HK1146050A

HK1146050A - Viral polymerase inhibitors

Info

Publication number: HK1146050A
Application number: HK11100205.8A
Authority: HK
Inventors: Pierre L. Beaulieu; Pasquale Forgione; Alexandre Gagnon; Cedrickx Godbout; Marc-André JOLY; Montse Llinas-Brunet; Julie Naud; Martin Poirier; Jean Rancourt
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2007-12-19
Filing date: 2008-12-03
Publication date: 2011-05-13

Description

Viral polymerase inhibitors

RELATED APPLICATIONS

Priority of U.S. serial No. 61/015123 filed on 19/12/2007 is hereby incorporated by reference.

Technical Field

The present invention relates to compounds, compositions and methods for treating Hepatitis C Virus (HCV) infection. In particular, the present invention provides novel inhibitors of hepatitis C virus NS5B polymerase, pharmaceutical compositions comprising such compounds, and methods of using these compounds to treat HCV infection.

Background

It is estimated that at least 1 hundred million and 7 million people worldwide are infected with Hepatitis C Virus (HCV). In most cases, acute HCV infection progresses to chronic infection, and in some infected individuals, chronic infection leads to severe liver diseases such as cirrhosis and hepatocellular carcinoma.

Currently, standard therapy for chronic hepatitis C infection involves the combined administration of pegylated (pegylated) interferon alfa and ribavirin. However, this therapy is not effective in reducing HCV RNA to undetectable levels in many infected patients and is often associated with intolerable side effects such as fever and other flu-like symptoms, depression, thrombocytopenia, and hemolytic anemia. Furthermore, some HCV-infected patients are also symptomatic with contraindications to this treatment.

Thus, there is a need for alternative therapies for hepatitis C virus infection. One possible strategy to address this need is to develop effective antiviral agents that can inactivate the virus or host cytokines necessary for viral replication.

HCV is an enveloped positive-strand RNA virus in the gene Hepacivirus (Hepacivirus) in the Flaviviridae (Flaviviridae) family. The single stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single Open Reading Frame (ORF) flanked by 5 'and 3' non-coding regions. The HCV 5' non-coding region is 341 nucleotides in length and functions as an internal ribosome entry site for initiating cap-independent translation. The open reading frame encodes a single large polyprotein of about 3000 amino acids that is cleaved at multiple positions by cellular and viral proteases to produce mature structural and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins. The viral NS2/3 protease is cleaved at the NS2-NS3 junction; while the viral NS3 protease mediated cleavage downstream of NS3 at the cleavage sites NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS 5B. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The NS4A protein acts as a cofactor for the NS3 protease and contributes to membrane localization of NS3 and other viral replicase components. Although NS4B and NS5A phosphoproteins are also likely to be components of replicase, their specific roles are unknown. The NS5B protein is an extended subunit of HCV replicase with RNA-dependent RNA polymerase (RdRp) activity.

The development of new and specific anti-HCV therapies is a prime task, and the virus-specific functions necessary for replication are the most compelling targets for drug development. The fact that RNA-dependent RNA polymerase is not present in non-human mammals and that this enzyme appears to be essential for viral replication means that NS5B polymerase is an ideal target for anti-HCV therapy. Mutations that disrupt NS5B activity have recently been shown to eliminate RNA infectivity in chimpanzee models (Kolykhalov, a.a.; Mihalik, k.; Feinstone, s.m.; Rice, c.m.; 2000; j.virol.74: 2046-.

WO2007/087717 discloses compounds of formula (a):

wherein R is²Is optionally substituted aryl, and R⁶Is optionally substituted (C)_5-7) Cycloalkyl or aryl for use in the treatment of hepatitis C virus infection.

Summary of The Invention

The present invention provides a novel series of compounds having inhibitory activity against HCV polymerase. In particular, the compounds of the present invention inhibit RNA synthesis by the RNA-dependent RNA polymerase of HCV, in particular the NS5B enzyme encoded by HCV. Another advantage of the compounds provided by the present invention is that they have low to very low or even no significant activity towards other polymerases. Other objects of the present invention will become apparent to those skilled in the art from the following description and examples.

One aspect of the present invention provides compounds of formula (I):

wherein:

x is selected from O and S;

R²is Het or aryl, optionally substituted by 1-5R²⁰Substituted by a substituent, wherein R²⁰Independently selected from:

a) halogen, cyano or nitro;

b)R⁷、-C(＝O)-R⁷、-C(＝O)-O-R⁷、-O-R⁷、-S-R⁷、-SO-R⁷、-SO₂-R⁷、-(C_1-6) alkylene-R⁷、-(C_1-6) alkylene-C (═ O) -R⁷、-(C_1-6) alkylene-C (═ O) -O-R⁷、-(C_1-6) alkylene-O-R⁷、-(C_1-6) alkylene-S-R⁷、-(C_1-6) alkylene-SO-R⁷Or- (C)_1-6) alkylene-SO₂-R⁷；

Wherein R is⁷Independently selected from H, (C) at each occurrence_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl, aryl and Het;

wherein (C) is_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl and (C)_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, - (C)_1-6) Alkyl (optionally substituted by-O- (C)_1-6) Alkyl substituted), halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl radical)₂Aryl, - (C)_1-6) Alkyl-aryl, Het, - (C)_1-6) alkyl-Het; and is

Wherein each aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:

i) halogen, cyano, oxo, thio, imino, -OH, -O- (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Haloalkyl, -C (═ O) - (C)_1-6) Alkyl, -SO₂(C_1-6) Alkyl, -C (═ O) -NH₂、-C(＝O)-NH(C_1-4) Alkyl, -C (═ O) -N ((C)_1-4) Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group;

ii) optionally-OH-substituted (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl or-O- (C)_1-6) An alkyl group; and is

iii) aryl or Het, wherein each aryl and Het is optionally substituted by halogen or (C)_1-6) Alkyl substitution; and is

c)-N(R⁸)R⁹、-C(＝O)-N(R⁸)R⁹、-O-C(＝O)-N(R⁸)R⁹、-SO₂-N(R⁸)R⁹、-(C_1-6) alkylene-N (R)⁸)R⁹、-(C_1-6) alkylene-C (═ O) -N (R)⁸)R⁹、-(C_1-6) alkylene-O-C (═ O) -N (R)⁸)R⁹Or- (C)_1-6) alkylene-SO₂-N(R⁸)R⁹(ii) a Wherein (C) is_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, - (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂；

R⁸Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

R⁹Independently at each occurrence selected from R⁷、-O-(C_1-6) Alkyl, - (C)_1-6) alkylene-R⁷、-SO₂-R⁷、-C(＝O)-R⁷、-C(＝O)OR⁷and-C (═ O) N (R)⁸)R⁷；

Wherein R is⁷And R⁸As defined above;

or R⁸And R⁹And together with the N to which they are attached, form a 4-to 7-membered heterocyclic ring optionally further containing 1-3 heteroatoms each independently selected from N, O and S, wherein each S heteroatom may be independently and if possible present in an oxidized state, and is further bonded to 1 or 2 oxygen atoms to form a group SO or SO₂；

Wherein the heterocycle is optionally substituted with 1-3 substituents each independently selected from the group consisting of: (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, halogen, oxo, -OH, SH, -O (C)_1-6) Alkyl, -S (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl, -NH₂、-NH(C_1-6) Alkyl, -N ((C)_1-6) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -C (═ O) (C)_1-6) Alkyl and-NHC (═ O) - (C)_1-6) An alkyl group;

R³、R^3aand R^3bSelected from H, halogen, CN, (C)_1-4) Alkyl, -OH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl) and-N ((C)_1-4) Alkyl radical)₂；

R⁵Is O-R⁵²Mono-, di-or tri-substituted R⁵¹，

Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵²Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, said aryl and Het being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution;

R⁶is (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het; optionally substituted with 1-5 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -SH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl and-N (R)⁸)R⁹(ii) a Wherein R is⁸And R⁹As defined above; and is

Het is a 4-to 7-membered saturated, unsaturated or aromatic heterocycle having 1-4 heteroatoms each independently selected from O, N and S, or a 7-to 14-membered saturated, unsaturated or aromatic heterocycle having 1-5 heteroatoms each independently selected from O, N and S, if possible; wherein each N heteroatom is present independently and if possible in an oxidized state, bonded to an oxygen atom to form a group N-oxide group, and wherein each S heteroatom is present independently and if possible in an oxidized state, bonded to 1 or 2 oxygen atoms to form a group SO or SO₂；

Or a salt or ester thereof.

Another aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, for use as a medicament.

Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

According to an embodiment of this aspect, the pharmaceutical composition of the invention further comprises at least one additional antiviral agent.

The invention also provides the use of a pharmaceutical composition as described above in the treatment of a hepatitis C virus infection in a mammal having or at risk of having the infection.

Another aspect of the present invention includes a method of treating a hepatitis C virus infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, or a composition thereof.

Another aspect of the present invention includes a method of treating a hepatitis C virus infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof in combination with at least one other antiviral agent; or a combination thereof.

The use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof as described herein in the treatment of hepatitis C virus infection in a mammal having or at risk of having the infection is also included within the scope of the present invention.

Another aspect of the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of a hepatitis C viral infection in a mammal having or at risk of having the infection.

Another aspect of the invention relates to an article of manufacture comprising a composition effective in treating hepatitis C viral infection; and a packaging material comprising a label indicating that the composition can be used to treat hepatitis C virus infection; wherein the composition comprises a compound of formula (I) of the present invention or a pharmaceutically acceptable salt or ester thereof.

Another aspect of the invention relates to a method of inhibiting hepatitis C virus replication comprising exposing the virus to an effective amount of a compound of formula (I) or a salt or ester thereof under conditions wherein hepatitis C virus replication is inhibited.

The use of a compound of formula (I) or a salt or ester thereof to inhibit replication of hepatitis C virus is also included within the scope of the present invention.

Detailed Description

Definition of

Unless otherwise indicated, the definitions provided below are used herein:

as used herein, unless otherwise specified, the term "substituent" refers to an atom, group of atoms, or group that can be bonded to a carbon atom, heteroatom, or any other atom that can form part of a molecule or fragment thereof, that will be bonded to at least one hydrogen atom. Substituents mentioned in the context of a particular molecule or fragment thereof may be those that result in a chemically stable compound, as would be understood by one skilled in the art.

The term "(C) as used herein_1-n) Alkyl "(where n is an integer), alone or in combination with other groups, refers to an acyclic, straight chain, or branched alkyl group containing 1 to n carbon atoms and includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviation Me stands for methyl, Et for ethyl, Pr for propyl, iPr for 1-methylethyl, Bu for butyl and tBu for 1, 1-dimethylethyl.

The term "(C) as used herein_1-n) Alkylene "(where n is an integer), alone or with other groupsWhen combined, refers to a non-cyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms, and includes, but is not limited to, -CH₂-、-CH₂CH₂-、

And

the term "(C) as used herein_2-n) Alkenyl "(where n is an integer), alone or in combination with other groups, refers to an unsaturated, acyclic, straight or branched chain group containing 2 to n carbon atoms wherein at least 2 carbon atoms are bonded to each other through a double bond. Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise indicated, the term "(C)_2-n) Alkenyl "is understood to include possible individual stereoisomers, including but not limited to (E) and (Z) isomers, and mixtures thereof. When (C)_2-n) When an alkenyl group is substituted, unless otherwise indicated, it is understood that the substitution is on any carbon atom thereof (which would otherwise carry a hydrogen atom) such that the substitution results in a chemically stable compound, as understood by those skilled in the art.

The term "(C) as used herein_2-n) Alkynyl "(where n is an integer), alone or in combination with other groups, refers to an unsaturated, acyclic, straight or branched chain group containing 2 to n carbon atoms with at least 2 of the carbon atoms bonded to each other through triple bonds. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. When (C)_2-n) When an alkynyl group is substituted, unless otherwise indicated, it is understood to be substituted on any of its carbon atoms (which would otherwise carry a hydrogen atom) such that the substitution results in a chemically stable compound, as will be appreciated by those skilled in the art.

The term "(C) as used herein_3-m) Ring (C)Alkyl "(where m is an integer), alone or in combination with other groups, refers to cycloalkyl groups containing 3 to m carbon atoms and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "(C) as used herein_3-m) Cycloalkyl- (C)_1-n) Alkyl- "(wherein n and m are each an integer), alone or in combination with other groups, refers to an alkyl group having 1 to n carbon atoms as defined above which is itself substituted with a cycloalkyl group containing 3 to m carbon atoms as defined above and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl. When (C)_3-m) Cycloalkyl- (C)_1-n) When an alkyl-group is substituted, it is understood that the substituent may be attached to either the cycloalkyl or alkyl portion thereof or both, unless otherwise indicated.

The term "aryl", alone or in combination with other groups, as used herein, refers to a monoaromatic carbocyclic group of 6 carbon atoms which may in turn be fused to a second aromatic, saturated or unsaturated 5-or 6-membered carbocyclic ring. Aryl groups include, but are not limited to, aryl, indanyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and dihydronaphthyl.

The term "aryl- (C) as used herein_1-n) Alkyl- "(wherein n is an integer), alone or in combination with other groups, refers to an alkyl group having 1 to n carbon atoms as defined above which is itself substituted with an aryl group as defined above. Aryl radical- (C)_1-n) Examples of alkyl-include, but are not limited to, benzyl (benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl. When aryl is- (C)_1-n) When alkyl-is substituted, it is understood that the substituent may be attached to either the aryl or alkyl portion thereof or both, unless otherwise indicated.

The term "Het", alone or in combination with other groups, as used herein, refers to a 4-to 7-membered saturated having 1-4 heteroatoms each independently selected from O, N and SAn unsaturated or aromatic heterocycle, or a 7-to 14-membered saturated, unsaturated or aromatic heteromulticycle, if possible, having 1-5 heteroatoms each independently selected from O, N and S; wherein each N heteroatom (independently and if possible) may be present in an oxidized state such that the oxygen atoms are bonded to form an N-oxide, and wherein each S heteroatom (independently and if possible) may be present in an oxidized state such that they are further bonded to 1 or 2 oxygen atoms to form a group SO or SO₂Unless otherwise indicated. When the Het group is substituted, it is to be understood that the substituent may be attached to any carbon or heteroatom thereof (which would otherwise carry a hydrogen atom) unless otherwise indicated.

As used herein, unless otherwise indicated, the term "Het- (C)_1-n) Alkyl- "(wherein n is an integer), alone or in combination with other groups, refers to an alkyl group having 1 to n carbon atoms as defined above which is itself substituted with a Het substituent as defined above. Het- (C)_1-n) Examples of alkyl-groups include, but are not limited to, thienylmethyl, furylmethyl, piperidinylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, quinolinylpropyl, and the like, when Het- (C)_1-n) When alkyl-is substituted, it is understood that the substituent may be attached to either Het or alkyl moiety or both, unless otherwise indicated.

The term "heteroatom" as used herein refers to O, S or N.

The term "heterocycle", as used herein, alone or in combination with other groups, means a 4-to 7-membered saturated, unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms each independently selected from O, N and S, unless otherwise specified; or a monovalent group derived by removing a hydrogen atom therefrom. Examples of such heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, triazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, tetrazole, piperidine, piperazine, aza-heterocycleDiaza, diazaPyran, 1, 4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine-N-oxide, pyridazine, pyrimidine, and heterocycles of:andand saturated, unsaturated and aromatic derivatives thereof.

The term "heteromulticyclic" as used herein, alone or in combination with other groups, means, unless otherwise stated, a heterocyclic ring as defined above fused to one or more other rings (including carbocyclic, heterocyclic or any other ring); or a monovalent group derived by removing a hydrogen atom therefrom. Examples of such heterocyclic rings include, but are not limited to, indole, isoindole, benzimidazole, benzothiophene, benzofuran, benzodioxole, benzothiazole, quinoline, isoquinoline, naphthyridine, as well as the following heterocyclic rings:andand saturated, unsaturated and aromatic derivatives thereof.

The term "halogen" as used herein refers to a halogen substituent selected from fluorine, chlorine, bromine or iodine.

The term "(C) as used herein_1-n) Haloalkyl "(wherein n is an integer), alone or in combination with other groups, refers to an alkyl group having 1 to n carbon atoms as defined above wherein one or more hydrogen atoms are each replaced with a halogen substituent. (C)_1-n) Examples of haloalkyl groups include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroAnd (4) ethyl.

The term "-O- (C) is used interchangeably herein_1-n) Alkyl or (C)_1-n) Alkoxy "(where n is an integer), alone or in combination with other groups, means that the oxygen atom is bonded to an alkyl group having 1 to n carbon atoms as defined above. -O- (C)_1-n) Examples of alkyl groups include, but are not limited to, methoxy (CH)₃O-), ethoxy (CH)₃CH₂O-), propoxy (CH)₃CH₂CH₂O-), 1-methylethoxy (i-propoxy; (CH)₃)₂CH-O-) and 1, 1-dimethylethoxy (tert-butoxy; (CH)₃)₃C-O-). when-O- (C)_1-n) When alkyl is substituted, it is understood to be in (C) thereof_1-n) Alkyl moieties are partially substituted.

The term "-S- (C) is used interchangeably herein_1-n) Alkyl or (C)_1-n) Alkylthio groups "(where n is an integer), alone or in combination with other groups, is a sulfur atom bonded to an alkyl group having 1 to n carbon atoms as defined above. -S- (C)_1-n) Examples of alkyl groups include, but are not limited to, methylthio (CH)₃S-), ethylthio (CH)₃CH₂S-), propylthio (CH)₃CH₂CH₂S-), 1-methylethylthio (isopropylthio; (CH)₃)₂CH-S-) and 1, 1-dimethylethylthio (tert-butylthio; (CH)₃)₃C-S-). When is-S- (C)_1-n) Alkyl or oxidised derivatives thereof (e.g. -SO- (C)_1-n) Alkyl or-SO₂-(C_1-n) Alkyl) is substituted, it is understood that in (C) thereof_1-n) Alkyl moieties are partially substituted.

The term "oxo group (oxo)" as used herein refers to an oxygen atom (═ O) as a substituent, attached to a carbon atom through a double bond.

The term "thio group (thioxo)" as used herein refers to a sulfur atom (═ S) as a substituent, attached to a carbon atom through a double bond.

The term "imino" as used herein refers to an NH group (═ NH) as a substituent, attached to a carbon atom through a double bond.

The term "cyano" or "CN", as used herein, refers to a nitrogen atom (C ≡ N) that is linked to a carbon atom by a triple bond.

The term "COOH" as used herein refers to a carboxyl group (-C (═ O) -OH). It is well known to those skilled in the art that the carboxyl group may be replaced by an equivalent functional group. Examples of equivalent functional groups encompassed by the present invention include, but are not limited to, esters, amides, imides, boronic acids, phosphonic acids, phosphoric acids, tetrazoles, triazoles, N-acyl sulfonamides (RCONHSO)₂NR₂) And N-acyl sulfonamides (RCONHSO)₂R)。

The term "functional group equivalent" as used herein refers to an atom or group that can replace another atom or group with similar electronic, hybridization, or binding properties.

The term "protecting group" as used herein refers to protecting Groups that may be used during synthetic transformations, including but not limited to the examples listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and its latest versions, which are incorporated herein by reference.

The following symbolsUsed in the sub-formula are chemical bonds to the rest of the defined molecule.

The term "salt thereof" as used herein refers to any acid and/or base addition salt of a compound of the present invention, including but not limited to pharmaceutically acceptable salts thereof.

The term "pharmaceutically acceptable salt" as used herein, means a salt of a compound of the invention which is, 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, are generally water or oil soluble or dispersible, and are effective for their intended use. The term includes medicamentsAcid addition salts and pharmaceutically acceptable base addition salts. Suitable salts are listed, for example, in s.m. berge et al, j.pharm.sci., 1977,66pp.1-19, which is incorporated herein by reference.

The term "pharmaceutically acceptable acid addition salts" as used herein refers to those salts which retain the biological potency and properties of the free base and which are not biologically or otherwise undesirable with inorganic acids including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with organic acids including, but not limited to, acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid (glycophospho acid), hemisulfuric acid (hemisulfinic acid), hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, carboxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, Oxalic acid, pamoic acid (pamoic acid), pectic acid (pectic acid), phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.

The term "pharmaceutically acceptable base addition salts" as used herein refers to those salts which retain the biological potency and properties of the free acid and which are not biologically or otherwise undesirable formed with inorganic bases including, but not limited to, ammonia, or the hydroxides, carbonates or bicarbonates of ammonium or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts formed with: primary, secondary and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, meglumine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N-dibenzylphenethylamine, diphenylhydroxymethylamine (1-ephenamine), N, N' -dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

The term "ester thereof" as used herein refers to any ester of the compounds of the present invention wherein any-COOH substituent is replaced by a-COOR substituent in the molecule, wherein the R portion of the ester is any carbon-containing group that forms a stable ester group, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, each of which is optionally further substituted. Term(s) for

"esters thereof" includes but is not limited to pharmaceutically acceptable esters thereof.

The term "pharmaceutically acceptable ester" as used herein refers to an ester of a compound of the present invention wherein any-COOH substituent of the molecule is replaced by a-COOR substituent, wherein the R moiety of the ester is selected from the group consisting of: alkyl (including but not limited to methyl, ethyl, propyl, 1-methylethyl, 1-dimethylethyl, butyl); alkoxyalkyl (including but not limited to methoxymethyl); acyloxyalkyl (including but not limited to acetoxymethyl); aralkyl (including but not limited to benzyl); aryloxyalkyl (including but not limited to phenoxymethyl); and optionally halogen, (C)_1-4) Alkyl or (C)_1-4) Alkoxy substituted aryl groups (including but not limited to phenyl). Other suitable esters can be found in Design of produgs, Bundgaard, h.ed.elsevier (1985), which is incorporated herein by reference. Such pharmaceutically acceptable esters will generally hydrolyze in vivo when injected into a mammal and convert to the acid form of the compounds of the invention. With regard to the above-mentioned esters,unless otherwise specified, any alkyl group present preferably contains from 1 to 16 carbon atoms, more preferably from 1 to 6 carbon atoms. Any aryl group present in such esters preferably comprises phenyl. In particular the ester may be (C)_1-16) Alkyl esters, unsubstituted benzyl esters or substituted by at least one halogen, (C)_1-6) Alkyl, (C)_1-6) Alkoxy-, nitro-or trifluoromethyl-substituted benzyl esters.

The term "mammal" as used herein includes humans as well as non-human mammals susceptible to infection by the hepatitis C virus. Non-human mammals include, but are not limited to, farm animals such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-farm animals.

As used herein, "treating" or "treatment" refers to administering a compound or composition of the present invention to reduce or eliminate the symptoms of a hepatitis C viral disease and/or to reduce the viral load of a patient. The term "treating" also includes administering a compound or composition of the invention to an individual after exposure to a virus but before symptoms of the disease have occurred, and/or before the virus is detected in the blood, to avoid symptoms of the disease from occurring and/or to avoid the virus reaching detectable amounts in the blood.

The term "antiviral agent" as used herein refers to an agent effective to inhibit the formation and/or replication of a virus in a mammal, including, but not limited to, agents that interfere with host or viral mechanisms required for the formation and/or replication of a virus in a mammal.

By "therapeutically effective amount" is meant an amount sufficient to treat a disease state, condition, or disorder with a compound of the present invention when administered to a patient in need thereof. Such amounts will be sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or physician. The amount of a compound of the present invention that constitutes a therapeutically effective amount will vary depending on the following factors: the compound and its physiological activity, the composition for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease state or disorder to be treated and its severity, and the age, body weight, health, sex and diet of the patient. Such therapeutically effective amounts can generally be determined by those skilled in the art in view of their own knowledge, the current state of the art, and the present disclosure.

Preferred embodiments

In the following preferred embodiments, the groups and substituents of the compounds of formula (I) are described in detail below:

X：

X-A: in one embodiment, X is O.

X-B: in another embodiment, X is S.

X-C: in another embodiment, X is O or S.

Any and every individual definition of X as set forth herein can be combined with R as set forth herein²、R²⁰、R³、R^3a、R^3b、R⁵And R⁶Any and each of which define combinations.

R²：

R²-A: in one embodiment, R²Is Het or aryl, optionally substituted by 1-5R²⁰Substituted by a substituent, wherein R²⁰As defined herein.

R²-B: in another embodiment, R²Is Het, wherein Het is a 5-or 6-membered heterocycle containing 1 to 3 heteroatoms each independently selected from O, N and S, or a 9-or 10-membered bicyclic heterocycle containing 1 to 3 heteroatoms each independently selected from O, N and S; wherein Het is optionally substituted by 1-5R²⁰Substituted by a substituent, wherein R²⁰As defined herein.

R²-C: in another embodiment, R²Is Het, wherein Het is a 5-or 6-membered heteroaromatic ring containing 1 or 2N heteroatoms, or a 9-or 10-membered bicyclic heterocyclic polycyclic ring containing 1 or 2N heteroatoms; wherein Het is optionally substituted by 1-3R²⁰Substituted by a substituent, wherein R²⁰As defined herein.

R²-D: in another embodiment, R²Is Het selected from the following formulae:

and

wherein Het is optionally substituted by 1-3R²⁰Substituted by a substituent, wherein R²⁰As defined herein.

R²-E: in another embodiment, R²Is Het selected from the following formulae:

and

R²-F: in another embodiment, R²Het of the formula:

R²-G: in another embodiment, R²Having the formula:

wherein R is²¹As defined below:

R²¹-A: in this embodiment, R²¹Selected from H, halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl and-O- (C)_1-6) A haloalkyl group.

R²¹-B: in this embodiment, R²¹Selected from H, Cl, Br, CH₃、CHF₂、CF₃Cyclopropyl, cyclobutyl and-OCF₃。

R²¹-C: in this embodiment, R²¹Is H, CHE₂、CF₃Or a cyclopropyl group.

R²¹-D: in this embodiment, R²¹Is H or CF₃。

R²¹-E: in this embodiment, R²¹Is CHF₂Or CF₃。

R²¹-F: in this embodiment, R²¹Is CF₃；

And R is²⁰As defined herein.

R as set forth herein²¹Any and each of the definitions of (a) and (b) can be combined withR as set forth herein²、R²⁰、R³、R^3a、R^3b、R⁵And R⁶Any and each of which define combinations.

R²-H: in another embodiment, R²Is a group of the formula:

wherein R is²⁰As defined herein.

R²-I: in another embodiment, R²Is naphthyl or phenyl, the phenyl being optionally substituted by 1-3R²⁰Is substituted in which R²⁰As defined herein.

R²-J: in another embodiment, R²Is phenyl, optionally substituted with 1-3R²⁰Is substituted in which R²⁰As defined herein.

R²-K: in an alternative embodiment, R²Is a group of the formula:

wherein R is²¹And R²⁰As defined herein.

R²-L: in another embodiment, R²Is a group of the formula:

wherein R is²⁰As defined herein.

R²-M: in another embodiment, R²Is phenyl or Het, all optionally substituted by 1 to 3R²⁰Substituted by a substituent, wherein R²⁰As defined herein; and Het is a 5-or 6-membered heteroaromatic ring containing 1 or 2N heteroatoms, or a 9-or 10-membered bicyclic heterocyclic polycyclic ring containing 1 or 2N heteroatoms.

R²-N: in another embodiment, R²Is phenyl or Het, wherein Het is selected from the following formulae:

and

wherein R is²Optionally substituted by 1-3R²⁰Substituted by a substituent, wherein R²⁰As defined herein.

R²-O: in another embodiment, R²Is phenyl or Het, wherein Het is selected from the following formulae:

and

R²-P: in another alternative embodiment, R²Selected from the following groups:

and

wherein R is²¹And R²⁰As defined herein.

R²-Q: in another alternative embodiment, R²Selected from the following groups:

and

wherein R is²⁰As defined herein.

R as set forth herein²Any and all respective definitions of (a) may be as set forth herein X, R²⁰、R³、R^3a、R^3b、R⁵And R⁶Any and each of which define combinations.

R²⁰-A：

R²⁰-A: in one embodiment, R²⁰Selected from:

a) halogen, cyano or nitro;

wherein (C) is_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl and (C)_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, optionally substituted by-O- (C)_1-6) Alkyl substituted- (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl radical)₂Aryl, - (C)_1-6) Alkyl-aryl, Het, - (C)_1-6) alkyl-Het; and is

ii) optionally-OH-substituted (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl or-O- (C)_1-6) An alkyl group; and

c)-N(R⁸)R⁹、-C(＝O)-N(R⁸)R⁹、-O-C(＝O)-N(R⁸)R⁹、-SO₂-N(R⁸)R⁹、-(C_1-6) alkylene-N (R)⁸)R⁹、-(C_1-6) alkylene-C (═ O) -N (R)⁸)R⁹、-(C_1-6) alkylene-O-C (═ O) -N (R)⁸)R⁹Or- (C)_1-6) alkylene-SO₂-N(R⁸)R⁹；

Wherein (C) is_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, - (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂；

R⁹Independently at each occurrence selected from R⁷、-O-(C_1-6) Alkyl, - (C)_1-6) alkylene-R⁷、-SO₂-R⁷、-C(＝O)-R⁷、-C(＝O)OR⁷and-C (═ O) N (R)⁸)R⁷(ii) a Wherein R is⁷And R⁸As defined above;

or R⁸And R⁹And the N to which they are attached are taken together to form a 4-to 7-membered heterocyclic ring, optionally further containing 1-3 heteroatoms each independently selected from N, O and S, which isWherein each S heteroatom may be present independently and in the oxidation state where possible, and is bonded to 1 or 2 oxygen atoms to form a group SO or SO₂；

Wherein the heterocycle is optionally substituted with 1-3 substituents each independently selected from the group consisting of: (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, halogen, oxo, -OH, SH, -O (C)_1-6) Alkyl, -S (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl, -NH₂、-NH(C_1-6) Alkyl, -N ((C)_1-6) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -C (═ O) (C)_1-6) Alkyl and-NHC (═ O) - (C)_1-6) An alkyl group.

R²⁰-B: in another embodiment, R²⁰Selected from:

b)R⁷、-C(＝O)-R⁷、-C(＝O)-O-R⁷、-(C_1-6) alkylene-R⁷、-(C _1-6) alkylene-C (═ O) -R⁷、-(C _1-6) alkylene-C (═ O) -O-R⁷、-(C _1-6) alkylene-O-R⁷、-(C _1-6) alkylene-S-R⁷；

c)-N(R⁸)R⁹、-(C_1-6) alkylene-N (R)⁸)R⁹、-(C_1-6) alkylene-C (═ O) -N (R)⁸)R⁹Or- (C)_1-6) alkylene-O-C (═ O) -N (R)⁸)R⁹(ii) a Wherein (C) is_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, - (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl radicalCyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂；

R⁸Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and R is⁹Such as R⁷Is defined in which R is⁷As defined above;

or R⁸And R⁹And the N to which they are attached are taken together to form a 4-to 7-membered heterocyclic ring, which optionally further contains 1-3 heteroatoms each independently selected from N, O and S, wherein each S heteroatom may be present independently and where possible in an oxidized state, bonded to 1 or 2 oxygen atoms to form a group SO or SO₂；

R²⁰-C: in another embodiment, R²⁰Selected from:

b)R⁷、-(C_1-6) alkylene-R⁷、-(C_1-6) alkylene-O-R⁷、-(C_1-6) alkylene-S-R⁷(ii) a Wherein R is⁷Independently selected from H, (C) at each occurrence_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl, aryl and Het;

wherein (C) is_1-6) Alkyl, (C)_1-6) A halogenated alkyl group,(C_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl and (C)_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, optionally substituted by-O- (C)_1-6) Alkyl substituted- (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl radical)₂、Het、-(C_1-6) alkyl-Het; and is

i) halogen, (C)_3-7) Cycloalkyl group, (C)_1-6) Haloalkyl, -C (═ O) -NH₂、-C(＝O)-NH(C_1-4) Alkyl, -C (═ O) -N ((C)_1-4) Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C _1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group;

c)-N(R⁸)R⁹Or- (C)_1-6) alkylene-N (R)⁸)R⁹(ii) a Wherein (C) is_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, - (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂；

R⁹Such as R⁷Is defined in which R is⁷As defined above.

R²⁰-D: in another embodiment, R²⁰Selected from:

b)R⁷or- (C)_1-6) alkylene-R⁷

Wherein R is⁷Independently selected from H, (C) at each occurrence_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl, phenyl and Het;

wherein each phenyl and Het is optionally substituted with 1 to 3 substituents each independently selected from:

i) halogen, (C)_3-7) Cycloalkyl group, (C)_1-6) Haloalkyl, -C (═ O) -NH₂、-C(＝O)-NH(C_1-4) Alkyl, -C (═ O) -N ((C)_1-4) Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group; and

c)-N(R⁸)R⁹Or- (C)_1-6) alkylene-N (R)⁸)R⁹；

R^{8 is in}In each caseIndependently selected from H, (C)_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

R⁹As shown by R⁷Definitions in which R⁷As defined above.

R²⁰-E: in another embodiment, R²⁰Selected from:

b)R⁷or- (C)_1-6) alkylene-R⁷

i) halogen, (C)_3-7) Cycloalkyl group, (C)_1-6) Haloalkyl, -C (═ O) -NH₂、-C(＝O)-NH(C_1-4) Alkyl, -C (═ O) -N ((C)_1-4)Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group; and

ii) optionally-OH-substituted (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl or-O- (C)_1-6) An alkyl group;

wherein Het is selected from:

andand is

c)-N(R⁸)R⁹Or- (C)_1-6) alkylene-N (R)⁸)R⁹

R⁹Is as R⁷Is defined in which R is⁷As defined above.

R²⁰-F: in another embodiment, R²⁰Selected from:

b)-(C_1-3) alkylene-R⁷；

Wherein R is⁷Is Het; wherein Het is a 5-or 6-membered heterocycle containing 1-4 heteroatoms each independently selected from N, O and S, or Het is a 9-or 10-membered heteropolycycle containing 1-4 heteroatoms each independently selected from N, O and S; wherein each N heteroatom is present independently and if possible in an oxidized state, thereby being bonded again to an oxygen atom to form an N-oxide group, and wherein each S heteroatom is present independently and if possible in an oxidized state, thereby being bonded again to 1 or 2 oxygen atoms to form a group SO or SO₂；

Wherein said Het is optionally substituted with 1-3 substituents each independently selected from the group consisting of: halogen, cyano, oxo, imino, -OH, -O- (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) A cycloalkyl group, a,-N((C_1-4) Alkyl radical)₂、-NH-C(＝O)(C_1-4) Alkyl, (C)_1-6) Alkyl and Het, wherein Het is a 5-or 6-membered heterocycle containing 1 to 4 heteroatoms each independently selected from N, O and S.

R²⁰-G: in another embodiment, R²⁰Selected from:

b)-CH₂-R⁷、-CH₂CH₂-R⁷，

wherein R is⁷Is Het; wherein Het is selected from:

andand is

Wherein said Het is optionally substituted with 1-3 substituents each independently selected from the group consisting of: halogen, cyano, oxo, imino, -OH, -O- (C)_1-6) Alkyl, -NH₂、-NH(C_1-4)

Alkyl, -N ((C)_1-4) Alkyl) 2, -NH-C (═ O) (C)_1-4) Alkyl and (C)_1-6) An alkyl group. R²⁰-H: in another embodiment, R²⁰Selected from:

b)-CH₂-R⁷、-CH₂CH₂-R⁷，

wherein R is⁷Is Het; wherein Het is selected from:

andand is

Wherein said Het is optionally substituted with 1-3 substituents each independently selected from the group consisting of: halogen, - (C)_1-6) Alkyl, -O- (C)_1-6) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂And (C)_1-6) An alkyl group.

R²⁰-I: in another embodiment, R²⁰Selected from:

and

R²⁰-J: in another embodiment, R²⁰Selected from:

and

r as set forth herein²⁰Any and all respective definitions of (a) may be as set forth herein X, R²、R³、R^3a、R^3b、R⁵And R⁶Any and each of which define combinations.

R³：

R³-A: in one embodiment, R³Selected from H, halogen, CN, (C)_1-4) Alkyl, -OH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂。

R³-B: in another embodiment, R³Selected from H, halogen, CN, (C)_1-4) Alkyl, -O- (C)_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)₂。

R³-C: in another embodiment, R³Selected from H, halogen, (C)_1-4) Alkyl and CN.

R³-D: in another embodiment, R³Selected from H, F, Cl, CH₃And CN.

R³-E: in another embodiment, R³Selected from H, F, Cl and CH₃。

R³-F: in another embodiment, R³Selected from H, F and CH₃。

R³-G: in another embodiment, R³Is H or F.

R³-H: in another embodiment, R³Is H.

R as set forth herein³Any and all respective definitions of (a) may be as set forth herein X, R²⁰、R²、R^3a、R^3b、R⁵And R⁶Any and each of which define combinations.

R^3a：

R^3a-A: in one embodiment, R^3aSelected from H, halogen, CN, (C)_1-4) Alkyl, -OH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂。

R^3a-B: in another embodiment, R^3aSelected from H, halogen, CN, (C)_1-4) Alkyl, -O- (C)_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)²。

R^3a-C: in another embodiment, R^3aSelected from H, halogen, (C)_1-4) Alkyl and CN.

R^3a-D: in another embodiment, R^3aSelected from H, F, Cl, CH₃And CN.

R^3a-E: in another embodiment, R^3aSelected from H, F, Cl and CH₃。

R^3a-F: in another embodiment, R^3aSelected from H, F and CH₃。

R^3a-G: in another embodiment, R^3aIs H or F.

R^3a-H: in another embodiment, R^3aIs H.

R as set forth herein^3aAny and all respective definitions of (a) may be as set forth herein X, R²⁰、R²、R³、R^3b、R⁵And R⁶Any and each of which define combinations.

R^3b：

R^3b-A: in one embodiment, R^3bSelected from H, halogen, CN, (C)_1-4) Alkyl, -OH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl and-N ((C)_1-4) Alkyl radical)₂。

R^3b-B: in another embodiment, R^3bSelected from H, halogen, CN, (C)_1-4) Alkyl, -O- (C)_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)₂。

R^3b-C: in another embodiment, R^3bSelected from H, halogen, (C)_1-4) Alkyl and CN.

R^3b-D: in another embodiment, R^3bSelected from H, F, Cl, CH₃And CN.

R^3b-E: in another embodiment, R^3bSelected from H, F, Cl and CH₃。

R^3b-F: in another embodiment, R^3bSelected from H, F and CH₃。

R^3b-G: in another embodiment, R^3bIs H or F.

R^3b-H: in another embodiment, R^3bIs H.

R as set forth herein^3bAny and all respective definitions of (a) may be as set forth herein X, R²⁰、R²、R³、R^3a、R⁵And R⁶Any and each of which define combinations.

R⁵：

R⁵-A: in one embodiment, R⁵Is O-R⁵²Mono-, di-or tri-substituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵²Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, said aryl and Het being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution.

R⁵-B: in one embodiment, R⁵Is O-R⁵²Mono-, di-or tri-substituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl or (C)_1-6) Alkyl-aryl, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵²Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl or (C)_1-6) Alkyl-aryl, said aryl being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution.

R⁵-C: in one embodiment, R⁵Is O-R⁵²Mono-or disubstituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl or (C)_1-6) Alkyl-aryl, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵²Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl or

(C_1-6) Alkyl-aryl, said aryl being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution. R⁵-D: in one embodiment, R⁵Is O-R⁵²Mono-or disubstituted R⁵¹，

Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7)Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl radical, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵-E: in one embodiment, R⁵Is O-R⁵²Mono-or disubstituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, optionally substituted by (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

R⁵²Is (C)_1-6) Alkyl, aryl or (C)_1-6) Alkyl-aryl, said arylOptionally is (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution.

R⁵-F: in one embodiment, R⁵Is O-R⁵²Mono-or disubstituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, optionally substituted by (C)_1-6) Alkyl is substituted, and

R⁵²is (C)_1-6) Alkyl, aryl or (C)_1-6) Alkyl-aryl, said aryl being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution.

R⁵-G: in one embodiment, R⁵Is O-R⁵²Mono-or disubstituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, optionally substituted by (C)_1-6) Alkyl is substituted, and R⁵²Is (C)_1-6) An alkyl group.

R⁵-H: in another embodiment, R⁵Selected from:

and

r as set forth herein⁵Any and all respective definitions of (a) may be as set forth herein X, R²⁰、R²、R³、R^3a、R^3bAnd R⁶Any and each of which define combinations.

R⁶：

R⁶-A: in one embodiment, R⁶Is (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het; optionally substituted with 1-5 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -SH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl and-N (R)⁸)R⁹(ii) a Wherein R is⁸Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

R⁹Independently at each occurrence selected from R⁷、-O-(C_1-6) Alkyl, - (C)_1-6) alkylene-R⁷、-SO₂-R⁷、-C(＝O)-R⁷、-C(＝O)OR⁷and-C (═ O) N (R)⁸)R⁷(ii) a Wherein R is⁷And R⁸

As defined above;

R⁶-B: in another alternative embodiment, R⁶Is (C)_3-7) Cycloalkyl, arylOr Het, optionally substituted by 1-3 substituents each independently selected from halogen, (C)_1-6) Alkyl and (C)_1-6) Substituted by a substituent of a haloalkyl group.

R⁶-C: in another alternative embodiment, R⁶Is (C)_3-7) Cycloalkyl, phenyl or Het, optionally substituted by 1-3 substituents each independently selected from halogen, (C)_1-6) Alkyl and (C)_1-6) Substituted with a substituent of haloalkyl;

wherein Het is selected from:

and

R⁶-D: in another alternative embodiment, R⁶Is (C)_5-6) Cycloalkyl, phenyl or Het, optionally substituted by 1 to 3 substituents each independently selected from halogen, (C)_1-4) Alkyl and (C)_1-4) Substituted with a substituent of haloalkyl; wherein

Het is a 4-to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 3 nitrogen heteroatoms.

R⁶-E: in another embodiment, R⁶Is phenyl, cyclohexyl or pyridine, optionally substituted by 1-3 substituents each independently selected from halogen, (C)_1-4) Alkyl and (C)_1-4) Substituted by a substituent of a haloalkyl group.

R⁶-F: in another embodiment, R⁶Is phenyl, optionally substituted by 1 to 3 substituents each independently selected from halogen and (C)_1-4) Alkyl substituents.

R⁶-G: in another embodiment, R⁶Is composed ofOptionally substituted with 1-3 substituents each independently selected from halogen.

R⁶-H: in another embodiment, R⁶Is composed of

R⁶-I: in another embodiment, R⁶Selected from:

and

r as set forth herein⁶Any and all respective definitions of (a) may be as set forth herein X, R²、R²⁰、R³、R^3a、R^3bAnd R⁵Any and each of which define combinations.

Examples of preferred subclass embodiments of the invention are set forth in the following table, wherein the various substituents of the various embodiments are defined according to the definitions set forth above:

detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-1

X-A

R²-A

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-I

E-2

X-A

R²-A

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-A

E-3

X-A

R²-A

R²⁰-I

R³-A

R^3a-F

R^3b-A

R⁵-A

R⁶-F

E-4

X-A

R²-A

R²⁰-B

R³-E

R^3a-H

R^3b-C

R⁵-B

R⁶-G

E-5

X-A

R²-A

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-C

R⁶-I

E-6

X-A

R²-A

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-H

E-7

X-A

R²-A

R²⁰-J

R³-B

R^3a-B

R^3b-G

R⁵-H

R⁶-E

E-8

X-A

R²-B

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-F

E-9

X-A

R²-B

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-G

E-10

X-A

R²-B

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-I

E-11

X-B

R²-B

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-A

R⁶-I

E-12

X-A

R²-C

R²⁰-F

R³-A

R^3a-D

R^3b-D

R⁵-A

R⁶-A

E-13

X-A

R²-C

R²⁰-A

R³-A

R^3a-G

R^3b-A

R⁵-C

R⁶-F

E-14

X-A

R²-C

R²⁰-B

R³-B

R^3a-A

R^3b-B

R⁵-D

R⁶-G

E-15

X-A

R²-C

R²⁰-G

R³-F

R^3a-F

R^3b-E

R⁵-H

R⁶-H

E-16

X-A

R²-C

R²⁰-E

R³-D

R^3a-E

R^3b-F

R⁵-H

R⁶-G

E-17

X-A

R²-C

R²⁰-B

R³-B

R^3a-H

R^3b-B

R⁵-H

R⁶-E

E-18

X-A

R²-D

R²⁰-D

R³-C

R^3a-F

R^3b-G

R⁵-E

R⁶-C

E-19

X-A

R²-D

R²⁰-E

R³-G

R^3a-E

R^3b-A

R⁵-G

R⁶-C

E-20

X-B

R²-D

R²⁰-E

R³-G

R^3a-E

R^3b-G

R⁵-G

R⁶-C

E-21

X-A

R²-D

R²⁰-J

R³-H

R^3a-E

R^3b-H

R⁵-H

R⁶-D

E-22

X-A

R²-E

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-I

Detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-23

X-A

R²-E

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-A

E-24

X-A

R²-E

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-F

E-25

X-A

R²-E

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-G

E-26

X-B

R²-E

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-C

R⁶-F

E-27

X-C

R²-E

R²⁰-H

R³-A

R^3a-H

R^3b-H

R⁵-D

R⁶-F

E-28

X-C

R²-E

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-F

E-29

X-A

R²-F

R²⁰-C

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁶-G

E-30

X-A

R²-F

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-I

E-31

X-A

R²-F

R²⁰-J

R³-B

R^3a-B

R^3b-G

R⁵-A

R⁶-E

E-32

X-A

R²-F

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-A

R⁶-I

E-33

X-A

R²-F

R²⁰-B

R³-E

R^3a-H

R^3b-C

R⁵-B

R⁶-G

E-34

X-A

R²-F

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-C

E-35

X-A

R²-F

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-F

R⁶-D

E-36

X-A

R²-G

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-A

R⁶-H

E-37

X-A

R²-G

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-C

R⁶-H

E-38

X-A

R²-G

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-39

X-A

R²-G

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-I

E-40

X-A

R²-G

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-41

X-A

R²-G

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-42

X-A

R²-H

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-43

X-A

R²-H

R²⁰-F

R³-A

R^3a-E

R^3b-B

R⁵-B

R⁶-F

E-44

X-A

R²-H

R²⁰-B

R³-F

R^3a-C

R^3b-H

R⁵-C

R⁶-G

E-45

X-A

R²-H

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-46

X-A

R²-H

R²⁰-D

R³-F

R^3a-H

R^3b-H

R⁵-H

R⁶-G

E-47

X-A

R²-H

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-E

E-48

X-A

R²-H

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-F

E-49

X-A

R²-I

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁵-A

R⁶-G

E-50

X-A

R²-I

R²⁰-B

R³-E

R^3a-H

R^3b-C

R⁵-B

R⁶-G

E-51

X-A

R²-I

R²⁰-J

R³-B

R^3a-B

R^3b-G

R⁵-H

R⁶-E

E-52

X-A

R²-J

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-I

E-53

X-A

R²-J

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-A

R⁶-H

E-54

X-A

R²-J

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-B

R⁶-H

E-55

X-A

R²-J

R²⁰-F

R³-A

R^3a-E

R^3b-B

R⁵-B

R⁶-F

Detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-56

X-C

R²-J

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-C

R⁶-H

E-57

X-A

R²-J

R²⁰-H

R³-G

R^3a-D

R^3b-H

R⁵-H

R⁶-A

E-58

X-A

R²-J

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-I

E-59

X-B

R²-J

R²⁰-H

R³-G

R^3a-D

R^3b-H

R⁵-H

R⁶-A

E-60

X-A

R²-K

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-G

E-61

X-B

R²-K

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-62

X-A

R²-K

R²⁰-F

R³-A

R^3a-C

R^3b-B

R⁵-B

R⁶-F

E-63

X-A

R²-K

R²⁰-B

R³-D

R^3a-C

R^3b-H

R⁵-C

R⁶-G

E-64

X-C

R²-K

R²⁰-F

R³-C

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-65

X-A

R²-K

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-F

R⁶-A

E-66

X-A

R²-K

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-D

E-67

X-A

R²-K

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-A

R⁶-I

E-68

X-A

R²-K

R²⁰-B

R³-E

R^3a-H

R^3b-D

R⁵-C

R⁶-A

E-69

X-A

R²-L

R²⁰-A

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-G

E-70

X-A

R²-L

R²⁰-D

R³-D

R^3a-D

R^3b-H

R⁵-C

R⁶-A

E-71

X-C

R²-L

R²⁰-A

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-G

E-72

X-A

R²-L

R²⁰-G

R³-G

R^3a-A

R^3b-E

R⁵-H

R⁶-E

E-73

X-A

R²-L

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-74

X-A

R²-L

R²⁰-G

R³-G

R^3a-E

R^3b-H

R⁵-H

R⁶-I

E-75

X-A

R²-M

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-I

E-76

X-A

R²-M

R²⁰-B

R³-E

R^3a-H

R^3b-C

R⁵-B

R⁶-G

E-77

X-A

R²-M

R²⁰-J

R³-D

R^3a-B

R^3b-G

R⁵-H

R⁶-E

E-78

X-A

R²-M

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-H

E-79

X-A

R²-M

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-E

R⁶-I

E-80

X-A

R²-M

R²⁰-J

R³-A

R^3a-F

R^3b-A

R⁵-F

R⁶-F

E-81

X-B

R²-M

R²⁰-I

R³-A

R^3a-F

R^3b-A

R⁵-F

R⁶-F

E-82

X-C

R²-M

R²⁰-I

R³-A

R^3a-F

R^3b-A

R⁵-F

R⁶-F

E-83

X-A

R²-N

R²⁰-D

R³-F

R^3a-D

R^3b-H

R⁵-A

R⁶-A

E-84

X-A

R²-N

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-85

X-A

R²-N

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-F

E-86

X-A

R²-N

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-87

X-A

R²-N

R²⁰-G

R³-G

R^3a-A

R^3b-C

R⁵-H

R⁶-A

E-88

X-A

R²-N

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-B

Detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-89

X-A

R²-N

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-90

X-A

R²-O

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-91

X-A

R²-O

R²⁰-F

R³-A

R^3a-E

R^3b-B

R⁵-B

R⁶-F

E-92

X-A

R²-O

R²⁰-B

R³-F

R^3a-C

R^3b-H

R⁵-C

R⁶-G

E-93

X-A

R²-O

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-F

E-94

X-A

R²-O

R²⁰-D

R³-D

R^3a-D

R^3b-H

R⁵-C

R⁶-A

E-95

X-A

R²-O

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-96

X-A

R²-O

R²⁰-G

R³-G

R^3a-A

R^3b-C

R⁵-H

R⁶-E

E-97

X-A

R²-O

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-98

X-A

R²-O

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-99

X-A

R²-O

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-100

X-A

R²-O

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-101

X-A

R²-O

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-A

R⁶-H

E-102

X-A

R²-O

R²⁰-J

R³-H

R^3a-H

R^3b-H

R⁵-C

R⁶-H

E-103

X-A

R²-O

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-F

E-104

X-A

R²-O

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-G

E-105

X-A

R²-O

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-106

X-A

R²-O

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-F

E-107

X-A

R²-O

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-G

E-108

X-A

R²-O

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-109

X-A

R²-O

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-F

E-110

X-A

R²-O

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-G

E-111

X-A

R²-O

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-I

E-112

X-A

R²-O

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-A

R⁶-H

E-113

X-A

R²-P

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-114

X-A

R²-P

R²⁰-F

R³-A

R^3a-E

R^3b-B

R⁵-B

R⁶-F

E-115

X-A

R²-P

R²⁰-B

R³-F

R^3a-C

R^3b-H

R⁵-C

R⁶-G

E-116

X-A

R²-P

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-F

E-117

X-A

R²-P

R²⁰-D

R³-D

R^3a-D

R^3b-H

R⁵-C

R⁶-A

E-118

X-B

R²-P

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-F

E-119

X-B

R²-P

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-E

E-120

X-A

R²-P

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-121

X-A

R²-P

R²⁰-G

R³-G

R^3a-A

R^3b-C

R⁵-H

R⁶-E

Detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-122

X-A

R²-P

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-C

R⁶-H

E-123

X-A

R²-P

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-D

R⁶-H

E-124

X-A

R²-P

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-H

E-125

X-A

R²-P

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-126

X-A

R²-P

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-F

E-127

X-A

R²-P

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-G

E-128

X-A

R²-P

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-I

E-129

X-A

R²-P

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-H

E-130

X-A

R²-Q

R²⁰-A

R³-E

R^3a-A

R^3b-D

R⁵-A

R⁶-E

E-131

X-A

R²-Q

R²⁰-F

R³-A

R^3a-E

R^3b-B

R⁵-B

R⁶-F

E-132

X-A

R²-Q

R²⁰-B

R³-F

R^3a-C

R^3b-H

R⁵-C

R⁶-G

E-133

X-A

R²-Q

R²⁰-C

R³-C

R^3a-H

R^3b-F

R⁵-C

R⁶-F

E-134

X-A

R²-Q

R²⁰-D

R³-D

R^3a-D

R^3b-H

R⁵-C

R⁶-A

E-135

X-A

R²-Q

R²⁰-F

R³-B

R^3a-G

R^3b-F

R⁵-D

R⁶-A

E-136

X-A

R²-Q

R²⁰-H

R³-B

R^3a-B

R^3b-B

R⁵-E

R⁶-I

E-137

X-A

R²-Q

R²⁰-G

R³-G

R^3a-A

R^3b-C

R⁵-H

R⁶-E

E-138

X-A

R²-Q

R²⁰-H

R³-A

R^3a-A

R^3b-C

R⁵-H

R⁶-G

E-139

X-A

R²-Q

R²⁰-I

R³-D

R^3a-D

R^3b-H

R⁵-H

R⁶-H

E-140

X-A

R²-Q

R²⁰-I

R³-E

R^3a-E

R^3b-F

R⁵-H

R⁶-K

E-141

X-A

R²-Q

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-H

E-142

X-A

R²-Q

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-F

R⁶-H

E-143

X-A

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-F

R⁶-H

E-144

X-A

R²-Q

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁵-F

R⁶-H

E-145

X-A

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-H

E-146

X-A

R²-Q

R²⁰-J

R³-H

R^3a-H

R^3b-H

R⁵-E

R⁶-H

E-147

X-A

R²-Q

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-F

E-148

X-A

R²-Q

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-G

E-149

X-A

R²-Q

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-E

R⁶-I

E-150

X-A

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R^5-D

R⁶-F

E-151

X-A

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-G

E-152

X-A

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-D

R⁶-I

E-153

X-A

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-F

E-154

X-A

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-G

Detailed description of the preferred embodiments

X

R²

R²⁰

R³

R^3a

R^3b

R⁵

R⁶

E-155

X-A

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-I

E-156

X-B

R²-Q

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-157

X-B

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-158

X-B

R²-Q

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-159

X-B

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-H

R⁶-H

E-160

X-C

R²-Q

R²⁰-H

R³-H

R^3a-H

R^3b-H

R⁵-G

R⁶-H

E-161

X-C

R²-Q

R²⁰-I

R³-G

R^3a-H

R^3b-H

R⁵-G

R⁶-H

E-162

X-C

R²-Q

R²⁰-I

R³-H

R^3a-H

R^3b-H

R⁵-G

R⁶-H

E-163

X-C

R²-Q

R²⁰-J

R³-G

R^3a-H

R^3b-H

R⁵-G

R⁶-H

E-164

X-B

R²-Q

R²⁰-A

R³-G

R^3a-H

R^3b-H

R⁵-G

R⁶-H

E-165

X-B

R²-Q

R²⁰-H

R³-G

R^3a-H

R^3b-H

R⁵-G

R⁶-H

The most preferred examples according to the invention are each the individual compounds listed in tables 1 and 4 below.

In general, the invention includes all tautomeric and isomeric forms of a chemical structure or compound, and mixtures thereof, e.g., individual geometric isomers, stereoisomers, atropisomers, enantiomers, diastereomers, racemates, racemic or non-racemic mixtures of stereoisomers, mixtures of diastereomers, or mixtures of any of the foregoing, unless a specific stereochemistry or isomeric form is specified in the compound name or structure. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms.

It is known in the art that the biological and pharmaceutical activity of a compound is quite sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including pharmacokinetic differences, including metabolism, protein binding, and the like, as well as differences in pharmacological properties, including the type of activity exhibited, the degree of activity, toxicity, and the like. Thus, one skilled in the art will recognize that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other or when separated from the other. Furthermore, the person skilled in the art will, from the disclosure of the present invention and the knowledge of the prior art, go through to the isolation, enrichment or selective preparation of enantiomers of the compounds of the invention.

The preparation of pure stereoisomers (e.g. enantiomers and diastereomers), or mixtures of the desired enantiomeric excesses (ee) or enantiomeric purities can be achieved by one or more of the following methods: (a) separation or resolution of enantiomers, or (b) enantioselective synthesis well known to those skilled in the art, or combinations thereof. These resolution methods typically rely on the identification of chirality and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliary agents, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally described in the Chiral Separation Techniques: a practical Aproach (2nd Ed.), G.Subramanian (Ed.), Wiley-VCH, 2000; beesley and r.p.w.scott, Chiral Chromatography, John Wiley & Sons, 1999; and satanderahuja, Chiral Separations by Chromatography, am. chem. soc., 2000, which are incorporated herein by reference. Furthermore, enantiomeric excess or purity quantification methods are well known methods, such as GC, HPLC, CE or NMR, as well as confirmation of absolute configuration and conformation, such as CD ORD, X-ray crystallography or NMR.

The compounds of the present invention are inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase and are therefore useful for inhibiting replication of hepatitis C virus RNA.

The compounds of the present invention may also be used as experimental or research reagents. For example, the compounds of the invention can be used as positive controls to validate tests, including but not limited to surrogate cell-based tests (surrogate cell-based assays) and in vitro or in vivo viral replication tests.

The compounds of the present invention may also be used as probes to study the mechanism of action of the hepatitis C virus NS5B polymerase, including but not limited to the mechanism of action of the polymerase, the conformational changes experienced by the polymerase under various conditions, and the interaction with entities that bind to or interact with the polymerase.

The compound of the present invention used as a probe may be labeled with a label that allows the compound to be directly or indirectly recognized so that it can be detected, measured, and quantified. Labels for use with the compounds of the present invention include, but are not limited to, fluorescent labels, chemiluminescent labels, colorimetric (colorimetric) labels, enzymatic labels, radioactive isotopes, affinity tags (tags), and photoactive groups.

The compounds of the invention used as probes may also be labeled with affinity tags whose strong affinity for the receptor may be used to extract the ligand-linked entity from solution. Affinity tags include, but are not limited to, biotin or a derivative thereof, a histidine polypeptide, polyarginine, an amylose sugar group, or a defined epitope that can be recognized by a particular antibody.

Furthermore, the compounds of the invention used as probes may be labeled with a photosensitive group which upon photoactivation is converted from an inert group into a reactive group, such as a free radical. Photoactive groups include, but are not limited to, photoaffinity labels, such as benzophenone and azido.

Furthermore, the compounds of the present invention can be used to treat or prevent viral contamination of substances, thus reducing the risk of viral infection of laboratory or medical personnel or patients in contact with substances such as blood, tissue, surgical equipment and clothing, laboratory equipment and clothing, and blood collection devices and materials.

Pharmaceutical composition

The compounds of the present invention can be administered to a mammal in need of treatment for hepatitis C virus infection as a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof; and one or more conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The specific formulation of the composition will be determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. The pharmaceutical composition of the present invention may be administered orally or systemically.

For oral administration, the compound or a pharmaceutically acceptable salt or ester thereof may be formulated into any orally acceptable dosage form, including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs, or tablets. For systemic administration, including but not limited to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal and intrapalpebral (intradivision) injection or infusion techniques, it is preferred to use solutions of the compounds or pharmaceutically acceptable salts thereof in pharmaceutically acceptable sterile aqueous carriers.

Pharmaceutically acceptable carriers, adjuvants, vehicles, excipients and additives, and methods of formulating pharmaceutical compositions for various modes of administration are well known to those skilled in the art and are described in the pharmaceutical literature, e.g., Remington: the Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005; and l.v. allen, n.g. popovish and h.c. ansel, pharmaceutical dosage Forms and Drug Delivery Systems, 8th edition, Lippincott Williams & Wilkins, 2004, which are incorporated herein by reference.

The dosage administered depends on known factors including, but not limited to, the activity and pharmacokinetic properties of the particular compound employed, as well as the mode, time and route of administration; age, diet, sex, weight, and general health of the recipient; the nature and extent of the symptoms; severity and course of infection; the kind of concurrent treatment; the frequency of treatment; the desired effect; and the judgment of the treating physician. In general, it is most desirable to administer the drug at a dosage that generally achieves an antiviral effective result without causing any harmful or adverse side effects.

The daily dose of the active ingredient may be from about 0.01 to about 200 mg per kg body weight, preferably from about 0.1 to about 50 mg/kg. Typically, the pharmaceutical compositions of the present invention are administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular route of administration. Typical formulations contain from about 5% to about 95% active compound (w/w). Preferably, the formulation contains from about 20% to about 80% of the active compound.

Combination therapy

Combination therapy refers to the co-administration (co-administerer) of a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, with at least one other antiviral agent. Other drugs may be combined with the compounds of the present invention to form a single dosage form. Or these other drugs may be administered separately, simultaneously or sequentially as part of a multiple dosage form.

When the pharmaceutical compositions of the present invention comprise a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other antiviral agents, both the compound and the other agent should be present in a dosage amount of from about 10 to 100%, and preferably from about 10 to 80%, of the normal dosage administered in a single course of treatment. In the case of synergy between the compounds of the present invention and other antiviral agents or agents, the dose of any or all of the active agents in the combination may be reduced as compared to the dose normally administered in a single course of treatment.

Antiviral agents for use in such combination therapies include drugs (compounds or biologicals) effective to inhibit virus formation and/or replication in a mammal, including but not limited to drugs that interfere with host or viral mechanisms required for virus formation and/or replication in a mammal. Such drugs may be selected from other anti-HCV drugs; (ii) an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those drugs effective to eliminate or prevent the development of symptoms or diseases associated with hepatitis C. Such agents include, but are not limited to, immunomodulators, HCV NS3 protease inhibitors, other HCV polymerase inhibitors, inhibitors of other targets in the HCV life cycle, and other anti-HCV drugs, including, but not limited to, ribavirin, amantadine, levovirin (levovirin), and vemidine (viramidine).

Immunomodulators include drugs (compounds or biologics) that are effective in enhancing or potentiating the immune system response of a mammal. Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimeprobidine), Vertex Pharmaceuticals, class I interferons, class II interferons, consensus interferons, asialo-interferon pegylated interferons, and conjugated interferons, including, but not limited to, interferons conjugated to other proteins including, but not limited to, human albumin. Class I interferons are interferons that both bind to class I receptors, including both naturally and synthetically produced class I interferons, while class II interferons both bind to class II receptors. Examples of class I interferons include, but are not limited to, alpha-, beta-, delta-, omega-and tau-interferons, while examples of class II interferons include, but are not limited to, gamma-interferons. In a preferred aspect, the other anti-HCV agent is an interferon. Preferably, the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon. In a preferred aspect, the composition comprises a compound of the invention, an interferon, and ribavirin.

Inhibitors of HCV NS3 protease include those drugs (compounds or biologicals) that are effective in inhibiting the function of the HCV NS3 protease in a mammal. Inhibitors of HCV NS3 protease, including, for example: WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO2004/103996, WO 2005/028501, WO 2005/070955, WO 2006/000085, WO2006/007700, WO 2006/007708, WO 007/009227 (all of the Boehringer Ingelheim applications), WO 02/060926, WO 03/053349, WO 03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (all of the BMS applications), WO 2004/072243, WO 00/59929, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by the Enanta applications), WO2005/037214(Intermune), WO 01/77113, WO 01/81325, WO 02/08187, WO02/08198, WO 02/08244, WO 02/08256, WO 02/48172, WO 03/062228, WO 03/062265, WO 2005/021584, WO 2005/030796, WO 2005/058821, WO 2005/051980, WO 2005/085197, WO 2005/085242, WO 2005/085275, WO 2005/087721, WO 2005/087725, WO 2005/087730, WO 2005/087731, WO 2005/107745 and WO 2005/113581 (all by the Schering applications), WO 2006/119061, WO 2007/016441, WO 2007/015855, WO 2007/015787 (all by the Merck applications), The compound of WO 2006/043145(Pfizer), which is incorporated herein by reference in its entirety; and candidate drugs VX-950, SCH-503034, ITMN-191, TMC 435350 and MK 7009.

Inhibitors of HCV polymerase include those drugs (compounds or biologicals) that are effective in inhibiting HCV polymerase function. Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of NS4A, NS5A, NS5B polymerase. Examples of inhibitors of HCV polymerase include, but are not limited to, the following compounds: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388, WO 2006/007693, WO2007/019674, WO2007/087717 (all proposed by Boehringer Ingelheim), WO01/47883 (Japanese tobacco), WO 03/000254 (Japanese tobacco), WO 2007/033032, WO2007/033175, WO 2006/020082, US 2005/0119318, WO 2005/034850, WO03/026587, WO 2007/092000, WO 2007/143521, WO 2007/136982, WO2007/140254, WO 2007/140200, WO 2007/092888 (all proposed by BMS), WO2007/095269, WO 2007/054741, WO 03/062211, WO 99/64442, WO 00/06529, WO 2004/110442, WO 2005/034941, WO 2006/119975, WO 2006/046030, WO 2006/046039, WO 2005/023819, WO 02/06246, WO 2007/065883, WO2007/129119, WO 2007/029029, WO 2006/029912, WO 2006/027628, WO2007/028789, WO 2006/008556, WO 2004/087714 (all proposed by IRBM), WO2005/012288(Genelabs), WO 2005/014543 (Japanese tobacco), WO 2005/049622 (Japanese tobacco) and WO 2005/121132(Shionogi), WO 2005/080399 (Japanese tobacco), WO2006/052013 (Japanese tobacco), WO 2006/119646(Virochem Pharma), WO2007/039146(SmithKline Beecham), WO 2005/021568(Biota), WO2006/094347(Biota), WO 2006/093801, WO 2005/019191, WO 2004/041818, US 2004/0167123, US 2005/0107364 (both submitted by Abbott laboratories), WO2007/034127(Arrow therapeutics, Inc.) (all incorporated by reference), and drug candidates HCV 796(ViroPharma/Wyeth), R-1626, R-1656, and R-7128(Roche), MK-283(Idenix/Novartis), VCH-759(Virochem), GS9190(Gilead), MK-608(Merck), and PF868554 (Pfizer).

The term "inhibitor of other targets in the HCV life cycle" as used herein refers to a drug (compound or biologic) that is effective in inhibiting HCV formation and/or replication in a mammal, rather than inhibiting HCV NS3 protease function. This includes agents that interfere with either the host or HCV viral target, which is essential for HCV life, or agents that specifically inhibit through undefined or incompletely defined mechanisms in HCV cell culture assays. Inhibitors of other targets in the HCV life cycle include, for example, agents that inhibit viral targets such as the core, E1, E2, p7, NS2/3 protease, NS3 helicase, Internal Ribosome Entry Site (IRES), HCV entry into assembly with HCV, or host targets such as Cyclophilin B, phosphatidylinositol 4-kinase III α, CD81, SR-B1, Claudin 1, VAP-A, VAP-B. Specific examples of inhibitors of other targets in the HCV life cycle include ISIS-14803(ISIS pharmaceuticals), GS9190(Gilead), GS9132(Gilead), A-831(AstraZeneca), MK-811(Novartis), and DEBIO-025(Debio Pharma).

It may occur that the patient is concurrently infected with hepatitis C virus and one or more other viruses including, but not limited to, Human Immunodeficiency Virus (HIV), Hepatitis A Virus (HAV), and Hepatitis B Virus (HBV). Thus combination therapy for co-administration of a compound of the invention and at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor to treat such co-infection is also included.

HIV inhibitors include those agents (compounds or biologicals) that are effective in inhibiting HIV formation and/or replication. Including but not limited to drugs that interfere with host or viral mechanisms required for HIV formation and/or replication in mammals. HIV inhibitors include, but are not limited to:

● NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors; including but not limited to zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), emtricitabine, abacavir succinate, Yewucitabine (elvucitabine), adefovir dipivoxil, Lobuvir (BMS-180194), lodenosine (Fdda), and tenofovir, including tenofovir disoproxil and tenofovir disoproxil fumarate, tenofovir disoproxil (Tenovirdiroxil), TRIZIVIRTM (containing abacavir, 3TC and AZT), TRUVADATM (containing tenofovir and emtricitabine), EPZITM (containing abacavir and COMTC 3);

● NNRTIs (non-nucleoside reverse transcriptase inhibitors; including but not limited to nevirapine, delavirdine, efavirenz, etavirenz (etravirine) and rilpivirine);

● protease inhibitors (including but not limited to ritonavir, tipranavir, saquinavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir (atazanavir), lopinavir, darunavir (daronavir), lacinavir, brecanavir (brecanavir), VX-385, and TMC-114;

● entry inhibitors, including but not limited to:

●CCR⁵antagonists (including but not limited to maraviroc, viliviroc, INCB9471 and TAK-652),

● CXCR4 antagonists (including but not limited to AMD-11070),

● fusion inhibitors (including but not limited to Enfuvirtide (T-20), TR1-1144 and TR1-999), and

● others (including but not limited to BMS-488043);

● integrase inhibitors (including but not limited to ritela (raltegravir) (MK-0518), BMS-707035 and also velvetela (GS 9137));

● TAT inhibitors;

● maturation inhibitors (including but not limited to belivitamat (beivimat) (PA-457));

● immunomodulators (including but not limited to levotetramisole); and

● other antiviral agents, including hydroxyurea, ribavirin, IL-2, IL-12 and flaxsapode.

HAV inhibitors include drugs (compounds or biologicals) that effectively inhibit HAV formation and/or replication. Including but not limited to drugs that interfere with host or viral mechanisms required for HAV formation and/or replication in mammals. HAV inhibitors include, but are not limited to, hepatitis A vaccine.

HBV inhibitors include drugs (compounds or biologicals) effective to inhibit HBV formation and/or replication in a mammal. Including but not limited to drugs that interfere with host or viral mechanisms required for HBV formation and/or replication in mammals. HBV inhibitors include, but are not limited to, drugs and HBV vaccines that inhibit HBV viral DNA polymerase.

Thus, according to one embodiment, the pharmaceutical composition of the invention further comprises a therapeutically effective amount of one or more antiviral agents.

Other embodiments of the present invention provide pharmaceutical compositions wherein the one or more antiviral agents include at least one other anti-HCV agent.

According to a more specific embodiment of the pharmaceutical composition of the present invention, said at least one other anti-HCV agent comprises at least one immunomodulatory agent.

According to another more specific embodiment of the pharmaceutical composition of the present invention, said at least one additional anti-HCV agent comprises at least one additional inhibitor of HCV polymerase.

According to another more specific embodiment of the pharmaceutical composition of the present invention, the at least one additional anti-HCV agent comprises at least one inhibitor of HCV NS3 protease.

According to another more specific embodiment of the pharmaceutical composition of the present invention, said at least one other anti-HCV agent comprises at least one inhibitor of other targets in the HCV life cycle.

Examples

Other features of the present invention will become apparent from the following non-limiting examples which illustrate, by way of example, the principles of the invention. As is well known to those skilled in the art, where it is necessary to protect the reaction components from air or moisture, the reaction is carried out in an inert gas (including but not limited to nitrogen or argon) as desired. The preparation of the compounds of the invention may involveAnd protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of suitable protecting groups, can be readily determined by one skilled in the art. The Chemistry of protecting groups can be found, for example, in Greene, "protective groups in Organic Chemistry", John Wiley&Sons, New York (1981), and its more recent version, are incorporated by reference. The temperature is expressed in degrees Celsius (. degree. C.). The solution percentages and ratios represent volume to volume relationships unless otherwise indicated. Flash chromatography on silica gel (SiO) according to the method of w.c. still et al, j.org.chem. (1978), 43, 2923₂) The above process is carried out. Mass spectral analysis was recorded using an electrospray mass spectrometer. Purification on Combiflash Using Isco Combiflash (column SiO)₂) The process is carried out. Preparative HPLC was performed under standard conditions using a SunFireTM preparation C18OBD 5 μ M reverse phase column, 19 × 50 mm, and a linear gradient (20 to 98%) using 0.1% TFA/acetonitrile and 0.1% TFA/water as solvents. When desired, the compound was isolated as a TFA salt. Analytical HPLC was performed under standard conditions using a CombioscreenTMODS-AQ C18 reverse phase column, YMC, 50X 4.6 mm I.D., 5. mu.M,at 220nM, with a linear gradient as described in the table below (solvent A is H in 0.06% TFA)₂O solution; solvent B as MeCN in 0.06% TFA):

time (minutes)	Flow (ml/min)	Solvent A (%)	Solvent B (%)
				0	3.0	95	5
0.5	3.0	95	5
				6.0	3.0	50	50
10.5	3.5	0	100

Abbreviations or symbols used herein include:

ac: acetyl;

AcOH: acetic acid;

BINAP: (2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl;

bn: benzyl (phenylmethyl);

BOC or BOC: a tert-butoxycarbonyl group;

bu: a butyl group;

n-BuLi: n-butyl lithium;

n-BuOAc: n-butyl acetate;

m-CPBA: meta-chloroperbenzoic acid;

DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene;

DCE: ethylene dichloride;

DCM: dichloromethane;

DEAD: diethyl azodicarboxylate;

the DIAD: diisopropyl azodicarboxylate;

DIPEA: diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DMF: n, N-dimethylformamide;

DMSO, DMSO: dimethyl sulfoxide;

EC₅₀: 50% effective concentration;

et: an ethyl group;

Et₃n: triethylamine;

Et₂o: diethyl ether;

EtOAc: ethyl acetate;

EtOH: ethanol;

HATU: 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate;

hex: hexane;

HPLC: high performance liquid chromatography;

IC₅₀: 50% inhibitory concentration;

iPr or i-Pr: 1-methylethyl (isopropyl);

LC-MS: liquid chromatography-mass spectrometry;

LDA: lithium diisopropylamide (lithium diisopropylamide);

me: a methyl group;

MeCN: acetonitrile;

MeI: methyl iodide;

MeOH: methanol;

MS: mass spectrometry (ES: electrospray);

NaHB(OAc)₃: sodium triacetoxyborohydride;

NaHMDS: sodium hexamethyldisilazide (sodium hexamethyldisilazide);

NIS: n-iodosuccinamide;

NMO: N-methylmorpholine-N-oxide;

NMP: n-methyl pyrrolidone;

NMR: nuclear magnetic resonance spectroscopy;

ph: a phenyl group;

pr: n-propyl;

psi: pounds per square inch;

rpm: revolutions per minute;

RT: room temperature (about 18 ℃ to 25 ℃);

tert-butyl or t-butyl: 1, 1-dimethylethyl;

tert-BuOH or t-BuOH: tert-butyl alcohol

TBABr: tetrabutylammonium bromide;

TBAF: tetrabutylammonium fluoride;

TBDPS: tert-butyl diphenylsilyloxy;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: thin layer chromatography.

Example 1A

Preparation of intermediate 1a10

Step 1

1a1(73 g, 35 mmol) was diluted in anhydrous THF (2L) under Ar. Benzyl alcohol (80.8 ml, 800 mmol) was added and the mixture was cooled to 0 ℃. Sodium bis (trimethylsilyl) amide (1.0M in THF, 800 ml, 800 mmol) was added dropwise. After stirring for about 1 hour, the mixture was taken up in saturated NH₄Partition between aqueous Cl and EtOAc. The organic phase was collected and washed with Na₂SO₄And (5) drying. The mixture was filtered and concentrated under reduced pressure.The solid formed, 1a2, was washed with cold EtOAc and dried.

Step 2

Carboxylic acid 1a2(112.8 g, 384 mmol) was diluted in anhydrous DMF (2 l). Potassium carbonate (108.1 g, 775 mmol) was added and the mixture was cooled to 0 ℃. Methyl iodide (110 g, 775 mmol) was added dropwise and after about 2 hours, by addition of saturated NH₄The reaction was terminated with an aqueous solution of Cl. The aqueous solution was extracted with EtOAc (2 ×). The combined organic extracts were washed with water and brine, then MgSO₄And (5) drying. Removal of the solvent gave methyl ester 1a 3.

Step 3

Step 3a

Nitro intermediate 1a3(63.8 g, 212 mmol) was diluted in THF (1 l). Aqueous HCl (1M, 500 ml, 500 mmol) was added followed by tin powder (55 g, 46 mmol). The mixture was stirred at room temperature for about 2 hours. The reaction mixture was diluted with EtOAc and the pH of the mixture was adjusted to about 7 by addition of 1N NaOH. The organic phase was separated, washed with water and brine, and Na₂SO₄Drying and removing the solvent to obtain aniline.

Step 3b

Aniline (97.1 g, 377 mmol) was reacted with anhydrous Et₂O (1 l) was mixed and then treated by slow addition of HCl (2M in ether, 2 l). The hydrochloride salt 1a4 formed was collected by filtration and washed with excess ether.

Step 4

Aniline hydrochloride 1a4(1.04 g, 3.33 mmol) was mixed with 1, 3-dihydroxyacetone (1.84 g, 20.4 mmol) in anhydrous MeOH (40 ml). After stirring for about 15 minutes, at which point the homogeneous solution turned a bright red color, a solution of sodium cyanoborohydride (1.05 g, 16.7 mmol) pre-dissolved in MeOH (5 ml) was slowly added for about 5 minutes. By slow addition of saturated NaHCO₃The reaction was neutralized with an aqueous solution (3 ml) and the mixture was concentratedAnd (5) condensing to be dry. The residual solid was purified by flash chromatography (gradient of 2% to 5% MeOH in DCM) to afford diol 1a 5.

Step 5

Diol 1a5(1.89 g, 5.40 mmol) and iodomethane (1.0 ml, 16.2 mmol) were dissolved in anhydrous DMF (20 ml) and cooled to 0 ℃. A suspension of sodium hydride (60% w/w, 453 mg, 11.3 mmol) in DMF (5 ml) was added slowly for about 15 min, and the reaction was stirred at rt. At 0 ℃ by addition of saturated NH₄The reaction was neutralized with aqueous Cl (10 ml). The mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with water (2x) and brine (1 x). The combined organic phases were washed with MgSO₄Dried, filtered and concentrated under reduced pressure. After purification by flash chromatography (10% to 25% EtOAc in hexanes gradient), dimethoxy 1a6 was isolated.

Step 6

To a mixture of compound 1a7(43.4 g, 305 mmol) in anhydrous DCM (400 ml) under Ar atmosphere was added oxalyl chloride (53.2 ml, 610 mmol) in DCM (305 ml) for about 1 hour. The mixture was stirred at room temperature for about 1 hour, and anhydrous DMF (1 ml) was added dropwise. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with pentane and filtered. The filtrate was concentrated under reduced pressure, diluted with pentane and filtered. Concentration under reduced pressure then afforded acid chloride 1a 8.

Step 7

Aniline 1a6(1.25 g, 3.31 mmol) was mixed with anhydrous pyridine (3 ml) and catalytic amount of DMAP (121 mg, 0.99 mmol). Acid chloride 1a8(1.35 g, 8.40 mmol) was then added in DCE

(4.2 ml) of the premixed solution. The mixture was heated to 115 ℃ overnight, then cooled and then saturated NaHCO₃Neutralizing with water solution. The mixture was extracted with EtOAc (3 ×). The combined organic phases were washed with brine, over MgSO₄Dried and concentrated under reduced pressure. Residue of the reactionPurification by Combiflash (EtOAc in hexanes gradient) afforded amide 1a 9.

And 8:

benzyl ether 1a9(1.28 g, 2.55 mmol) was dissolved in MeOH (10 ml) and EtOAc (20 ml) and the mixture was taken up with N₂Scrubbing (2 ×). 10% Pd/C (20 mg) was added and the vessel was placed in H₂The (cylinder) atmosphere was maintained for about 2 hours. Then, pass throughThe pad filters the mixture and is rinsed with excess MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (2% to 5% MeOH in DCM) to give 1a 10.

Example 1B

Preparation of intermediate 1b8

Step 1

Compound 1b7 was converted to compound 1b8 using the procedure described in step 6, example 1A.

Example 1C

Preparation of intermediate 1c8

Step 1

Compound 1c7 was converted to compound 1c8 using the procedure described in step 6, example 1A.

Example 1D

Preparation of intermediate 1d8

Step 1

Compound 1d7 was converted to compound 1d8 using the procedure described in step 6, example 1A.

Example 2A

Preparation of intermediate 2a5

Step 1

Aniline hydrochloride 2a1 (preparation described in WO 2007/087717) was coupled with 1, 3-dihydroxyacetone according to the conditions described in step 4 of example 1A to give diol 2a 2.

Step 2

Compound 2a2 was converted to dimethoxy 2a3 using the procedure of step 5, example 1A.

Step 3

Compound 2a3 was converted to compound 2a4 using the procedure of step 7, example 1A.

Step 4

The benzyl ether 2a4 was converted to compound 2a5 using the procedure of step 8, example 1A.

Example 3A

Preparation of intermediate 3a6

Step 1

Aniline hydrochloride 1a4(25.0 g, 90.7 mmol) was dissolved in anhydrous THF (60 ml) under Ar. 1, 4-cyclohexanedione monoethylene ketal (1, 4-cyclohexanedione ethylene ketone) (14.3 g, 91.6 mmol) was added at room temperature, followed by dibutyltin dichloride (1.38 g, 4.54 mmol). The mixture was stirred for about 15 minutes, then phenylsilane (23.0 ml, 99.8 mmol) was added slowly. The mixture was stirred at room temperature for about 2 days. The solvent was partially removed and the residue was dissolved in EtOAc and washed with saturated NaHCO₃The aqueous solution, followed by water and brine. Na for organic phase₂SO₄Drying, filtration, and removal of the solvent under reduced pressure gave an oily solid. The crude material was redissolved in EtOAc and an equal volume of hexane was added, followed by cooling at 0 ℃. Thus, a two-phase mixture with solids is obtained. The liquid was decanted and the solid formed was washed with hexane. After drying, 3a1 was isolated.

Step 2

To a solution of the ketal 3a1(15.0 g, 36.1 mmol) in toluene (100 ml) under Ar was added the acid chloride 1a8(9.73 g, 59.1 mmol), followed by pyridine (10 ml, 123 mmol). The mixture was heated to reflux overnight. EtOAc was added and the organic layer was washed with water, 10% citric acid solution, saturated NaHCO₃The solution and brine were washed sequentially. Mixing the mixture with Na₂SO₄Dried and the solvent removed under reduced pressure. After purification by flash chromatography (10% EtOAc in hexanes), the product 3a2 was isolated.

Step 3

To a solution of the ketal 3a2(13.8 g, 25.5 mmol) in toluene (50 ml) was added TFA (50 ml). After about 1 hour, water (3 ml) was added and the mixture was stirred overnight. The solvent was evaporated, and the crude residue was dissolved in EtOAc. The organic material was dosed at 5% K₂CO₃The aqueous solution, water and brine were washed in order, then Na was added₂SO₄And (5) drying. Removal of the solvent under reduced pressure gave 3a3, which was used as isNo further purification was required.

Step 4

To a cold solution (0 ℃) of ketone 3a3(13.5 g, 25.5 mmol) in MeOH (200 mL) was added NaBH in portions₄(0.40 g, 12.7 mmol). The reaction was stirred at 0 ℃ until complete conversion, then 1M HCl solution was slowly added. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic material was treated with saturated NaHCO₃The aqueous solution, water and brine were washed successively, followed by Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (EtOAc in hexanes) to give the trans alcohol 3a 4.

Step 5

Alcohol 3a4(5.0 g, 10.1 mmol) was dissolved in DMF (50 ml) and cooled to 0 ℃, then NaH (0.81 g, 29.1 mmol) was added followed by MeI (42 g, 301 mmol). After stirring at 0 ℃ for about 2 hours, the reaction was terminated by addition of 1M HCl solution. A large amount of EtOAc was added and the organic material was washed with saturated NaHCO₃The aqueous solution, water and brine were washed in order, then Na was added₂SO₄And (5) drying. Removal of the solvent under reduced pressure gave 3a5, which was used directly without further purification.

Step 6

In Parr Hydrogenorator (TM), ether 3a5(5.0 g, 9.77 mmol) was dissolved in MeOH (120 mL) and 10% Pd/C (0.75 g) was added. Pressurizing the vessel to 30psi H₂And stirred overnight. Passing the mixture throughThe pad was filtered and then concentrated in vacuo to afford phenol 3a 6.

Example 3B

Preparation of intermediate 3b6

Step 1

Aniline hydrochloride 2a1 (preparation described in WO 2007/087717) was coupled with 1, 4-cyclohexanedione monoethylketal according to the conditions described in example 3A, step 1, to give the ketal 3b 1.

Step 2

Compound 3b1 was converted to the amide 3b2 using the procedure of step 2, example 3A.

Step 3

The ketal 3b2 is converted to the ketone 3b3 using the procedure of step 3, example 3A.

Step 4

Ketone 3b3 was converted to alcohol 3b4 using the procedure of step 4, example 3A.

Step 5

Alcohol 3b4 was converted to compound 3b5 using the procedure of step 5, example 3A.

Step 6

Ether 3b5 was converted to phenol 3b6 using the procedure of step 6, example 3A.

Example 4A

Preparation of intermediate 4a4

Step 1

To a stirred mixture of 4a1(25 g, 24 mmol) in MeCN (500 ml) and DMF (50 ml) cooled to-5 ℃, DBU (15.4 ml, 103 mmol) was added followed by slow addition of MeI (8.8 ml, 141 mmol). The mixture was warmed to room temperature and stirred overnight. Pouring the mixture into water(1 liter); then extracted with EtOAc (500 ml x 3). The combined organic extracts were washed with brine and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude ester 4a2 was used directly without further purification.

Step 2

To a mixture of iodoaromatic ring 4a2(22.3 g, 79 mmol) in dioxane (200 ml) was added tributylvinyltin (20 ml, 68 mmol). The mixture was degassed with Ar and then added (Ph)₃P)₄Pd (2.4 g, 2.1 mmol). The mixture was refluxed for about 1 hour, followed by stirring at room temperature overnight. The mixture was concentrated under reduced pressure and the residue formed was subjected to flash chromatography to isolate the alkene 4a 3.

Step 3

To a mixture of alkene 4a3(9.6 g, 89 mmol) in THF (360 ml) and water (270 ml) was added OsO₄(2.5% solution in t-BuOH, 5.4 mL) followed by the addition of NaIO in portions₄(34 g, 160 mmol). The mixture was stirred at rt for about 2 h, then partially concentrated and diluted in EtOAc. The organic phase was washed with brine and Na₂SO₄Dried, filtered, and concentrated. The residue was subjected to flash chromatography to isolate aldehyde 4a 4.

Example 5A

Preparation of intermediates 5a6 and 5a7

Step 1

2-hydroxy-3-trifluoromethylpyridine (500 g, 3.06 mol) was placed in a 22L round bottom flask under Ar. Anhydrous DMF (8 l) was added followed by potassium carbonate (430 g, 1 eq) and N-iodosuccinimide (700 g, 1 eq). The mixture was stirred under Ar and heated to an internal temperature of 55 ℃ forLasting for about 2 hours. The heat was removed and the suspension was stirred overnight. The mixture was filtered and the solvent was removed. The residue was dissolved in DCM (8 l) and water (4 l) was added. The mixture was stirred and acidified to about pH 3-4 with HCl. The organic phase was separated and the aqueous phase was extracted with additional DCM. The combined organic was washed with brine and MgSO₄And (5) drying. Cooling of DCM and concentration gave product 5a2 as a precipitate.

Step 2

Phenol 5a2(125 g, 424 mmol) was placed in a 3-neck 2-liter flask. Phenylphosphonic dichloride (500 ml) was added and the mixture was heated to 136 ℃ under Ar and stirred. After consumption of the starting material (about 4-5 hours), the reaction was cooled to room temperature and carefully quenched by slow addition of the reaction mixture to crushed ice (note: extreme exotherm). A white solid formed which was filtered. The solid was dissolved in EtOAc (2 l) and aqueous NaOH was added and stirred. NaOH solution was added until the aqueous layer was neutral. The EtOAc layer was separated, washed with water and brine, and washed with anhydrous Na₂SO₄And (5) drying. The solvent was removed to give a white solid which was washed with cold hexane to give chloride 5a 3.

Step 3

Iodide 5a3(10 g, 32.5 mmol) was mixed with a 1: 3 mixture of anhydrous THF and anhydrous toluene (100 mL) under an Ar atmosphere. The mixture was cooled to-78 ℃ and then n-BuLi (1.6M in hexane, 24 ml, 38.4 mmol) was added slowly via syringe over about 40 minutes. Stirring was continued for about 1 hour, then ethyl formate (3.2 ml, 39.7 mmol) in THF (10 ml) was added over a period of about 40 minutes. The mixture was stirred for about 1 hour, then the reaction was quenched by the addition of 2M HCl. The mixture was dissolved in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic phase was collected, washed with brine and Na₂SO₄And (5) drying. The mixture was filtered and concentrated under reduced pressure. Purification was performed by flash chromatography, in which silica gel was washed with 3% Et₃Pretreatment of N in hexaneThen eluted at 1: 1 EtOAc/hexanes to isolate aldehyde 5a 4.

Step 4

A mixture of aldehyde 5a4(19 g, 81 mmol) in MeOH (225 ml) was cooled to 0 ℃. Sodium borohydride (4.1 g, 109 mmol) was added portionwise and the mixture was stirred at 0 ℃ for about 1.5 hours. Adding another portion of NaBH₄(1 g) and the mixture was stirred for about 30 minutes. By adding NaHSO₄The reaction was quenched (5% aq) and then diluted in EtOAc (500 ml). The organic phase was separated and then washed with water (500 ml) and brine. Na for organic phase₂SO₄Dried, filtered and then concentrated under reduced pressure. The residue was subjected to flash chromatography (1: 1 EtOAc/hexanes) to isolate alcohol 5a 5.

Step 5

To crude aldehyde 5a4(2 g, 9.5 mmol) in 45 ml DCE was added difluoropiperidine-HCl salt (1.6 g, 10.5 mmol) and sodium triacetoxyborohydride (2.8 g, 13.4 mmol). The reaction was stirred at rt overnight. The mixture was diluted with EtOAc (300 ml) and washed with water (100 ml) and brine (100 ml). The organic phase is then MgSO₄Dried, filtered, and concentrated. The residue was purified by flash chromatography (Combiflash, 15-40% EtOAc/hexanes) to give 5a6 as an orange oil.

Step 6

Alcohol 5a5(10.5 g, 48 mmol) was mixed with triazole (3.42 g, 48 mmol) and triphenylphosphine (14.3 g, 54 mmol) in dry THF (500 ml). The mixture was cooled to 0 ℃ and DIAD (10.6 ml, 54 mmol) was added dropwise. Stirring was continued at 0 ℃ for about 1 hour, then the mixture was warmed to room temperature, followed by stirring overnight. The mixture was diluted in EtOAc and washed with water (500 ml) and brine (500 ml) then Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography (1: 3 EtOAc/hexane) to give the benzyl-type triazole 5a 7.

Example 5B

Preparation of intermediates 5b4 and 5b5

Step 1

To a solution of iodide 5a3(300 mg, 0.98 mmol) in THF (3 ml) at-40 ℃, was added i-PrMgCl (0.54 ml, 2.0M in THF). The reaction mixture was stirred for about 30 minutes, then allyl bromide (0.13 ml, 1.5 mmol) was added. The mixture was stirred at-40 ℃ for about 15 minutes, followed by continued stirring at room temperature for about 30 minutes. The mixture was quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. A light brown oil 5b1 was obtained, which was used in the subsequent step without further purification.

Step 2

The olefin 5b1 was converted to the aldehyde 5b2 using the method described in step 3, example 4A.

Step 3

Aldehyde 5b2 was converted to alcohol 5b3 using the method described in step 4, example 5A.

Step 4

Aldehyde 5b2 was converted to compound 5b4 using the procedure of step 5, example 5A.

Step 5

Alcohol 5b3 was converted to triazole 5b5 using the method of example 5A, step 6.

Example 6A

Preparation of Compounds 1001 and 1002

Step 1

In an 8 ml glass vial, K is added in sequence₂CO₃(46 mg, 0.33 mmol), aldehyde 4a4(50 mg, 0.275 mmol in 0.5 ml DMSO), and 2-methoxyethylamine (103.9 mg, 1.4 mmol). Mixing the mixture withStir overnight at 70 ℃ on an orbital shaker (270 rpm). Water (1 ml) and concentrated HCl (0.7 ml) were added to the mixture. The mixture was heated at 70 ℃ for about 3H, extracted with EtOAc (2 ml) and washed with H₂O wash (3 ×). After concentration, crude aniline 6a1 was obtained and used as such in the following step.

Step 2

To a crude aldehyde 6a1(1.5 ml in an 8 ml vial) dissolved in MeOH, hydrogen peroxide (43. mu.l of a 30% aqueous solution) was added successively at 2 ℃ with concentrated H₂SO₄(20. mu.l). Mixing the mixture withOn an orbital shaker (290rpm), stir at 2 ℃ for about 15 minutes, followed by addition of saturated aqueous NaCl solution (2 mL). The mixture was extracted with EtOAc (2 ml) and the combined organic extracts were washed with water (1 ml) followed by brine (1 ml). The organic phase is MgSO₄Drying, filtration, and concentration gave crude phenol 6a2, which was used as such in the following step.

Step 3

To the crude phenol 6a2 obtained above in anhydrous DMSO (0.5 ml), K was added in sequence₂CO₃(133 mg, 0.96 mmol) with 2-fluoro-3-trifluoromethylpyridine (40. mu.l, 0.33 mmol). Placing the suspension inStir overnight at 85 ℃ on an orbital shaker (290 rpm). Aqueous NaOH (5N, 250 μ l) was added at room temperature and the reaction mixture was stirred at 50 ℃ for about 3 hours. When 1N KHSO is used₄After acidification of the aqueous solution, the mixture was extracted with EtOAc (3 ×). The combined organic extracts were washed with water and brine in sequence, over MgSO₄Dried and filtered. After concentration, the residue was dissolved in a mixture of DMSO and AcOH (1.5 ml) and purified by reverse phase preparative LC-MS. Conditions; column: agilent SB-C18, 5 micron, 21.2 mm x 50 mm; gradient liquid: 5% to 100% H₂O0.06% TFA/MeCN 0.06% TFA; flow rate: 30 ml/min for 13.5 min; supplementing: 25% H₂O0.05% ammonium formate/75% MeCN; 1 ml/min. After lyophilization, the desired ether 6a3 was isolated.

Step 4

To a mixture of aniline 6a3(10.0 mg, 0.028 mmol) in DCE (0.3 ml) was added acid chloride 1b8(6.31 mg, 0.039 mmol) and pyridine (9.8 μ l, 0.121 mmol). The mixture was heated in a microwave at 150 ℃ for 15 minutes. After concentration, the residue was dissolved in DMSO and AcOH and purified by reverse phase preparative LC-MS. Conditions; column: agilent SB-C18, 5 micron, 21.2 mm x 50 mm; gradient liquid: 5% to 100% H₂O0.06% TFA/MeCN 0.06% TFA; flow rate: 30 ml/min for 13.5 min; supplementing: 25% H₂O0.05% ammonium formate/75% MeCN; 1 ml/min. After lyophilization, compound 1001 is isolated.

Step 5

Amine 6a3 was converted to compound 1002 using the procedure in step 2, example 3 a.

Example 7A

Preparation of Compound 1007

Step 1

In a pressure tube, 2-bromoethyl methyl ether (2.22 g, 15.9 mmol) was added to aniline 2a1(712.0 mg, 2.42 mmol) dissolved in anhydrous DMF (8.0 ml). KI (2.0 g, 12.0 mmol) was added followed by DIPEA (2.72 ml, 16.0 mmol) and the mixture was heated at 120 ℃ for about 16 hours. The mixture was cooled to room temperature and saturated NaHCO was used₃The aqueous solution (100 ml) was diluted and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc in hexanes) to give 7a 1.

Step 2

The benzyl ether 7a1 was converted to phenol 7a2 using the method described in step 8, example 1A.

Step 3

Potassium carbonate (19 mg, 1.4 mmol) was added to a DMSO solution (3.0 ml) of phenol 7a2(100 mg, 0.44 mmol) and chloropyridine 5a7(6.6 mg, 0.44 mmol). The mixture was heated at 70 ℃ for about 20 hours. The solution was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% EtOAc in hexanes) to give triazole 7a3(158.0 mg, 79% yield).

Step 4

Pyridine (27 μ l, 0.33 mmol) was added to a DCE solution (0.5 ml) of aniline 7a3(50 mg, 0.11 mmol) and acid chloride 1a8(21.4 mg, 0.113 mmol). The mixture was heated in a microwave at 150 ℃ for 15 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMSO (1 ml) and then 2.5N NaOH (0.4 ml) was added. The solution was stirred at 50 ℃ for about 1 hour; subsequent acidification with AcOH and purification by preparative HPLC gave 1007.

Example 8A

Preparation of Compound 1008

Step 1

Aniline 1a4 was converted to compound 8a1 using the procedure described in step 1, example 7A.

Step 2

Benzyl ether 8a1 was converted to compound 8a2 using the procedure described in step 8, example 1A.

Step 3

Phenol 8a2 was converted to triazole 8a3 using the method described in step 3, example 7A.

Step 4

Amine 8a3 is converted to compound 1008 using the method described in step 4, example 7A.

Example 9A

Preparation of Compounds 1009 and 1010

Step 1

To phenol 3b6(1.15 g, 2.85 mmol) and K₂CO₃(0.59 g, 4.2 mmol) in anhydrous DMSO (20 ml) pyridine 5a4(500 mg, 2.92 mmol) was added. The resulting mixture was stirred at 100 ℃ for about 30 minutesAfter this time, it was diluted with EtOAc and washed with water, brine in that order, and concentrated under reduced pressure. After purification by column chromatography on silica gel (50% EtOAc in hexanes) on Combiflash, 9a1 was isolated.

Step 2

Reacting NaBH₄(0.11 g, 2.8 mmol) was added portionwise to a cold solution (0 ℃) of aldehyde 9a1(1.10 g, 1.91 mmol) in MeOH. After stirring for about 1 hour, the reaction mixture was evaporated to dryness and redissolved in EtOAc. The mixture was treated with 10% NaHSO₄Aqueous solution, saturated NaHCO₃The aqueous solution and brine were washed sequentially. Mixing organic substance with Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography on Combiflash (50% EtOAc in hexanes) to give alcohol 9a 2.

Step 3

To a solution of alcohol 9a2(1.0 g, 1.7 mmol) in anhydrous DCM (25 ml) was added thionyl chloride (0.25 ml, 3.4 mmol) followed by a catalytic amount of DMF (2 drops). The resulting solution was stirred at room temperature for about 30 minutes, diluted with DCM, and saturated NaHCO₃The solution was washed with brine. Mixing organic substance with Na₂SO₄Drying, filtration and concentration gave chloride 9a3, which was used directly in the next step.

Step 4

Chloride 9a3(120 mg, 0.22 mmol), 1, 2, 3-triazole (17 mg, 0.25 mmol), Cs₂CO₃(124 mg, 0.38 mmol) and KI (16 mg, 0.099 mmol) were mixed in DMF (2 ml). The mixture was warmed to 70 ℃ for about 2 hours, then cooled to room temperature. Then a solution of NaOH (2.5N, 0.8 ml, 2 mmol) and DMSO (0.5 ml) was added. The mixture was warmed to 50 ℃ for about 1 hour, neutralized with AcOH at room temperature and injected onto a preparative HPLC, separating 1009 from 1010.

Example 10A

Preparation of Compounds 1040, 1041 and 1014

Step 1

Potassium carbonate (400 mg, 2.89 mmol) is added to a DMSO (4.0 ml) solution of fluoride 4a4(438 mg, 2.4 mmol) and (S) - (+) -1-methoxy-2-propylamine (858 mg, 9.63 mmol). The mixture was heated at 70 ℃ for about 20 hours, cooled to room temperature, and diluted with water. Concentrated HCl was then added. The solution was stirred at room temperature for about 1 hour, basified with 2.5N aqueous NaOH, and extracted with EtOAc. The organic phase was washed with brine and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product 10a1 was used directly in the next step.

Step 2

Hydrogen peroxide (374 microliters, 3.3 mmol) was added to a solution of aldehyde 10a1 and sulfuric acid (180 microliters, 2.9 mmol) in 0 ℃ MeOH (3.0 ml). The solution was stirred at 0 ℃ for about 2 hours, basified with 2.5n naoh aqueous solution, and extracted with EtOAc. The organic phase was washed with brine and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give phenol 10a2 as a yellow solid.

Step 3

Potassium carbonate (829 mg, 6.0 mmol) is added to a DMSO (8.0 ml) solution of phenol 10a2(337 mg, 1.41 mmol) and 2-fluoro-3- (trifluoromethyl) pyridine (247 mg, 1.5 mmol). The mixture was stirred at 85 ℃ for about 6 hours, then cooled to room temperature and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give ether 10a3 as a white solid.

Step 4

Pyridine (100 μ l) was added to a DCE (1 ml) solution of aniline 10a3(50 mg, 0.13 mmol) and acid chloride 1c8(105 mg, 0.60 mmol). The mixture was stirred in a microwave at 150 ℃ for 15 minutes, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMSO (2.0 ml) and 2.5N aqueous NaOH (200 μ l) was added. The reaction mixture was stirred at room temperature for about 2 hours, acidified with AcOH, and purified by preparative HPLC to afford 1040.

Step 5

Pyridine (500 μ l) was added to a DCE (1 ml) solution of aniline 10a3(490 mg, 1.27 mmol) and acid chloride 1a8(422 mg, 2.62 mmol). The mixture was stirred in a microwave at 150 ℃ for about 15 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in DMSO (2.0 ml) and 2.5N aqueous NaOH (200 μ l) was added. The reaction mixture was stirred at room temperature for about 2 hours, acidified with AcOH, and purified by preparative HPLC to afford 1014.

Step 6

Pyridine (40 μ l) was added to a DCE (1 ml) solution of aniline 10a3(41 mg, 0.11 mmol) and acid chloride 1b8(48.8 mg, 0.22 mmol). The mixture was stirred in a microwave at 150 ℃ for 15 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in DMSO (2.0 ml) and 2.5N aqueous NaOH (200 μ l) was added. The reaction mixture was stirred at room temperature for about 2 hours, acidified with AcOH, and purified by preparative HPLC to give 1041.

Example 11A

Preparation of Compound 1042

Step A

Compound 2a1 was converted to compound 11a3 using the procedure in steps 2 and 3 of example 8A.

Step 1

1, 3-dihydroxyacetone 11a1(964 mg, 10.7 mmol) was dissolved in DCM (25 mL) and imidazole (2.19 g, 32.1 mmol) was added followed by tert-butyldiphenylchlorosilane (5.8 mL, 22.5 mmol). The mixture was stirred at room temperature until the reaction was complete, then water was added. Separating the liquid layer; the organic material was washed with MgSO₄Drying, filtration, and concentration under reduced pressure gave 11a2, which was used directly without further purification.

Step 2

Aniline hydrochloride 11a3(200 mg, 0.57 mmol), ketone 11a2(651 mg, 1.15 mmol) was dissolved in DCM (10 ml). After stirring for about 10 minutes, NaBH (OAc) is added₃(243 mg, 1.15 mmol) and the mixture is refluxed. By addition of saturated NaHCO₃Neutralizing the mixture with an aqueous solution; then extracted with DCM (3 ×). The organic material was washed with brine, over MgSO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (2% EtOAc in hexanes) to give aniline 11a 4.

Step 3

To a solution of compound 11a4(674 mg, 0.78 mmol) in THF (10 ml) was added TBAF solution (1.0M in THF, 1.6 ml, 1.6 mmol). The solution was stirred at room temperature until the reaction was complete, with saturated NH₄Aqueous Cl was diluted and extracted with DCM (3 ×). The combined organic material was washed with brine, over MgSO₄Dried, filtered and concentrated under reduced pressure. After purification by flash chromatography (2% to 8% MeOH in DCM), diol 11a5 was isolated.

Step 4

The diol 11A5 was converted to dimethoxy 11A6 using the procedure of step 5, example 1A.

Step 5

Dimethoxy 11a6(37 mg, 0.089 mmol), pyridine (36 μ l, 0.45 mmol) and DMAP (1.1 mg, 9 μmol) were combined in DCE (1 ml) in a microwave tube. Acid chloride 1a8(91 mg, 0.57 mmol) was added and the tube sealed and placed in a microwave at 175 ℃ for 15 minutes. The mixture was diluted in EtOAc and saturated NaHCO₃Aqueous wash (3 ×). The organic material was washed with MgSO₄Dried and concentrated. The crude residue was redissolved in THF (1 ml)/MeOH (0.5 ml)/H₂O (0.5 ml) mixture and aqueous NaOH (10N, 45 μ l, 0.45 mmol) was added. The mixture was stirred overnight, then acidified with AcOH, filtered, and injected onto a preparative HPLC to isolate compound 1042.

Example 12A

Preparation of Compound 1043

Step 1

Potassium carbonate (193 mg, 1.40 mmol) was added to a DMSO (6.0 ml) solution of phenol 10a2(136.6 mg, 0.571 mmol) and chloropyridine 5a7(150 mg, 0.571 mmol). The mixture was stirred at 80 ℃ for about 12 hours, cooled to room temperature, and 2.5N aqueous NaOH (0.90 mg, 2.25 mmol) was added. The solution was stirred at room temperature for about 1 hour, diluted with water, and acidified with AcOH. The solid was filtered and dried to give acid 12a1 as a beige solid.

Step 2

Pyridine (49 μ l) was added to a DCE (1 ml) solution of aniline 12a1(60 mg, 0.133 mmol) and acid chloride 1c8(47.5 mg, 0.270 mmol). The mixture was stirred in a microwave at 150 ℃ for 15 minutes, cooled to room temperature, acidified with AcOH, and purified by preparative HPLC to give 1043.

Example 13A

Preparation of compound 1044

Step 1

Potassium carbonate (650 mg, 4.703 mmol) was added to a DMSO (15.0 ml) solution of phenol 10a2(456.0 mg, 1.906 mmol) and chloropyridine 5a7(500 mg, 1.904 mmol). The mixture was stirred at 80 ℃ for about 12 hours, cooled to room temperature, and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (30% EtOAc in hexanes) to afford triazole 13a 1.

Step 2

Pyridine (404 μ l, 5.0 mmol) was added to a DCE (1 ml) solution of aniline 13a1(433 mg, 0.930 mmol) and acid chloride 1a8(450 mg, 2.801 mmol). The mixture was stirred in a microwave at 140 ℃ for 60 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in MeOH/THF (1: 2) and 1N aqueous NaOH (660. mu.l) was added. The mixture was stirred at room temperature for about 2 days, acidified with aqueous HCl, and purified by preparative HPLC to give 1044.

Example 14A

Preparation of compound 1046

Step 1

Using the procedure of example 13A, step 1, compound 14a1 was produced via the reaction between compounds 10a2 and 5b 5.

Step 2

Compound 14a1 was converted to compound 14a2 using the procedure of step 5, example 11A.

Step 3

To a solution of 14a2(190 mg, 0.32 mmol) in MeCN/deionized water was added aqueous NaOH (0.32 ml, 1M). It was stirred at room temperature for about 96 hours. An additional amount of aqueous NaOH (0.64 ml, 1M) was added and the resulting solution was stirred for about 18 hours. At 0 ℃, 1M aqueous HCl was added until an acidic pH. The solution was extracted with EtOAc (4 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. A pale yellow oil (194 mg) was obtained, which was dissolved in MeCN/deionized water (100 ml, 1: 1) and 1 equivalent of 1M aqueous NaOH was added. The solvent was then removed by lyophilization (-2 days) to afford 1046.

Example 15A

Preparation of compounds 1047 and 1048

Step 1

Sulfuric acid (1 ml) was added to a solution of acid 15a1(5.00 g, 17.6 mmol) in MeOH (100 ml). The solution was stirred at 80 ℃ overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc (300 ml) and saturated NaHCO₃Aqueous (3X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (100% hexanes followed by 5% to 10% EtOAc in hexanes) to give methyl ester 15a2 as an oil, which solidified upon standing under high vacuum.

Step 2

(S) - (+) -1-methoxy-2-propylamine (1.47 g, 16.7 mmol) was added to a solution of fluoride 15a2(3.30 g, 11.1 mmol) and potassium carbonate (2.28 g, 16.7 mmol) in DMF (30 mL). The mixture was stirred at 90 ℃ overnight, cooled to room temperature and quenched with saturated NaHCO₃The aqueous solution (200 ml) was diluted and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated NaHCO₃Aqueous (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (100% hexanes followed by 5% to 20% EtOAc in hexanes) to afford amine 15a3 as an oil.

Step 3

Pd (PPh)₃)₄(774 mg, 0.67 mmol) was added to a mixture of iodide 15a3(2.46 g, 0.670 mmol) and tributylvinyltin (2.2 ml, 0.73 mmol) in DMF (30 ml). The mixture was degassed by bubbling Ar simultaneously and sonicating the solution for about 15 minutes. The mixture was stirred at 110 ℃ for about 2.5 hours, cooled to room temperature, and saturated NaHCO was used₃The aqueous solution (200 ml) was diluted and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated NaHCO₃Aqueous (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (100% hexanes followed by 5% to 10% EtOAc in hexanes) to afford vinyl compound 15a4 as an oil.

Step 4

Vinyl compound 15a4(1.00 g, 3.75 mmol) was dissolved in a mixture of acetone/tert-butanol/water (20 ml: 8 ml: 4 ml). The solution was cooled to 0 ℃ and NMO (572 mg, 5.62 mmol) was added, followed by OsO₄(2.5% t-butanol solution, 1.96 ml, 0.18 mmol). The solution was stirred at 0 ℃ for about 2 hours, diluted with 10% aqueous sodium thiosulfate (100 ml) and extracted with EtOAc (2 × 100 ml). Will mergeWas washed with 10% aqueous thiosulfate (100 ml), brine (2X 100 ml), and Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude diol, which was dissolved in THF (30 ml) and water (15 ml). The solution was cooled to 0 ℃ and NaIO was added₄(1.2 g, 5.6 mmol). The solution was stirred at 0 ℃ for about 4 hours. With saturated NaHCO₃The reaction mixture was diluted with aqueous solution (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (100% hexanes followed by 5% to 20% EtOAc in hexanes) to afford aldehyde 15a5 as an oil.

Step 5

Sulfuric acid (0.162 ml, 2.6 mmol) was added to a solution of aldehyde 15a5(500 mg, 1.86 mmol) in 0 ℃ MeOH (10 ml), followed by 30% aqueous hydrogen peroxide (0.295 ml, 2.6 mmol). The solution was stirred at 0 ℃ for about 1 hour, followed by 10% KH₂PO₄The aqueous solution (50 ml) was diluted and extracted with ether (2 × 100 ml). The combined organic phases were washed with 10% KH₂PO₄Aqueous solution (2X 100 ml), brine (2X 100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude phenol 15a6 was used directly in the next step without further purification.

Step 6

Phenol 15a6 was converted to triazole 15a7 using the method described in step 1, example 13A.

Step 7

Amine 15a7 is converted to compound 1047 using the procedure described in step 2, example 13A.

And 8:

amine 15a7 is converted to compound 1048 using the procedure described in step 4, example 10A.

Example 16A

Preparation of compounds 1051 and 1052

Step 1

To phenol 3a6(701 mg, 1.66 mmol) and Cs₂CO₃(737 mg, 2.27 mmol) in anhydrous DMSO (8 ml) was added chloropyridine 5a7(397 mg, 1.51 mmol). The resulting mixture was stirred at 80 ℃ for about 2 hours, then diluted with EtOAc and washed with water, brine in order, and concentrated under reduced pressure. After purification by Combiflash (15% EtOAc in hexanes), the intermediate methyl ester was isolated. The ester was redissolved in a THF (20 ml)/MeOH (10 ml) mixture and aqueous NaOH (10N, 0.8 ml, 8.0 mmol) was added. The mixture was stirred overnight, then acidified with AcOH, filtered and injected onto preparative HPLC. The combined fractions were lyophilized and the solid was dissolved in EtOAc. The organic solution was washed with 1M NaOH (3 ×). The combined aqueous fractions were acidified with 1M HCl until pH6 and extracted with EtOAc (3 ×). The organic material was washed with MgSO₄Dried and concentrated. The product was redissolved in MeCN and water and lyophilized to give 1051.

Step 2

The coupling of phenol 3a6 with pyridine 5b5 was performed as described previously in example 16A, step 1. Saponification of the crude methyl ester (0.18 mmol) was performed in MeOH (1 ml) with NaOH (1M, 0.9 ml, 0.9 mmol). After complete conversion, the mixture is acidified with AcOH, filtered, and then injected onto preparative HPLC to afford 1052.

Example 17A

Preparation of Compound 1054

Step 1

To phenol 1a10(1.96 g, 4.77 mmol) and Cs₂CO₃(1.83 g, 5.64 mmol) in anhydrous DMSO (30 ml) pyridine 5b5(1.20 g, 4.34 mmol) was added. The resulting mixture was stirred at 95 ℃ overnight, then poured into water and treated with Et₂O extraction (3 ×). The combined organic fractions were concentrated under reduced pressure. After purification by Combiflash (10% to 50% EtOAc in hexanes), the intermediate methyl ester was isolated. The ester was redissolved in MeOH (2 ml) and aqueous NaOH (1N, 2.34 ml, 2.34 mmol) was added. The mixture was stirred overnight and then Et₂O wash, then acidify with 1M HCl at 0 ℃ and extract with EtOAc (4 ×). The combined fractions were dried and concentrated. The product was washed with pentane/Et₂The O (3: 1) mixture was triturated (3X), dissolved in MeCN and water, and lyophilized to give 1054 as the sodium salt.

Example 18A

Preparation of Compound 1059

Step 1

Vinyl compound 18a1 (prepared according to the same method described in example 25A, step 2) was converted to aldehyde 18a2 using the method in example 15A, step 4.

Step 2

To a solution of aldehyde 18a2(60 mg, 0.11 mmol) in DCM (1 ml) were added morpholine (34 μ l, 0.56 mmol), HCl solution (4M in dioxane, 28 μ l, 0.11 mmol) and nabh (oac) in that order₃(47 mg, 0.22 mmol). Placing reactants in a chamberStir warm and then concentrate to dryness. The mixture was redissolved in MeOH (1 ml) and NaOH (10N, 0.1 ml, 1 mmol) was added. When complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC to isolate 1059.

Example 19A

Preparation of Compound 1060

Step 1

Using the procedure of example 16A, step 1, compound 19a1 was produced via the reaction between compounds 5a6 and 15a 6.

Step 2

Intermediate 19a1(75 mg, 0.14 mmol) was dissolved in pyridine (1 ml) in a microwave tube, followed by the addition of a solution of acid chloride 1a8 (2M in DCE, 0.5 ml, 0.90 mmol), followed by the addition of catalytic amounts of DMAP (7 mg, 56 μmol). The tube was sealed and placed in a microwave at 150 ℃ for 20 minutes. The mixture was diluted in EtOAc and washed with water (2x) and brine (1 x). The combined organic material was washed with MgSO₄Dried, filtered, and concentrated. The crude residue was purified by flash chromatography (5% to 70% EtOAc in hexanes) to give 19a 2.

Step 3

Methyl ester 19a2(16 mg, 24. mu. mol) was dissolved in a 2: 1THF/MeOH mixture (0.5 mL) and aqueous NaOH (1.0M, 25. mu.L, 25. mu. mol) was added. The reaction was stirred at room temperature, diluted in water and the aqueous layer was washed with Et₂O wash (2 ×) to remove organic impurities. The aqueous fraction was lyophilized and compound 1060 was isolated as its sodium salt.

Example 20A

Preparation of Compound 1061

Step 1

Chloride 9a3(60 mg, 0.10 mmol) was dissolved in degassed DMF (2 ml, degassed by bubbling Ar with sonication for about 10 min) in a microwave tube. Then 2- (tributyltin-yl) pyridine (92 mg, 0.25 mmol) and Pd (PPh) were added₃)₄Catalyst (12 mg, 10 micromoles). The mixture was degassed again and the tube sealed and placed in a microwave at 120 ℃ for 20 minutes. The mixture was diluted in EtOAc and washed with water (2x) and brine (2 x). The combined organic material was washed with MgSO₄Dried, filtered, and concentrated. The crude residue was purified by flash chromatography (25% to 75% EtOAc in hexanes) to give 20a 1.

Step 2

Intermediate 20a1(35 mg, 0.055 mmol) was dissolved in THF (3 ml)/MeOH (0.5 ml)/H₂O (0.5 ml) mixture and aqueous NaOH (10N, 27 μ l, 0.27 mmol) was added. When complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC and isolated 1061.

Example 21A

Preparation of Compound 1072

Step 1

Using the procedure of example 13A, step 1, compound 21a1 was produced via the reaction between compounds 5b5 and 15a 6.

Step 2

Compound 21A1 was converted to compound 21A2 using the procedure of step 5, example 11A.

Step 3

Compound 21a2 was converted to compound 1072 using the procedure of step 3, example 14A.

Example 22A

Preparation of Compound 1082

Step 1

Using the procedure of steps 2 and 3 of example 8A, compound 22a1 was produced via the reaction of compound 1a6 with 2-fluoro-3-trifluoromethylpyridine.

Step 2

In a 25 ml flask, 22a1(60 mg, 0.14 mmol), pyridine (0.25 ml, 3.1 mmol), acid chloride 1d8(99 mg, 0.42 mmol), and DMAP (5.1 mg, 0.04 mmol) were added. The mixture was heated to 150 ℃ for about 4 hours, then cooled and stirred at room temperature for about 65 hours. With NaHCO₃It was quenched (saturated), extracted with DCM (3 ×), passed through a phase separator and concentrated under reduced pressure to give crude 22a2, which was used in the subsequent step without further purification.

Step 3

Compound 22a2 dissolved in THF/MeOH/H₂To O (2: 1 mL), NaOH (10M, 0.07 mL) was added and the reaction was stirred at room temperature for about 36 hours. A minimum amount of aqueous AcOH solution was added, the solution was neutralized, and the solvent was evaporated. Purification by preparative HPLC gave compound 1082 as a white lyophilized solid.

Example 23A

Preparation of compounds 1092 and 1093

Step 1

Compound 1c8 was reacted with 1a6 using the method in step 2, example 19A. Deprotection of the benzyl ether was carried out in the same manner as in step 2 of example 8A to give compound 23a 1.

Step 2 and step 3:

to a solution of phenol (50 mg, 0.12 mmol) in DMSO (1 ml) was added CsCO₃(57 mg, 0.18 mmol) followed by the addition of chloropyridine 5b5(90 mg, 0.33 mmol). It was stirred at 105 ℃ for about 18 hours and then cooled to room temperature. MeOH (1 ml), NaOH (1 eq, 1M aq) and LiOH (1 eq) were added and stirred at rt for about 4 h. The mixture was then concentrated, diluted in AcOH (4 ml) and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to give two products 1093 and 1092.

Example 24A

Preparation of compound 1094

Step 1

Compound 2a1 was converted to compound 24a1 using the procedure in steps 4 and 5 of example 1A.

Step 2

Compound 24a1 was converted to compound 24a2 using the procedure in step 8, example 1A.

Step 3

Compound 24a2 was mixed with 5a6 using the method in step 3, example 8A to form compound 24a 3.

And 4, step 5:

compound 24a3 was converted to 24a4 and then to compound 1094 using the procedures described in example 22A, steps 2 and 3, respectively.

Example 25A

Preparation of compound 1099

Step 1

To a solution of phenol 1a10(400 mg, 0.97 mmol) in DMSO (5 mL) was added CsCO₃(474 mg, 1.4 mmol) and chloropyridine 5a3(430 mg, 1.40 mmol). The solution was stirred at 75 ℃ for about 4 hours and then washed with water and brine. Then, the solution was treated with anhydrous Na₂SO₄Dry, filter under vacuum, and concentrate under reduced pressure. Purification by flash chromatography using (20: 80 to 60: 40) EtOAc/hexane afforded 25a 1.

Step 2

To a solution of iodide 25a1(370 mg, 0.54 mmol) in dioxane (4 ml) was added tributyl (vinyl) tin (0.2 ml, 0.69 mmol) at room temperature. Argon was bubbled through the solution, followed by addition of bis (triphenylphosphine) palladium dichloride (42 mg, 0.06 mmol). Heating the reaction mixture at reflux for about 1 hour; then concentrated and purified by flash chromatography using (10: 90 to 70: 30) EtOAc/hexanes to give 25a 2.

Step 3

To a solution of alkene 25a2(40 mg, 0.07 mmol) in DMF (1 ml) was added bromopyridine (18 mg, 0.10 mmol), TBABr (35 mg, 0.21 mmol), Et at room temperature₃N (0.014 ml, 0.10 mmol) and BPalladium (1.5 mg, 0.007 mmol) acid. This was stirred in a microwave at 120 ℃ for 10 minutes, followed by heating at 140 ℃ (oil bath) for about 16 hours. The reaction mixture was quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. THF (2 ml), MeOH (1 ml) and NaOH (1M in water, 5 equivalents) were added, which was then stirred at rt for about 14 h. The reaction mixture was diluted with AcOH (1 ml) and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to give 1099.

Example 26A

Preparation of Compound 1102

Step 0

To a microwave tube containing DMF (2 mL) were added 2-bromo-6-methylpyridine (300 mg, 1.74 mmol), trimethylsilylacetylene (257 mg, 2.62 mmol), CuI (33 mg, 0.17 mmol), Pd (PPh)₃)₄(201 mg, 0.17 mmol) and Et₃N (1.2 ml). The tube was sealed and placed in a microwave at 120 ℃ for 10 minutes. The mixture was then diluted with EtOAc, washed with water and brine, and Na₂SO₄Dried, filtered, and concentrated. The crude residue was purified by flash chromatography (hexanes/EtOAc, 20% to 80%) to give pyridine 26a 1.

Step 1

To a solution of alkyne 26a1(33 mg, 0.18 mmol) in DMF (1 ml) was added TBAF (0.18 ml, 1M in THF) at room temperature. This was stirred for about 10 minutes, then iodide 25a1(40 mg, 0.06 mmol), CuI (1.1 mg, 0.006 mmol), Et were added at room temperature₃N (0.04 mL, 0.3 mmol) and Pd (PPh)₃)₄(6.8Mg, 0.006 mmol). The mixture was stirred in a microwave at 120 ℃ for 12 minutes. The reaction mixture was quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. Purification by flash chromatography using (40: 60 to 90: 10) EtOAc/hexane afforded 26a 2.

Step 2

Compound 26a2 was dissolved in MeOH, Pd/C (10% w/w, 33 mg) was added, and the mixture was washed with H₂Scrubbing (3 ×). Mixing the mixture with H₂Stir under atmospheric (balloon) for about 1 hour, filter, and concentrate under reduced pressure. The residue was dissolved in MeOH and NaOH (1M in water, 1 ml) was added followed by LiOH (3 equivalents). The mixture was stirred at rt for 2 h, concentrated, dissolved in AcOH (2 ml) and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to give compound 1102.

Example 27A

Preparation of Compound 1104

Step 1

Compound 3A6 was converted to compound 27a1 using the procedure in step 1, example 13A.

Step 2

Iodide 27a1(90 mg, 0.13 mmol), ethynylpyridine (27 mg, 0.26 mmol), CuI (2.5 mg, 0.013 mmol), Pd (PPh)₃)₄(15 mg, 0.013 mmol) and Et₃A mixture of N (0.09 ml, 0.7 mmol) in degassed DMF was heated in a microwave at 120 ℃ for 20 min. This mixture was dissolved in EtOAc (50 ml), washed with water and brine, and dried (MgSO)₄) And concentrated. Purifying by flash chromatographyAlkylation (1/2, followed by 1/1 EtOAc/hexanes) provided 27a2 as a light yellow foam.

Step 3

To alkyne 27a2(70 mg, 0.10 mmol) in MeOH (2 ml) was added Pd/C catalyst (10% w/w, 70 mg) which was then charged at-15 psi of H at room temperature₂Hydrogenation for about 2.5 hours. The catalyst was filtered and the residue was concentrated to dryness. The crude product 27a3 was isolated and used in subsequent reactions without further purification.

Step 4

To a solution of ester 27a3(68 mg, 0.10 mmol) dissolved in DMSO (2 ml), MeOH (1 ml) and water (0.3 ml) was added aqueous NaOH (10N, 0.06 ml) at room temperature. It was stirred at room temperature for about 5 hours and then kept at 0 ℃ overnight. The reaction was quenched with aqueous TFA and purified by preparative HPLC. The fractions were combined and lyophilized to give 1104.

Example 28A

Preparation of Compound 1105

Step 1

Using the procedure of example 13A, step 1, compound 28a1 was generated via the reaction of compound 10a2 with compound 5a 3.

Step 2

Compound 28a1 was converted to compound 28a2 using the procedure of step 5, example 11A.

Step 3

Iodide 28a2(500 mg, 0.79 mmol), benzyl acrylate (1.3 g, 7.9 mmol), Pd (OAc)₂(50 mg, 0.23 mmol), Et₃N (5.0 mL) and MeCN (20 mL)) The mixture of (4) was stirred in a sealed tube at 60 ℃ for about 4 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated. Purification by flash chromatography (7: 3 to 1: 1 hexanes: EtOAc) gave an oil which was dissolved in EtOH (20 mL). Pd/C (10%, 50 mg) was added, followed by addition of hydrogen peroxide to the reaction mixture₂Stir for about 30 minutes. In thatThe reaction mixture was filtered and concentrated to give 28a3 as a white foam.

And 4, step 5:

to acid 28a3(50 mg, 0.09 mmol) in DMF (2.0 ml) was added Et₃N (0.06 ml, 0.4 mmol) and HATU (40 mg, 0.11 mmol). The reaction was stirred for about 10 minutes; amidoxime (amidoxime) (8.8 mg, 0.09 mmol) was then added and stirring continued for about 2 hours. The reaction mixture was poured into Et₂In O, with H₂O (3x), saturated NH₄Cl (1X) washing with MgSO 2₄Dried, filtered, and concentrated in vacuo. The residue was redissolved in THF (3 ml); TBAF (0.1 ml, 1.0M in THF) was then added and stirred at 45 ℃ for about 1 hour. The mixture was concentrated in vacuo, then the residue was dissolved in DMSO (2 ml). Aqueous NaOH (1M, 1 ml) was added and the solution was stirred at room temperature for about 1 hour. AcOH was added and purified by preparative HPLC followed by lyophilization to afford compound 1105.

Example 29A

Preparation of compound 1109

Step 1

Using the procedure of example 8A, step 3, compound 29a1 was generated via the reaction of compound 5a7 with 24a 2.

Step 2

Compound 29a1 was converted to compound 29a2 using the procedure of step 2, example 22A.

Step 3

Compound 29a2 was converted to compound 1109 using the procedure of step 3, example 22A.

Example 30A

Preparation of Compound 1110

Step 1 and step 2:

compounds 5a7 and 1a6 were converted to compound 30a1, produced using the methods of steps 2 and 3, example 8A, followed by the method of step 2, example 22A, to compound 30a 2.

Step 3

Compound 30a2 was converted to compound 1110 using the procedure of step 3, example 22A.

Example 31A

Preparation of compound 1113

Step 1

Compound 31A1 (produced according to the condensation of 5a3 and 24a2 using the method described in example 24, step 3) was acylated using the method of example 22A, step 2 using 31A2 (synthesized according to the method described in example 1, step 6) to give compound 31A 3.

Step 2

Compound 31a3 was converted to compound 31a4 using the procedure of step 2, example 25A.

Step 3 and step 4:

compound 31a4 was converted to 31a5 and then to compound 31a6 using the procedures of example 5B, steps 2 and 3, respectively.

Step 5

Compound 31a6 was converted to compound 31a7 using the procedures of example 9A, step 3, respectively.

Step 6 and step 7:

to a solution of chloride 31a7(56 mg, 0.09 mmol) in DMF (1 ml) was added Pd (PPh) at room temperature₃)₄(9.9 mg, 0.009 mmol) and 5- (tri-butylstannyl) thiazole (64 mg, 0.17 mmol). The solution was stirred at 120 ℃ for about 12 minutes. MeOH (1 ml) and aqueous NaOH (1M, 1 ml) were added and stirring was continued at room temperature for about 3 hours. The reaction mixture was concentrated, diluted in AcOH (4 ml) and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to give compound 1113.

Example 32A

Preparation of compounds 1114 and 1118

Step 1

Chloride 32a1(356 mg, 0.639 mmol), prepared from phenol 10a2 using the method described in steps 1 to 3 of example 9A, was dissolved in DMSO (1 ml) and NaCN (63 mg, 1.28 mmol) was added. The reaction was stirred at room temperature for about 1 hour, followed by addition of water. The mixture was extracted with DCM (3 ×), the organic material was dried and concentrated. Purification by flash chromatography (1% to 5% MeOH in DCM) afforded the nitrile 32a 2.

Step 2

Nitrile 32a2(42 mg, 0.08 mmol) was dissolved in THF (1 mL)/MeOH (0.5 mL)/H₂O (0.5 ml) mixture and aqueous NaOH (10N, 77 μ l, 0.77 mmol) was added. When the reaction is complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC and compound 1114 is isolated.

Step 3

Nitrile 32a2(49 mg, 0.09 mmol) and iodomethane (22 ml, 0.36 mmol) were dissolved in DMF (1 ml) at 0 ℃ and a suspension of NaH (95% w/w, 4.5 mg, 0.18 mmol) in DMF (0.5 ml) was added slowly. After about 2 hours, the reaction was neutralized with water, extracted with DCM (3 ×), and the organic material was concentrated. The crude residue was redissolved in THF (1 ml)/MeOH (0.5 ml)/H₂O (0.5 ml) mixture and aqueous NaOH (10N, 90 μ l, 0.90 mmol) was added. When the reaction is complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC and compound 1118 is isolated.

Example 33A

Preparation of Compound 1115

Step 1

To a solution of chloride 32a1(75 mg, 0.14 mmol) in DMF (1.5 ml) was added 2-aminopyrimidine (43 mg, 0.46 mmol) with a catalytic amount of KI (11 mg, 0.07 mmol). The mixture was warmed at 80 ℃ for about 2 hours and then cooled to room temperature. Acetonitrile (1 ml) and aqueous NaOH (2.5N, 240 μ l, 0.6 mmol) were added and the mixture was warmed at 50 ℃ for about 2 hours, then neutralized with AcOH at room temperature and injected onto preparative HPLC to isolate compound 1115.

Example 34A

Preparation of Compound 1116

Step 1

To a solution of the ketal 3a1(1.5 g, 3.6 mmol) in toluene (7 ml) was added TFA (7 ml). The mixture was stirred for about 1 hour, followed by the addition of water (0.4 ml). Stirring was continued overnight and the mixture was concentrated. The resulting residue was diluted with EtOAc and Na₂CO₃(1M), water and brine, Na₂SO₄Drying, filtration, evaporation, and concentration gave 34a 1.

Step 2

Ketone 34a1(1.7 g, 4.6 mmol) was suspended in MeOH (40 ml) and the solution was cooled to 0 ℃. Addition of NaBH₄(87 mg, 2.3 mmol) and the mixture is stirred for about 1 hour. The reaction was quenched with 1MHCl and the MeOH was evaporated under reduced pressure. The residue was diluted with EtOAc and saturated NaHCO₃Aqueous solution, water and brine. Then, the residue was taken up with Na₂SO₄Dried, filtered, evaporated, and used in subsequent reactions without further purification.

Step 3

Benzyl ether 34a2(410 mg, 1.1 mmol) was dissolved in MeOH (3 ml) and EtOAc (6 ml). 10% Pd/C (4 mg) was added and the flask was placed under an atmosphere of hydrogen. After about 2 hours, inThe mixture was filtered and DMSO (9 ml) was added to the organic phase. MeOH was removed under reduced pressure. Chloropyridine 5a7(258 mg, 0.98 mmol) and cesium carbonate (448 mg, 1.4 mmol) were added, and the mixture was stirred at 70 ℃ for about 4 hours. The reaction mixture was then diluted with EtOAcFor release, saturated NaHCO is used₃The aqueous solution was washed with brine and MgSO₄Dried, filtered and evaporated. Purification by flash chromatography (10: 90 to 50: 50 EtOAc: hexane) afforded 34a 3.

Step 4

Alcohol 34a3(400 mg, 1.1 mmol) was dissolved in DMF (10 ml) and methyl iodide (1.7 ml, 27 mmol) was added. The solution was cooled to 0 ℃, then sodium hydride (133 mg, 3.3 mmol, 60% in oil) was added and the mixture was stirred for about 4 hours. Addition of saturated NH₄Cl (10 ml), followed by addition of EtOAc (100 ml) and water (40 ml), and the mixture was shaken in a separatory funnel. The layers were separated and the organic layer was washed with brine, over MgSO₄Drying, filtration, evaporation, concentration, and purification by flash chromatography (100% hexane to 60% hexane/EtOAc) afforded 34a 4.

Step 5

Compound 34a4 was converted to compound 34a5 using the procedure of step 2, example 22A.

Step 6

Compound 34a5 was converted to compound 1116 using the procedure of step 3, example 22A.

Example 35A

Preparation of Compound 2001

Step 1

Sulfuric acid (3 ml) was added to a solution of 35a1(16.3 g, 57.4 mmol) in MeOH (200 ml). The solution was stirred at 80 ℃ overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc (300 ml), washed with saturated aqueous sodium bicarbonate (3 × 100 ml), brine (100 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (10% EtOAc in hexanes) to give methyl ester 35a2 as an oil, which solidified upon standing under high vacuum.

Step 2

(S) - (+) -1-methoxy-2-propylamine (1.90 g, 21.3 mmol) was added to a solution of 35a2(4.53 g, 15.2 mmol) and potassium carbonate (3.15 g, 22.8 mmol) in DMF (30 mL). The mixture was stirred at 75 ℃ overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (200 ml) and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (100% hexanes followed by 5% to 20% EtOAc in hexanes) to give 35a3 as an oil.

Step 3

Pd (PPh)₃)₄(297 mg, 0.26 mmol) was added to a mixture of iodide 35a3(2.36 g, 6.43 mmol) and tributylvinyltin (2.06 ml, 7.07 mmol) in DMF (25 ml). The mixture was degassed by bubbling Ar simultaneously and sonicating the solution for about 15 minutes. The mixture was stirred at 90 ℃ for about 30 minutes, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (200 ml) and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (100% hexanes followed by 5% to 10% EtOAc in hexanes) to give 35a4 as an oil.

Step 4

Vinyl compound 35a4(1.45 g, 5.42 mmol) was dissolved in a mixture of acetone/tert-butanol/water (40 ml: 10 ml: 9.6 ml). The solution was cooled to 0 ℃ and NMO (956 mg, 8.14 mmol) was added, followed by OsO₄(2.5% t-butanol solution, 276. mu.l, 0.027 mmol). The solution was stirred at 0 ℃ overnight, diluted with 10% aqueous sodium thiosulfate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with 10% aqueous thiosulfate (100 ml), brine (2X 100 ml), Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude diol, which was dissolved in THF (10 ml) and water (10 ml). The solution was cooled to 0 ℃ and NaIO was added₄(1.60 g, 7.47 mmol) and then stirred at 0 ℃ for about 4 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (100% hexanes followed by 5% to 20% EtOAc in hexanes) to give 35a6 as an oil.

Step 5

Sulfuric acid (223 μ l, 3.56 mmol) was added to a solution of 35a6(640 mg, 2.38 mmol) in 0 ℃ MeOH (20 ml), followed by 30% aqueous hydrogen peroxide (404 μ l, 3.57 mmol). The solution was stirred at 0 ℃ for about 1 hour and then treated with 10% KH₂PO₄The aqueous solution (50 ml) was diluted and extracted with ether (2 × 100 ml). The combined organic phases were washed with 10% KH₂PO₄Aqueous solution (2X 100 ml), brine (2X 100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude phenol 35a7 was used directly in the next step without further purification.

Step 6

Compound 35a7 was converted to compound 35a8 using the procedure of step 1, example 13A.

Step 7

Compound 35a8 was converted to compound 2001 using the procedure of step 2, example 13A.

Example 36A

Preparation of Compound 2002

Step 1

Sulfuric acid (3 ml) was added to a solution of 36a1(15.0 g, 36.9 mmol) in MeOH (200 ml) and the resulting solution was stirred at 80 ℃ overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc (300 ml), washed with saturated aqueous sodium bicarbonate (3 × 100 ml), brine (100 ml), and Na₂SO₄Drying, filtration, and concentration under reduced pressure gave methyl ester 36a 2.

Step 2

(S) - (+) -1-methoxy-2-propylamine (1.49 g, 16.8 mmol) was added to a solution of 36a2(3.84 g, 12.9 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in DMF (30 mL). The mixture was stirred at 75 ℃ overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (200 ml) and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (100% hexanes followed by 5% to 20% EtOAc in hexanes) to give a mixture of isomers 36a3 and 36a 4.

Step 3

Pd (PPh)₃)₄(315 mg, 0.272 mmol) was added to a mixture of iodides 36a3 and 36a4(2.00 g, 5.45 mmol) and tributylvinyltin (1.91 ml, 6.54 mmol) in DMF (40 ml). The mixture was degassed by bubbling Ar simultaneously and by sonicating the solution for about 15 minutes. Stirring the mixture at 100 deg.C for about 2.5 hr, cooling to room temperature, and adding waterAnd aqueous sodium bicarbonate (200 ml) and extracted with EtOAc (2 × 200 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2X 100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (100% hexanes followed by 5% to 10% EtOAc in hexanes) to give a mixture of compound 36a5 and 36a 6.

Step 4

Vinyl compounds 36a5 and 36a6(1.19 g, 4.45 mmol) were dissolved in a mixture of acetone/tert-butanol/water (40 ml: 10 ml: 9.6 ml). The solution was cooled to 0 ℃ and NMO (732 mg, 6.23 mmol) was added, followed by OsO₄(2.5% t-butanol solution, 226. mu.l, 0.022 mmol). The solution was stirred at 0 ℃ overnight, diluted with 10% aqueous sodium thiosulfate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with 10% aqueous thiosulfate (100 ml), brine (2X 100 ml), Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude diol, which was dissolved in THF (10 ml) and water (10 ml). The solution was cooled to 0 ℃ and sodium meta-periodate (1.38 g, 6.45 mmol) was added. The solution was stirred at 0 ℃ for about 2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (100% hexanes followed by 5% to 10% EtOAc in hexanes) to afford compound 36a7 (first eluate) and 36a8 as oils.

Step 5

Sulfuric acid (147 μ l, 2.35 mmol) was added to a solution of 36a8(400 mg, 1.49 mmol) in 0 ℃ MeOH (10 ml), followed by 30% aqueous hydrogen peroxide (252 μ l, 2.23 mmol). The solution was stirred at 0 ℃ for about 1 hour and then treated with 10% KH₂PO₄The aqueous solution (50 ml) was diluted and extracted with ether (2 × 100 ml). The combined organic phases were washed with 10% KH₂PO₄Aqueous solution (2X 100 ml), brine (2X 100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude phenol 36a9 was used directly in the next step without further purification.

Step 6

Compound 36a9 was converted to compound 36a10 using the procedure described in step 1, example 13A.

Step 7

Compound 36a10 was converted to compound 2002 using the procedure described in step 2, example 13A.

Example 37A

Preparation of Compound 3001

Step 1

Phenol 2a5(1.0 g, 2.54 mmol) was reacted with K₂CO₃(878 mg, 6.35 mmol) and 37a1(586 mg, 3.05 mmol) were mixed in DMSO (15 ml). The mixture was heated at 60 ℃ under Ar until complete conversion, and then cooled to room temperature. Then saturated NaHCO was added₃An aqueous solution. The mixture was extracted with EtOAc (3 ×), the combined organic material was MgSO₄Dried, filtered, and concentrated under reduced pressure to give crude 37a2, which was used without further purification.

Step 2

To a solution of 37a2(100 mg, 0.18 mmol) and 3, 3-difluoropiperidine hydrochloride (31 mg, 0.20 mmol) in DCE (1.5 mL) was added NaBH (OAc)₃(52 mg, 0.25 mmol). The mixture was stirred at room temperature overnight, thenWater was added. The mixture was extracted with DCM (3 ×), the organic material was dried and concentrated under reduced pressure. Purification by Combiflash (15% EtOAc in hexanes) afforded 37a 3.

Step 3

Compound 37a3 was converted to compound 3001 using the procedure of step 2, example 32A.

Example 38A

Preparation of Compound 3002

Step 1

Aldehyde 37a2(1.30 g, 2.30 mmol) was dissolved in MeOH (25 ml) at 0 ℃ and NaBH was added₄(104 mg, 2.76 mmol). After stirring for about 1 hour, the reaction was quenched with saturated aqueous citric acid and extracted with EtOAc (3 ×). The organic material was washed with MgSO₄Dried, filtered, and concentrated. Purification by Combiflash yielded alcohol 38a 1.

Step 2

Alcohol 38a1(700 mg, 1.23 mmol) was dissolved in DCM (15 ml) and thionyl chloride (0.19 ml, 2.59 mmol) and catalytic amount of DMF (10 μ l) was added. The reaction was stirred at room temperature; then using saturated citric acid aqueous solution and NaHCO₃And brine were washed sequentially. Mixing organic substance with Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude chloride 38a2 was used as such without further purification.

Step 3

Chloride 38a2(75 mg, 0.13 mmol), 5- (tributyltin-yl) thiazole (96 mg, 0.26 mmol) was placed in degassed DMF (1 ml, degassed by bubbling a volume of Ar while sonicating for about 10 min) in a microwave tube. Addition of Pd (PPh)₃)₄Catalyst (15 mg, 13 micromoles) and the tube sealed and placed in a microwave at 125 ℃ for 20 minutes. The mixture was diluted in EtOAc and washed with water (2x) and brine (2 x). The combined organic material was washed with MgSO₄Dried, filtered, and concentrated. The crude residue was passed through a short silica gel column (20% to 70% EtOAc in hexanes) to remove most of the impurities and concentrate the combined fractions. The resulting yellow oil was redissolved in THF (1 mL)/MeOH (0.5 mL)/H₂O (0.5 ml), and NaOH (10N, 0.13 ml, 1.3 mmol) was added. When complete, the reaction was neutralized with AcOH and injected onto preparative HPLC and 3002 was isolated.

Example 39A

Preparation of Compounds 3005 and 3006

Step 1

1, 2, 3-triazole (15 μ l, 0.13 mmol) was added to a suspension of NaH (60% w/w, 10 mg, 0.26 mmol) in THF (0.5 ml) and stirred at room temperature for about 15 minutes. The mixture was transferred to a solution of chloride 38a2(75 mg, 0.13 mmol) in anhydrous DMF (1 ml) and stirred overnight. The mixture was partially concentrated under reduced pressure and pre-adsorbed on silica gel and purified by Combiflash (50% to 100% EtOAc in hexanes). Two products were recovered, corresponding to each isomeric triazole intermediate. After combining and concentrating, each intermediate was redissolved in THF (2 ml)/MeOH (1 ml) and NaOH (10N, 0.13 ml, 1.3 mmol) was added. When complete, each reaction was neutralized with AcOH and injected onto preparative HPLC to separate 3005 from 3006.

Example 40A

Preparation of Compound 1121

Step 1

Compound 9a3 was converted to compound 40A1 using the procedure of step 1, example 20A.

Step 2

To methyl ester 40a1(27 mg, 41 micromoles) in MeOH and THF (1: 1 mixture, 1 ml) was added aqueous NaOH (1.0M, 41 μ l, 41 micromoles). The mixture was stirred at room temperature for about 2 days, then water was added. With Et₂The aqueous layer was O washed (2 ×) and lyophilized. Compound 1121 was obtained quantitatively as its sodium salt.

Example 41A

Preparation of Compound 1133

Step 1

Iodide 27a1(72 mg, 0.104 mmol) was dissolved in MeOH (5 ml) and 10% Pd/C (50 mg) was added. Stirring the mixture in hydrogen balloon atmosphere for about 1 hourThe mixture was filtered and concentrated under reduced pressure. The crude residue was redissolved in DMSO (3 ml) and water (0.5 ml) and aqueous NaOH (10N, 50 μ l, 0.50 mmol) was added. When complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC for isolation 1133.

Example 42A

Preparation of Compound 1139

Step 1

Using the procedure of example 16A, step 1, compound 42a1 was produced via reaction of 2a5(715 mg, 2.33 mmol) with pyridine 5a3(879 mg, 2.23 mmol).

Step 2

A mixture of iodide 42a1(56.7 mg, 85 micromoles), morpholine (42.5 mg, 0.49 mmol) and cesium carbonate (184 mg, 0.57 mmol) was prepared in dry toluene (3 ml). The mixture was sonicated and purged with an Ar balloon atmosphere for about 10 minutes. To this mixture, palladium acetate (1.9 mg, 9 micromolar) and BINAP (8.0 mg, 13 micromolar) were added and the heterogeneous mixture was again sonicated/scrubbed for about 10 minutes at which time it dissolved. The reaction was left at reflux for about 16 h, cooled to room temperature, then EtOAc was added and the mixture was washed with saturated NaHCO₃Aqueous wash (2 ×). The organic material was washed with MgSO₄Dried and concentrated. The crude residue was redissolved in THF (1 ml)/MeOH (0.5 ml)/water (0.5 ml) and NaOH (10N, 85 μ l, 0.85 mmol) was added. When complete, the reaction is neutralized with AcOH and injected onto a preparative HPLC for isolation 1139.

Example 43A

Preparation of Compounds 1160 and 1161

Step 1

Diol 11a5(221 mg, 0.57 mmol) was dissolved in DMF (3 ml) and cooled to 0 ℃. Allyl iodide (0.11 ml, 1.20 mmol) and sodium hydride (95%, 30.3 mg, 1.20 mmol) were added sequentially, and the mixture was stirred at room temperature for about 1 hour. Water was added and the mixture was extracted (3 ×) with DCM. The organic phase was dried and concentrated. The crude residue was purified by Combiflash (hexane/EtOAc, 15% to 25%) to give aniline 43a 1.

Step 2

Compound 43a1 was converted to compound 43a2 using the procedure of step 4, example 7A.

Step 3

Compound 43a2 was converted to compound 1160 using the procedure of step 2, example 32A.

Step 4

Compound 1160(18 mg, 31 micromoles) was dissolved in MeOH (3 ml) and activated raney nickel (50% slurry in water, 20 mg) was added. The reaction flask was purged and filled with hydrogen. After stirring for about 1 hour, the mixture is stirredThe mixture was filtered and washed thoroughly with MeOH. Concentrating the filtrate; the residue was redissolved in water/MeCN, filtered through a micro-disc and then lyophilized to give 1161.

Example 44A

Preparation of intermediate 44a4

Reference: loren, j.c.; krasinski, a.; fokin, v.v.; sharpless, k.b. synlett2005, 18, 2847.

Step 1

To a suspension of chloromethyl pivalate 44a1(20 ml, 186 mmol) in water (37 ml) was added sodium azide (18.1 g, 279 mmol) and the mixture was warmed at 90 ℃ for about 12 hours. Then water was added and the liquid phase was separated. Passing the organic layer through a filter containing MgSO₄To give azide 44a 2.

Step 2

Azide 44a2(100 mg, 0.64 mmol) and cyclopropylacetylene (54.7 mg, 0.83 mmol) were dissolved in t-butanol (0.5 ml) and water (0.5 ml). Aqueous copper sulfate (0.3M, 0.43 ml, 0.13 mmol) was added followed by aqueous sodium ascorbate (1.0M, 0.51 ml, 0.51 mmol). After stirring at room temperature for about 16 hours, the mixture was diluted in EtOAc and water and the liquid phase was separated. The organic substance is mixed with 5% NH₄Aqueous OH/brine solution (2X) then MgSO₄Dried and the solvent removed in vacuo. The oil corresponding to 44a3 was used as such in the next step.

Step 3

To ester 44a3(102 mg, 0.46 mmol) in MeOH (1 ml) was added aqueous NaOH (1N, 1 ml, 1 mmol). The reaction was stirred at room temperature for about 30 minutes, then neutralized with aqueous HCl (1M, 1 ml, 1 mmol) and diluted in water. The mixture was extracted with EtOAc (3 ×), washed with brine, dried, and the solvent removed under reduced pressure. The crude oil corresponding to 44a4 was used as such.

Example 44B

Preparation of compound 1167

Step 1

Compound 44b1 was produced via reaction of 1a10 with chloropyridine 5a4 using the method of step 1, example 9A.

Step 2

To aldehyde 44b1(1.25 g, 2.14 mmol) in MeOH (20 ml) which had been cooled at 0 ℃ was added NaBH₄(98 mg)2.6 mmol). When the reaction was complete, saturated aqueous citric acid was added. The mixture was extracted with EtOAc (3X), over MgSO₄Dried and concentrated. Purification by Combiflash (hexanes/EtOAc, 15% to 50%) gave 44b 2.

Step 3

To a solution containing alcohol 44b2(100 mg, 0.17 mmol), PPh₃(54 mg, 0.21 mmol) and triazole 44a4(28 mg, 0.21 mmol) in cooled (0 ℃ C.) THF (2 mL), DEAD (38. mu.L, 0.21 mmol) was slowly added. The reaction was slowly warmed to room temperature for about 16 hours. When the reaction was complete, the solvent was removed in vacuo and the crude residue was directly purified by Combiflash (hexane/EtOAc, 15% to 50%) to give 44b 3.

Step 4

Saponification using 1 equivalent NaOH was performed using the method described in step 2 of example 32A to afford 1167 as the sodium salt.

Example 44C

Preparation of intermediate 44c2

Step 1

In a sealed tube, azide 44a2(1.50 g, 9.54 mmol) was mixed with 1- (trimethylsilyl) -1-propyne (1.61 g, 14.32 mmol) in DCE (6 ml). The mixture was warmed at 80 ℃ for about 16 hours, followed by concentration of the solvent in vacuo to give triazole 44c1, which was used directly in the next step.

Step 2

Triazole 44c1(1.9 g, 7.05 mmol) was dissolved in MeOH (14 ml) and NaOH solution (10N, 1.55 ml, 15.5 mmol) was added. The reaction was stirred at room temperature for about 16 hours. The solvent was concentrated under reduced pressure to give crude triazole 44c2 as the sodium salt.

Example 45A

Preparation of Compound 1170

Step 1

To alcohol 44b2(105 mg, 0.18 mmol) in DCM (2 ml) was added thionyl chloride (28 μ l, 0.38 mmol). To this solution, DMF (50 μ l) was slowly added, and the reaction was performed at room temperature for about 1 hour. Then, a saturated aqueous citric acid solution was added thereto, and the layers were separated. The organic material was treated with saturated NaHCO₃The solution was washed with brine, MgSO₄Drying, filtration and concentration gave chloride 45a1, which was used as such in the next step.

Step 2

Chloride 45a1(150 mg, 0.25 mmol) and 44c2(53 mg, 0.30 mmol) were mixed in DMF (2 ml) and stirred at rt overnight. The mixture was diluted in EtOAc and washed with water (2x) and brine (1x), over MgSO₄Dried, filtered, and concentrated. After purification by flash chromatography (hexane/EtOAc, 15% to 40%), all the isomeric triazole intermediates were isolated in the same fractions. These isomers were re-separated on preparative HPLC. The lower polarity fraction corresponds to 45a 2.

Step 3

To compound 45a2(17 mg, 23 micromole) in THF (1 ml) was added TBAF (1.0M solution in THF, 70 μ l, 70 micromole). When the reaction was complete, the solvent was removed in vacuo and the crude residue containing 45a3 was used directly in the following step.

Step 4

Compound 45a3 was converted to compound 1170 using the procedure of step 2, example 32A.

Example 46A

Preparation of Compound 4001

Step 1

To compound 1a9(101 mg, 0.20 mmol) in THF (2 ml)/MeOH (1 ml)/water (1 ml) was added aqueous NaOH (10N, 0.2 ml, 2.0 mmol) and the mixture was stirred at rt. When the reaction was complete, AcOH was added, the reaction was neutralized, and the solvent was removed under reduced pressure to give crude 46a1, which was used directly in the next step.

Step 2

Crude 46a1(98 mg, 0.2 mmol) was dissolved in MeOH (3 ml)/EtOAc (5 ml) and activated Pd/C (10% w/w, 10 mg) was added. The mixture was scrubbed and filled with hydrogen. When the reaction is complete, the mixture is passed overThe pad was filtered, rinsed well with MeOH, and concentrated overnight. Acetonitrile and water were added and the mixture was lyophilized to give 46a 2.

Step 3

Formamidine acetate (15.3 g, 147 mmol) was mixed with 1, 3, 3, 3-tetrafluoro-1-methoxy-2- (trifluoromethyl) prop-1-ene (20.8 g, 98 mmol) in DCM (100 ml) and water (100 ml) at 0 ℃. To this vigorously stirred mixture, aqueous NaOH (6N, 71 ml, 424 mmol) was slowly added over a period of about 30 minutes. Stirring was then continued for about 35 minutes. The layers were separated and the organic layer was concentrated. The crude residue was purified by bulb-bulb distillation (80 ℃, 3 mm Hg) and further purified by Vigreux distillation under reduced pressure to give 46a 3.

Step 4

Pyrimidine 46a3(55 mg, 0.28 mmol) was reacted with phenol 46a2(112 mg, 0.28 mmol), K₂CO₃(132 mg, 0.96 mmol) in DMSO (2 ml). The mixture was stirred at room temperature for about 15 hours, then at 60 ℃ for about 1 hour. The mixture was filtered to remove the solid residue. The filtrate was acidified with AcOH and injected onto a preparative HPLC and 4001 was isolated.

Example 47A

Preparation of Compound 4008

Step 1

Phenol 2a5(100 mg, 0.25 mmol), 3-hydroxytetrahydrofuran (31 mg, 0.36 mmol) and PPh₃The mixture (100 mg, 0.38 mmol) was mixed in THF (2 ml) and cooled at 0 ℃. DIAD (70 μ l, 0.38 mmol) was added slowly for about 10 minutes and the reaction was stirred at room temperature. If necessary, more reagents are added to complete the conversion. Silica gel was then added directly and the solvent was removed under reduced pressure. The crude product was quickly passed through a silica gel column, eluting with a mixture of hexane/EtOAc (20% to 70%) to remove most of the triphenylphosphine oxide. The combined fractions were combined and concentrated under reduced pressure. The residue was redissolved in THF (2 ml)/MeOH (1 ml) followed by addition of NaOH (1N, 1 ml, 1 mmol). When complete, the reaction was neutralized with AcOH and injected onto a preparative HPLC and 4008 was isolated.

Example 48A

Preparation of compound 4010

Step 1

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (50 mg, 0.22 mmol), N- (2-methoxyethyl) methylamine (20 mg, 0.22 mmol) and K₂CO₃A suspension (90 mg, 0.65 mmol) was prepared in DMSO (2 ml) and stirred at room temperature. When the reaction was complete, phenol 46a2(81 mg, 0.21 mmol) was added and the mixture was warmed at 65 ℃ until the reaction was complete. When complete, the reaction was cooled and filtered through a micro-disk to remove undissolved material. The homogeneous solution is then neutralized with AcOH and injected onto a preparative HPLC and 4010 isolated.

Example 48B

Preparation of Compound 4021

Step 1

2, 6-dichloro-3- (trifluoromethyl) pyridine (75 mg, 0.35 mmol), morpholine (33 mg, 0.38 mmol) and K₂CO₃A suspension of (144 mg, 1.04 mmol) was prepared in DMSO (2 ml) and stirred at 60 ℃ for about 6 hours. When the reaction was complete, phenol 1a10(30 mg, 0.073 mmol) was added and the mixture was warmed at 100 ℃ for about 20 hours. When complete, the reaction was diluted in water and the (3 ×) mixture was extracted with DCM and concentrated. The residue was then dissolved in THF (2 ml)/MeOH (1 ml)/water (1 ml) and NaOH solution (10N, 75 μ l, 0.75 mmol) was added. When complete, the mixture is filtered and the homogeneous solution is neutralized with AcOH and injected onto a preparative HPLC to isolate 4021.

Example 49A

Preparation of Compound 1124

Step 1

Copper (I) iodide (28 mg, 0.147 mmol) was added to a solution of iodide 42a1(195 mg, 0.286 mmol), dibenzyl malonate (207 μ l, 0.829 mmol), picolinic acid (35 mg, 0.286 mmol), and cesium carbonate (382 mg, 1.172 mmol) in dioxane (2 ml). Argon was bubbled into the reaction mixture for about 2 minutes, and the reaction vessel was sealed and heated at 70 ℃ for about 20 hours. The reaction mixture was cooled to room temperature and more copper (I) iodide (28 mg, 0.147 mmol) was added, followed by 70 ℃ for about 20 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (50 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was dissolved in EtOH (10 mL) and Pd/C (10% w/w, 80 mg) was added. The reaction flask was evacuated and filled with hydrogen at atmospheric pressure. The mixture was stirred at room temperature for about 4 hours, passingFiltered, washed with EtOH and heated to 80 ℃ for about 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 49a1, which was used directly in the next step.

Step 2

49a1(214 mg, 0.35 mmol) was dissolved in DCM (8 mL) followed by the addition of oxalyl chloride (0.3 mL, 0.2M in DCM, 0.60 mmol) and DMF (0.01 mL). The mixture was stirred at 40 ℃ for about 1 hour and then concentrated in vacuo. The residue was redissolved in DCM (10 ml) and CH was added dropwise₂N₂(6.0 mL, 0.12M Et₂The solution of the oxygen is dissolved in the water,0.72 mmol). The solution was stirred for about 30 minutes and then concentrated in vacuo. The yellow oil was redissolved in THF (20 ml), cooled to 0 ℃, and HBr (0.1 ml, 48%, 0.93 mmol) was slowly added. It was stirred for about 20 minutes. Slowly add saturated NaHCO₃Then, the reaction was diluted with EtOAc and H₂O(1x)、NaHCO₃(1X), brine (1X) washing with MgSO₄Dried, filtered and concentrated in vacuo to afford yellow oil 49a 2.

Step 3

Bromide 49a2(80 mg, 0.12 mmol) was dissolved in iPrOH (3 ml) and thiourea 49a3(19 mg, 0.18 mmol) was added. The mixture was heated at 70 ℃ for about 4 hours. The mixture was cooled to room temperature, then NaOH (0.2 ml, 0.25M) was added and stirred for about 2 hours. The mixture was diluted with AcOH and purified by preparative HPLC to afford the desired compound 1124.

Example 50A

Preparation of Compound 1127

Step 1

Compound 42a1 was converted to compound 50a1 using the procedure of step 3, example 28A.

Step 2

Compound 50a1 was converted to compound 50a2 using the procedure of step 2, example 49A.

Step 3

Compound 50a2 was converted to compound 1127 using the procedure of step 3, example 49A.

Example 51A

Preparation of intermediates 51a3 and 51a4

Step 1

To a solution of iodide 5a3(191 mg, 0.62 mmol) in DMSO (3 ml) was added CsCO₃(216 mg, 0.66 mmol) and 23a1(189 mg, 0.44 mmol). It was stirred at 75 ℃ for about 4 hours and then cooled to room temperature. The mixture was washed with water and brine, and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. Purification by flash chromatography using (20: 80 to 60: 40) EtOAc/hexanes afforded 51a1 as an off-white solid.

Step 2

To a solution of 51a1(256 mg, 0.37 mmol) in dioxane (3 ml) was added tributyl (vinyl) tin (0.14 ml, 0.48 mmol) at room temperature. The solution was degassed by bubbling Ar into it. Bis (triphenylphosphine) palladium dichloride (26 mg, 0.04 mmol) was added and the reaction mixture was heated at reflux for about 1.5 h. The mixture was concentrated and purified by flash chromatography using (10: 90 to 70: 30) EtOAc/hexanes to give 51a 2.

Step 3

To a solution of 51a2(181 mg, 0.30 mmol) in water (0.5 ml), acetone (2 ml) and MeOH (0.4 ml) was added OsO at room temperature₄(0.04 ml, 2.5% t-BuOH solution) with NMO (40 mg, 0.34 mmol). It was stirred at room temperature for about 1.5 hours. Sodium periodate (71 mg, 0.33 mmol) was then added and the reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was poured into saturated Na₂S₂O₃Aqueous solution, followed by extraction with EtOAc (4 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. The residue was dissolved in MeOH (2 ml) and NaBH was slowly added₄(58 mg, 1.5Millimole) and stirred at room temperature for about 1 hour. The reaction mixture was poured into saturated NH₄Aqueous Cl, then extracted with EtOAc (3 ×). The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. Purification by flash chromatography using (30: 70 to 80: 20) EtOAc/hexane afforded a mixture of aldehyde 51a3 and alcohol 51a 4.

Example 51B

Preparation of Compound 1132

Step 1

Compound 51a3 was converted to compound 1132 using the procedure of step 5, example 5A.

Example 51C

Preparation of Compound 1135

Step 1

Compound 51a4 was converted to compound 51c1 using the procedure of step 2, example 38A.

Step 2

Compound 51c1 was converted to compound 1135 using the procedure of step 3, example 38A.

Example 52A

Preparation of Compound 1147

Step 1

Compound 25a1 was converted to compound 52a1 using the procedure of step 3, example 28A.

Step 2

Compound 52a1 was converted to compound 52a2 using the procedure of step 2, example 49A.

Step 3

Compound 52a2 was converted to compound 1147 using the procedure of step 3, example 49A.

Example 53A

Preparation of compound 1152

Step 1

Compound 25a1 was converted to compound 53a1 using the procedure of step 1, example 49A.

Step 2

Compound 53a1 was converted to compound 53a2 using the procedure of step 2, example 49A.

Step 3

Compound 53a2 was converted to compound 1152 using the procedure of step 3, example 49A.

Example 54A

Preparation of compound 1165

Step 1

To a solution of 7-azaindole (15 mg, 0.13 mmol) dissolved in anhydrous DMF (1 ml) was added cesium carbonate (55 mg, 0.17 mmol) at room temperature, followed by benzyl chloride 9a3 (dissolved in anhydrous DMF, 0.5 ml) and then KI (3.5 mg, 0.02 mmol). It was heated at 110 ℃ for about 14 hours, then cooled to room temperature. THF (1 ml), MeOH (1 ml) and NaOH (1M, 1 ml) were added, which was then stirred at room temperature for about 24 hours. The mixture is then concentrated, diluted with AcOH, and purified by preparative HPLC to afford the desired product 1165.

Example 55A

Preparation of compound 1166

Step 1

Compound 45a1 was converted to compound 1166 using the procedure described in step 1, example 54A.

Example 56A

Preparation of compound 1168

Step 1

Compound 56a1 was converted to compound 1168 using the procedure of step 1, example 55A.

Example 57A

Preparation of intermediate 57a1

Step 1

Using the method of example 37A, step 1, compound 57A1 was produced via the reaction of compound 37A1 and 46a 2.

Example 57B

Preparation of Compound 3008

Step 1

Compound 57a1 was converted to compound 3008 using the procedure of step 5, example 5A.

Example 57C

Preparation of intermediate 57c2

Step 1

Compound 57a1 was converted to compound 57c1 using the procedure of step 2, example 9A.

Step 2

Compound 57c1 was converted to compound 57c2 using the procedure of step 3, example 9A.

Example 57D

Preparation of Compounds 3009 and 3010

Step 1

To a solution of 57c1(49 mg, 0.08 mmol) in THF (1 ml) was added PPh₃(24 mg, 0.09 mmol) with triazole (0.005 ml, 0.08 mmol). The solution was cooled to 0 ℃ and DEAD (0.017 ml, 0.09 mmol) was added. It was stirred at 0 ℃ for about 45 minutes, warmed to room temperature, and stirred continuously for about 72 hours. MeOH (1 ml) and NaOH (1 ml, 1M solution in water) were added, and the mixture was stirred at room temperature for about 24 hours. The reaction mixture was then concentrated, dissolved in AcOH/MeOH (4 mL, 1: 1), and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to give 3010 and 3009.

Example 58A

Preparation of Compound 3011

Step 1

Compound 57c2 was converted to compound 3011 using the procedure of step 3, example 38A.

Example 59A

Preparation of Compound 3015

Step 1

Compound 57c2 was converted to compound 3015 by the method of step 1, example 33A, using 2-mercaptopyrimidine.

Example 60A

Preparation of Compound 4004

Step 1

Alcohol 2a5 was converted to compound 4004 using thiophene 60a1, as in step 1, example 25A.

Example 61A

Preparation of intermediate 61a5

Step 1

The dihydroxypyridine 61a1(24 g, 216 mmol), K₂CO₃A mixture of (29.9 g, 216 mmol) and water (240 ml) was heated to 100 ℃ until it became homogeneous. Addition of the solid I in portions₂(54.8 g, 216 mmol) (note: outgassing!). When iodine was consumed, the reaction was quenched with potassium hydrogen sulfate (216 ml, 216 mmol), which produced a precipitate. The precipitate was collected by filtration and washed with water and brine₂Drying under air flow gave 61a 2.

Step 2

A mixture of diol 61a2(49.3 g, 208 mmol), DMF (0.161 ml, 2.08 mmol) and phosphorus oxychloride (252 ml, 2704 mmol) was heated to 90 ℃ overnight. The reaction mixture was concentrated with saturated NaHCO₃The reaction was quenched with aqueous solution, extracted with DCM, dried and concentrated to give 61a 3.

Step 3

Di-chloride 61a3(49 g, 179 mmol) in MeOH (550 ml) was stirred with NaOMe (43.2 ml, 233 mmol) at rt overnight. The reaction mixture was extracted with EtOAc and water and concentrated. Upon standing, crystals formed. The crystals were collected and washed with a small amount of isopropyl ether. The crystals were transferred with heptane to a glass filter and dried under a stream of air to give 61a 4.

Step 4

A solution/suspension of iodide 61a4(1 g, 3.71 mmol), KF (0.216 g, 3.71 mmol) and CuI (0.707 g, 3.71 mmol) in NMP (10 ml) was degassed with Ar in a microwave tube. Methyl 2-chloro-2, 2-difluoroacetate (3.64 ml, 34.5 mmol) was added and the vessel was closed under Ar and heated to 120 ℃ in a microwave over 30 minutes (note: pressure increase was found, proper care was taken). The mixture was cooled to room temperature and the excess pressure was slowly released. Adding a salt water solution; then, using Et₂And O, extracting the reaction mixture. The combined organic layers were washed with brine, dried, and concentrated, followed by multiple purifications by flash column chromatography to afford 61a 5.

Example 61B

Preparation of compound 4013

Step 1

Using the procedure of example 16A, step 1, compound 4013 was generated via the reaction of compound 61a5 with 3a 6.

Example 62A

Preparation of Compound 1122

Step 1

Pd/C (10%, 50 mg) was added to a solution of Compound 1a6(640 mg, 1.69 mmol) in EtOAc/MeOH (2: 1, 9 mL). The flask was sealed with a septum, placed under vacuum, filled with hydrogen at atmospheric pressure, and stirred at room temperature for about 2 hoursThen (c) is performed. Placing the reaction vessel under vacuum, filling with Ar, and dissolving the solution inAnd (4) filtering. DMSO (6 ml) was added to the solution, which was then concentrated to a minimum volume under reduced pressure. Cesium carbonate (661 mg, 2.03 mmol) was added followed by chloropyridine 5b5(422 mg, 1.53 mmol). The resulting mixture was heated at 75 ℃ for about 12 h, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10% to 40% EtOAc/hexanes) to give compound 62a 1.

Step 2

DMAP (7.7 mg, 0.063 mmol) and pyridine (0.152 ml, 1.88 mmol) were added to a DCE (4 ml) solution of aniline 62a1(166 mg, 0.315 mmol) and acid chloride 1d8(299 mg, 1.259 mmol). The reaction mixture was heated at 150 ℃ for 1h under microwave conditions, cooled to room temperature, diluted with EtOAc (100 ml) and washed with saturated aqueous sodium bicarbonate (2 × 50 ml) and brine (2 × 50 ml) in that order. Na for organic phase₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (80% EtOAc/hexanes) to give compound 62a 2.

Step 3

Aqueous 5M NaOH (0.115 mL, 0.577 mmol) was added dropwise to a 0 ℃ MeOH/THF solution (1: 1, 2 mL) of ester 62a2(63 mg, 0.086 mmol). The solution was stirred at room temperature for about 2 hours, acidified with AcOH (1 ml) and purified by preparative HPLC to give compound 1122.

Example 63A

Preparation of Compound 1136

Step 1

Potassium carbonate (414 mg, 3.00 mmol) was added to a solution of chloropyridine 5b5(380 mg, 1.37 mmol) and phenol 24a2(412 mg, 1.53 mmol) in DMSO (10 ml) at room temperature. The reaction mixture was heated at 80 ℃ overnight. The solution was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (30% to 75% EtOAc/hexanes) to give 63a 1.

Step 2

DMAP (1.2 mg, 0.010 mmol) and pyridine (0.024 ml, 0.31 mmol) were added to a DCE (2 ml) solution of aniline 63a1(52.1 mg, 0.102 mmol) and acid chloride 1d8(60.6 mg, 0.255 mmol). The reaction mixture was heated in a microwave at 150 ℃ for 1h, cooled to room temperature, diluted with EtOAc (100 ml) and washed with saturated aqueous sodium bicarbonate (2 × 50 ml) and brine (2 × 50 ml) in succession. Na for organic phase₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (80% to 100% EtOAc/hexanes) to give compound 63a 2.

Step 3

Aqueous 5M NaOH (0.140 mL, 0.700 mmol) was added dropwise to a 0 ℃ MeOH/THF solution (1: 1, 2 mL) of ester 63a2(50 mg, 0.070 mmol). The solution was stirred at rt for about 2 h, acidified with AcOH (1 ml) and purified by preparative HPLC to give compound 1136.

Example 64A

Preparation of Compound 1143

Step 1

Pd/C (10%, 24 mg) was added to a solution of Compound 1a6(715 mg, 1.89 mmol) in EtOAc/MeOH (2: 1, 9 mL). The flask was sealed with a septum, placed under vacuum, filled with hydrogen at atmospheric pressure, and stirred at room temperature for about 2 hours. Placing the reaction vessel under vacuum, filling with Ar, and dissolving the solution inAnd (4) filtering. DMSO (6 ml) was added to the solution, which was then concentrated to a minimum volume under reduced pressure. Cesium carbonate (739 mg, 2.27 mmol) was added followed by chloropyridine 5a6(357 mg, 1.14 mmol). The resulting mixture was heated at 75 ℃ for about 12 h, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (20% to 60% EtOAc/hexanes) to give compound 64a 1.

Step 2

DMAP (7.7 mg, 0.063 mmol) and pyridine (0.078 ml, 0.973 mmol) were added to a DCE (4 ml) solution of aniline 64a1(100 mg, 0.177 mmol) and acid chloride 1b8(116 mg, 0.530 mmol). The reaction mixture was heated at 150 ℃ for 1h under microwave conditions, cooled to room temperature, diluted with EtOAc (100 ml) and washed with saturated aqueous sodium bicarbonate (2 × 50 ml) and brine (2 × 50 ml) in that order. Na for organic phase₂SO₄Dried, filtered and concentrated under reduced pressure. The crude 64a2 was used directly in the next step.

Step 3

Aqueous 5M NaOH (0.695 ml, 3.475 mmol) was added dropwise to a 0 ℃ solution of crude ester 64a2 in THF/DMSO (2: 1, 3 ml). The solution was stirred at rt for about 2 h, acidified with AcOH (1 ml) and purified by preparative HPLC to give compound 1143.

Example 65A

Preparation of compound 1162

Step 1

Potassium carbonate (103 mg, 0.744 mmol) was added to a DMSO (4 ml) solution of chloropyridine 5a6(175 mg, 0.558 mmol) and phenol 3b6(150 mg, 0.372 mmol). The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (30% EtOAc/hexanes to 100% EtOAc) to give 65a 1.

Step 2

Aqueous 5M NaOH (0.486 mL, 2.43 mmol) was added dropwise to a 0 ℃ solution of ester 65a1(166 mg, 0.243 mmol) in THF/MeOH (2: 1, 3 mL). The solution was stirred at room temperature for about 5 days, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1162.

Example 66A

Preparation of compound 1163

Step 1

Palladium acetate (14 mg, 0.021 mmol) was added to a solution of 1, 10-phenanthroline (3.6 mg, 0.020 mmol) in ethyl vinyl ether (5 ml). The mixture was stirred at room temperature for about 15 minutes and a solution of alcohol 3b4(500 mg, 1.04 mmol) in ethyl vinyl ether (5 ml) was added. The reaction mixture was heated at 60 ℃ for about 46 hours and cooled to room temperature. Silica gel was added and the mixture was concentrated under reduced pressure. The solid was applied to a silica gel column and eluted with 20% EtOAc in hexanes to provide vinyl ether 66a 1.

Step 2

Pd/C (10%, 14 mg) was added to a solution of benzyl ether 66a1(135 mg, 0.267 mmol) in MeOH (10 ml). The reaction vessel was sealed with a septum, placed under vacuum, and backfilled with hydrogen at atmospheric pressure. The reaction mixture was stirred under hydrogen overnight. The reaction vessel was placed under vacuum and backfilled with Ar. The reaction mixture is added toFiltered over and washed with EtOAc (100 ml). The organic phase is concentrated under reduced pressure and the residue 66a2 is used as crude in the following step.

Step 3

Potassium carbonate (71 mg, 0.512 mmol) was added to a DMSO (2 ml) solution of chloropyridine 5a6(89 mg, 0.282 mmol) and phenol 66a2(107 mg, 0.256 mmol). The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (30% to 80% EtOAc/hexanes) to give 66a 3.

Step 4

Aqueous 5M NaOH (0.122 mL, 0.610 mmol) was added dropwise to a 0 ℃ solution of ester 66a3(85 mg, 0.122 mmol) in THF/MeOH (2: 1, 3 mL). The solution was stirred at room temperature for about 5 days, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1163.

Example 67A

Preparation of compound 1164

Step 1

Diazomethane (5 ml, 0.6M in ether) was added to an ice-cold solution of vinyl ether 66a1(170 mg, 0.336 mmol) and palladium acetate (10 mg, 0.045 mmol) in ether (10 ml). The reaction mixture was stirred at room temperature overnight withFiltered, washed with EtOAc (50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (10% to 40% EtOAc in hexanes) to give compound 67a 1.

Step 2

Pd/C (10%, 10 mg) was added to a solution of benzyl ether 67a1(132 mg, 0.254 mmol) in MeOH (10 ml). The reaction vessel was sealed with a septum, placed under vacuum, and backfilled with hydrogen at atmospheric pressure. The reaction mixture was stirred under hydrogen overnight. The reaction vessel was placed under vacuum and backfilled with Ar. The reaction mixture is added toFiltered over and washed with EtOAc (100 ml). The organic phase was concentrated under reduced pressure to give crude 67a2, which was used as crude in the following step.

Step 3

Potassium carbonate (212 mg, 1.53 mmol) was added to a DMSO (10 ml) solution of chloropyridine 5a6(241 mg, 0.768 mmol) and crude phenol 67a 2. The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (30% to 80% EtOAc/hexanes) to give 67a 3.

Step 4

Aqueous 5M NaOH (0.354 mL, 1.77 mmol) was added dropwise to a 0 ℃ solution of ester 67a3(125 mg, 0.177 mmol) in THF/MeOH (2: 1, 3 mL). The solution was stirred at room temperature for about 5 days, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1164.

Example 68A

Preparation of intermediate 68a1

Step 1

N-butyllithium (2.1M in hexane, 8.82 ml, 18.5 mmol) was added dropwise to an ice-cold hexane (10 ml) solution of N, N-dimethylethanolamine (0.900 ml, 9.063 mmol). The reaction mixture was stirred at 0 ℃ for about 30 minutes, at which time a solution of 2-cyclopropylpyridine (360 mg, 3.02 mmol) in hexane (10 ml) was added. The reaction mixture was stirred at 0 ℃ for about 45 minutes, then cooled to-78 ℃ and a solution of tributyltin chloride (3.44 g, 10.5 mmol) in hexane (10 ml) was added. The mixture was stirred at-78 ℃ for about 30 minutes, warmed to room temperature for about 30 minutes, diluted with water (100 ml) and washed with waterEther (2 × 50 ml) was extracted. The combined organic phases were washed with brine (2X 50 ml) and Na₂SO₄Dried, filtered, and concentrated under reduced pressure to give crude 68a 1.

Example 68B

Preparation of compound 1169

Step 1

Chloride 57c2(102 mg, 0.169 mmol), tin base 68a1(241 mg, 0.177 mmol) was placed in degassed DMF (2 ml, degassed by bubbling a volume of Ar while sonicating for about 10 min) in a microwave tube. Addition of Pd (PPh)₃)₄(49 mg, 0.017 mmol), the tube is sealed and left at 125 ℃ for 20 minutes in a microwave. The mixture was diluted in EtOAc and washed with water (2x) and brine (2 x). The combined organic material was washed with MgSO₄Dried, filtered, and concentrated. The crude residue was passed through a short silica gel column (20% to 70% EtOAc in hexanes) to give compound 68b 1.

Step 2

Aqueous 5M NaOH (0.301 ml, 1.505 mmol) was added dropwise to a 0 ℃ solution of ester 68b1(85 mg, 0.124 mmol) in THF/DMSO (2: 1, 3 ml). The solution was stirred at room temperature for about 5 days, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1169.

Example 69A

Preparation of Compounds 1172, 1173 and 1174

Step 1

Bis (tri-tert-butylphosphine) palladium (38 mg, 0.075 mmol) was added to a DMF solution (4 ml) of compound 25a1(510 mg, 0.747 mmol) and stannane (285 mg, 0.822 mmol). The reaction mixture was degassed by bubbling Ar through the solution for about 15 minutes, stirred at 100 ℃ for about 2 hours, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% to 60% EtOAc in hexanes) to give compound 69a 1.

Step 2

Diazomethane (5 ml, 0.6M) was added to an ice-cold diethyl ether solution (10 ml) of compound 69a1(100 mg, 0.163 mmol) and palladium acetate (10 mg, 0.045 mmol). The reaction mixture was stirred at room temperature overnight atFiltered, washed with EtOAc (50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (50% to 90% EtOAc in hexanes) to give methyl ether 69a3 and alcohol 69a 2.

Step 3

Aqueous 5M NaOH (0.112 mL, 0.560 mmol) was added dropwise to a 0 ℃ solution of ester 69a3(36 mg, 0.056 mmol) in THF/MeOH (2: 1, 3 mL). The solution was stirred at room temperature for about 24 hours, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1172.

Step 4

Thionyl chloride (12 μ l, 0.163 mmol) was added to a 0 ℃ solution of alcohol 69a2(40 mg, 0.065 mmol) in DMF (2 ml), followed by a drop of DMF. The reaction mixture was stirred at room temperature for about 3 hours, diluted with saturated aqueous sodium bicarbonate (50 ml), andextracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. Crude compound 69a4 was used directly in the following step.

Step 5

Sodium hydride (60% in mineral oil, 5.2 mg, 0.130 mmol) was added to an ice-cold solution of 1, 2, 3-triazole (8.9 mg, 0.130 mmol). The solution was transferred to an ice-cold DMF solution of chloride 69a4(41.8 mg, 0.065 mmol) and stirred at rt overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF/MeOH (2: 1, 3 mL) and cooled to 0 ℃.5N aqueous sodium hydroxide (64. mu.l, 0.320 mmol) was added. The solution was stirred at rt for about 5 days, acidified with AcOH (1 ml) and purified by preparative HPLC to afford 1174 and 1173.

Example 70A

Preparation of intermediates

Step 1

Iodine monochloride (5.00 g, 30.8 mmol) was slowly added to a room temperature glacial acetic acid solution (40 ml) of 2-hydroxytrifluorotoluene (2-hydroxybenzotrifluoride)70a1(5.00 g, 30.8 mmol). The reaction mixture was stirred at room temperature overnight and then poured onto water (200 ml). The mixture was extracted with EtOAc (3 × 100 ml) and the combined organic phases were washed with water (100 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure.The crude residue was purified by column chromatography (100% hexanes followed by 2% to 20% EtOAc/hexanes) to give compound 70a 2.

Step 2

Sodium hydride (60% in mineral oil, 312 mg, 7.82 mmol) was added to a solution of phenol 70a2(1.50 g, 5.21 mmol) in DMF at 0 ℃. The solution was stirred at 0 ℃ for about 5 minutes and chloromethyl methyl ether (514 μ l, 6.77 mmol) was added. The reaction mixture was stirred at rt overnight, diluted with saturated aqueous sodium bicarbonate (100 ml), and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with water (2X 50 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (100% hexanes followed by 2% to 20% EtOAc/hexanes) to give compound 70a 3.

Step 3

N-butyllithium (2.5M in hexane, 1.66 ml, 4.14 mmol) was slowly added to a-78 ℃ solution of iodophenol 70a3(1.18 g, 3.54 mmol) in ether (35 ml). The reaction mixture was stirred at-78 ℃ for about 15 minutes and DMF (418 μ l, 5.40 mmol) was added. The reaction mixture was stirred at rt for about 1h, diluted with saturated aqueous sodium bicarbonate (100 ml), and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with water (2X 50 ml), brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (100% hexanes followed by 2% to 20% EtOAc/hexanes) to give compound 70a 4.

Step 4

Sodium borohydride (143 mg, 3.79 mmol) was added to a solution of aldehyde 70a4(740 mg, 3.16 mmol) in MeOH (30 ml) at 0 ℃. The reaction was stirred at 0 ℃ for about 2 h, diluted with saturated aqueous sodium bicarbonate (50 ml), concentrated under reduced pressure, and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (100% hexanes followed by 2% to 20% EtOAc/hexanes) to give compound 70a 5.

Step 5

Thionyl chloride (377 μ l, 5.17 mmol) was added to a solution of alcohol 70a5(610 mg, 2.58 mmol) in DCM (20 ml) at 0 ℃. The reaction mixture was stirred at rt for about 1h, diluted with saturated aqueous sodium bicarbonate (50 ml) and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue 70a6 was used directly in the next step.

Step 6

Sodium hydride (60% in mineral oil, 196 mg, 4.90 mmol) was added to a 0 ℃ solution of 1, 2, 3-triazole (336 mg, 4.87 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 ℃ for about 30 minutes and transferred onto a solution of benzyl chloride 70a6(620 mg, 2.44 mmol) in DMF at 0 ℃ (20 ml). The reaction mixture was stirred at rt for about 2 h, diluted with saturated aqueous sodium bicarbonate (50 ml), and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (100% hexane followed by 20% to 80% EtOAc/hexane) to give a mixture of compound 70a7 and 70a 8.

Step 7

Aqueous 1N HCl (2.0 ml) was added to a solution of compound 70a7 and 70a8(699 mg, 2.44 mmol) in THF at 0 ℃ (10 ml). The reaction mixture was warmed to room temperature and then heated at 65 ℃ for about 3 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (50 ml) and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (100 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. Removing the crude residueThe material was purified by column chromatography (30% EtOAc/hexanes to 100% EtOAc) to give a mixture of compound 70a9 (first eluate) and 70a 10.

Example 70B

Preparation of Compound 2003

Step 1

3-fluoro-2-methylbenzoic acid (5.0 g, 32.4 mmol) was dissolved in sulfuric acid (35 ml) and the resulting mixture was cooled to 0 ℃. Nitric acid (4.0 ml) was added dropwise over a period of about 10 minutes. The reaction mixture was stirred at 0 ℃ for about 2 hours, poured onto ice, and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with Na₂SO₄Drying, filtration, and concentration under reduced pressure gave crude 70b 1.

Step 2

Potassium carbonate (2.05 g, 14.8 mmol) was added to a solution of acid 70b1(1.48 g, 7.32 mmol) in rt DMF (60 ml), followed by benzyl bromide (1.06 ml, 8.91 mmol). The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, poured onto water and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with brine (2X 100 ml) and MgSO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (20% EtOAc in hexanes) to give ester 70b 2.

Step 3

Cesium carbonate (1.41 g, 4.36 mmol) was added to a DMSO solution of ester 70b2(1.050 g, 3.63 mmol) and phenol 70a9(883 mg, 3.63 mmol). The reaction mixture was stirred at 75 ℃ for about 2 hours. After cooling to room temperature, the solution was diluted with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate(2X 50 ml), brine (50 ml) and MgSO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (20% to 50% EtOAc/hexanes) to give 70b 3.

Step 4

Saturated aqueous ammonium chloride (20 ml) was added to a room temperature solution of nitro 70b3(855 mg, 1.67 mmol) in 2-propanol (20 ml). Iron powder (652 mg, 11.5 mmol) was added and the resulting reaction mixture was stirred at 60 ℃ for about 3 hours. Cooling the mixture to room temperature, passing throughFiltered and washed with EtOAc. The organic phase was collected, washed with brine (2X 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. When about half of the material was saponified to the acid, the crude residue was redissolved in DMF (50 ml) and potassium carbonate (461 mg, 3.37 mmol) and benzyl bromide (0.245 ml, 2.02 mmol) were added. The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, poured onto water, and extracted with EtOAc (2 × 100 ml). The combined organic phases were washed with brine (2X 100 ml) and MgSO₄Dried, filtered and concentrated under reduced pressure. The crude aniline 70b4 was used directly in the next step.

Step 5

Crude aniline 70b4(550 mg, 1.14 mmol) was dissolved in MeOH (1 ml) and 2M HCl in ether (1 ml) was added. The mixture was stirred at room temperature for about 1 hour and concentrated under reduced pressure. The resulting residue was dissolved in MeOH (10 ml) and dihydroxyacetone (649 mg, 7.21 mmol) was added in MeOH (3 ml). The reaction mixture was stirred at room temperature for about 1 hour, and a solution of sodium cyanoborohydride (266 mg, 4.24 mmol) in MeOH (3 ml) was added. The reaction mixture was stirred at rt for about 1h, diluted with saturated aqueous sodium bicarbonate (50 ml), concentrated to minimum volume under reduced pressure, and extracted with EtOAc (2 × 50 ml). The combined organic phases are treated with saturated bicarbonateAqueous sodium solution (2X 50 ml), brine (50 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (50% EtOAc/hexanes to 100% EtOAc) to give 70b 5.

Step 6

A suspension of sodium hydride (95%, 44 mg, 1.74 mmol) in DMF (2 ml) was added to a solution of compound 70b5(440 mg, 0.791 mmol) and iodomethane (247 μ l, 3.95 mmol) in DMF at 0 ℃. The reaction mixture was stirred at 0 ℃ for about 1 hour, then more sodium hydride (95%, 44 mg, 1.74 mmol in 2 ml DMF) was added. The reaction mixture was stirred at 0 ℃ for about 1 hour, diluted with saturated aqueous ammonium chloride (50 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude 70b6 was used directly in the next step without further purification.

Step 7

DMAP (1.6 mg, 0.014 mmol) was added to a DCE (1 ml) solution of aniline 70b6(40 mg, 0.068 mmol), acid chloride 1a8(44 mg, 0.27 mmol) and pyridine (32 μ l, 0.41 mmol). The reaction mixture was heated in a microwave at 150 ℃ for about 45 minutes. The reaction mixture was cooled to room temperature and then pyridine (32 μ l, 0.41 mmol) and acid chloride 1a8(44 mg, 0.27 mmol) were added. The reaction mixture was then microwaved (45 min at 150 ℃), cooled to room temperature, diluted with 1N aqueous HCl (10 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (20% EtOAc/hexanes to 100% EtOAc) to give 70b 7.

And 8:

10% Palladium on charcoal (15 mg) was added to a solution of benzyl ester 70b7(12 mg, 0.017 mmol) in EtOAc/MeOH (2: 1, 6 mL). The reaction mixture was evacuated and backfilled with hydrogen at atmospheric pressure. The reaction mixture was stirred at room temperature for about 15 minutes atFiltered, washed with EtOAc, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford 2003.

Example 71A

Preparation of Compound 4002

Potassium carbonate (277 mg, 0.854 mmol) was added to a DMSO solution (5 ml) of phenol 2a5(160 mg, 0.407 mmol) and chloroisoquinoline (73 mg, 0.477 mmol). The reaction mixture was stirred at 150 ℃ for about 10 minutes, cooled to room temperature, and filtered. To the resulting solution, 2.5N aqueous NaOH (0.3 ml, 0.750 mmol) was added. The reaction mixture was stirred at room temperature for about 3 hours, acidified with glacial AcOH (2 ml) and purified by preparative HPLC to give compound 4002.

Example 72A

Preparation of Compound 4003

Cesium carbonate (208 mg, 0.640 mmol) was added to a DMSO solution (5 ml) of phenol 2a5(120 mg, 0.305 mmol) and chloroquinoline (50 mg, 0.305 mmol). The reaction mixture was stirred at 150 ℃ for about 10 minutes, cooled to room temperature, and filtered. To the resulting solution, 2.5N aqueous NaOH (0.3 ml, 0.750 mmol) was added. The reaction mixture was stirred at room temperature for about 3 hours, acidified with glacial AcOH (2 ml) and purified by preparative HPLC to give compound 4003.

Example 73A

Preparation of Compound 4006

Step 1

Copper (I) chloride (13 mg, 0.13 mmol) was added to a solution of phenol 2a5(100 mg, 0.254 mmol), iodide (77 mg, 0.35 mmol), cesium carbonate (166 mg, 0.508 mmol) and 2, 2, 6, 6-tetramethylheptane-3, 5-dione (5 μ l, 0.025 mmol) in NMP (3 ml). The reaction mixture was evacuated and filled with nitrogen. The cycle was repeated 5 times, then the reaction mixture was stirred at 120 ℃ for about 2 hours, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with EtOAc (50 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (50 ml), over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (20% EtOAc/hexanes to 60% EtOAc) to give 73a 1.

Step 2

Aqueous 5M NaOH (0.265 mL, 1.32 mmol) was added dropwise to a 0 ℃ solution of ester 73a1(46 mg, 0.089 mmol) in THF/DMSO (1: 1, 2 mL). The solution was stirred at 40 ℃ for about 2 hours, acidified with AcOH (1 ml) and purified by preparative HPLC to give compound 4006.

Example 74A

Preparation of compound 1175

Step 1

To a solution of chloride 57c2(200 mg, 0.33 mmol) in DMF (2 ml) was added trimethylsilylacetylene (162 mg, 1.65 mmol), CuI (6.3 mg, 0.033 mmol), Et at room temperature₃N (0.230 mL, 1.65 mmol) and Pd (PPh)₃)₄(38 mg, 0.033 mmol). The mixture was stirred in a microwave at 120 ℃ for 10 minutes. TBAF (1.65 ml of a 1M solution in THF) was added at room temperature and the reaction mixture was stirred for about 30 minutes. Addition of saturated NH₄Aqueous Cl solution, and Et₂O extract (3 ×) the mixture. The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered, and concentrated. The crude residue was then purified by flash chromatography using (20: 80 to 60: 40) EtOAc/hexane to afford compound 74a 1.

Step 2

To a solution of alkyne 74a1(123 mg, 0.21 mmol) in water (1 ml) was added azide 44a2(97 mg, 0.62 mmol) at room temperature. The mixture was stirred at 120 ℃ for about 3 hours, followed by 85 ℃ for about 16 hours. With Et₂O extract (3 ×) the reaction mixture. The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried, filtered under vacuum, and concentrated. The crude residue was purified by flash chromatography using (20: 80 to 70: 30) EtOAc/hexanes to provide compound 74a 2.

Step 3

To a solution of ester 74a2 in MeOH (1 ml) was added aqueous NaOH (5N, 0.024 ml, 0.12 mmol) at room temperature. The mixture was stirred for about 5 hours, then acidified with 1M HCl and extracted with EtOAc (4 ×). The combined fractions were dried and concentrated. The residue was redissolved in MeOH (2 ml) and (trimethylsilyl) diazomethane (0.120 ml, 2M Et) was added at 0 ℃₂O solution). Mixing the reactionThe mixture was stirred at 0 ℃ for about 1 hour, followed by concentration. The residue was redissolved in a mixture of THF (1 ml)/MeOH (1 ml) and aqueous NaOH (5N, 0.024 ml, 0.12 mmol) was added at room temperature. The mixture was stirred for about 3 hours and then concentrated. The residue was redissolved in a MeOH (1 ml)/AcOH (1 ml) mixture and purified by preparative HPLC. The fractions were combined and the solvent was removed by lyophilization to afford pure compound 1175.

Example 75A

Preparation of compound 4016

Step 1

Cesium carbonate (2.48 g, 7.62 mmol) was added to a DMSO solution (10 ml) of phenol 2a5(1.78 g, 6.61 mmol) and 4, 5-dibromo-thiophene-2-carbaldehyde (35 ml, 5.08 mmol). The reaction mixture was stirred at 80 ℃ for about 16 hours, cooled to room temperature, poured onto water and treated with Et₂O (3X 50 ml). The combined organic phases were concentrated under reduced pressure. The crude residue was purified by column chromatography (30% to 70% EtOAc in hexanes) to give compound 75a 1.

Step 2

Sodium trifluoroacetate (383 mg, 2.82 mmol) was added to a solution of bromide 75a1(410 mg, 0.704 mmol) and copper iodide (268 mg, 1.41 mmol) in NMP (2 ml). The reaction mixture was stirred in a microwave at 160 ℃ for 10 minutes, then at 180 ℃ for another 10 minutes and cooled to room temperature. The reaction mixture was poured onto water and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (2X 50 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% to 70% EtOAc in hexanes) to afford compound 75a2 and compound 75a 3.

Step 3

Compound 75a3 was converted to compound 4016 using the procedure described in steps 2 and 3, example 37A.

Example 76A

Preparation of compound 4017

Step 1

Compound 75A3 was converted to compound 4017 using the procedure described in step 3, example 75A.

Example 77A

Preparation of compound 4018

Step 1

Compound 75A2 was converted to compound 4018 using the procedure described in step 3, example 75A.

Example 78A

Preparation of compounds 4019 and 4020

Step 1a

Pd (PPh)₃)₄(1.35 mg, 0.005 mmol) and sodium carbonate (2M in water, 0.375 mL, 0.750 mmol) were added to bromide 75a2(150 mg, 0.258 mmol) and trimethylcyclotriboroxane (97 mg)0.773 mmol) in DMF (1 ml). The reaction mixture was stirred in a microwave at 120 ℃ for 20 minutes, cooled to room temperature, poured onto water and treated with Et₂O (3X 50 ml). The combined organic phases were washed with brine (2X 50 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% to 80% EtOAc in hexanes) to afford compound 78a 1.

Step 2 a:

compound 78a1 was converted to compound 4019 using the procedure described in steps 2 and 3, example 37A.

Step 1 b:

pd (PPh)₃)₄(1.35 mg, 0.005 mmol) and sodium carbonate (2M in water, 0.386 ml, 0.773 mmol) are added to a DMF solution (1 ml) of bromide 75a2(150 mg, 0.258 mmol) and cyclopropylboronic acid (66 mg, 0.773 mmol). The reaction mixture was stirred in a microwave at 120 ℃ for 20 minutes, cooled to room temperature, poured onto water and treated with Et₂O (3X 50 ml). The combined organic phases were washed with brine (2X 50 ml) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% to 80% EtOAc in hexanes) to afford compound 78a 2.

And step 2 b:

compound 78a2 was converted to compound 4020 using the procedures described in steps 2 and 3, example 37A.

Example 79A

Preparation of compounds 4014 and 4015

Step 1

Compound 75a2 was converted to compound 79a1 using the procedure described in step 1, example 57C.

Step 2

Compound 79a1 was converted to compounds 4014 and 4015 using the procedure described in step 1, example 57D.

Example 80A

Preparation of Compound 1053

Step 1

Phenol 1a10(16.8 mg, 0.041 mmol) was reacted with K₂CO₃(16.9 mg, 0.122 mmol) and 2-fluoro-3-trifluoromethylpyridine (39.0 mg, 0.24 mmol) were mixed in DMSO (1 mL). The mixture was heated at 75 ℃ under Ar until complete conversion, then cooled to room temperature. Water and DCM were added, the mixture was extracted with DCM (3 ×), and the combined organic fractions were concentrated under reduced pressure. The crude residue was dissolved in THF (1 mL)/MeOH (0.5 mL)/H₂O (0.5 ml) mixture and aqueous NaOH (10N, 41 μ l, 0.41 mmol) was added. The mixture was stirred overnight, then acidified with AcOH, filtered, and injected onto preparative HPLC to isolate compound 1053.

Example 81A

Preparation of compound 1171

Step 1

Potassium carbonate (67 mg, 0.488 mmol) was added to a DMF solution (2 mmol) of acid 53a1(150 mg) and benzyl bromide (35. mu.L, 0.293 mmol)Liters). The reaction mixture was stirred at 80 ℃ overnight, cooled to room temperature, poured onto water and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (20% EtOAc in hexanes) to give compound 81a 1.

Step 2

Sodium hydride (13 mg, 0.511 mmol) was added to a solution of ester 81a1(120 mg, 0.170 mmol) in DMF (12 ml) at 0 ℃ followed by methyl iodide (42 μ l, 0.681 mmol). The reaction mixture was stirred at rt for about 2 h, diluted with saturated aqueous sodium bicarbonate (50 ml) and extracted with EtOAc (2 × 50 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was dissolved in 80% EtOAc in hexanes and passed through a silica gel packed column. The organic phase formed was concentrated under reduced pressure to give a residue which was redissolved in EtOH (25 ml). The reaction flask was evacuated and backfilled with hydrogen at atmospheric pressure. The mixture was stirred at room temperature for about 4 hours, passingFiltration, washing with EtOH and concentration under reduced pressure gave crude 81a2, which was used directly in the next step.

Step 3

Isobutyl chloroformate (30 μ l, 0.23 mmol) was added to a solution of acid 81a2(100 mg, 0.156 mmol) and triethylamine (39 μ l, 0.28 mmol) in THF (2 ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for about 30 minutes and filtered directly over a suspension of sodium borohydride (18 mg, 0.467 mmol) in water (0.2 ml). The reaction mixture was stirred at 0 ℃ for about 20 minutes, diluted with saturated aqueous sodium bicarbonate (50 ml), and extracted with EtOAc (2 × 50 ml). Will be provided withThe combined organic phases were washed successively with saturated aqueous sodium bicarbonate (2X 50 ml), brine (2X 50 ml) and Na₂SO₄Drying, filtration, and concentration under reduced pressure gave crude 81a 3.

Step 4

Aqueous 5M NaOH (1.0 ml, 5.0 mmol) was added dropwise to a 0 ℃ DMSO solution (2 ml) of ester 81a3(20 mg, 0.032 mmol). The solution was stirred at room temperature for about 2 hours, acidified with AcOH (1 ml) and purified by preparative HPLC to afford compound 1171.

Example 82

Inhibition of NS5B RNA-dependent RNA polymerase activity

Representative compounds of the invention were tested for their inhibitory activity against hepatitis C virus RNA-dependent polymerase (NS5B), according to the test described in WO2007/087717, which is incorporated by reference.

Example 83

Specificity of NS5B RNA-dependent RNA polymerase inhibition

Representative compounds of the invention were tested for poliovirus RNA-dependent RNA polymerase and calf thymus DNA-dependent RNA polymerase II as described in McKercher et al, (2004) Nucleic Acids res.32: 422, 431, as described above, is incorporated by reference.

Example 84

Cell-based luciferase reporter HCV RNA replication assay

Representative compounds of the invention were tested for activity as inhibitors of hepatitis C viral RNA replication in cells expressing stable subgenomic HCV replicons using the assay described in WO 2005/028501 (which is incorporated by reference).

List of compounds

The following table shows the inventionRepresentative compounds. Representative compounds listed in tables 1 and 4 below were tested in the test of example 82 and found to be IC₅₀The value was less than 30. mu.M. Representative compounds listed in tables 1 and 4 below were tested in the test of example 84 and found to be EC₅₀The value was less than 30. mu.M.

Retention time (t) of the respective Compounds_R) Measured using standard analytical HPLC conditions as described in the examples. As is well known to those skilled in the art, retention time values are sensitive to stable measurement conditions. Thus, even if the same conditions of solvent, flow rate, linear gradient, etc. are used, the retention time values may be different when measured on e.g. different HPLC equipment. Even if measured on the same equipment, the values measured when using, for example, different individual HPLC columns may be different, or measured on the same equipment and on the same individual columns, the values may differ between individual measurements for different occasions. The synthetic methods for synthesizing each of the compounds in tables 1-4 are listed in the tables. One skilled in the art will recognize that modifications to the synthesis may be required for each of the specific compounds in tables 1-4.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

Each reference, including all patents, patent applications, and publications, cited in this application is hereby incorporated by reference in its entirety as if each reference were individually incorporated by reference. Further, it should be understood that within the above description of the invention, certain changes or modifications may be effected by those skilled in the art and that such equivalents are within the scope of the invention as defined by the claims appended hereto.

Claims

1. An isomer, racemate, enantiomer or diastereomer of a compound of formula (I):

wherein:

x is selected from O and S;

R²is Het or aryl, optionally substituted by 1-5R²⁰Substituted by a substituent, wherein R²⁰In a variety ofIndependently from each other:

a) halogen, cyano or nitro;

i) halogen, cyano, oxo, thio, imino, -OH, -O- (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) A halogenated alkyl group,-C(＝O)-(C_1-6) Alkyl, -SO₂(C_1-6) Alkyl, -C (═ O) -NH₂、-C(＝O)-NH(C _1-4) Alkyl, -C (═ O) -N ((C)_1-4) Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group;

R⁵Is O-R⁵²Mono-, di-or tri-substituted R⁵¹，

R⁶is (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het; which is optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -SH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl and-N (R)⁸)R⁹(ii) a Wherein R is⁸And R⁹As defined above; and is

Het is a 4-to 7-membered saturated, unsaturated or aromatic heterocycle having 1-4 heteroatoms each independently selected from O, N and S, or a 7-to 14-membered saturated, unsaturated or aromatic heterocycle having 1-5 heteroatoms each independently selected from O, N and S, if possible; wherein each N heteroatom is present independently and optionally in an oxidized state, thereby being bonded to an oxygen atom again to form a group N-oxide group, and wherein each S heteroatom is present independently and optionally in an oxidized state, thereby being bonded to 1 or 2 oxygen atoms again to form a group SO or SO₂(ii) a Or a salt or ester thereof.

2. The compound of claim 1, wherein X is O, and R²、R³、R^3a、R^3b、R⁵And R⁶As defined in claim 1.

3. The compound of claim 1 or 2, wherein R²Is aryl, optionally substituted with 1-5R²⁰Substituted by a substituent, and R²⁰As defined in claim 1.

4. The compound of claim 1 or 2, wherein R²Is phenyl or Het, each optionally substituted by 1 to 3R²⁰Substituted by a substituent, wherein R²⁰As defined in claim 1; and Het is a 5-or 6-membered heteroaromatic ring containing 1 or 2N heteroatoms, or a 9-or 10-membered bicyclic heterocyclic polycyclic ring containing 1 or 2N heteroatoms.

5. The compound of claim 1 or 2, wherein R²Is Het; and Het is a 5-or 6-membered aromatic heterocycle containing 1 or 2N heteroatoms, or a 9-or 10-membered bicyclic heteromulticycle containing 1 or 2N heteroatoms; wherein Het is optionally substituted by 1-3R²⁰Substituted by a substituent, and R²⁰As defined in claim 1.

6. The compound of claim 5, wherein R²Is Het selected from:

and

and wherein Het is optionally substituted by 1-3R as defined in claim 1²⁰Substituted by a substituent.

7. The compound of claim 4, wherein R²Is of the formula:

or

R²¹Selected from H, halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl and-O- (C)_1-6) A haloalkyl group; and R is²⁰As defined in claim 1.

8. The compound of any one of claims 1-7, wherein R²⁰Selected from:

wherein (C) is_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl and (C)_1-6) Alkylene is optionally substituted with 1 or 2 substituents each independently selected from: -OH, optionally substituted by-O- (C)_1-6) Alkyl substituted- (C)_1-6) Alkyl, halogen, - (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -O- (C)_1-6) Alkyl, cyano, COOH, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl radical)₂、Het、-(C_1-6) alkyl-Het; and is

i) halogen, (C)_3-7) Cycloalkyl group, (C)_1-6) Haloalkyl, -C (═ O) -NH₂、-C(＝O)-NH(C_1-4) Alkyl, -C (═ O) -N ((C)_1-4) Alkyl radical)₂、-C(＝O)-NH(C_3-7) Cycloalkyl, -C (═ O) -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -N ((C)_1-4) Alkyl radical)₂、-NH(C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl or-NH-C (═ O) (C)_1-4) An alkyl group;

iii) an aryl group or Het,wherein each aryl and Het is optionally substituted by halogen or (C)_1-6) Alkyl substitution; and

R⁸Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and R is⁹As shown by R⁷Definitions in which R⁷As defined above.

9. The compound of any one of claims 1-7, wherein R²⁰Selected from:

b)R⁷or- (C)_1-6) alkylene-R⁷

Wherein R is⁷Independently selected from H, (C) at each occurrence_1-6) Alkyl, (C)_3-7) A cycloalkyl group, a,

(C_3-7) Cycloalkyl- (C)_1-6) Alkyl, phenyl and Het;

wherein Het is selected from:

andand is

c)-N(R⁸)R⁹Or- (C)_1-6) alkylene-N (R)⁸)R⁹；

R⁹As shown by R⁷Definitions in which R⁷As defined above.

10. The compound of any one of claims 1-7, wherein R²⁰Selected from:

b)-(C_1-3) alkylene-R⁷；

Wherein R is⁷Is Het; wherein Het is a 5-or 6-membered heterocycle containing 1-4 heteroatoms each independently selected from N, O and S, or Het is a 9-or 10-membered heterocycle containing 1-4 heteroatoms each independently selected from N, O and S; wherein each N heteroatom is independently and optionally present in an oxidized state, thereby being further bonded to an oxygen atom to form an N-oxide group, and wherein each S heteroatom is independently and optionally presentPossibly in an oxidized state, to form a group SO or SO in combination with 1 or 2 oxygen atoms₂；

Wherein said Het is optionally substituted with 1-3 substituents each independently selected from the group consisting of: halogen, cyano, oxo, imino, -OH, -O- (C)_1-6) Alkyl, -O- (C)_1-6)

Haloalkyl, (C)_3-7) Cycloalkyl, -NH₂、-NH(C_1-4) Alkyl, -NH (C)_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl) (C_3-7) Cycloalkyl, -N ((C)_1-4) Alkyl radical)₂、-NH-C(＝O)(C_1-4) Alkyl, (C)_1-6) Alkyl and Het, wherein Het is a 5-or 6-membered heterocycle containing 1-4 heteroatoms each independently selected from N, O and S.

11. The compound of any one of claims 1-7, wherein R²⁰Selected from:

and

12. the compound of claim 7, wherein R²¹Is H or CF₃And R is²⁰As defined in any one of claims 8, 9, 10 or 11.

13. The compound of any one of claims 1-12, wherein R³Selected from H, halogen, CN, (C)_1-4) Alkyl, -O- (C)_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)₂。

14. The compound of claim 13, wherein R³Selected from H, F, Cl and CH₃。

15. The compound of any one of claims 1-14, wherein R^3aSelected from H, halogen, (C)_1-4) Alkyl and CN.

16. The compound of claim 15, wherein R^3aSelected from H, F and CH₃。

17. The compound of any one of claims 1-16, wherein R^3bSelected from H, halogen, CN, (C)_1-4) Alkyl, -O- (C)_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)₂。

18. The compound of claim 17, wherein R^3bSelected from H, F, Cl, CH₃And CN.

19. The compound of any one of claims 1-18, wherein R⁵Is O-R⁵²Mono-, di-or tri-substituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and R is⁵²Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het, said aryl and Het being optionally substituted by (C)_1-6) Alkyl or O- (C)_1-6) Alkyl substitution.

20. The compound of claim 19, wherein R⁵By O-R⁵²Mono-or di-substituted R⁵¹Wherein R is⁵¹Is (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl radical, each R⁵¹Optionally quilt (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl substitution; and is

21. The compound of any one of claims 1-20, wherein R⁶Is (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, aryl, (C)_1-6) Alkyl-aryl, Het or (C)_1-6) alkyl-Het; which is optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -SH, -O- (C)_1-4) Alkyl, -S- (C)_1-4) Alkyl and-N (R)⁸)R⁹(ii) a Wherein R is⁸Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

22. The compound of claim 21, wherein R⁶Is (C)_5-6) Cycloalkyl, phenyl or Het, optionally substituted with 1-3 substituents each independently selected from: halogen, (C)_1-4) Alkyl and (C)_1-4) A haloalkyl group; wherein Het is a 4-to 7-membered saturated, unsaturated or aromatic heterocycle having 1-3 nitrogen heteroatoms.

23. The compound of claim 21, wherein R⁶Is phenyl, cyclohexyl or pyridine, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, (C)_1-4) Alkyl and (C)_1-4) A haloalkyl group.

24. The compound of claim 1, having the formula:

wherein R is²⁰、R³、R⁵And R⁶As defined below:

a pharmaceutically acceptable salt or ester thereof.

25. The compound of claim 1, having the formula:

wherein R is²⁰、R^3a、R^3b、X、R⁵And R⁶Is defined as follows

A pharmaceutically acceptable salt or ester thereof.

26. The compound of claim 1, having the formula:

wherein R is²⁰、R³And R⁵Is defined as follows

A pharmaceutically acceptable salt or ester thereof.

27. The compound of claim 1, having the formula:

wherein R is²、R³And R⁵As defined below:

a pharmaceutically acceptable salt or ester thereof.

28. A pharmaceutical composition comprising a compound of any one of claims 1-27, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

29. The pharmaceutical composition of claim 28, further comprising at least one additional antiviral agent.

30. The pharmaceutical composition of claim 29, wherein the at least one other antiviral agent is selected from the group consisting of NNRTIs, NRTIs, protease inhibitors, HIV entry inhibitors, and integrase inhibitors.

31. Use of a pharmaceutical composition according to any one of claims 28-30 for the treatment of HCV infection in a mammal having or at risk of having the infection.

32. A method of treating an HCV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 27, a pharmaceutically acceptable salt or ester thereof, or a composition of any one of claims 28 to 30.

33. A method of treating an HCV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or ester thereof, in combination with at least one other antiviral agent.

34. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or ester thereof, for the treatment of HCV infection in a mammal having or at risk of having the infection.

35. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for treating HCV infection in a mammal having or at risk of having the infection.

36. An article of manufacture comprising a composition effective to treat HCV infection; and a packaging material comprising a label indicating that the composition can be used to treat HCV infection; wherein the composition comprises a compound of any one of claims 1-27, or a pharmaceutically acceptable salt or ester thereof.

37. A method of inhibiting HCV replication comprising exposing a virus to an effective amount of a compound of any one of claims 1-27, or a salt or ester thereof, under conditions that inhibit HCV replication.

38. Use of a compound of any one of claims 1-39, or a salt or ester thereof, for inhibiting HIV replication.