DCM was added DIEA and cyclopentylchloro formate. The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCθ3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 772.26 [M+H].
13C(CDCB): 5173.0, 172.8, 168.7, 156.5, 153.6, 141.6, 140.3, 135.1, 132.5, 131.3, 130.2, 129.4, 128.4, 128.0, 121.9, 119.8, 118.5, 82.3, 78.0, 60.2, 57.5, 53.2, 41.4, 39.9, 35.2, 34.1, 32.8, 32.7, 32.5, 31.1, 29.4, 28.4, 26.0, 25.7, 25.6, 23.6, 6.5, 5.9.
Figure imgf000102_0001
To a solution of the compound from Step HOg (0.08mmol) in acetonitrile (2ml) was added Boc-Cha-OH (33mg), HATU (50mg) and DIEA (84μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification.
MS (ESI): m/z = 774.48 [M+H].
Figure imgf000102_0002
Step 120a
To a flask containing the compound from Example 119 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 674.37 [M+H]. Step 120b
To the solution of the compound from step 120a in 2ml DCM was added DIEA and cyclopentylchloro formate. The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCθ3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 786.35 [M+H].
13C(CDCB): 5174.4, 172.6, 168.5, 156.6, 153.8, 141.6, 140.3, 135.1, 132.4, 131.4, 130.3, 130.2, 129.4, 128.4, 128.0, 121.9, 119.9, 118.5, 82.5, 78.0, 60.2, 52.6, 50.6, 41.5, 39.5, 35.0, 33.9, 33.8, 32.8, 32.6, 32.2, 31.1, 26.3, 26.2, 25.9, 23.6, 6.4, 5.9, 1.8.
Figure imgf000103_0001
To a solution of compound from step 3b of Example 3 in DCM was added CDI. The reaction mixture was stirred at 4O0C for Ih and then added pyrrolidine- 1-sulfamide and DBU. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 763.28 [M+H].
Example 122. Compound of formula C, wherein Rx = ° / , L= r\ W=
Step 122a
To a flask containing the compound from Example 121 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification.
MS (ESI): m/z = 663.43 [M+H]. Step 122b
To the solution of the compound from step 122a in 2ml DCM was added DIEA (0.175mmol) and isobutylchloroformate (lOμl). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCCh, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 775.44 [M+H].
13C(CD3OD): 5172.9, 172.3, 167.9, 156.4, 153.5, 141.5, 140.3, 135.2, 131.2, 130.2, 130.1, 129.4, 128.4, 127.9, 121.9, 119.8, 118.3, 82.1, 77.8, 59.7, 59.1, 53.8, 48.7, 41.7, 35.5, 34.0, 32.8, 32.4, 26.5, 26.4, 26.2, 25.7, 23.6, 22.3.
Figure imgf000104_0001
To a solution of compound from step 3b of Example 3 in DCM was added CDI. The reaction mixture was stirred at 4O0C for Ih and then added thiophene-2-sulfonamide and DBU. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 776.22 [M+H].
Example 124. Compound of formula C, wherein Rx = / , L= I , W=
Figure imgf000104_0002
Step 124a To a flask containing the compound from Example 123 (0.08mmol) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 676.36 [M+H]. Step 124b
To the solution of the compound from step 124a in 2ml DCM was added DIEA (0.175mmol) and isobutylchloroformate (lOμl). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCCh, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 788.38 [M+H].
13C(CD3OD): δ 172.8, 172.3, 167.8, 156.4, 153.6, 141.5, 140.3, 139.2, 135.1, 134.9, 133.4, 132.1, 131.2, 130.2, 129.4, 128.4, 128.0, 126.8, 121.9,119.8, 118.4, 82.1, 77.8, 59.8, 59.1, 53.8, 41.7, 35.6, 34.0, 32.8, 32.4, 26.5, 26.2, 23.6, 22.5.
Example 125. Compound of formula C, wherein Rx = -*V 7 , LL^= V P\, W=
Figure imgf000105_0001
The title compound was prepared with compound from Example 123 with ethylchloro formate via the similar conditions described in Example 124. MS (ESI): m/z = 748.29 [M+H].
13C(CDCB): δ 173.0, 172.5, 167.9, 156.7, 153.7, 141.5, 140.3, 139.0, 135.1, 135.0, 133.5, 132.1, 131.3, 130.2, 129.4, 128.3, 128.0, 126.8, 121.8, 119.8, 118.4, 82.1, 77.2, 61.2, 59.9, 59.3, 58.6, 53.9, 50.7, 41.6, 35.6, 34.1, 16.5, 22.6, 18.1, 14.3.
Example 126. Compound of formula C, wherein Rx = H, L= r\ W=
Figure imgf000105_0002
o..o
AN* n=l. Z= CH=CH7 and G = H V
To a flask containing the compound from Example 14 (1.9g) was added 4N HCl/dioxane (20ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 634.29 [M+H]. Example 127. Compound of formula C, wherein Rx α, «V.L ,W=
Figure imgf000106_0001
To the solution of the compound from Example 126 (O.Oβlmmol) in 2ml DCM was added DIEA (64μl) and (R)-tetrahydro-furan-3-yl-chloroformate. The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 748.40 [M+H].
13C(CD3OD): δ 174.0, 171.8, 169.5, 156.9, 153.6, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 117.4, 82.8, 75.4, 72.6, 66.6, 59.8, 59.6, 54.1, 41.3, 35.1, 35.0, 34.8, 34.4, 32.6, 30.9, 25.8, 22.5, 5.5, 5.3.
Example 128. Compound of formula C, wherein Rx -<V^ P, W=
Figure imgf000106_0002
The title compound was prepared with compound from Example 126 with (S)- tetrahydro-furan-3-yl-chloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 748.39 [M+H].
13C(CDCB): 5172.8, 172.1, 168.5, 155.9, 153.5, 141.5, 140.2, 135.1, 132.5, 131.3, 130.2, 129.3, 128.3, 128.0, 121.9, 119.8, 118.6, 82.1, 75.5, 75.3, 66.8, 59.8, 59.2, 59.1, 53.9, 41.7, 41.6, 35.5, 35.4, 33.9, 32.4, 31.2, 26.4, 22.5, 6.2, 6.1.
Example 129. Compound of formula C, wherein Rx .OrV .w.
Figure imgf000106_0003
The title compound was prepared with compound from Example 126 with 1- pyrrolidinecarbonyl chloride via the similar conditions described in Example 127. MS (ESI): m/z = 731.28 [M+H]. 13C(CD3OD): δ 173.9, 172.7, 169.6, 157.5, 153.6, 141.7, 140.5, 135.2, 133.1,
131.3, 130.3, 130.2, 129.3, 128.2, 127.9, 121.6, 119.9, 117.3, 82.8, 60.2, 58.5, 54.0, 45.3, 41.2, 35.4, 35.0, 34.4, 31.0, 26.0, 25.1, 22.8, 5.6, 5.3.
Figure imgf000107_0001
The title compound was prepared with compound from Example 126 with 4- morpholinecarbonyl chloride via the similar conditions described in Example 127.
MS (ESI): m/z = 747.41 [M+H].
13C(CD3OD): δ 173.9, 172.6, 169.6, 158.4, 153.6, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.2, 127.9, 121.6, 119.9, 117.3, 82.8, 66.3, 60.1, 58.9,
54.0, 44.1, 41.2, 35.3, 34.9, 34.3, 31.0, 26.0, 22.8, 5.6, 5.3.
Example 131. Compound of formula C, wherein Rx = ° / , L= P, W=
Figure imgf000107_0002
To a solution of compound from step 3b of Example 3 in DCM was added CDI. The reaction mixture was stirred at 4O0C for Ih and then added azitidine-1-sulfamide and DBU. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 749.23 [M+H]. Example 132. Compound of formula C, wherein Rx = C / λ< w=
Figure imgf000108_0001
The title compound was prepared with compound from Example 126 with N-(2- imidazol-l-yl-ethoxycarbonyloxy)succinimide via the similar conditions described in Example 127. MS (ESI): m/z = 772.26 [M+H].
13C(CD3OD): δ 173.9, 171.8, 169.5, 159.7, 156.3, 153.5, 141.7, 140.4, 135.7, 135.2, 133.1, 130.3, 130.2, 129.3, 128.2, 128.0, 122.6, 121.6, 119.9, 119.8, 117.4, 82.8, 62.5, 60.0, 54.1, 53.9, 48.6, 48.4, 41.2, 35.0, 34.8, 34.3, 30.9, 25.8, 22.6, 5.6, 5.3.
Example 133. Compound of formula C, wherein Rx = OJy S-< w__
Figure imgf000108_0002
Step 133a
To a solution of N-Boc-cis-4-hydroxyl-L-proline methylester (5g) in DCM 20ml was added DIEA 10.65ml and methanesulfonyl chloride 2.4ml at O0C. The resulting reaction mixture was stirred at O0C for 3hrs. 100 mL EtOAc was then added and followed by washing with 5% citric acid 2x20 ml, water 1x20 ml, IM NaHCO3 2x20 ml and brine 1x20 ml, respectively. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated, yielding the title compound mesylate (6.7g) that was used for next step synthesis without further purification. MS (ESI): m/z = 224.11 [M+H].
Step 133b
To a solution of the mesylate from step 133a (lOmmol) in 30 mL DMF, was added 2.93g of 9-Fluorenone oxime and anhydrous cesium carbonate (9.77g). The resulting reaction mixture was stirred vigorously at 5O0C for 12 hours. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCθ3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 3.0 of desired product. MS (ESI): m/z = 423.35 [M+H].
Step 133c
To a flask containing the compound from Example 133b (200mg) was added 4N HCl/dioxane (8ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification.
MS (ESI): m/z = 323.15 [M+H].
Step 133d
To a solution of the compound from Step 133c (0.474mmol) in acetonitrile (5ml) was added Boc-Tle-OH (220mg), HATU (360mg) and DIEA (412μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 536.20 [M+H].
Step 133e
The compound from step 133d was hydro lyzed with LiOH in THF/MeOH/H2O (2:1 :1) overnight. The reaction mixture was acidified with IN HCl, extracted with 5 mL EtOAc, and washed with brine 2x1 ml. The organic phase was dried over anhydrous Na2SO4 and then evaporated to give desired acid without further purification. MS (ESI): m/z = 522.15 [M+H].
Step 133f
To a solution of the compound from Step 133e (50mg) in DCM (2ml) was added methyl 1-amino-cyclopropanecarboxylate hydrochloride (30mg), EDCHCl (37mg) and DIEA (84μl) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCCh, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 619.31 [M+H].
Step 133g
The solution of the compound from step 133f in 4NHCl/dioxane (5ml) was stirred at room temperature for Ih. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (2ml). To this solution was added cyclopentylchloroformate (83μl) and DIEA (87μl). The reaction mixture was stirred at room temperature for Ih. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was hydrolyzed with INLiOH in THF/MeOH overnight. The reaction mixture was acidified with IN HCl, extracted with 3 mL EtOAc, and washed with brine 2x1 ml. The organic phase was dried over anhydrous Na2SO4 and then evaporated to give desired acid without further purification. MS (ESI): m/z = 617.32 [M+H].
Step 133h
To a solution of compound from step 133g in DCM was added CDI. The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide and DBU. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 720.31 [M+H].
13C(CD3OD): δ 174.1, 172.5, 172.0, 157.3, 153.6, 141.1, 140.5, 135.2, 131.3, 130.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 82.8, 77.8, 60.1, 59.4, 54.0, 35.1, 34.6, 34.5, 34.3, 32.5, 32.3, 30.9, 25.8, 32.3, 18.4, 18.1, 5.4, 5.2.
Figure imgf000111_0001
Example 134. Compound of formula C, wherein Rx =Boc, L= I , W= o.,o A. s'
. n=0. Z= CH=CH7 and G = 1 Y Step 134a
To a solution of Boc-L-allylglicine lOOmg in DCM was added CDI 122mg. The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide 121mg and DBU 135μl. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatograph to give desired product. MS (ESI): m/z = 319.16 [M+H].
Step 134b
To a flask containing the compound from Example 134a (84.5mg) was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 219.07 [M+H].
Step 134c To a solution of the compound from Step 133e of Example 133 (50mg) in acetonitrile (5ml) was added the compound from step 134b (37mg), HATU (55mg) and DIEA (150μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 722.36 [M+H].
Example 135. Compound of formula C, wherein Rx = ° / , L= P, W=
Figure imgf000111_0002
V Step 135a
To a flask containing the compound from Example 134 was added 4N HCl/dioxane (5ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 622.28 [M+H].
Step 135b
The title compound was prepared with compound from step 135a with cyclopentylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 734.32 [M+H].
Example 136. Compound of formula C, wherein Rx .W-
Λ °sp
ONH7 . n=l. Z= CH=CH7 and G = H V;
Step 136a To a solution of D-β-vinyl cyclopropane amino acid (2.8g) in DCM (30ml) was added CDI (2.8g). The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide 2.98g and DBU 3.69ml. The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was added 4N HCl/dioxne. The reaction mixture was stirred at room temperature for Ih. The mixture was then concentrated to give desired product without further purification.
MS (ESI): m/z = 231.10 [M+H]. Step 136b
To a solution of N-Boc-cis-L-hydroxylproine (5.106g), N-hydroxylphthalamide
(3.75Ig) and PPh3 (5.9Ig) in 75ml THF was added DIAD (5.7ml) at O0C. The reaction mixture was stirred overnight at room temperature, and then was concentrated to remove THF (~5 ml), followed by the treatment with 38ml 4N HCL/dioxane. The reaction mixture was stirred at room temperature for ~lh (MS showed the reaction was complete), and was concentrated to ~5ml. To the residue, ~ 50 ml (or more) of MTBE was charged. The HCl salt was precipitated and collected by filtration. The HCl salt was dissolved in 100ml CH3CN (to form a clear solution).
Ill To the solution, DIEA (~5eq), Boc-tLeu (8.907g) and HATU (~1.5eq) were added sequentially at O0C. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated and diluted with EtOAc. The organic solution was washed with 1% HCl, NaHCO3, brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography to give 8.5g of desired product. MS (ESI): m/z = 504.26 [M+H].
Step 136c
To a solution of the compound from step 136b (6.2g), in 37ml THF, 12ml MeOH and 12 ml H2O was added LiOH. H2O (1.65g). The reaction mixture was stirred at RT overnight and concentrated to remove organic solvents. The residue was diluted with brine, acidified with 6N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 6.8g of desired product. MS (ESI): m/z = 508.18 [M+H].
Step 136d
To a solution of the compound from step 136c (3.193g) in 100 ml CH3CN and
3.3ml DIEA was added HATU (2.714g). The resulted solution was stirred at RT for 3h. The compound from step 136a (1.9g), DIEA (3ml) and HATU (2.8g) was added. The reaction mixture was stirred at RT for 3h and concentrated to remove CH3CN (~5ml). The residue was diluted with brine, acidified with 6N HCl and extracted with EtOAc. The organic layer was washed with 1% HCl, NaHCO3, 1% HCl, brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography to give 3.552g desired product. MS (ESI): m/z = 702.31 [M+H].
Step 136e
2.552g of the compound from step 136d was dissolved in 10ml 4N HCl/dioxane. The resulting solution was stirred at RT for Ih and then concentrated. The residue was charged with MTBE. The precipitates were collected by filtration. To the solution of the precipitates in 28ml DCM was added DIEA (1.9ml) and cyclopentylchloroformate (2eq) at O0C. The reaction mixture was stirred for 30 min to 60min and diluted with EtOAc. The organic layer was washed with, NaHCO3, 1% HCl, brine, dried over Na2SO4, and concentrated to give 2.24g desired product. MS (ESI): m/z = 714.31 [M+H].
Step 136f
To a solution of the compound from stepl36e (2.24g) in 22ml DCM was added anhydrous hydrazine (5eq). The reaction mixture was stirred at RT for 30min and filtered. The filtration was diluted with CHCI3. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the desired product (1.56g). MS (ESI): m/z = 584.29 [M+H].
Example 137. Compound of formula C, wherein Rx ΞOJy
Figure imgf000114_0001
The mixture of the compound from Example 136 (0.07mmol), 2-biphenyl-carbox aldehyde (O.lmmol), HOAc (0.3mmol) and pyridine (O.lmmol) in MeOH (ImI) was stirred at RT. After the reaction was complete, the reaction mixture was concentrated and extracted with EtOAc. The organic layer was washed with,
NaHCO3, 1% HCl, brine, dried over Na2SO4, and concentrated. The crude product was purified by prep HPLC to give the desired compound.
MS (ESI): m/z = 748.41 [M+H].
13C(CD3OD): 5174.1, 171.6, 169.6, 157.4, 149.0, 142.5, 139.7, 133.1, 130.0, 129.8, 129.6, 129.5, 128.3, 127.5, 126.3, 117.3, 81.2, 77.8, 60.0, 59.3, 53.9, 41.2,
35.4, 34.9, 34.2, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 5.5, 5.3.
Example 138. Compound of formula C, wherein Rx = °*Vu
Figure imgf000114_0002
The title compound was prepared with compound from Example 136 with 1- naphthaldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 722.38 [M+H]. 13C(CD3OD): 5174.1, 171.6, 169.6, 157.4, 150.5, 134.2, 133.1, 130.7, 130.6, 128.6, 128.0, 127.9, 127.2, 126.1, 125.1, 124.6, 117.4, 81.3, 77.7, 60.2, 59.3, 54.1, 41.3, 35.4, 34.9, 34.5, 32.6, 32.4, 32.2, 31.0, 25.8, 23.2, 22.6, 5.6, 5.3.
Example 139. Compound of formula C, wherein Rx ΞOJy
Figure imgf000115_0001
The title compound was prepared with compound from Example 136 with 2- naphthaldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 722.40 [M+H].
13C(CD3OD): δ 174.1, 171.7, 169.6, 157.4, 150.4, 134.5, 133.4, 133.1, 130.0, 128.8, 128.3, 128.2, 127.7, 127.0, 126.5, 122.7, 117.4, 81.2, 77.7, 60.1, 59.3, 54.0, 41.3, 35.4, 34.9, 34.4, 32.4, 32.2, 31.0, 25.8, 23.2, 22.6, 5.6, 5.3.
Figure imgf000115_0002
The title compound was prepared with compound from Example 126 with isobutylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 734.37 [M+H].
13C(CD3OD): δ 174.0, 171.9, 169.5, 157.7, 153.6, 141.7, 140.5, 135.2, 133.1, 131.3, 130.3, 129.2, 128.2, 127.9, 121.6, 119.9, 117.4, 82.8, 71.0, 59.8, 59.5, 54.1, 41.3, 35.1, 34.8, 34.4, 30.9, 27.9, 25.8, 22.5, 18.0, 5.5, 5.3.
Example 141. Compound of formula C, wherein Rx = H / , L= T", W=
Figure imgf000115_0003
The title compound was prepared with compound from Example 126 with t-butyl isocynate via the similar conditions described in Example 127. MS (ESI): m/z = 733.37 [M+H].
13C(CD3OD): 5174.1, 172.9, 169.6, 158.2, 153.5, 141.8, 140.5, 135.2, 133.1, 131.2, 130.2, 129.2, 128.3, 127.9, 121.6, 119.8, 117.3, 82.9, 59.8, 57.7, 53.9, 49.4, 41.3, 35.2, 34.8, 34.6, 30.9, 28.4, 25.9, 22.5, 5.5, 5.3.
Example 142.
Figure imgf000116_0001
Figure imgf000116_0002
To the solution of the compound from Example 126 in methanol was added cyclopentane carboxaldehyde, HOAc and NaBH3CN. After the reaction was complete, the reaction mixture was concentrated and extracted with EtOAc. The organic layer was washed with, NaHCO3, 1% HCl, brine, dried over Na2SO4, and concentrated. The crude product was purified by prep HPLC to give the desired compound.
MS (ESI): m/z = 716.38 [M+H].
13C(CD3OD): 5173.2, 169.1, 167.0, 153.7, 142.0, 140.6, 134.9, 132.9, 131.9, 130.7, 130.0, 128.9, 128.3, 128.1, 121.6,1 20.3, 120.2, 117.6, 82.7, 66.8, 60.8, 54.6,
53.4, 41.4, 35.6, 35.3, 34.4, 34.0, 30.9, 30.0, 25.6, 25.5, 24.4, 22.1, 5.6, 5.5.
Figure imgf000116_0003
The title compound was prepared with compound from Example 126 with 2- thiophenesulfonyl chloride via the similar conditions described in Example 127. MS (ESI): m/z = 780.23 [M+H].
13C(CD3OD): 5173.6, 170.7, 169.5, 153.6, 141.9, 141.8, 140.5, 135.2, 133.1, 131.6, 131.5, 130.5, 130.3, 129.7, 128.4, 128.1, 126.9, 121.6, 120.0, 117.4, 82.9, 62.0, 60.2, 53.9, 41.2, 35.9, 34.8, 34.1, 31.0, 26.0, 22.7, 5.6, 5.3. LvVrV
Example 144. Compound of formula C, wherein Rx = O .1,Vw-
Figure imgf000117_0001
To a solution of the compound from Examplel26 (0.0272mmol) in acetonitrile (2ml) was added Boc-Chg-OH (8.5mg), HATU (13.5mg) and DIEA (18μl) at O0C. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was added 4NHCl/dioxane. The reaction mixture was concentrated after Ih. The residue was dissolved in DCM. To this solution were added EDCHCl, HOBt and DIEA. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by hPLC to give the deired product. MS (ESI): m/z = 879.39 [M+H]. 13C(CD3OD): δ 173.8, 171.7, 171.0, 169.6, 163.5, 153.4, 147.6, 147.5, 143.6,
143.5, 141.8, 140.5, 135.2, 133.1, 131.3, 130.3, 130.2, 129.4, 128.5, 127.9, 121.7, 119.9, 117.4, 82.8, 59.8, 57.8, 57.7, 54.0, 41.2, 40.8, 35.3, 34.9, 34.3, 31.0, 29.4, 28.7, 26.0, 25.8, 25.5, 25.4, 22.6, 5.6, 5.3.
Example 145. Compound of formula C, wherein Rx = ^^ f „ L= P, W=
Figure imgf000117_0002
:
The title compound was prepared with compound from Example 126 with 3,3- dimethylbutyraldehyde via the similar conditions described in Example 142.
MS (ESI): m/z = 718.45 [M+H].
13C(CD3OD): 5173.2, 169.1, 167.0, 153.8, 142.1, 140.7, 134.9, 132.9, 131.8, 130.6, 130.1, 129.0, 128.3, 128.0, 121.6, 120.2, 120.1, 117.6, 82.7, 67.0, 60.8, 54.6,
45.0, 41.1, 38.4, 35.2, 34.4, 34.1, 30.9, 28.7, 27.6, 25.7, 22.2, 5.6, 5.5. Example 146. Compound of formula C, wherein Rx -Cr-Yi . w-
Figure imgf000118_0001
The title compound was prepared with compound from Example 126 with cyclopentanemethylchloroformate via the similar conditions described in Example
127.
MS (ESI): m/z = 760.42 [M+H].
13C(CD3OD): 5174.0, 172.0, 169.5, 157.8, 153.6,1 41.7, 140.5, 135.2, 133.1,
131.3, 130.3, 129.2, 128.2, 127.9, 121.6, 119.9, 117.4, 82.8, 68.9, 59.8, 59.5, 54.1,
41.3, 38.9, 35.1, 35.0, 34.8, 34.4, 30.9, 28.9, 25.8, 24.9, 22.5, 5.5, 5.3.
Figure imgf000118_0002
The title compound was prepared with compound from Example 126 with cyclobutanemethylchloroformate via the similar conditions described in Example 127.
MS (ESI): m/z = 746.40 [M+H].
13C(CD3OD): 5174.0, 172.0, 169.5, 157.8, 153.6, 141.7, 140.5, 135.2, 133.1, 130.3, 129.2, 128.2, 127.9, 121.6, 119.9, 117.4, 82.8, 68.7, 59.8, 59.6, 54.1, 47.0, 41.3, 35.1, 34.8, 34.4, 30.9, 25.8, 24.3, 22.5, 17.9, 5.5, 5.3.
Example 148. Compound of formula C, wherein Rx = \ , L= T^, W=
- o!--'N
Figure imgf000118_0003
The title compound was prepared with compound from Example 126 with isopropoxy-acetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 720.41 [M+H]. Example 149.
Figure imgf000119_0001
Figure imgf000119_0002
V:
The title compound was prepared with compound from Example 126 with phenylacetaldehyde via the similar conditions described in Example 142.
MS (ESI): m/z = 738.47 [M+H].
13C(CD3OD): 5173.3, 169.1, 166.9, 153.9, 141.9, 140.7, 135.4, 134.9, 132.9,1
31.6, 130.4, 129.9, 128.6, 128.4, 128.0, 127.8, 127.7, 126.8, 121.3, 120.2, 120.1,
117.6, 82.6, 66.4, 60.9, 54.6, 49.0, 41.5, 35.4, 34.3, 31.3, 30.9, 25.6, 22.1, 5.6, 5.5.
Figure imgf000119_0003
Example 150. Compound of formula C, wherein Rx = ^"
Figure imgf000119_0004
The title compound was prepared with compound from Example 126 with 3- phenylpropionaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 752.47 [M+H].
13C(CD3OD): δ 173.3, 169.1, 166.9, 153.8, 142.1, 140.6, 139.6, 134.9, 132.9, 132.0, 130.8, 128.9, 128.4, 128.2, 127.8, 126.0, 121.6, 120.5, 120.4, 117.6, 82.7, 66.7, 60.8, 54.8, 41.5, 35.1, 34.3, 34.2, 31.6, 30.9, 26.8, 25.6, 22.1, 5.6, 5.5.
Figure imgf000119_0005
Example 151. Compound of formula C, wherein Rx =
Figure imgf000119_0006
:
The title compound was prepared with compound from Example 126 with phenylglyoxal monohydrate via the similar conditions described in Example 142. MS (ESI): m/z = 752.45 [M+H]. Example 152. Compound of formula C, wherein Rx = ^V 7 ,. L L== ^ F\. W=
Figure imgf000120_0001
The title compound was prepared with compound from Example 126 with Cyclopentyl-acetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 730.48 [M+H].
13C(CD3OD): 5173.2, 169.1, 166.9, 153.7, 142.0, 140.6, 134.9, 132.9, 131.9, 130.7, 130.0, 128.9, 128.3, 128.1, 121.6, 120.3, 120.2, 117.6, 82.7, 66.6, 60.8, 54.7, 41.4, 37.1, 35.1, 34.4, 34.2, 32.0, 31.7, 31.3, 30.9, 25.6, 24.3, 22.1, 5.6, 5.5.
Figure imgf000120_0002
The title compound was prepared with compound from Example 136 with 3a-Aza- cyclopenta[a]inden-8-one via the similar conditions described in Example 137. MS (ESI): m/z = 735.45 [M+H].
Example 154. Compound of formula C, wherein Rx = ^ L= ^. W=
Figure imgf000120_0003
V,:
The title compound was prepared with compound from Example 126 with 3,3,3- Trifluoro-propionaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 730.35 [M+H].
13C(CD3OD): 5173.2, 169.0, 166.5, 153.9, 142.0, 140.7, 134.9, 132.9, 131.7, 130.5, 130.0, 128.7, 127.9,1 21.4, 120.1, 120.0, 117.6, 82.7, 67.4, 60.6, 54.5, 41.5, 40.8, 35.3, 34.2, 30.9, 30.0, 29.8, 25.8, 25.7, 22.0, 5.5, 5.5.
Example 155. Compound of formula C, wherein Rx = o , L= F\ W=
Figure imgf000120_0004
The title compound was prepared with compound from Example 126 with 1-Bromo- 3,3-dimethyl-butan-2-one via the similar conditions described in Example 142. MS (ESI): m/z = 732.45 [M+H]. 13C(CD3OD): 5207.0, 173.1, 169.1, 166.7, 153.8, 142.0, 140.6, 135.0, 132.9,
131.8, 130.7, 130.1, 129.1, 128.3, 128.1, 121.6, 120.2, 117.5, 82.9, 67.2, 61.1, 54.8, 50.6, 42.7, 41.4, 35.8, 34.4, 34.3, 30.9, 25.6, 24.9, 24.5, 22.3, 5.5, 5.5.
Example 156. Compound of formula C, wherein Rx = o , L= P, W=
Figure imgf000121_0001
The title compound was prepared with compound from Example 126 with glyoxylic acid via the similar conditions described in Example 142. MS (ESI): m/z = 692.41 [M+H].
Example 157. Compound of formula C, wherein Rx = '" i o , L= P, W=
Figure imgf000121_0002
The title compound was prepared with compound from Example 126 with glyoxylic acid via the similar conditions described in Example 142.
MS (ESI): m/z = 747.46 [M+H].
13C(CD3OD): 5173.1, 169.2, 166.8, 163.4, 153.7, 141.9, 140.6, 135.0, 132.9,
131.7, 130.6, 130.1, 129.1, 128.3, 128.1, 121.6, 120.2, 120.1, 117.5, 82.9, 67.0, 61.0, 54.8, 51.2, 41.4, 35.6, 34.5, 34.4, 30.9, 27.2, 25.6, 22.3, 5.6, 5.5.
Figure imgf000121_0003
Example 158. Compound of formula C, wherein Rx =
Figure imgf000121_0004
;
The title compound was prepared with compound from Example 126 with 2- fluorophenylacetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 756.43 [M+H]. 13C(CD3OD): 5173.3, 169.1, 166.9, 163.7, 161.8, 153.8, 141.9, 140.6, 138.0, 134.8, 132.9, 131.6, 130.5, 130.1, 129.8, 128.5, 127.9, 127.8, 123.5, 121.3, 120.2, 117.6, 116.8, 114.7, 114.5, 113.8, 113.6, 82.6, 66.5, 60.9, 54.6, 48.7, 41.5, 35.5, 34.3, 34.2, 30.9, 30.8, 25.6, 22.1, 5.6, 5.5.
Example 159.
Figure imgf000122_0001
Figure imgf000122_0002
The title compound was prepared with compound from Example 126 with 3- fluorophenylacetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 756.43 [M+H].
13C(CD3OD): 5173.3, 169.1, 166.9, 163.7, 161.8, 153.8, 141.9, 140.6, 138.0, 134.8, 132.9, 131.6, 130.5, 130.1, 129.8, 128.5, 127.9, 127.8, 123.5, 121.3, 120.2, 117.6, 116.8, 114.7, 114.5, 113.8, 113.6, 82.6, 66.5, 60.9, 54.6, 48.7, 41.5, 35.5, 34.3, 34.2, 30.9, 30.8, 25.6, 22.1, 5.6, 5.5.
Figure imgf000122_0003
Example 160. Compound of formula C, wherein Rx =
o.o
-i- . n=l. Z= CH=CH7 and G = H V^
The title compound was prepared with compound from Example 126 with 4- fluorophenylacetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 756.43 [M+H].
13C(CD3OD): 5173.3, 169.1, 167.0, 162.5, 160.6, 153.8, 141.8, 140.6, 134.8, 132.9, 131.6, 131.2, 130.5, 129.9, 129.4, 129.3, 128.6, 128.0, 127.9, 121.3, 120.2, 120.1, 117.6, 116.8, 115.2, 115.0, 114.5, 82.6, 66.4, 60.9, 54.6, 48.9, 41.5, 35.4, 34.4, 34.2, 30.9, 30.3, 25.6, 22.1, 5.6, 5.5.
Example 161.
Figure imgf000122_0004
Figure imgf000122_0005
The title compound was prepared with compound from Example 126 with 1- Adamentane-aldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 782.48 [M+H].
13C(CD3OD): 5173.0, 169.1, 167.0, 153.8, 142.1, 140.6, 134.9, 132.9, 132.0, 130.7, 130.1, 129.0, 128.4, 128.1,1 21.7, 120.3, 120.1, 117.6, 82.6, 77.0, 72.8, 70.1, 69.5, 61.5, 60.8, 54.4, 41.4, 39.2, 39.1, 38.9, 38.6, 37.3, 37.2, 37.1, 37.0, 36.7, 36.6, 35.7, 35.3, 34.4, 33.9, 32.0, 30.9, 28.7, 28.5, 28.4, 28.3, 28.1, 27.9, 25.8, 25.7, 22.2, 5.6, 5.5.
Example 162.
Figure imgf000123_0001
Figure imgf000123_0002
The title compound was prepared with compound from Example 126 with 2-(l- naphthyl)-ethylaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 788.45 [M+H].
13C(CD3OD): 5173.3, 169.1, 167.1, 153.8, 141.5, 140.5, 134.7, 133.9, 132.9, 131.4, 131.2, 131.1, 130.2, 129.6, 128.7, 128.2, 127.8, 127.7, 127.6, 126.3, 126.1, 125.5, 125.0, 122.2, 121.1, 120.0, 119.9, 117.6, 82.6, 66.6, 60.8, 54.6, 41.5, 35.6, 34.3, 34.2, 30.9, 28.5, 25.7, 22.1, 5.65, 5.61.
Figure imgf000123_0003
Example 163. Compound of formula C, wherein Rx =
Figure imgf000123_0004
The title compound was prepared with compound from Example 126 with 2- naphthene-ethylaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 788.45 [M+H].
13C(CD3OD): 5173.3, 169.1, 167.0, 153.8, 141.5, 140.4, 134.6, 133.5, 132.9, 132.8, 132.5, 131.3, 130.2, 129.6, 128.3, 128.2, 127.7, 127.6, 125.9, 125.6, 125.5, 121.1, 119.9, 119.8, 117.6, 82.6, 66.4, 60.9, 54.6, 48.9, 41.5, 35.5, 34.3, 31.4, 30.9, 25.7, 22.1, 5.6, 5.5. Example 164. Compound of formula C, wherein Rx = °/ 7 ,. LL= F\. W=
Figure imgf000124_0001
The title compound was prepared with compound from Example 126 with cyclohexanone via the similar conditions described in Example 142.
MS (ESI): m/z = 716.40 [M+H].
13C(CD3OD): 5173.3, 169.1, 167.4, 153.8, 142.0, 140.5, 135.0, 132.9, 132.0,
130.7, 130.1, 128.9, 128.4, 128.1, 121.6, 120.3, 120.1, 117.6, 82.9, 63.7, 61.2, 59.1,
55.0, 41.4, 35.4, 34.4, 33.9, 30.9, 28.9, 28.0, 25.4, 24.2, 24.0, 23.9, 22.2, 5.6, 5.5.
Example 165. Compound of formula C, wherein Rx - ^i .l .w-
Figure imgf000124_0002
The title compound was prepared with compound from Example 126 with 1- adamantane-ethylaldehyde via the similar conditions described in Example 142.
MS (ESI): m/z = 796.50 [M+H].
13C(CD3OD): 5173.2, 169.1, 166.9, 153.8, 142.1, 140.7, 135.0, 132.9, 131.8, 130.6, 130.1, 129.0, 128.3, 128.0, 121.5, 120.3, 120.2, 117.6, 82.7, 66.4, 61.0, 54.7,
43.4, 42.3, 41.5, 38.8, 36.7, 36.3, 35.3, 34.4, 34.3, 31.3, 30.9, 28.8, 28.3, 25.6, 22.2,
5.6, 5.5.
Example 166. Compound of formula C, wherein Rx -l&y. .w-
Figure imgf000124_0003
The title compound was prepared with compound from Example 126 with 2- adamantanone via the similar conditions described in Example 142. MS (ESI): m/z = 768.45 [M+H].
13C(CD3OD): 5172.9, 169.1, 167.7, 153.9, 142.1, 140.5, 134.9, 132.9, 132.0, 130.7, 130.1, 129.1, 128.4, 128.1, 121.6, 120.3, 120.1,1 17.6,8 3.0, 74.1, 67.3, 66.6, 61.6, 54.8, 41.3, 37.6, 36.4, 36.3, 36.2, 36.1, 35.9, 34.6, 34.5, 33.6, 31.0, 30.9, 29.8, 29.5, 29.1, 27.9, 27.4, 26.5, 26.4, 25.3, 22.4, 5.6, 5.5.
Example 167. Compound of formula C, wherein Rx =
Figure imgf000125_0001
CF3 , L= P*, W=
Figure imgf000125_0002
The title compound was prepared with compound from Example 126 with 2- trifluoromethylphenylacetaldehyde via the similar conditions described in Example 142.
MS (ESI): m/z = 806.44 [M+H].
13C(CD3OD): 5173, 169.1, 166.9, 156.9, 153.8, 141.8, 140.6, 134.8, 132.9, 131.6, 130.4, 129.9, 129.6, 128.6, 128.0, 127.8, 123.4, 121.3, 120.5, 120.2, 120.1, 117.6, 110.2, 82.6, 66.4, 60.8, 54.5, 54.4, 41.5, 35.4, 34.4, 34.3, 30.9, 26.6, 25.6, 22.2, 5.6, 5.5.
Example 168. Compound of formula C, wherein Rx =
Figure imgf000125_0003
, L= P, W=
Figure imgf000125_0004
The title compound was prepared with compound from Example 126 with 2- methoxyphenylacetaldehyde via the similar conditions described in Example 142. MS (ESI): m/z = 768.46 [M+H].
13C(CD3OD): 5173.3, 169.1, 166.9, 156.9, 153.8, 141.8, 140.6, 134.8, 132.9, 131.6, 130.4, 129.9, 129.6, 128.6, 128.0, 127.8, 123.4, 121.3, 120.5, 120.2, 120.1, 117.6, 110.2, 82.6, 66.4, 60.8, 54.5, 54.4, 41.5, 35.4, 34.4, 34.3, 30.9, 26.6, 25.6, 22.2, 5.6, 5.5.
Example 169. Compound of formula C, wherein Rx ΞOJy
Figure imgf000125_0005
The title compound was prepared with compound from Example 136 with T- fluorobiphenyl-2-aldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 766.43 [M+H].
13C(CD3OD): 5174.0, 171.6, 169.5, 160.6, 158.7, 157.4, 148.4, 136.0, 133.1, 131.9, 130.6, 130.3, 130.1, 130.0, 129.8, 128.2, 127.2, 126.0, 124.4, 117.3, 115.6, 115.4, 81.3, 77.8, 60.0, 59.3, 53.8, 41.2, 35.4, 34.9, 34.2, 32.5, 32.4, 30.9, 25.8, 23.3, 22.6, 5.6, 5.3.
Example 170. Compound of formula C, wherein Rx = °*Vu
Figure imgf000126_0001
The title compound was prepared with compound from Example 136 with 3'- fluorobiphenyl-2-aldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 766.43 [M+H].
13C(CD3OD): 5174.1, 171.7, 169.5, 163.8, 161.8, 157.4, 148.6, 142.1, 142.0, 141.0, 133.1, 130.1, 129.9, 129.5, 128.0, 126.5,125.6, 117.3, 116.3, 116.2, 114.3, 114.2, 81.3, 77.8, 60.0, 59.3, 53.9, 41.2, 35.4, 34.9, 34.2, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 5.5, 5.3.
Example 171. Compound of formula C, wherein Rx = °»Vu
Figure imgf000126_0002
The title compound was prepared with compound from Example 136 with 4'- fluorobiphenyl-2-aldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 766.43 [M+H].
13C(CD3OD): 5174.0, 171.6, 169.5, 163.6, 161.7, 157.4,1 48.9, 141.3, 135.9, 133.1, 131.5, 131.4, 130.1, 129.9, 129.6, 127.7, 126.5, 117.3, 115.1, 115.0, 81.2, 77.8, 60.0, 59.3, 53.9, 41.2, 35.4, 34.9, 34.2, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 5.5, 5.3. Example 172. Compound of formula C, wherein Rx S>J/
Figure imgf000127_0001
The title compound was prepared with compound from Example 136 with T- methoxybiphenyl-2-aldehyde via the similar conditions described in Example 137.
MS (ESI): m/z = 778.43 [M+H].
13C(CD3OD): 5174.0, 171.6, 169.6, 157.4, 156.7, 149.3, 139.2, 133.1, 131.1,
130.6, 130.3, 129.6, 129.5, 128.4, 127.3, 125.2, 120.6, 117.3, 111.0, 81.0, 77.9,
60.0, 59.3, 54.8, 53.9, 41.2, 35.5, 34.9, 34.2, 32.6, 32.5, 32.4, 30.9, 25.8, 23.3, 22.6,
5.5, 5.3.
Example 173. Compound of formula C, wherein Rx ΞOJy
Figure imgf000127_0002
The title compound was prepared with compound from Example 136 with 3'- methoxybiphenyl-2-aldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 778.42 [M+H].
Example 174. Compound of formula C, wherein Rx = ° / , L= l \
Figure imgf000127_0003
= H V . The title compound was prepared with compound from Example 136 with 4'- methoxybiphenyl-2-aldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 778.43 [M+H]. 13C(CD3OD): 5174.1, 171.7, 169.6, 159.6, 157.4, 149.4, 142.2, 133.1, 131.8, 130.7, 130.1, 129.8, 129.5, 127.1, 126.3, 117.4, 116.5, 114.2, 113.7, 81.1, 77.8, 60.0, 59.3, 54.6, 53.9, 41.2, 35.4, 34.9, 34.2, 32.5, 32.3, 31.0, 25.8, 23.3, 22.6, 5.6, 5.3. Example 175. Compound of formula C, wherein Rx S>J/
Figure imgf000128_0001
The title compound was prepared with compound from Example 136 with 2- pyridine-3-yl-benzaldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 749.25 [M+H].
Example 176. Compound of formula C, wherein Rx = ° / , L= T\
W=
Figure imgf000128_0002
. n=l. Z= CH=CH2 and G = "H' V^
The title compound was prepared with compound from Example 136 with 2- pyrimidine-3-yl-benzaldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 750.38 [M+H].
Figure imgf000128_0003
Example 177. Compound of formula C, wherein Rx =
M °.P
W≡-!- . n=l. Z= CH=CH2 and G = ^ V^
The title compound was prepared with compound from Example 136 with 4-chloro- 2-(l-pyrolidino)-5-thiazolecarboxyaldehyde via the similar conditions described in Example 137.
MS (ESI): m/z = 782.38,784.38 [M+H].
Example 178. Compound of formula C, wherein Rx = °*Vu
Figure imgf000128_0004
The title compound was prepared with compound from Example 136 with 2- phenylindol-3-carboxyaldehyde via the similar conditions described in Example
137. MS (ESI): m/z = 787.42 [M+H].
Example 179. Compound of formula C, wherein Rx JUy
Figure imgf000129_0001
The title compound was prepared with compound from Example 136 with 1-methyl- 5-imidazole-carboxaldehyde via the similar conditions described in Example 137. MS (ESI): m/z = 676.38 [M+H].
Example 180. Compound of formula C, wherein Rx = °*Vu
Figure imgf000129_0002
The title compound was prepared with compound from Example 136 with 1- acetonaphthone via the similar conditions described in Example 137. MS (ESI): m/z = 736.41 [M+H].
Example 181.
Figure imgf000129_0003
Figure imgf000129_0004
The title compound was prepared with compound from step 113a of Example 113 with t-butylisocynate via the similar conditions described in Example 127. MS (ESI): m/z = 719.41 [M+H].
13C(CD3OD): 5174.2, 173.5, 169.6, 158.4,1 53.5, 141.7, 140.5, 135.2, 133.0, 131.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 117.4, 83.0, 59.6, 59.8, 53.3, 49.5, 41.3, 34.5, 34.3, 30.9, 28.4, 22.9, 18.7,17.6, 5.5, 5.2.
Example 182. Compound of formula C, wherein Rx = H / , L= T , W=
Figure imgf000129_0005
. The title compound was prepared with compound from step 113a of Example 113 with cyclopentyllisocynate via the similar conditions described in Example 127. MS (ESI): m/z = 731.42 [M+H].
13C(CD3OD): 5174.1, 173.5, 169.6, 158.9, 153.5, 141.7, 140.5, 135.2, 133.0, 131.3, 130.2, 129.3, 128.3, 127.9, 121.6, 119.9, 117.3, 83.0, 59.9, 57.1, 53.1, 51.7, 41.3, 34.5, 34.2, 33.0, 32.8, 30.9, 30.8, 23.3, 22.9, 18.7, 17.6, 5.5, 5.2.
Example 183.
Figure imgf000130_0001
Figure imgf000130_0002
The title compound was prepared with compound from step 113a of Example 113 via the similar conditions described in Example 144. MS (ESI): m/z = 865.48 [M+H]. 13C(CD3OD): 5173.9, 171.9, 171.5, 169.6, 163.5, 147.6,1 44.5, 143.6, 143.5,1
41.8, 140.5, 135.3, 133.0, 131.4, 130.3, 129.4, 128.5, 127.9, 121.7, 119.9, 117.4,
82.9, 59.9, 58.0, 56.9, 53.2, 41.2, 40.8, 34.5, 34.1, 30.9, 30.5, 29.5, 28.6, 25.9, 25.5, 23.0, 18.5, 17.9, 5.6, 5.2.
Example 184. Compound of formula C, wherein Rx ■ /. .W
Figure imgf000130_0003
The title compound was prepared with compound from step 113a of Example 113 with isobutylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 720.38 [M+H].
13C(CD3OD): 5174.1, 172.9, 169.6, 157.6, 153.6, 141.7, 140.5, 135.3, 133.0, 131.3, 130.3, 129.3, 128.3,1 27.9, 121.6, 119.9, 117.4, 82.9, 70.9, 60.0, 58.7, 53.3, 41.2, 34.5, 34.2, 30.9, 30.4, 27.9, 23.0, 18.6, 18.0, 17.8, 5.5, 5.2.
Figure imgf000131_0001
Example 185. Compound of formula C, wherein Rx . . >
Figure imgf000131_0002
:
The title compound was prepared with compound from step 113a of Example 113 with cyclobutylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 718.36 [M+H].
13C(CD3OD): 5174.1, 172.8, 169.6, 156.7, 153.6, 141.7, 140.5, 135.3, 133.0, 131.3, 130.3, 129.2, 128.3,1 27.9, 121.6, 119.9, 117.4, 82.9, 69.0, 60.0, 58.6, 53.3, 41.2, 34.5, 34.2, 30.9, 30.4, 30.3, 29.7, 23.0, 18.6, 17.8, 12.7, 5.5, 5.2.
Figure imgf000131_0003
The title compound was prepared with compound of Example 184 with via the similar conditions described in Example 114.
MS (ESI): m/z = 720.31 [M+H].
13C(CD3OD): δ 174.1, 172.8, 170.5, 156.8, 153.6, 141.7, 140.5, 135.3, 131.3, 130.3, 129.2, 128.3, 127.9, 121.6, 119.8, 82.9, 69.0, 59.9, 58.6, 53.3, 39.1, 34.2,
34.1, 30.8, 30.4, 30.2, 29.7, 22.9, 19.4, 18.6, 17.8, 12.7, 12.6, 5.5, 5.0.
Example 187. Compound of formula C, wherein Rx = (XnX /y , L= A< I , W=
Figure imgf000131_0004
^
The title compound was prepared with compound from Example 136 with 6- methoxychromanone via the similar conditions described in Example 137. Two isomers were separated by HPLC. Pl : MS (ESI): m/z = 744.48 [M+H]. P2: MS (ESI): m/z = 744.48 [M+H]. 13C(CD3OD): 5174.1, 171.7, 169.6, 157.4, 154.3, 151.5, 150.7, 133.1, 119.2, 118.4, 118.3, 117.4, 106.4, 81.2,7 7.8, 64.9, 60.3, 59.3, 55.0, 54.2, 41.3, 35.3, 34.9, 34.5, 32.5, 32.4, 32.0, 25.8, 24.1, 23.3, 22.6, 5.6, 5.3.
Example 188.
Figure imgf000132_0001
Figure imgf000132_0002
The title compound was prepared with compound from step 11 Og of ExamplellO with Boc-Thr-OH via the similar conditions described in Example 115. MS (ESI): m/z = 122 Al [M+H].
Example 189. Compound of formula C, wherein Rx = / , L= I , W=
Figure imgf000132_0003
The title compound was prepared with compound of Example 188 with cyclopentylchloro formate via the similar conditions described in Example 116. MS (ESI): m/z = 734.33 [M+H]. 13C (CDC13): 5173.2, 171.7, 169.5, 157.9, 153.9, 141.7, 140.6, 135.3, 132.1, 131.3, 130.5, 130.4, 129.8, 128.9, 128.2, 122.2, 120.0, 119.4, 82.7, 78.3, 67.9, 60.2, 55.3, 52.8, 40.6, 36.3, 34.9, 32.9, 32.7, 31.1, 24.5, 23.8, 23.6, 18.2, 6.6, 6.1.
Example 190. Compound of formula C, wherein Rx = ^y 7 , L L== Y OH , W=
O..O
O'N A ΛNN''S^«V,
-!- . n=l. Z= CH=CH7 and G = H V: The title compound was prepared with compound from step 11 Og of ExamplellO with Boc-allo-Thr-OH via the similar conditions described in Example 115. MS (ESI): m/z = 722.42 [M+H].
Example 191. Compound of formula C, wherein Rx = (XnX /./ , L= z-γ OH , W=
Figure imgf000132_0004
The title compound was prepared with compound of Example 190 with cyclopentylchloro formate via the similar conditions described in Example 116. MS (ESI): m/z = 734.44 [M+H].
13C (CDC13): 5172.9, 172.2, 169.2, 156.6, 153.9, 141.8, 140.5, 135.3, 132.6, 131.5, 130.5, 129.6, 128.7, 128.2, 122.1, 120.1, 118.9, 82.3, 78.5, 69.7, 60.3, 56.4, 53.5, 41.1, 36.0, 34.7, 33.0, 32.7, 31.4, 24.5, 23.8, 23.7, 20.2, 6.5, 6.3.
Figure imgf000133_0001
O..O crN Λ ΛNN-'S"'V7
-!- . n=l. Z= CH=CH7 and G = H V^
The title compound was prepared with compound from step 11 Og of ExamplellO with Boc-(S)-2-amino-3-hydroxy-3 -methyl butanoic acid via the similar conditions described in Example 115. MS (ESI): m/z = 736.41 [M+H].
Example 193. Compound of formula C, wherein Rx = ° / , L= I OH, W=
Figure imgf000133_0002
The title compound was prepared with compound of Example 192 with cyclopentylchloro formate via the similar conditions described in Example 116. MS (ESI): m/z = 748.36 [M+H].
13C (CDC13): 5172.4, 169.3, 157.1, 153.9, 148.5, 141.7, 140.5, 135.4, 132.6, 131.4, 130.5, 130.4, 129.7, 128.9, 128.2, 122.1, 120.1, 120.0, 118.8, 83.8, 82.4, 78.2, 72.1, 60.0, 57.7, 53.5, 41.0, 36.1, 34.9, 33.1, 32.6, 32.5, 31.4, 27.2, 26.5, 24.6, 23.8, 23.7, 23.6, 6.4, 6.3.
Figure imgf000133_0003
The title compound was prepared with compound of Example 126 with Boc-Chg- OH via the similar conditions described in Example 144. MS (ESI): m/z = 873.44 [M+H].
13C(CD3OD): 5173.9, 173.0, 171.0, 169.6, 156.7, 153.4, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 117.3, 82.8, 79.2,
59.8, 59.6, 57.5, 41.9, 41.3, 39.8, 35.6, 34.8, 34.4, 31.0, 29.4, 28.6, 27.5, 25.9, 25.6, 25.5, 22.6, 5.5, 5.3.
Example 195. Compound of formula C, wherein Rx =
Figure imgf000134_0001
k 6 — , . LL== Λf P\. W=
Figure imgf000134_0002
The title compound was prepared with compound of Example 196 with bezoic acid via the similar conditions described in Example 144.
MS (ESI): m/z = 877.47 [M+H].
13C(CD3OD): 5173.9, 172.3, 171.0, 169.6, 169.1, 153.4, 141.8, 140.5, 135.2,
134.3, 133.1, 131.5, 131.4, 130.3, 130.2, 129.3, 128.5, 128.4, 127.9, 127.2, 121.6, 119.9, 117.4, 82.8, 59.8, 58.8, 57.5, 54.1, 41.3, 39.6, 35.6, 34.8, 34.4, 31.0, 29.4,
29.2, 25.9, 25.5, 25.3, 22.6, 5.6, 5.3.
Example 196.
Figure imgf000134_0003
Figure imgf000134_0004
: The title compound was prepared with compound of Example 126 with cyclopentylisocynate via the similar conditions described in Example 127. MS (ESI): m/z = 745.41 [M+H].
13C(CD3OD): 5174.1, 172.8, 169.5, 158.8, 153.6, 141.7, 140.5, 135.2, 133.1, 131.2, 130.2, 129.4, 128.3, 127.9, 121.6, 119.8, 117.3, 82.8, 59.7, 58.0, 53.9, 51.6, 41.3, 35.1, 34.7, 34.5, 33.1, 32.8, 30.9, 25.9, 23.2, 22.4, 5.5, 5.3. Example 197.
Figure imgf000135_0001
Figure imgf000135_0002
The title compound was prepared with compound of Example 126 with cyclohexylisocynate via the similar conditions described in Example 127.
MS (ESI): m/z = 759.41 [M+H].
13C(CD3OD): 5174.1, 172.8, 169.5, 158.4, 153.6, 141.7, 140.5, 135.2, 133.1,1
31.2, 130.2, 129.4,1 28.3, 127.9, 121.6, 119.9, 119.8, 117.3, 82.8, 59.7, 58.0, 53.9,
48.5, 341.3, 35.1, 34.7, 34.5, 33.5, 33.2, 30.9, 25.9, 25.5, 24.8, 24.7, 22.4, 5.5, 5.3.
Figure imgf000135_0003
The title compound was prepared with compound of Example 126 with dicylcohexylacetic acid via the similar conditions described in Example 127. MS (ESI): m/z = 840.54 [M+H].
13C(CD3OD): 5175.5, 173.9, 173.8, 171.5, 169.6, 153.3, 141.8, 140.5, 135.3, 133.1, 131.3, 130.3, 130.2, 129.3, 128.4, 127.9, 121.7, 119.9, 119.8, 117.4, 82.8,
60.0, 57.5, 57.1, 54.1, 41.2, 36.7, 36.2, 35.4, 35.0, 34.9, 34.3, 31.4, 31.3, 31.0, 29.8, 29.2, 26.5, 26.4, 26.3, 26.2, 25.9, 22.7, 5.6, 5.3.
Example 199. Compound of formula C, wherein Rx = ° / , L= P, W=
Figure imgf000135_0004
The title compound was prepared with compound of Example 126 with Cyclopent-3- enylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 744.41 [M+H]. 13C(CD3OD): 5174.0, 171.9, 169.5, 157.4, 153.6, 141.8, 140.5, 135.2, 133.1, 131.3, 130.3, 129.2, 128.3, 127.9, 127,7, 121.6, 119.9, 82.8, 74.9, 59.9, 59.5, 54.1, 41.3, 39.4, 39.2, 35.1, 34.8, 34.4, 30.9, 25.8, 22.5, 5.5, 5.3.
Example 200.
Figure imgf000136_0001
Figure imgf000136_0002
The title compound was prepared with compound of Example 126 with 2- indanylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 794.43 [M+H].
13C(CDCB): 5173.1, 173.0, 172.4, 168.7, 156.4, 153.8, 141.8, 140.6, 140.5, 135.4, 132.7, 131.5, 130.5, 129.6, 128.6, 126.9, 124.8, 122.2, 120.1, 118.8, 82.4, 59.9, 59.4, 54.1, 42.0, 41.8, 40.0, 39.5, 35.7, 35.6, 34.1, 31.4, 26.6, 22.6, 6.4, 6.3.
Example 201.
Figure imgf000136_0003
Figure imgf000136_0004
The title compound was prepared with compound of Example 126 with 2-thiophene carboxylic acid via the similar conditions described in Example 127. MS (ESI): m/z = 744.31 [M+H].
13C(CD3OD): 5173.8, 171.3, 169.5, 162.8, 153.8, 141.6, 140.5, 138.1, 135.1, 133.1, 131.2, 131.0, 130.2, 129.1, 128.9, 128.3, 127.8,1 27.6, 121.5, 119.8, 82.6,
59.8, 57.8, 54.1, 41.2, 35.7, 34.9, 34.4, 31.0, 26.0, 22.7, 5.6, 5.3.
Example 202.
Figure imgf000136_0005
Figure imgf000136_0006
The title compound was prepared with compound of Example 126 with pyrazine carboxylic acid via the similar conditions described in Example 127. MS (ESI): m/z = 740.42 [M+H]. 13C(CD3OD): 5174.0, 170.9, 169.4, 163.0, 153.9, 147.4, 143.9, 143.4, 143.3, 141.6, 140.3, 135.0, 133.1, 130.3, 130.0, 128.9, 128.0,1 27.8, 121.5, 119.9, 119.8, 82.6, 60.0, 57.2, 54.4, 41.4, 35.6, 34.6, 34.4, 30.9, 25.8, 22.3, 5.5, 5.3.
Figure imgf000137_0001
The title compound was prepared with compound of Example 126 with Cyclohexyl- phenethyl-amine and CDI via the similar conditions described in Example 127. MS (ESI): m/z = 863.23 [M+H].
13C(CD3OD): 5174.2, 173.1, 170.0, 158.1, 153.9, 142.1, 140.8,1 39.4, 135.5, 133.5, 131.6, 130.6, 129.5, 129.0, 128.7,1 28.6, 128.3, 126.5, 121.9, 120.3, 83.2,
60.6, 59.1, 55.8, 54.5, 44.8, 41.5, 36.9, 36.1, 35.3, 34.6, 31.5, 31.4, 31.3, 26.5, 26.2, 26.1, 25.6, 23.2, 5.9, 5.7.
Example 204.
Figure imgf000137_0002
Figure imgf000137_0003
The title compound was prepared with compound of Example 126 with Cyclohexyl-
(3-methyl-butyl)-amine and CDI via the similar conditions described in Example
127.
MS (ESI): m/z = 829.26 [M+H].
13C(CD3OD): 5173.8, 172.7, 169.7, 157.8, 153.6, 141.7, 140.5, 135.2, 133.2, 131.2, 130.3, 130.2, 129.3, 128.3, 127.9, 121.6, 119.9, 82.8, 60.2, 58.7, 55.0, 54.0,
41.2, 40.9, 39.3, 35.7, 35.0, 34.3, 31.2, 31.1, 30.9, 26.6, 26.1, 25.8, 25.3, 22.8, 21.8,
21.6, 5.5, 5.2. H °
Example 205. Compound of formula C, wherein Rx = k — , L= P, W=
Figure imgf000138_0001
The title compound was prepared with compound of Example 126 with Boc-Chg- OH and methylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 831.22 [M+H].
13C(CD3OD): δ 173.8, 172.8, 171.7, 169.6, 158.0, 153.4, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 117.3, 82.8, 60.5, 59.8, 57.5, 54.0, 51.4, 41.2, 39.9, 35.5, 34.8, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 5.6, 5.3.
Example 206.
Figure imgf000138_0002
Figure imgf000138_0003
The title compound was prepared with compound of Example 126 with Boc-Chg- OH and ethylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 845.26 [M+H]. 13C(CD3OD): 5173.9, 172.7, 171.0, 169.6, 157.5, 153.4, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 117.3, 82.8, 60.8, 59.8, 57.4, 54.0, 41.3, 39.9, 35.5, 34.8, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 13.7, 5.6, 5.3.
Example 207.
Figure imgf000138_0004
Figure imgf000138_0005
The title compound was prepared with compound of Example 126 with Boc-Chg- OH and isopropylchloroformate via the similar conditions described in Example
127. MS (ESI): m/z = 859.42 [M+H].
13C(CD3OD): δ 173.9, 172.9, 171.1, 169.6, 157.1, 153.4, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 117.3, 82.8, 69.3, 59.8, 57.5, 54.0, 41.3, 39.8, 35.5, 34.8, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 21.2, 5.6, 5.3.
Example 208. Compound of formula C, wherein Rx = ^^ , L= r\ W=
The title compound was prepared with compound of Example 126 with Boc-Chg- OH and isobutylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 873.40 [M+H].
13C(CD3OD): 5173.9, 172.8, 171.1, 169.6, 157.7, 153.4, 141.7, 140.5, 135.2, 133.1, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 117., 82.8, 71.0, 59.9, 59.8, 57.5, 54.0, 41.3, 39.8, 35.5, 34.8, 34.3, 31.0, 29.3, 28.6, 28.1, 25.9, 25.6, 25.4, 22.6, 18.1, 5.6, 5.3.
Example 209. Compound of formula C. wherein Rx = ° / . L= Ϊ\W=
Figure imgf000139_0002
^
The title compound was prepared with compound of Example 14 with via the similar conditions described in Example 114. MS (ESI): m/z = 736.24 [M+H].
Example 210. Compound of formula C, wherein Rx = H, L=
Figure imgf000139_0003
o.,o A. s' n=l. Z= CH7CH^ and G = 1 V:
The title compound was prepared via the similar conditions described in Example
126.
MS (ESI): m/z = 636.22 [M+H].
Figure imgf000140_0001
The title compound was prepared with compound of Example 210 via the similar conditions described in Example 194.
MS (ESI): m/z = 875.37 [M+H]. o
Example 212. Compound of formula C, wherein Rx = ^^ , L= r\ W=
Figure imgf000140_0002
. n=l. Z= CH7CH^ and G = H V1
The title compound was prepared via the similar conditions described in Example 126. MS (ESI): m/z = 775.23 [M+H].
Example 213.
Figure imgf000140_0003
Figure imgf000140_0004
^
The title compound was prepared with compound of Example 212 with pyrazinecarboxylic acid via the similar conditions described in Example 194. MS (ESI): m/z = 881.26 [M+H].
13C(CD3OD): 5173.9, 173.8, 171.8, 171.0, 170.5, 163.5, 153.3, 147.6, 144.5, 143.6, 143.5, 141.8, 140.5, 135.2, 131.3, 130.3, 130.2, 129.4, 128.5, 127.9, 121.7, 119.9, 82.8, 59.8, 57.9, 57.8, 54.0, 40.8, 39.2, 35.3, 34.6, 34.3, 31.0, 29.4, 28.7, 26.0, 25.8, 25.5, 25.4, 22.7, 19.5, 12.7, 5.5, 5.1. Example 214.
Figure imgf000141_0001
Figure imgf000141_0002
The title compound was prepared with compound of Example 126 with pyrazine-2- carboxylic acid N'-cyclohexyl-hydrazide and CDI via the similar conditions described in Example 127. MS (ESI): m/z = 880.26[M+H].
Figure imgf000141_0003
Step 215a
To a solution of Boc-Chg-OH (lmmol) in DMF 5ml was added methyl iodide 498μl and silver oxide 927mg. The reaction mixture was stirred at 4O0C overnight. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ESI): m/z = 286.07[M+H].
Step 215b
To a flask containing the compound from step 215a was added 4N HCl/dioxane (8ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification. MS (ESI): m/z = 186.10 [M+H].
Step 215c To a solution of compound (lOOmg) from step 215b in DCM was added pyrazine-2- carbonyl chloride and DIEA 393μl. The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The organic extracts were washed with 1% HCl, NaHCCh, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give desired product. MS (ESI): m/z = 292.09[M+H].
Step 215d
To a solution of the compound from step 215c in THF ImI and ImI MeOH was added 2NLiOH 0.5ml. The reaction mixture was stirred at RT overnight and concentrated to remove organic solvents. The residue was diluted with brine, acidified with 2N HCl and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give desired product. MS (ESI): m/z = 278.08[M+H].
Step 215e
The title compound was prepared with compound of Example 126 with the compound from step 215d via the similar conditions described in Example 127. MS (ESI): m/z = 893.27 [M+H].
Example 216. Compound of formula C, wherein Rx ΞOJy
Figure imgf000142_0001
The title compound was prepared with compound from Example 136 with benzaldehyde via the similar conditions described in Example 137.
MS (ESI): m/z = 672.15 [M+H].
13C(CD3OD): 5174.1, 171.6, 169.6, 157.4, 150.3, 133.1, 132.3, 130.0, 128.6, 127.1, 117.3, 81.2, 77.8, 60.0, 59.3, 53.9, 41.2, 35.5, 34.9, 34.3, 32.5, 32.4, 31.0,
25.8, 23.3, 22.6, 5.6, 5.3.
Example 217.
Figure imgf000142_0002
Figure imgf000142_0003
The title compound was prepared with compound from Example 136 with benzophenone via the similar conditions described in Example 137. MS (ESI): m/z = 748.17 [M+H].
13C(CD3OD): 5174.1, 171.7, 169.5, 159.1, 157.4, 136.3, 133.4, 133.1, 129.5, 129.0, 128.7, 128.1, 128.0, 127.9, 117.3, 81.4, 77.8, 60.2, 59.3, 54.2, 41.2, 35.5, 34.8, 34.1, 32.5, 31.0, 25.8, 23.3, 22.5, 5.6, 5.3.
Example 218.
Figure imgf000143_0001
Figure imgf000143_0002
The title compound was prepared with compound from Example 212 with methylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 833.14 [M+H].
13C(CD3OD): 5173.9, 173.8, 172.8, 171.1, 170.5, 157.9, 153.4, 141.7, 140.5, 135.2, 131.3, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 82.7, 60.0, 59.8, 57.5, 54.1, 51.4, 39.9, 39.2, 39.1, 35.5, 34.6, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 19.5, 12.7, 5.5, 5.1.
Example 219.
Figure imgf000143_0003
Figure imgf000143_0004
The title compound was prepared with compound from Example 212 with ethylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 847.21 [M+H].
13C(CD3OD): 5173.8, 172.8, 172.7, 171.0, 170.5, 157.5, 153.4, 141.7, 140.5, 135.2, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 82.7, 60.8, 59.9, 59.8, 57.5, 57.4, 54.1, 39.9, 39.1, 35.5, 34.5, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 19.5, 13.7, 12.7, 5.5, 5.1.
Figure imgf000144_0001
The title compound was prepared with compound from Example 212 with isopropylchloro formate via the similar conditions described in Example 127. MS (ESI): m/z = 861.23 [M+H].
13C(CD3OD): 5173.9, 172.8, 171.0, 170.5, 157.1, 153.4, 141.7, 140.5, 135.2, 131.4, 130.3, 130.2, 129.3, 128.5, 127.9, 121.6, 119.9, 82.7, 68.3, 59.8, 57.4, 54.0, 39.8, 39.1, 35.5, 34.5, 34.3, 31.0, 29.3, 28.6, 25.9, 25.6, 25.4, 22.6, 21.2, 19.5, 12.7, 5.5, 5.1.
Example 221. Compound of formula C. wherein Rx = ° /. L= F\ W=
Figure imgf000144_0002
To a solution of the compound from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then 2- methylbenzenesulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 782.2 [M+H].
Example 222. Compound of formula C, wherein Rx = α»V 7 , L= /-< P\ W=
Figure imgf000144_0003
To a solution of the compound from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then 3-chloro-4- methylbenzenesulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 816.1 [M+H].
Example 223. Compound of formula C, wherein Rx = ° / , L= P, W=
Figure imgf000145_0001
To a solution of the compound from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then 4- fluorobenzenesulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 786.1 [M+H].
Example 224. Compound of formula C, wherein Rx = ° / , L= T"*, W=
Figure imgf000145_0002
To a solution of the compound from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then 4- methoxybenzenesulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 815.1 [M+H].
Example 225. Compound of formula C, wherein Rx = AJ 7z , L1= P\. W=
Figure imgf000145_0003
To a solution of the compound from step 3b of Example 3 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then 4-methyl-2- pyridinesulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 783.0 [M+H].
Example 226. Compound of formula C, wherein Rx = ° / , L= T , W=
Figure imgf000146_0001
^ Step 226a
The compound was prepared using (2S,4S)-l-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid and (lR,2S)-ethyl l-amino-2- vinylcyclopropanecarboxylate via conditions similar to those described in step Ic of Example 1.
Step 226b
The compound was prepared using the compound from step 226a of example 226 and 2,7-dibromo-9H-fluoren-9-one oxime via conditions similar to those described in step 10b of Example 10.
Step 226c
The compound was prepared with the compound from step 226b of example 226 via conditions similar to those described in step Ie of Example 1.
Step 226d
The compound was prepared with the compound from step 226c of example 226 and (S)-2-(cyclopentyloxycarbonylamino)-3-methylbutanoic acid via conditions similar to those described in step Ia of Example 1. MS (ESI): m/z = 815.3 [M+2+H].
Step 226e
To a solution of the compound from step 226e of Example 226 in DMF was added
CDI. The reaction mixture was stirred at 40 0C for 1 h and then cyclopropylsulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 890.0 [M+H].
Example 227. Compound of formula C, wherein Rx = / , L= I , W=
Figure imgf000147_0001
Step 227a
The compound was prepared using the compound from step 6c of example 6 and (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid via conditions similar to those described in step Ia of Example 1. MS (ESI): m/z = 829.2 [M+2+H].
Step 227b
The compound was prepared with the compound from step 7a of example 7 via conditions similar to those described in step 3b of Example 3. MS (ESI): m/z = 801.2 [M+2+H].
Step 227c
To a solution of the compound from step 7b of Example 7 in DMF was added CDI. The reaction mixture was stirred at 40 0C for 1 h and then cyclopropylsulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): m/z = 904.1 [M+2+H].
Example 228. Compound of formula C, wherein Rx = / , L= I , W=
Figure imgf000147_0002
V Step 228a
The compound was prepared using the compound from step 6c of example 6 and (2S,3S)-2-(cyclopentyloxycarbonylamino)-3-methylpentanoic acid via conditions similar to those described in step Ia of Example 1. MS (ESI): m/z = 829.2 [M+2+H].
Step 228b
The compound was prepared with the compound from step 8a of example 8 via conditions similar to those described in step 3b of Example 3. MS (ESI): m/z = 801.2 [M+2+H].
Step 228c
To a solution of the compound from step 8b of Example 8 in DMF was added CDI.
The reaction mixture was stirred at 40 0C for 1 h and then cyclopropylsulfonamide and DBU were added. The reaction mixture was stirred at 40 0C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product.
MS (ESI): m/z = 903.5 [M+2+H]. The compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease. The following examples describe assays in which the compounds of the present invention can be tested for anti-HCV effects.
Example 229 NS3/NS4a Protease Enzyme Assay HCV protease activity and inhibition is assayed using an internally quenched fluorogenic substrate. A DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.
The assay is run in Corning white half-area 96-well plates (VWR 29444-312 [Corning 3693]) with full-length NS3 HCV protease Ib tethered with NS4A co factor (final enzyme concentration 1 to 15 nM). The assay buffer is complemented with 10 μM NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8). RET Sl (Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser- LyS-(DABCYL)-NH2, AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate. The assay buffer contains 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME. The enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
The peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu- Met-Glu-Glu-Cys-OH, [-200C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac- Asp-Glu-Dif-Cha-Cys-OH, are used as reference compounds. IC50 values are calculated using XLFit in ActivityBase (IDBS) using equation 205: y=A+((B-A)/(l+((C/x)ΛD))).
Example 230 Cell-Based Replicon Assay
Quantification of HCV replicon RNA (HCV Cell Based Assay) is accomplished using the Huh 11-7 cell line (Lohmann, et al Science 285:110-113, 1999). Cells are seeded at 4x103 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non-essential amino acids. Cells are incubated in a 7.5% CO2 incubator at 37 0C. At the end of the incubation period, total RNA is extracted and purified from cells using Ambion RNAqueous 96 Kit (Catalog No. AMI 812). To amplify the HCV RNA so that sufficient material can be detected by an HCV specific probe (below), primers specific for HCV (below) mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169). The nucleotide sequences of the RT-PCR primers, which are located in the NS5B region of the HCV genome, are the following: HCV Forward primer "RBNS5bfor"
5 'GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCV Reverse primer "RBNS5Brev" 5 'CAAGGTCGTCTCCGCATAC (SEQ ID NO 2).
Detection of the RT-PCR product is accomplished using the Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is degraded during the PCR reaction. The increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product. Specifically, quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997). The data is analyzed using the ABI SDS program version 1.7. The relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
The RT-PCR product was detected using the following labeled probe: 5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA (SEQ ID NO: 3) FAM= Fluorescence reporter dye. TAMRA :=Quencher dye.
The RT reaction is performed at 480C for 30 minutes followed by PCR.
Thermal cycler parameters used for the PCR reaction on the ABI Prism 7500
Sequence Detection System are: one cycle at 950C, 10 minutes followed by 40 cycles each of which include one incubation at 950C for 15 seconds and a second incubation for 600C for 1 minute.
To normalize the data to an internal control molecule within the cellular
RNA, RT-PCR is performed on the cellular messenger RNA glyceraldehyde-3- phosphate dehydrogenase (GAPDH). The GAPDH copy number is very stable in the cell lines used. GAPDH RT-PCR is performed on the same RNA sample from which the HCV copy number is determined. The GAPDH primers and probesare contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E).
The ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication. Activity of compounds as inhibitors of HCV replication (Cell based Assay) in replicon containing Huh-7 cell lines. The effect of a specific anti-viral compound on HCV replicon RNA levels in Huh-1 l-7cells is determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the DMSO vehicle (negative control). Specifically, cells are seeded at 4x 103 cells/well in a 96 well plate and are incubated either with: 1) media containing 1% DMSO (0% inhibition control), or 2) media/1 %DMS0 containing a fixed concentration of compound. 96 well plates as described above are then incubated at 370C for 4 days (EC50 determination). Percent inhibition is defined as: % Inhibition= 1OO-1OO*S/C1 where
S= the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;
Cl= the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0% inhibition control (media/1 %DMSO). The dose-response curve of the inhibitor is generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a specific compound at 1.5 uM and ending with the lowest concentration of 0.23 nM. Further dilution series (500 nM to 0.08 nM for example) is performed if the EC50 value is not positioned well on the curve. EC50 is determined with the IDBS Activity Base program "XL Fit" using a 4-paramater, non-linear regression fit (model # 205 in version 4.2.1, build 16).
In the above assays, representative compounds of the present invention are found to have HCV replication inhibitory activity and HCV NS3 protease inhibitory activity. For instance, representative compounds of formulae III and IV, as depicted above, showed significant HCV replication inhibitory activity. These compounds were also effective in inhibiting HCV NS3 proteases of different HCV genotypes including genotypes 1, 2, 3 and 4. As a non-limiting example, representative compounds in the preferred examples of formulae III and IV showed EC50s in the range of from less than 0.2 nM to about 10 nM using cell-based replicon assays. Representative compounds of these preferred examples also inhibited HCV NS3 proteases of different HCV genotypes, such as genotypes Ia, Ib, 2a, and 4a, with IC50s in the range of from less than 0.2 nM to about 50 nM.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by the formula I:
Figure imgf000152_0001
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
Ri and R2 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl; e) substituted heteroaryl; f) heterocyclic or substituted heterocyclic; g) -C1-C8 alkyl, -C2-Cs alkenyl, or -C2-Cs alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, or substituted -C2- C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C3-C12 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; k) -Q-R3, where Q is (CO), (CO)O, (CO)NR4, (SO), (SO2), (SO2)NR4; and R3 and R4 are independently selected from the group consisting of:
(i) Hydrogen; (ii) aryl;
(iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocyclic; (vii) substituted heterocyclic;
(viii) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or
N;
(ix) substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (x) -C3-C12 cycloalkyl, or -C3-C12 cycloalkenyl;
(xi) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; or Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from: substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic; or substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more R3;
G is -E-R3, where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO2)NH or NHSO2; A is selected from the group consisting of R5, (CO)R5, (CO)OR5, (CO)NHR5, SO2R5, (SO2)OR5 and SO2NHR5;
R5 is selected from the group consisting of: a) aryl; b) substituted aryl; c) heteroaryl; d) substituted heteroaryl; e) heterocyclic; f) substituted heterocyclic; g) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl; B is H or CH3; L and Z are independently selected from the group consisting of:
(I) hydrogen; (2) aryl;
(3) substituted aryl;
(4) heteroaryl;
(5) substituted heteroaryl;
(6) heterocyclic; (7) substituted heterocyclic;
(8) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(9) substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(10) -C3-Ci2 cycloalkyl, Or -C3-Ci2 cycloalkenyl;
II 1) substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl; m = 0, 1, 2 or 3; n = 1 , 2 or 3 and h = 0, 1, 2, or 3.
2. A compound according to Claim 1 represented by formula II:
Figure imgf000154_0001
where A, G, L, Ri and Z are as previously defined in claim 1.
3. A compound according to claim 2, wherein Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, and substituted -C3-C12 cycloalkenyl. A is selected from the group consisting of -C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C2-Cs alkenyl, -
C2-Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, substituted - C2-Cs alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. L and Z can be independently selected from Ci-Cs alkyl, -C2-Cs alkenyl, -C2-Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, substituted -C2-Cs alkynyl, -C3-C12 cycloalkyl,
-C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. G can be -0-R3, -NH-C(O)-R3, -NH-SO2-NH-R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
4. A compound according to Claim 1 represented by formula III:
Figure imgf000155_0001
where A, G, L, R1, R2 and Z are as previously defined in claim 1.
5. A compound according to claim 4, wherein Ri and R2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, and substituted -C3-Ci2 cycloalkenyl; or Ri and R2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from aryl, heteroaryl, heterocyclic, substituted aryl, substituted heteroaryl, or substituted heterocyclic. A can be selected from the group consisting of -C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C8 alkyl, -C2-C8 alkenyl, - C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted - C2-C8 alkynyl, -C3-C12 cycloalkyl, -Cs-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. G can be -0-R3, -NH-C(O)-R3, -NH-SO2-NH-R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
6. A compound represented by formula IV:
Figure imgf000156_0001
wherein V is absent, or V is CO, O, S, SO, SO2, NH or NCH3, or (CH2)q; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of: aryl; substituted aryl; heteroaryl; substituted heteroaryl; heterocyclic; substituted heterocyclic; where A, G, L and Z are as previously defined in claim 1.
7. A compound according to claim 6, wherein
Figure imgf000157_0001
is selected from
Figure imgf000157_0003
, and
Figure imgf000157_0002
, wherein X1-X8 are independently selected from CH and N and X1-X8 can be further substituted when it is a CH, and Y1-Y3 are independently selected from CH, N, NH, S and O and Y1-Y3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A can be selected from the group consisting of -C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C1-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -C1-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. L and Z can be independently selected from C1-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -C1-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl. G can be -0-R3, -NH-C(O)-R3, -NH-SO2-NH- R3 or -NHSO2-R3, where R3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3- C12 cycloalkenyl.
8. A compound according to claim 6 wherein
Figure imgf000157_0004
wherein X1-X8 are independently selected from CH and N and X1-X8 can be further substituted when it is a CH; V is absent, CO, O, S, NH, or (CH2)q, where q is 1, 2 or 3. A is -C(O)-O-R5, where R5 is -C3-C12 cycloalkyl or substituted - C3-C12 cycloalkyl. L is selected from -C1-C8 alkyl or substituted -C1-C8 alkyl. Z is selected from C1-C8 alkyl, substituted -C1-C8 alkyl, -C2-C8 alkenyl or substituted -C2-Cg alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl.
9. A compound according to claim 6 wherein
Figure imgf000158_0001
is
Figure imgf000158_0002
, wherein Ra and Rb is independently selected from hydrogen or halogen. A is -C(O)-O-R5, where R5 is -C3-Ci2 cycloalkyl or substituted -C3-C12 cycloalkyl. L is selected from -Ci-Cs alkyl or substituted - Ci-C8 alkyl. Z is selected from Ci-C8 alkyl, substituted -Ci-C8 alkyl, -C2-C8 alkenyl or substituted -C2-C8 alkenyl. G is -NHSO2-R3, where R3 is selected from -C3-C12 cycloalkyl or substituted -C3-C12 cycloalkyl.
10. A compound represented by formula V:
Figure imgf000158_0003
Where X1-X4 are independently selected from CO, CH, NH, O and N; X1-X4 can be further substituted when any one OfXi-X4 is a CH or NH; where R6 and R7 are independently R3; where A, G, L, V and Z are as previously defined in claim 1.
11. A compound according to claim 8, wherein R6 and R7 taken together with the carbon atoms to which they are attached form a cyclic moiety selected from C3- C12 cycloalkyl, substituted C3-Ci2 cycloalkyl, C3-Ci2 cycloalkenyl, substituted C3- C12 cycloalkenyl, aryl, heteroaryl, heterocyclic, substituted aryl, substituted heteroaryl or substituted heterocyclic. A is selected from the group consisting of - C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. G can be -0-R3', -NH-C(O)-R3', -NH-SO2-NH-R3' or -NHSO2- R3', where R3' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
12. A compound represented by formula VI:
Figure imgf000159_0001
Where YrY3 are independently selected from CO, CH, NH, N, S and O; and Yi-Y3 can be further substituted when any one OfYi-Y3 is CH or NH; Y4 is selected from C, CH and N; where A, G, L, R6, R7, V and Z are as previously defined in claim 1.
13. A compound according to claim 10, wherein R6 and R7 taken together with the carbon atoms to which they are attached form a cyclic moiety selected from C3- Ci2 cycloalkyl, substituted C3-Ci2 cycloalkyl, C3-Ci2 cycloalkenyl, substituted C3- Ci2 cycloalkenyl, aryl, heteroaryl, heterocyclic, substituted aryl, substituted heteroaryl or substituted heterocyclic. A is selected from the group consisting of - C(O)-R5, -C(O)-O-R5 and -C(O)-NH-R5, where R5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, substituted -C2-Cg alkynyl, -C3-C12 cycloalkyl, -Cs-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. L and Z can be independently selected from Ci-Cg alkyl, -C2-Cg alkenyl, -C2-Cg alkynyl, substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3- Ci2 cycloalkenyl. G can be -0-R3', -NH-C(O)-R3', -NH-SO2-NH-R3' or -NHSO2- R3', where R3' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, substituted -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkenyl.
14. A compound represented by formula IX:
Figure imgf000160_0001
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
Mi is selected from the group consisting of:
Figure imgf000160_0002
wherein R31 and R32 are independently selected from the group consisting of: g) hydrogen; h) aryl; substituted aryl; i) heteroaryl; substituted heteroaryl; j) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N; optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; k) -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic;
1) -A-R30, where A is (CO), (CO)O, (CO)NR40, (SO), (SO2), (SO2)NR40; and R30 and R40 are independently selected from the group consisting of: (i) Hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl (iii) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic; with added proviso that when A= CO, (CO)O, (SO), (SO2), R30 is not hydrogen; with added proviso that when R31= hydrogen, R32 is not hydrogen; alternatively, R31 and R32 are taken together with the carbon atom to which they are attached to form the group consisting of: d) -C3-Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl heterocyclic or substituted heterocyclic; e) -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkyl, -C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic fused with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkyl, - C3-Ci2 cycloalkenyl, or substituted -C3-Ci2 cycloalkenyl; heterocyclic or substituted heterocyclic; f)
Figure imgf000162_0001
wherein V is absent, or V is O, S, SO, SO2, NR50, or
(CH2)q; where R50 is selected from H, OH, OCH3, -0-Ci-C8 alkyl, -Ci-C8 alkyl, -0-C3-C8 cycloalkyl, -C3-C8 cycloalkyl, -O- C3-C8 cycloalkenyl; -C3-C8 cycloalkenyl; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of:
(i) aryl; substituted aryl; (ii) heteroaryl; substituted heteroaryl; (iii) heterocyclic; substituted heterocyclic;
(2) NR30R40; NR5(CO)R30; NR50(CO)OR30; NR50(CO)NR30R40;
NR50(SO2)OR30; NR50(SO2)NR30R40; where R30, R40 and R50 are as previously defined; alternatively, for formula (I), R30 and R40 are taken together with the nitrogen atom to which they are attached to form the group consisting of: heterocyclic, or substituted heterocyclic; heteroaryl, or substituted heteroaryl; M2 is selected from the group consisting of:
(4) oxygen;
(5) sulfur; (6) NR60; where R60 is selected from H, OH, OCH3, -O-CrC8 alkyl, -CrC8 alkyl;
G is -E-R30; and where E is absent, or E is O, CO, (CO)O, (CO)NH, NH, NH(CO),
NH(CO)NH, NH(CNR50)NH, NH(SO2)NH or NHSO2; where R30 and R50 are as previously defined; n = O, 1, 2, 3 or 4;
U is CH, CF or N;
R70 is selected from the group consisting of H, OH, OCH3, -0-Ci-C8 alkyl, -Ci-C8 alkyl;
J is selected from the group consisting of CO, (CO)O, (CO)NR50, SO2, (SO2)O or SO2NR50; Rgo is selected from the group consisting of:
(1) hydrogen;
(2) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(3) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-C12 cycloalkyl, or substituted - C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; with added proviso that when J= CO, (CO)O, (SO), (SO2), R80 is not hydrogen; L is selected from the group consisting of:
(1) protected or unprotected side chain of natural amino acid;
(6) Side chain of unnatural amino acid as described in M. G. Natchus and X. Tian, " The asymmetric synthesis of unnatural α-amino acids as building blocks for complex molecule synthesis", Organic Synthesis:
Theory and Applications, 5: 89-196 (2001); and R.M. Williams, " Synthesis of Optically Active α-amino Acids", Pergamon, Oxford (1989);
(7) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; Q is selected from the group consisting of:
(1) hydrogen;
(2) CH=CH2;
(3) CHF2;
(8) SH; SR30; where R30 is as previously defined; (9) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkyl; -C3-C12 cycloalkenyl, or substituted -C3-C12 cycloalkenyl; heterocyclic or substituted heterocyclic; m = 0, 1, 2 or 3; and s = 0, 1, 2 or 3.
15. A compound represented by formula XVI,
Figure imgf000164_0001
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein: Rioi and R102 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl fused with 0, 1, 2, or 3 more group selected from heteroaryl and aryl; e) substituted heteroaryl fused with 0, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; f) heterocyclic, substituted heterocyclic, oxo substituted heterocyclic; wherein oxo refer to substituted by independent replacement of two of the hydrogen atoms thereon with =0; g) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted - C2-Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C3-C12 cycloalkyl, or -C3-Ci2 cycloalkenyl; j) substituted -C3-C12 cycloalkyl, or substituted -C3-C12 cycloalkenyl; k) oxo substituted -C3-C12 cycloalkyl, or oxo substituted -C3-C12 cycloalkenyl;
1) -Q-R103, where Q is (CO), (CO)O, (CO)NRi04, (SO), (SO2), (SO2)NRi04; and Ri03 and Ri04 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl; (iii) substituted aryl; (iv) heteroaryl fused with O, 1,2, or 3 more group selected from aryl and heteroaryl;
(v) substituted heteroaryl fused with O, 1,2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; (vi) heterocyclic;
(vii) substituted heterocyclic;
(viii) oxo substituted heterocyclic;
(ix) -C1-C8 alkyl, -C2-Cs alkenyl, or -C2-Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N;
(x) substituted -Ci-Cs alkyl, substituted -C2-Cs alkenyl, or substituted -C2-Cs alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (xi) -C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; (xii) substituted -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkenyl, oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl; or Rioi and Ri02 taken together with the carbon atom to which they are attached form a cyclic moiety selected from: substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic; substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each substituted an oxo; substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more Ri03; or oxo substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more
Gi is -E-R103, where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO2)NH or NHSO2; A is selected from the group consisting of R105, (CO)Ri05, (CO)ORi05, (CO)NHRios, SO2Ri05, (SO2)ORi05 and SO2NHRi05; Ri05 is selected from the group consisting of: aryl; a) hydrogen; b) substituted aryl; c) heteroaryl fused with O, 1 , 2, or 3 more group selected from heteroaryl and aryl; d) substituted heteroaryl fused with O, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; e) heterocyclic; f) substituted heterocyclic; g) oxo substituted heterocyclic; h) -Ci-Cg alkyl, -C2-Cg alkenyl, or -C2-Cg alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; i) substituted -Ci-Cg alkyl, substituted -C2-Cg alkenyl, or substituted -C2-Cg alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; j) -C3-C12 cycloalkyl, or -C3-Ci2 cycloalkenyl; k) substituted -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkenyl, oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl; Bi is H or CH3; Li and Zi are independently selected from the group consisting of:
(1) hydrogen;
(2) aryl;
(3) substituted aryl;
(4) heteroaryl fused with O, 1, 2, or 3 more group selected from heteroaryl and aryl;
(5) substituted heteroaryl fused with 0, 1, 2, or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl;
(6) heterocyclic; (7) substituted heterocyclic;
(8) oxo substituted heterocyclic;
(9) -Ci-C8 alkyl, -C2-C8 alkenyl, or -C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(lθ)substituted -Ci-C8 alkyl, substituted -C2-C8 alkenyl, or substituted -C2- C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(11)-C3-Ci2 cycloalkyl, or -C3-Ci2 cycloalkenyl; (12)substituted -C3-Ci2 cycloalkyl, substituted -C3-Ci2 cycloalkenyl, oxo substituted -C3-Ci2 cycloalkyl, or oxo substituted -C3-Ci2 cycloalkenyl; m = 0, 1, 2 or 3; n = 1 , 2 or 3 and h = 0, 1, 2, or 3.
16. A compound having the Formula A:
Figure imgf000167_0001
wherein Rx , G and W are delineated in Table 1 :
TABLE 1
Figure imgf000167_0002
17. A compound having the Formula B selected from compounds (3)-(109) of Table
2:
Figure imgf000168_0001
where Ri and R2 are taken together with the carbon to which they are attached to form RiR2;
TABLE 2
Figure imgf000168_0002
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
18. A compound of Claim 1 having the Formula C selected from compounds (HO)-
(228) of Table 3:
Figure imgf000175_0002
W, Rx, L, n, Z and G are delineated for each example in TABLE 3 :
TABLE 3
Example Rx L W n Z G
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
19. A compound having a formula selected from formulae I, X, XI, XII, XIII, XIV, XV or XVII, as described in the specification, or a pharmaceutically acceptable salt, ester or prodrug thereof.
20. A pharmaceutical composition comprising (1) a compound having a formula selected from formulae I, II, III, IV, V, VI, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII, as described in the specification, or (2) a pharmaceutically acceptable salt, ester or prodrug of said compound.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
22. A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 20.
23. A method of inhibiting the replication of hepatitis C virus, the method comprising contacting a hepatitis C virus with an effective amount of a compound of claim 1.
24. A method of claim 23 further comprising administering concurrently an additional anti-hepatitis C virus agent.
25. The method of claim 24, wherein said additional anti-hepatitis C virus agent is selected from the group consisting of α-interferon, β-interferon, ribavarin, and adamantine.
26. The method of claim 24, wherein said additional anti-hepatitis C virus agent is an inhibitor of other targets in the hepatitis C virus life cycle which is selected from the group consisting of helicase, polymerase, metalloprotease, and IRES.
27. A process of making a compound having a formula selected from formulae I, II, III, IV, V, VI, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII, as described in the specification, according to the schemes and examples described therein.
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WO2008070358A2 (en) * 2006-11-16 2008-06-12 Phenomix Corporation N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain
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US8268777B2 (en) 2007-12-05 2012-09-18 Enanta Pharmaceuticals, Inc. Oximyl macrocyclic derivatives
US8361958B2 (en) 2007-12-05 2013-01-29 Enanta Pharmaceuticals, Inc. Oximyl HCV serine protease inhibitors
US8193346B2 (en) 2007-12-06 2012-06-05 Enanta Pharmaceuticals, Inc. Process for making macrocyclic oximyl hepatitis C protease inhibitors
US8222203B2 (en) 2007-12-14 2012-07-17 Enanta Pharmaceuticals, Inc. Macrocyclic oximyl hepatitis C serine protease inhibitors
US8283309B2 (en) 2007-12-20 2012-10-09 Enanta Pharmaceuticals, Inc. Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors
US8372802B2 (en) 2008-03-20 2013-02-12 Enanta Pharmaceuticals, Inc. Fluorinated macrocyclic compounds as hepatitis C virus inhibitors
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US9284307B2 (en) 2009-08-05 2016-03-15 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors
US9353100B2 (en) 2011-02-10 2016-05-31 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
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