HK1160839A

HK1160839A - Inhibitors of human immunodeficiency virus replication

Info

Publication number: HK1160839A
Application number: HK12100383.1A
Authority: HK
Inventors: Rebekah J. Carson; Lee Fader; Stephen Kawai; Serge Landry; Youla S. Tsantrizos; Christian Brochu; Sébastien MORIN; Mathieu Parisien; Bruno Simoneau
Original assignee: Gilead Sciences, Inc.
Priority date: 2007-11-15
Filing date: 2008-11-03
Publication date: 2012-08-17

Description

Inhibitors of human immunodeficiency virus replication

RELATED APPLICATIONS

Priority of U.S. serial No. 60/988342, filed on 11/15/2007, is hereby incorporated by reference.

Technical Field

The present invention relates to compounds, compositions and methods for treating Human Immunodeficiency Virus (HIV) infection. In particular, the present invention provides novel inhibitors of HIV replication, pharmaceutical compositions comprising such compounds, and methods of using these compounds to treat HIV infection. More specifically, the present invention provides novel inhibitors of HIV integrase, pharmaceutical compositions comprising such compounds, and methods of using these compounds to reduce HIV replication and treat HIV infection.

Background

Acquired immunodeficiency syndrome (AIDS) is caused by the Human Immunodeficiency Virus (HIV), particularly the HIV-1 strain. For HIV infection, most currently licensed therapies target viral reverse transcriptases and proteases. There is also a licensed drug targeting gp41 to inhibit viral entry and a licensed drug targeting integrase. Within the class of reverse transcriptase inhibitors and protease inhibitors, there is a problem of resistance of HIV to existing drugs. Therefore, it is important to discover and develop new antiretroviral compounds.

Disclosure of Invention

The present invention provides a series of novel compounds having anti-HIV replication inhibitory activity. In addition, representative compounds of the present invention have activity as inhibitors in cell-based HIV replication assays. The compounds of the invention have affinity for HIV integrase. Thus, the compounds of the present invention are useful for inhibiting the activity of HIV integrase and for reducing HIV replication. 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 invention provides isomers, racemates, enantiomers or enantiomers of the compound of formula (I)

Diastereoisomers:

wherein

Represents a single bond or a double bond;

x is S or CR⁵；

Y is S or CR⁷；

Wherein one of X or Y is S;

R²、R⁵、R⁶and R⁷Each independently selected from:

a) halogen;

b)R⁸、-C(＝O)-R⁸、-C(＝O)-O-R⁸、-O-R⁸、-S-R⁸、SO-R⁸、-SO₂-R⁸、-(C_1-6) alkylene-R⁸、-(C_1-6) alkylene-C (═ O) -R⁸、-(C_1-6) alkylene-C (═ O) -O-R⁸、-(C_1-6) alkylene-SO-R⁸Or- (C)_1-6) alkylene-SO₂-R⁸、-(C_1-6) alkylene-O-R⁸Or- (C)_1-6) alkylene-S-R⁸；

Wherein R is⁸Independently 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, aryl and Het;

and is

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

i) halogen, oxo, thio, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -O (C)_1-6) Haloalkyl, -SH, -S (C)_1-6) Alkyl, -SO (C)_1-6) Alkyl, -SO₂(C_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂；

ii)(C_1-6) Alkyl, optionally substituted by-OH, -O- (C)_1-6) Haloalkyl or-O- (C)_1-6) Alkyl substitution; and

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

c)-N(R⁹)R¹⁰、-C(＝O)-N(R⁹)R¹⁰、-O-C(＝O)-N(R⁹)R¹⁰、-SO₂-N(R⁹)R¹⁰、-(C_1-6) alkylene-N (R)⁹)R¹⁰、-(C_1-6) alkylene-C (═ O) -N (R)⁹)R¹⁰、-(C_1-6) alkylene-O-C (═ O) -N (R)⁹)R¹⁰Or- (C)_1-6) alkylene-SO₂-N(R⁹)R¹⁰；

Wherein

R⁹Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

R¹⁰In each caseLower is independently selected from R⁸、-(C_1-6) alkylene-R⁸、-SO₂-R⁸、-C(＝O)-R⁸、-C(＝O)OR⁸and-C (═ O) N (R)⁹)R⁸(ii) a Wherein R is⁸And R⁹As defined above;

R³is (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-, Het- (C)_1-6) alkyl-or-W-R³¹And bond c is a single bond; or

R³Is (C)_1-6) Alkylidene, and bond c is a double bond;

wherein W is O or S, and R³¹Is (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl, aryl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-or Het- (C)_1-6) Alkyl-;

wherein each (C)_1-6) Alkylidene, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-, Het- (C)_1-6) alkyl-and-W-R³¹Optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: (C)_1-6) Alkyl, halogen, cyano, oxo and-O (C)_1-6) An alkyl group;

R⁴is aryl or Het, wherein each aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N (, (ii)C_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy, -O (C)_1-6) Alkyl, cyano or oxo;

and is

Wherein Het is a 4-to 7-membered saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7-to 14-membered saturated, unsaturated or aromatic heterocyclic ring having 1 to 5 heteroatoms each independently selected from O, N and S, at any possible position; wherein each N heteroatom may be present independently and where possible in an oxidized state such that it is in turn bonded to an oxygen atom to form an N-oxide, and wherein each S heteroatom may be present independently and where possible in an oxidized state such that it is in turn bonded to one or two 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 for the treatment of HIV infection in a mammal having or at risk of having the infection.

Another aspect of the present invention is directed to a method of treating HIV infection in a mammal having or at risk of having the infection, which comprises administering to said 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 relates to a method of treating HIV infection in a mammal having or at risk of having the infection, which comprises administering to said 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 for the treatment of HIV 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 HIV 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 HIV infection; and a packaging material comprising a label indicating that the composition can be used to treat HIV 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 present invention is directed to a method of inhibiting HIV replication comprising exposing the virus to an effective amount of a compound of formula (I) or a salt or ester thereof under conditions that inhibit HIV replication.

Further included within the scope of the present invention is the use of a compound of formula (I) to inhibit HIV integrase activity.

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

Detailed Description

Definition of

The following definitions are used herein unless otherwise indicated:

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 from 1 to n carbon atoms. "(C)_1-6) Alkyl "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 in combination with other groups, refers to a non-cyclic, straight-chain or branched divalent alkyl radical containing from 1 to n carbon atoms. "(C)_1-6) Alkylene "includes but is not limited to-CH₂-、-CH₂CH₂-、

The term "(C) as used herein_1-n) Alkylidene (where n is an integer), alone or in combination with other groups, means an acyclic, straight-chain or branched alkyl group containing from 1 to n carbon atoms, bonded to the molecule or fragment thereof by a double bond as a substituent thereof. "(C)_1-6) Alkylidene "includes but is not limited to CH₂＝、CH₃CH＝、CH₃CH₂CH＝、A group. Unless otherwise indicated, the term "(C) shall be understood_2-n) Alkylidene "in possibilityIndividual stereoisomers are included in the case of (a), including but not limited to (E) and (Z) isomers, and mixtures thereof. When (C)_2-n) When an alkylidene 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 understood by those skilled in the art.

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 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_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 from 2 to n carbon atoms, at least 2 of which are 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) Cycloalkyl "(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 cycloheptylAnd (4) a base.

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 as defined above having 1 to n carbon atoms which is itself substituted with a cycloalkyl group as defined above containing 3 to m carbon atoms. (C)_3-7) Cycloalkyl- (C)_1-6) Examples of alkyl-include, but are 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 alkyl-is substituted, it is understood that the substituent may be attached to either the cycloalkyl or alkyl portion thereof or both, unless otherwise indicated, such that the substitution results in a chemically stable compound, as understood by those skilled in the art.

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, such that the substitution results in a chemically stable compound, as understood by those skilled in the art.

The term "carbocycle", alone or in combination with other groups, as used herein, refers to an aromatic or non-aromatic, saturated or unsaturated cyclic compound in which all the ring atoms are carbon atoms. A carbocycle may contain 5 or 6 carbon atoms and may be further fused to a second 5-or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. The carbocyclic ring may be substituted. When a carbocyclic ring is substituted, it is understood that the substituent may be attached to any carbon atom which otherwise carries a hydrogen atom, unless otherwise indicated, such that the substitution results in a chemically stable compound, as will be appreciated by those skilled in the art.

The term "Het", alone or in combination with other groups, as used herein, refers to a 4-to 7-membered saturated, unsaturated or aromatic heterocyclic ring having 1-4 heteroatoms each independently selected from O, N and S, or a 7-to 14-membered saturated, unsaturated or aromatic heterocyclic ring having 1-5 heteroatoms each independently selected from O, N and S, where possible; wherein each N heteroatom (independently and if possible) may be present in an oxidized state to form a N-oxide bonded to an oxygen atom and wherein each S heteroatom (independently and if possible) may be present in an oxidized state to form a group SO or SO bonded to 1 or 2 oxygen atoms₂Unless otherwise indicated. When the Het group is substituted, it is understood that the substituent may be attached to any carbon or heteroatom thereof (which would otherwise carry a hydrogen atom) and that the substitution, unless otherwise stated, would result in a chemically stable compound, as would be understood by one skilled in the art.

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, such that the substitution results in chemical stabilizationA compound, as would be understood by one skilled in the art.

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 3-to 7-membered saturated, unsaturated, or aromatic heterocycle 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, thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, tetrazole, piperidine, piperazine, aza-azaneDiaza, diazaPyran, 1, 4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine-N-oxide, pyridazine and pyrimidine, and 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, benzopyran, benzodioxole (benzodioxole), benzodioxadiene (benzodioxane), benzothiazole, quinoline, isoquinoline, and naphthyridine, and 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 difluoroethyl.

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 further 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) The alkyl moiety, such that the substitution results in a chemically stable compound, as will be appreciated by those skilled in the art.

The term "-O- (C)_1-n) Haloalkyl groups "(wherein n is an integer), alone or in combination with other groups, means that the oxygen atom is further bound to a haloalkyl group having 1 to n carbon atoms as defined above. when-O- (C)_1-n) When haloalkyl 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 group in which the sulfur atom is further 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) The alkyl moiety, such that the substitution results in a chemically stable compound, as will be appreciated by those skilled in the art.

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

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

The term "cyano", as used herein, refers to a carbon atom that is attached as a substituent to a nitrogen atom through 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 bonding 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 pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Suitable salts are shown, 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 (glycophosphophosphoric acid), hemisulfuric acid (hemisulfinc 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, succinic acid, adipic acid, fumaric acid, 2, 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, aminobenzenesulfonic acid (sulfanonic 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. The term "ester thereof" includes, but is not limited to, pharmaceutically acceptable esters thereof.

The term "pharmaceutically acceptable ester" as used herein refers to the present inventionAn ester of a compound 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 respect to the above 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 HIV infection. 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, "treatment" refers to the administration of a compound or composition of the present invention to reduce or eliminate the symptoms of HIV infection and/or to reduce the viral load in a patient. The term "treating" also encompasses administering a compound or composition of the invention to an individual after exposure to a virus but before symptoms of the disease appear, and/or before the virus is detected in the blood, to avoid symptoms of the disease and/or to avoid the virus reaching detectable amounts in the blood, and administering a compound or composition of the invention to prevent the prenatal and postnatal transmission of HIV from the mother to the infant by administering to the mother before birth and within the first few days of birth.

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.

The term "inhibitor of HIV replication" as used herein refers to an agent that is capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro (in vitro), ex vivo (ex vivo) or in vivo (invivo).

The terms "HIV integrase" or "integrase" used interchangeably herein refer to the integrase encoded by the human immunodeficiency virus type 1.

The term "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective, when administered to a patient in need thereof, to treat the disease state, condition or disorder for which the compound is useful. This amount will be sufficient to elicit the biological or medical response of the tissue system or patient (which is sought by the researcher or clinician). The amount of a compound of the present invention that constitutes a therapeutically effective amount will vary depending upon factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the disease state or disorder being treated and its severity, the drug being used in combination or concomitantly with the compound of the present invention, and the age, body weight, general health, sex, and diet of the patient. Such therapeutically effective amounts can be routinely determined by those skilled in the art based on their own knowledge, the 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) according to the invention are described in detail:

the core is as follows:

core-A: in this embodiment, the compounds of the invention are represented by formula (Ia):

wherein c, X, Y, R²、R³、R⁴And R⁶Are as defined herein.

It will be apparent to those skilled in the art that when the bond c is a single bond, the bond to-COOH and R³The carbon atoms of the substituents may exist in two possible stereochemical configurations, as shown in formulae (Ib) and (Ic) below:

x, Y, R therein²、R³、R⁴And R⁶Are as defined herein.

It has been found that the compounds of formula (Ib) have improved activity compared to the compounds of formula (Ic).

core-B: thus, in one embodiment, the compounds of the invention are represented by formula (Ib):

x, Y, R therein²、R³、R⁴And R⁶Are as defined herein.

core-C: in another embodiment, the compounds of the present invention are represented by formula (Ic):

x, Y, R therein²、R³、R⁴And R⁶Are as defined herein.

core-D: in another embodiment, the compounds of the invention are represented by formula (Id):

wherein c and R²、R³、R⁴、R⁵And R⁶Are as defined herein.

It will be apparent to those skilled in the art that when the bond c is a single bond, the bond to-COOH and R³The carbon atoms of the substituents may exist in two possible stereochemical configurations, as shown in formulae (Ie) and (If) below:

wherein R is²、R³、R⁴、R⁵And R⁶Are as defined herein.

core-E: in another embodiment, the compounds of the invention are represented by formula (Ie):

wherein R is²、R³、R⁴、R⁵And R⁶Are as defined herein.

core-F: in another embodiment, the compounds of the present invention are represented by formula (If):

wherein R is²、R³、R⁴、R⁵And R⁶Are as defined herein.

core-G: in another embodiment, the compounds of the present invention are represented by formula (Ig):

wherein c and R²、R³、R⁴、R⁶And R⁷Are as defined herein.

It will be apparent to those skilled in the art that when the bond c is a single bond, the bond to-COOH and R³The carbon atoms of the substituents may exist in two possible stereochemical configurations, as shown in formulae (Ih) and (Ii) below:

wherein R is²、R³、R⁴、R⁶And R⁷Are as defined herein.

core-H: in one embodiment, the compounds of the present invention are represented by formula (Ih):

wherein R is²、R³、R⁴、R⁶And R⁷Are as defined herein.

core-I: in an alternative embodiment, the compounds of the invention are represented by formula (Ii):

wherein R is²、R³、R⁴、R⁶And R⁷Are as defined herein.

Any and each individual definition of core as set forth herein can be combined with c, X, Y, as set forth herein,

R²、R³、R⁴、R⁵、R⁶And R⁷Any and each of which define combinations.

R²：

R²-A: in one embodiment, R2 is selected from:

a) halogen;

and is

Wherein

R¹⁰Independently at each occurrence selected from R⁸、-(C_1-6) alkylene-R⁸、-SO₂-R⁸、-C(＝O)-R⁸、-C(＝O)OR⁸and-C (═ O) N (R)⁹)R⁸(ii) a Wherein R is⁸And R⁹As defined above.

R²-B: in an alternative embodiment, R²Is (C)_1-6) Alkyl or-O (C)_1-6) An alkyl group.

R²-C: in another embodiment, R²Is (C)_1-4) An alkyl group.

R²-D: in another embodiment, R²Is selected from (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, Het, aryl, (C)_1-6) alkyl-Het and (C)_1-6) Alkyl-aryl groups.

R²-E: in another embodiment, R²Is selected from (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_1-6) Alkyl radical- (C)_3-7) Cycloalkyl, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl, -N ((C)_1-6) Alkyl radical)₂Het, aryl, (C)_1-6) alkyl-Het and (C)_1-6) Alkyl-aryl groups.

R²-F: in another embodiment, R²is-CH₃、-CH₂CH₃、-CH(CH₃)₂or-OCH₃。

R²-G: in another embodiment, R²is-CH₃or-CH₂CH₃。

R²-H: in another embodiment, R²is-CH₃。

R as set forth herein²Any and each of the definitions of (A) and (B) may be combined with core, c, X, Y, R as set forth herein³、R⁴、R⁵、R⁶And R⁷Any and each of which define combinations.

R³：

R³-A: in one embodiment, R³Is (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-, Het- (C)_1-6) alkyl-or-W-R³¹And bond c is a single bond; or

R³Is (C)_1-6) Alkylidene, and bond c is a double bond;

wherein each (C)_1-6) Alkylidene, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-, Het- (C)_1-6) alkyl-and-W-R³¹Optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: (C)_1-6) Alkyl, halogen, cyano, oxo and-O (C)_1-6) An alkyl group.

R³-B: in one embodiment, R³Is (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-or Het- (C)_1-6) Alkyl-; wherein each (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, (C)_2-6) Alkenyl, (C)_2-6) Alkynyl, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, aryl- (C)_1-6) Alkyl-and Het- (C)_1-6) Alkyl-is optionally selected from 1 to 3 each independentlySubstituted with a substituent (b): (C)_1-6) Alkyl, halogen, cyano, oxo and-O (C)_1-6) An alkyl group; and is

The bond c is a single bond.

R³-C: in another embodiment, R³Is (C)_1-6) Alkyl or (C)_2-6) An alkenyl group; and the bond c is a single bond.

R³-D: in an alternative embodiment, R³is-W- (C)_1-6) Alkyl, -W- (C)_1-6) Haloalkyl, -W- (C)_2-6) Alkenyl, -W- (C)_2-6) Alkynyl, -W- (C)_3-7) Cycloalkyl, -W-aryl, (C)_3-7) Cycloalkyl- (C)_1-6) alkyl-W-, aryl- (C)_1-6) alkyl-W-or Het- (C)_1-6) alkyl-W-;

wherein W is O or S; and is

Wherein each is-W- (C)_1-6) Alkyl, -W- (C)_2-6) Alkenyl, -W- (C)_2-6) Alkynyl, -W- (C)_3-7) Cycloalkyl, -W-aryl, (C)_3-7) Cycloalkyl- (C)_1-6) alkyl-W-, aryl- (C)_1-6) alkyl-W-and Het- (C)_1-6) alkyl-W-is optionally substituted with 1 to 3 substituents each independently selected from: (C)_1-6) Alkyl, halogen, cyano, oxo and-O (C)_1-6) An alkyl group; and is

The bond c is a single bond.

R³-E: in another embodiment, R³is-O- (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, -O- (C)_2-6) Alkenyl, -O- (C)_2-6) Alkynyl, -O- (C)_3-7) Cycloalkyl, -O-aryl, (C)_3-7) Cycloalkyl- (C)_1-6) alkyl-O-, aryl- (C)_1-6) alkyl-O-or Het- (C)_1-6) alkyl-O-;

wherein each-O- (C)_1-6) Alkyl, -O- (C)_2-6) Alkenyl, -O- (C)_2-6) Alkynyl, -O- (C)_3-7) Cycloalkyl, -O-aryl, (C)_3-7) Cycloalkyl- (C)_1-6) alkyl-O-, aryl- (C)_1-6) alkyl-O-and Het- (C)_1-6) alkyl-O-is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: (C)_1-6) Alkyl, halogen, cyano, oxo and-O (C)_1-6) An alkyl group; and is

The bond c is a single bond.

R³-F: in another embodiment, R³is-O (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, -O- (C)_2-6) Alkenyl, -O (C)_2-6) Alkynyl, -O- (C)_3-7) Cycloalkyl, -O-aryl, (C)_3-7) Cycloalkyl- (C)_1-3) alkyl-O-or Het- (C)_1-3) alkyl-O-;

wherein Het is a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms each independently selected from N, O and S; and is

Wherein each-O (C)_1-6) Alkyl, -O- (C)_3-7) Cycloalkyl and Het- (C)_1-3) alkyl-O-is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: (C)_1-3) Alkyl, cyano, oxo and-O (C)_1-6) An alkyl group; and is

The bond c is a single bond.

R³-G: in another embodiment, R³is-O (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, -O (C)_2-6) Alkenyl, -O (C)_2-6) Alkynyl or-O- (C)_3-7) A cycloalkyl group;

wherein each-O (C)_1-6) Alkyl and-O- (C)_3-7) Cycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: (C)_1-3) Alkyl, cyano, oxo and-O (C)_1-6) An alkyl group; and is

The bond c is a single bond.

R³-H: in another embodiment, R³is-O (C)_1-4) An alkyl group; wherein the-O (C)_1-4) Alkyl radical orIs selected from 1 to 2 groups each independently selected from cyano, oxo and-O (C)_1-6) Alkyl is substituted by a substituent; and is

The bond c is a single bond.

R³-I: in another embodiment, R³is-OC (CH)₃)₃(ii) a And the bond c is a single bond.

R³-J: in another embodiment, R³Selected from:

-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、

-OCH₂CH₂CH₂CH₃、-OCH(CH₃)CH₂CH₃、

-OCH₂CH(CH₃)₂、-OC(CH₃)₃、

c and R as set forth herein³Any and all of the individual definitions of (a) may be combined with the core, X, Y, R, as set forth herein²、R⁴、R⁵、R⁶And R⁷Any and each of which define combinations.

R⁴：

R⁴-A: in one embodiment, R⁴Is aryl or Het, wherein each aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy, -O (C)_1-6) Alkyl, cyano or oxo groups.

R⁴-B: in one embodiment, R⁴Is aryl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy, -O (C)_1-6) Alkyl, cyano or oxo groups.

R⁴-C: in another embodiment, R⁴Is phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, (C)_1-4) Alkyl, (C)_2-4) Alkenyl, (C)_1-4) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -O (C)_1-4) Alkyl, -SH, -S (C)_1-4) Alkyl, -NH₂、-NH(C_1-4) Alkyl and-N ((C)_1-4) Alkyl radical)₂。

R⁴-D: in another embodiment, R⁴Is phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: F. cl, Br, NH₂、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、CH₂F、CF₃and-CH₂CH₂F。

R⁴-E: in another embodiment, R⁴Selected from:

R⁴-F: in an alternative embodiment, R⁴Is Het, optionally substituted with 1 to 3 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy or-O (C)_1-6) Alkyl substitution.

R⁴-G: in another alternative embodiment, R⁴Is Het, optionally substituted by 1 or 2 substituents each independently selected from halogen, (C)_1-6) Alkyl and-O (C)_1-6) Alkyl is substituted by a substituent;

wherein Het is a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms each independently selected from N, O and S; or Het is a 9-or 10-membered heteropolycyclic ring having 1 to 3 heteroatoms each independently selected from N, O and S.

R⁴-H: in another alternative embodiment, R⁴Is aryl or Het, optionally substituted with 1 to 3 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, NH₂and-O (C)_1-6) An alkyl group;

wherein aryl is selected from:

and is

Wherein Het is selected from:

R⁴-I: in another alternative embodiment, R⁴Selected from:

those skilled in the art will recognize that when R is present⁴Substituent for connecting R⁴Where the axis of rotation of the chemical bond to the core is not symmetrically substituted, rotamers or atropisomers may be present. Compounds of the invention (wherein R⁴Substituent for connecting R⁴The axis of rotation of the chemical bond to the core is not symmetrically substituted, and wherein the bond to-COOH and R³The carbon atoms of the substituents are chiral, as described above) have two centers of symmetry, one chiral carbon atom and one axis of asymmetric rotation, and thus atropisomers will exist as diastereomers. However, individual diastereomeric atropisomers may or may not be detectable and/or separable, depending on the relative amounts of each atropisomer formed that are present at equilibrium during synthesis, as well as the degree of steric hindrance to rotation about the C-4 chiral axis, and thus, the rate of interconversion between these existing atropisomers. Once separated, the individual atropisomers may be very stable, or interconvert rapidly or slowly with one another to form an equilibrium mixture of atropisomers.

R⁴-J: in another alternative embodiment, R⁴Selected from:

R⁴-K: in another alternative embodiment, R⁴Selected from:

r as set forth herein⁴Any and each of the definitions of (A) and (B) may be combined with core, c, X, Y, R as set forth herein²、R³、R⁵、R⁶And R⁷Any and each of which define combinations.

R⁵：

R⁵-A: in one embodiment, R⁵Selected from:

a) halogen;

and is

Wherein

R¹⁰Independently at each occurrence selected from R⁸、-(C_1-6) alkylene-R⁸、-SO₂-R⁸、

-C(＝O)-R⁸、-C(＝O)OR⁸and-C (═ O) N (R)⁹)R⁸(ii) a Wherein R is⁸And R⁹As defined above.

R⁵-C: in another embodiment, R⁵Is (C)_1-4) An alkyl group.

R⁵-D: in another embodiment, R⁵Is H or (C)_1-4) An alkyl group.

R⁵-E: in another embodiment, R⁵Is H or CH₃。

R⁵-F: in another embodiment, R⁵Is H, (C)_1-6) Alkyl or (C)_1-6) A haloalkyl group.

R as set forth herein⁵Any and each of the definitions of (A) and (B) may be combined with core, c, X, Y, R as set forth herein²、R³、R⁴And R⁶Any and each of which define combinations.

R⁶：

R⁶-A: in one embodiment, R⁶Selected from:

a) halogen;

and is

ii)(C_1-6) Alkyl, optionally substituted by-OH, -O- (C)_1-6) Haloalkyl or-O- (C)_1-6) Alkyl substitution;

Wherein

R⁹In a variety ofIndependently selected from H, (C)_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and is

R¹⁰Independently at each occurrence selected from R⁸、-(C^1-6) alkylene-R⁸、-SO₂-R⁸、-C(＝O)-R⁸、-C(＝O)OR⁸and-C (═ O) N (R)⁹)R⁸(ii) a Wherein R is⁸And R⁹As defined above.

R⁶-B: in another embodiment, R⁶Is H, (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or-O (C)_1-6) An alkyl group.

R⁶-C: in another embodiment, R⁶Is (C)_1-4) An alkyl group.

R⁶-D: in another embodiment, R⁶Is H or (C)_1-4) An alkyl group.

R⁶-E: in another embodiment, R⁶Is H or CH₃。

R⁶-F: in another embodiment, R⁶Is H, (C)_1-6) Alkyl or (C)_1-6) A haloalkyl group.

R as set forth herein⁶Any and each of the definitions of (A) and (B) may be combined with core, c, X, Y, R as set forth herein²、R³、R⁴、R⁵And R⁷Any and each of which define combinations.

R⁷：

R⁷-A: in one embodiment, R⁷Selected from:

a) halogen;

and is

Wherein

R⁷-B: in another embodiment, R⁷Is H, (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or-O (C)_1-6) An alkyl group.

R⁷-C: in another embodiment, R⁷Is (C)_1-4) An alkyl group.

R⁷-D: in another embodiment, R⁷Is H or (C)_1-4) An alkyl group.

R⁷-E: in another embodiment, R⁷Is H or CH₃。

R⁷-F: in another embodiment, R⁷Is H, (C)_1-6) Alkyl or (C)_1-6) A haloalkyl group.

R as set forth herein⁷Any and each of the definitions of (A) and (B) may be combined with core, c, X, Y, R as set forth herein²、R³、R⁴And R⁶Any and each of which define combinations.

Examples of preferred subgeneric embodiments of the invention are shown in the following table, wherein the substituents of the various embodiments are defined according to the definitions mentioned above:

detailed description of the preferred embodiments

Core

R²

R³

R⁴

R⁵

R⁶

R⁷

E-1

nucleus-A

R²-B

R³-C

R⁴-B

-

R⁶-D

R⁷-B

E-2

nucleus-A

R²-B

R³-D

R⁴-C

-

R⁶-F

R⁷-A

E-3

nucleus-A

R²-E

R³-B

R⁴-E

-

R⁶-C

R⁷-C

E-4

nucleus-A

R²-B

R³-I

R⁴-E

-

R⁶-F

R⁷-F

E-5

nucleus-A

R²-C

R³-D

R⁴-G

-

R⁶-B

R⁷-B

E-6

nucleus-A

R²-H

R³-I

R⁴-J

-

R⁶-D

R⁷-D

E-7

nucleus-A

R²-H

R³-I

R⁴-J

-

R⁶-E

R⁷-E

Detailed description of the preferred embodiments

Core

R²

R³

R⁴

R⁵

R⁶

R⁷

E-8

nucleus-A

R²-B

R³-C

R⁴-B

R⁵-E

R⁶-D

-

E-9

nucleus-A

R²-B

R³-D

R⁴-C

R⁵-B

R⁶-F

-

E-10

nucleus-A

R²-E

R³-B

R⁴-E

R⁵-C

R⁶-C

-

E-11

nucleus-A

R²-B

R³-I

R⁴-E

R⁵-C

R⁶-F

-

E-12

nucleus-A

R²-C

R³-D

R⁴-G

R⁵-F

R⁶-B

-

E-13

nucleus-A

R²-H

R³-I

R⁴-K

R⁵-D

R⁶-D

-

E-14

nucleus-A

R²-H

R³-I

R⁴-K

R⁵-E

R⁶-E

-

E-15

nucleus-A

R²-H

R³-I

R⁴-J

R⁵-D

R⁶-D

-

E-16

nucleus-A

R²-H

R³-I

R⁴-J

R⁵-E

R⁶-E

-

E-17

nucleus-B

R²-D

R³-G

R⁴-A

-

R⁶-B

R⁷-F

E-18

nucleus-B

R²-F

R³-B

R⁴-G

-

R⁶-E

R⁷-A

E-19

nucleus-B

R²-C

R³-E

R⁴-D

-

R⁶-C

R⁷-C

E-20

nucleus-B

R²-H

R³-I

R⁴-J

-

R⁶-D

R⁷-D

E-21

nucleus-B

R²-H

R³-I

R⁴-J

-

R⁶-E

R⁷-E

E-22

nucleus-B

R²-D

R³-G

R⁴-A

R⁵-B

R⁶-B

-

E-23

nucleus-B

R²-F

R³-B

R⁴-G

R⁵-A

R⁶-E

-

E-24

nucleus-B

R²-C

R³-E

R⁴-D

R⁵-D

R⁶-C

-

E-25

nucleus-B

R²-H

R³-I

R⁴-J

R⁵-D

R⁶-D

-

E-26

nucleus-B

R²-H

R³-I

R⁴-J

R⁵-E

R⁶-E

-

E-27

nucleus-B

R²-H

R³-I

R⁴-K

R⁵-D

R⁶-D

-

E-28

nucleus-B

R²-H

R³-I

R⁴-K

R⁵-E

R⁶-E

-

E-29

nucleus-C

R²-A

R³-H

R⁴-C

-

R⁶-E

R⁷-E

E-30

nucleus-C

R²-D

R³-B

R⁴-A

-

R⁶-B

R⁷-F

E-31

nucleus-C

R²-A

R³-H

R⁴-C

R⁵-A

R⁶-E

-

E-32

nucleus-C

R²-D

R³-B

R⁴-A

R⁵-D

R⁶-B

-

E-33

nucleus-D

R²-G

R³-I

R⁴-E

R⁵-D

R⁶-D

-

E-34

nucleus-D

R²-H

R³-J

R⁴-H

R⁵-E

R⁶-E

-

E-35

nucleus-D

R²-G

R³-I

R⁴-I

R⁵-D

R⁶-E

-

E-36

nucleus-D

R²-H

R³-J

R⁴-H

R⁵-D

R⁶-E

-

E-37

nucleus-D

R²-C

R³-I

R⁴-A

R⁵-B

R⁶-E

-

E-38

nucleus-D

R²-A

R³-F

R⁴-E

R⁵-A

R⁶-E

-

Detailed description of the preferred embodiments

Core

R²

R³

R⁴

R⁵

R⁶

R⁷

E-39

nucleus-D

R²-G

R³-H

R⁴-H

R⁵-F

R⁶-D

-

E-40

nucleus-D

R²-F

R³-E

R⁴-C

R⁵-D

R⁶-B

-

E-41

nucleus-D

R²-H

R³-J

R⁴-B

R⁵-A

R⁶-D

-

E-42

nucleus-D

R²-H

R³-I

R⁴-J

R⁵-D

R⁶-D

-

E-43

nucleus-D

R²-H

R³-I

R⁴-J

R⁵-E

R⁶-E

-

E-44

nucleus-D

R²-H

R³-I

R⁴-K

R⁵-D

R⁶-D

-

E-45

nucleus-D

R²-H

R³-I

R⁴-K

R⁵-E

R⁶-E

-

E-46

core-E

R²-G

R³-I

R⁴-E

R⁵-D

R⁶-D

-

E-47

core-E

R²-H

R³-J

R⁴-H

R⁵-E

R⁶-E

-

E-48

core-E

R²-G

R³-I

R⁴-I

R⁵-D

R⁶-E

-

E-49

core-E

R²-H

R³-J

R⁴-I

R⁵-E

R⁶-D

-

E-50

core-E

R²-A

R³-C

R⁴-B

R⁵-E

R⁶-A

-

E-51

core-E

R²-D

R³-F

R⁴-F

R⁵-C

R⁶-C

-

E-52

core-E

R²-E

R³-J

R⁴-G

R⁵-E

R⁶-D

-

E-53

core-E

R²-H

R³-I

R⁴-D

R⁵-E

R⁶-C

-

E-54

core-E

R²-E

R³-G

R⁴-C

R⁵-B

R⁶-F

-

E-55

core-E

R²-H

R³-I

R⁴-J

R⁵-D

R⁶-D

-

E-56

core-E

R²-H

R³-I

R⁴-J

R⁵-E

R⁶-E

-

E-57

core-E

R²-H

R³-I

R⁴-K

R⁵-D

R⁶-D

-

E-58

core-E

R²-C

R³-I

R⁴-K

R⁵-D

R⁶-D

-

E-59

nucleus-F

R²-A

R³-H

R⁴-C

R⁵-A

R⁶-B

-

E-60

nucleus-F

R²-D

R³-B

R⁴-A

R⁵-D

R⁶-E

-

E-61

nucleus-G

R²-G

R³-I

R⁴-E

-

R⁶-D

R⁷-E

E-62

nucleus-G

R²-H

R³-J

R⁴-H

-

R⁶-E

R⁷-D

E-63

nucleus-G

R²-H

R³-I

R⁴-I

-

R⁶-D

R⁷-D

E-64

nucleus-G

R²-G

R³-I

R⁴-E

-

R⁶-E

R⁷-D

E-65

nucleus-G

R²-B

R³-A

R⁴-C

-

R⁶-D

R⁷-D

E-66

nucleus-G

R²-G

R³-D

R⁴-G

-

R⁶-F

R⁷-E

E-67

nucleus-G

R²-D

R³-B

R⁴-F

-

R⁶-B

R⁷-A

E-68

nucleus-G

R²-B

R³-F

R⁴-A

-

R⁶-E

R⁷-E

E-69

nucleus-G

R²-H

R³-J

R⁴-D

-

R⁶-D

R⁷-F

Detailed description of the preferred embodiments

Core

R²

R³

R⁴

R⁵

R⁶

R⁷

E-70

nucleus-G

R²-H

R³-I

R⁴-J

-

R⁶-D

R⁷-D

E-71

nucleus-G

R²-H

R³-I

R⁴-J

-

R⁶-E

R⁷-E

E-72

nucleus-G

R²-H

R³-I

R⁴-K

-

R⁶-D

R⁷-D

E-73

nucleus-G

R²-H

R³-I

R⁴-K

-

R⁶-E

R⁷-E

E-74

nucleus-H

R²-G

R³-I

R⁴-E

-

R⁶-D

R⁷-E

E-75

nucleus-H

R²-H

R³-J

R⁴-H

-

R⁶-E

R⁷-D

E-76

nucleus-H

R²-H

R³-I

R⁴-I

-

R⁶-D

R⁷-D

E-77

nucleus-H

R²-G

R³-I

R⁴-H

-

R⁶-D

R⁷-E

E-78

nucleus-H

R²-G

R³-J

R⁴-D

-

R⁶-F

R⁷-A

E-79

nucleus-H

R²-C

R³-H

R⁴-H

-

R⁶-A

R⁷-B

E-80

nucleus-H

R²-H

R³-I

R⁴-E

-

R⁶-C

R⁷-C

E-81

nucleus-H

R²-G

R³-C

R⁴-B

-

R⁶-E

R⁷-F

E-82

nucleus-H

R²-H

R³-I

R⁴-E

-

R⁶-E

R⁷-C

E-83

nucleus-H

R²-H

R³-I

R⁴-J

-

R⁶-D

R⁷-D

E-84

nucleus-H

R²-H

R³-I

R⁴-J

-

R⁶-E

R⁷-E

E-85

nucleus-H

R²-H

R³-I

R⁴-K

-

R⁶-D

R⁷-D

E-86

nucleus-H

R²-C

R³-I

R⁴-K

-

R⁶-D

R⁷-D

E-87

nucleus-I

R²-C

R³-E

R⁴-D

-

R⁶-C

R⁷-A

E-88

nucleus-I

R²-D

R³-G

R⁴-A

-

R⁶-B

R⁷-F

Examples of the most preferred compounds according to the invention are the individual compounds listed in tables 1 to 4 below.

In general, the invention includes all tautomeric and isomeric forms of a chemical structure or compound, and mixtures thereof, e.g., individual tautomers, 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.

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 pharmacological property differences, including differences in 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, those skilled in the art will know from the present disclosure and the knowledge of the prior art how to isolate, enrich or selectively prepare 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, the quantitative methods for enantiomeric excess or purity are known methods, such as GC, HPLC, CE or NMR, and confirmation of absolute configuration and conformation, such as CDORD, X-ray crystallography or NMR.

Pharmaceutical composition

The compounds of the present invention may be administered to a mammal in need of treatment for HIV 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.

When one enantiomer of a chiral active ingredient has different biological activity compared to another, it will be understood that the pharmaceutical composition according to the invention may comprise a racemic mixture of the active ingredients, a mixture enriched in one enantiomer of the active ingredient or a pure enantiomer of the active ingredient. A mixture enriched in one enantiomer of the active ingredient may contain from greater than 50% to about 100% of one enantiomer of the active ingredient, and from about 0% to less than 50% of the other enantiomer of the active ingredient. Preferably, when the composition comprises a mixture of enantiomers enriched in the active ingredient or a pure enantiomer of the active ingredient, the composition comprises from greater than 50% to about 100% or only the more physiologically active enantiomer and/or the less toxic enantiomer. It is known that one enantiomer of an active ingredient may be more physiologically active for one therapeutic indication, while another enantiomer of the active ingredient may be more physiologically active for a different therapeutic indication; thus, the preferred enantiomeric composition of the pharmaceutical composition may vary with the use of the composition in the treatment of different therapeutic indications.

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, diluents, vehicles, diluents, 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, 21^stVersion, Lippincott Williams&Wilkins, 2005; and L.V.Allen, N.G.Popovish and H.C.Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8^thVersion, Lippincott Williams&Wilkins, 2004, which is 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 used, 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 0.001 to about 100 mg per kg of body weight, with a preferred dose being from about 0.01 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.

Thus, according to one embodiment, the pharmaceutical composition of the invention comprises a racemic mixture of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

Another embodiment provides a pharmaceutical composition comprising a mixture enriched in one enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

Another embodiment provides a pharmaceutical composition comprising a pure enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

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 a drug may be selected from:

● NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors) include, but are not limited to: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), emtricitabine, abacavir succinate, jewucitabine (elvucitabine), adefovir dipivoxil, lobecarvir (BMS-180194), lodenosine (Fdda), and tenofovir, including tenofovir disoproxil (tenofovir disoproxil) and tenofovir disoproxil (tenofovir disoproxil) fumarate, COMBIVIR^TM(containing 3TC and AZT) and TRIZIVIR^TM(containing abacavir, 3TC and AZT), TRUVADA^TM(containing tenofovir and emtricitabine), EPZICOM^TM(containing abacavir and 3 TC);

● 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) (TMC-114), lacinavir and brecanavir (brecanavir) (VX-385);

● entry inhibitors (entry inhibitors), including but not limited to:

● CCR5 antagonists (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 include hydroxyurea, ribavirin, IL-2, IL-12 and flaxsapode.

In addition, the compounds of the present invention may be used with at least one other compound of the present invention or with one or more antifungal or antibacterial agents, including but not limited to fluconazole (fluconazole).

Thus, according to one embodiment, the pharmaceutical composition of the invention additionally comprises one or more antiviral agents.

Another embodiment provides a pharmaceutical composition of the invention, wherein the one or more antiviral agents comprises at least one NNRTI.

According to another embodiment of the pharmaceutical composition of the present invention, the one or more antiviral agents comprises at least one NRTI.

According to another embodiment of the pharmaceutical composition of the present invention, the one or more antiviral agents comprises at least one protease inhibitor.

According to another embodiment of the pharmaceutical composition of the present invention, the one or more antiviral agents comprises at least one entry inhibitor.

According to another embodiment of the pharmaceutical composition of the present invention, the one or more antiviral agents comprises at least one integrase inhibitor.

The compounds according to the invention can also be used as laboratory or research reagents. For example, the compounds of the invention may be used as a positive control group to confirm tests, including but not limited to, alternative cell-based tests, and in vitro or in vivo viral replication tests.

In addition, the compounds of the present invention may be used to treat or prevent viral contamination of substances, thereby reducing the risk of viral infection in laboratories or medical personnel or patients coming into contact with such substances (e.g., blood, tissue, surgical instruments and clothing, laboratory instruments and clothing, and blood collection devices and substances).

Derivatives comprising a detectable marker

Another aspect of the invention provides a derivative of a compound of formula (I), which derivative comprises a detectable marker. The identifier allows for the identification of the derivative, whether directly or indirectly, such that it can be detected, measured or quantified. A detectable marker may be detectable, measurable or quantifiable by itself, or it may interact with one or more other moieties which themselves comprise one or more detectable markers, such that the interaction therebetween allows the derivative to be detected, measured or quantified.

Such derivatives can be used as probes to study HIV replication, including but not limited to studying the mechanism of action of viruses and host proteins involved in HIV replication, studying conformational changes carried out by such viruses and host proteins under different conditions, and studying interactions with individuals that bind to or interact with these viruses and host proteins. The derivatives according to this aspect of the invention may be used in assays to identify compounds that interact with viral and host proteins, including but not limited to displacement assays that measure the extent to which derivatives are displaced from interacting with viral and host proteins. A preferred use of the derivatives according to this aspect of the invention is in the identification of replacement tests confirming HIV integrase inhibitors. Such derivatives may also be used to form covalent or non-covalent interactions with viral and host proteins, or to identify residues of viral and host proteins that interact with the compounds of the invention.

Detectable labels for use with derivatives of the compounds of the present invention include, but are not limited to, fluorescent labels, chemiluminescent labels, chromophores, antibodies, enzyme labels, radioisotopes, affinity labels, and photoactive groups.

A fluorescent marker is a marker that fluoresces, emitting light of one wavelength upon absorption of light of a different wavelength. Fluorescent markers include, but are not limited to, fluorescein; texas red (TexasRed); aminomethylcoumarin; a nodamide dye including, but not limited to, Tetramethylnodamide (TAMRA); alexa dyes, including but not limited to Alexa555; cyanine dyes including, but not limited to, Cy 3; europium or lanthanide-based fluorescent molecules, and the like.

A chemiluminescent marker is a marker that undergoes a chemical reaction that produces light. Chemiluminescent markers include, but are not limited to, luminol, luciferin, lucigenin, and the like.

A chromophore is a marker that selectively absorbs certain wavelengths of visible light while transmitting or reflecting other wavelengths, thereby causing a compound containing the chromophore to display color. Chromophores include, but are not limited to, natural and synthetic dyes.

An antibody is a protein produced by the mammalian immune system in response to a specific antigen, which binds specifically to the antigen. Antibodies intended for use as detectable markers of the present invention include, but are not limited to, antibodies directed to: poly-histidine tag, glutathione-S-transferase (GST), Hemagglutinin (HA),Epitope tag, Myc tag, Maltose Binding Protein (MBP), Green Fluorescent Protein (GFP), and the like.

An enzyme label is an enzyme whose presence can be detected using a test specific for the catalytic activity of the enzyme. Enzyme labels intended for use as detectable markers according to the present invention include, but are not limited to, luciferase, horseradish peroxidase (HRP), beta-galactosidase, and the like.

A radioisotope is an isotope of atoms that produces radiation upon radioactive decay. Radioisotopes include, but are not limited to¹⁴C、³H、³¹P、¹²¹I、¹²⁵I, and the like.

An affinity tag is a marker that has a strong affinity for a group at another moiety (referred to herein as a binding partner). Such affinity labels may be used to form a complex with the binding partner, such that the complex may be selectively detected or separated from the mixture. Affinity tags include, but are not limited to, biotin or a derivative thereof, a histidine polypeptide, polyarginine, a sol starch sugar moiety, or a defined epitope recognizable by a specific antibody; suitable epitopes include, but are not limited to, glutathione-S-transferase (GST), Hemagglutinin (HA), and,Epitope tag, Myc tag, Maltose Binding Protein (MBP), Green Fluorescent Protein (GFP), and the like.

Furthermore, the compounds of the invention used as probes may be labelled with a photoactive group which, when activated by light, is converted from an inert group into a reactive species, such as a free radical. Such groups may be used to activate the derivative so that it can form a covalent bond with one or more residues of the viral or host protein. Photoactive groups include, but are not limited to, photoaffinity markers such as benzophenone and azide groups.

Methodology and Synthesis

The synthesis of the compounds of formula (I) according to the invention is conveniently obtained according to the general procedure outlined in the reaction scheme below, wherein c, X, Y, R²、R³、R⁴、R⁵、R⁶And R⁷Are as defined herein. Further description will be given to those skilled in the art by specific examples set forth below.

Reaction equation 1: inhibitor assembly

Wherein R is⁴²、R⁴³、R⁴⁴、R⁴⁵And R⁴⁶Is a substituent on a phenyl group, or (R)⁴²And R⁴³)、(R⁴³And R⁴⁴)、(R⁴⁴And R⁴⁵) Or (R)⁴⁵And R⁴⁶) May be linked to form a carbocyclic or heterocyclic ring, W is iodine, bromine, chlorine or OTf, V is B (OH)₂Or borates, e.g. B (OCH)₃)₂And B (OC (CH)₃)₂C(CH₃)₂O), iodine, SnR₃Wherein R is (C)_1-6) Alkyl, ZnX, wherein X is halogen and P is a protecting group, such as commonly used protecting groups for carboxylic acids, including but not limited to methyl or ethyl esters.

Those skilled in the art will recognize intermediate (I) (i.e., the thienopyridine skeleton) and intermediate II (i.e., R)⁴Substituents) are used. For example, but not limited to, Suzuki cross-coupling between boronic acid or boronic ester derivatives of intermediate II and halo-or triflate derivatives of intermediate I, copper catalyzed Ullmann cross-coupling between intermediate I and iodo derivatives of II, Negishi cross-coupling between arylzinc reagents of intermediate II and iodo-or triflate derivatives of intermediate I, and Stille coupling between aryltin reagents of intermediate II and bromo-or iodo derivatives of intermediate I, as shown above, after saponification, the compounds of formula (I) of the present invention are obtained.

Alternatively, the same cross-coupling method can be used by interchanging coupling partners as shown below. For example, Suzuki, Negishi and Stille type cross-couplings between boronic acid or boronic ester derivatives of thienopyridine intermediate III, arylzinc reagents or aryltin reagents and the desired iodo, bromo, chloro or triflate derivatives of intermediate IV can also give compounds of formula (I) after saponification.

Wherein R is⁴²、R⁴³、R⁴⁴、R⁴⁵And R⁴⁶And P are as defined above, and W is iodine, bromine, chlorine or OTf, V is B (OH)₂Or borates, e.g. B (OCH)₃)₂And B (OC (CH)₃)₂C(CH₃)₂O)，SnR₃Wherein R is (C)_1-6) Alkyl, and ZnX, wherein X is halogen.

In addition, downstream changes to the product can be made, such as conversion of a aniline-type amine to a chloro or bromo substituent via a Sandmeyer reaction or alkylation, or dehalogenation via a reduction reaction.

Reaction equation 2: synthesis of thienopyridine skeleton

In an alternative approach to the compounds of general formula I, exemplified by compound Ia, thiophene (1, 2-disubstituted with amino and protected carboxylate), which is condensed with ethyl 3-ethoxybut-2-enoate, gives an imine, which is then cyclized to give thienopyridine Ib. It will be apparent to those skilled in the art that there are many possible reaction conditions that may be used to achieve this condensation-cyclization step. Then, the phenol group is reacted with POCl₃Treated to be exchanged for a chloro group and subsequently exchanged for an iodo group in the presence of NaI under acidic conditions to give the aryl iodide Id. It is clear to one skilled in the art that the phenol functionality can be converted to a number of different functionalities including but not limited to Cl, Br, I and OTf to give intermediate II. Then, of IdThe ester group is reduced to its corresponding benzyl alcohol Ie, preferably but not limited to by treatment with DIBAL. It will be apparent to those skilled in the art that this routine conversion can be carried out under a wide range of reaction conditions. The oxidation of the alcohol Ie to the aldehyde If, followed by the addition of TMSCN, gives the cyanohydrin derivative Ig. It is apparent that oxidation of Ie to If, and conversion of aldehyde to Ig, can be achieved by a number of different existing synthetic steps. In a preferred embodiment, by using SO₃Pyridine complex, oxidation treated in the presence of DMSO, followed by zinc iodide catalyzed addition of TMSCN, providing Ig from Ie. Acid catalyzed methanolysis of Ig gave ester Ih. Subsequently, reacting the secondary alcohol with R³Derivatization of the groups gives compound Ii. It will be apparent to those skilled in the art that this can be accomplished in a number of ways, including to construct ether linkages, such as but not limited to SN₁Or SN₂Reaction, or acid catalyzed addition to olefins. The methyl ester is saponified to give the acid Ij which is then derivatized with an enantiomerically pure chiral auxiliary such as Ik to give a mixture of diastereomers which can be separated to give Im. It is clear to the person skilled in the art that many different chiral auxiliary agents can be used for the conversion of the racemic acid Ij into a mixture of diastereomers and it is obvious that chemical resolution methods for stereoisomers clearly exist in the prior art. In a preferred embodiment, the acid Ij is activated by conversion to its corresponding acid chloride, which is then converted in situ to the imide Im. It is also apparent that this particular transformation can be achieved by a variety of known methods, including but not limited to sequential variations of the same method, and activation of the acid Ij by other means known to those skilled in the art. The imide Im, once separated from its diastereoisomers, is then hydrolysed and the carboxylate formed is converted to the ester I (in a preferred embodiment by a standard two-step process).

Alternatively, modifications of the method as outlined in equation 3 can also be used to prepare the thienopyridine skeleton.

Reaction equation 3: alternative synthesis of thienopyridine frameworks

In this process, the appropriately substituted benzoylacetonitrile may be condensed with the appropriate ketone or aldehyde by standard methods known in the literature in the presence of sulfur. Intermediate IIIb is condensed with a suitable α, γ -dioxo ester reagent by methods known to those skilled in the art or as set forth in the examples below to give an intermediate of formula IIIc wherein P is an ester protecting group, such as methyl or ethyl. Intermediate IIIc is reduced by methods known to those skilled in the art or as set forth in the examples below to give an intermediate of formula IIId. As is known to the person skilled in the art, this reduction can be achieved in an enantioselective manner using methods known from the literature. The secondary alcohol is then derivatized to tert-butyl ether using tert-butyl acetate. It will be apparent to those skilled in the art that this can be achieved in more than one way, including SN₁Reaction or acid catalyzed addition to isobutylene. The ester protecting group of intermediate IIIe is hydrolyzed by methods known to those skilled in the art or as set forth in the examples below to provide the compound of formula IIIf. Furthermore, the thienopyridine skeleton may be obtained in an enantioselective manner, as outlined in reaction equation 2.

Reaction equation 4: alternative synthesis of thienopyridine frameworks

In another route to compounds of general formula I, it is known that the aldehyde VIa is converted to a terminal alkyne VIb. It will be apparent to those skilled in the art that there are many ways to achieve this conversion, such as, but not limited to, the Bestmann-Ohira reaction or the Corey-Fuchs reaction. Then, R is added⁴The group is linked to the alkyne using conditions known to those skilled in the art, preferably through the alkyne and R⁴Of radicalsSonogashira coupling between aryl iodide derivatives gives the intermediate alkyne VIc. Other methods may include a Castro-Stevens reaction, or alkyne VIb with R⁴Silver-catalyzed, palladium-catalyzed coupling of boronic acid or ester derivatives of fragments as reported by Zou and colleagues (Tetrahedron lett.2003, 44, 8709-one 8711). And then, carrying out cyclization condensation on the intermediate alkyne VIc and the amide VId to obtain the thienopyridine VIe. It will be appreciated by those skilled in the art that this may involve activation of the amide VId to aid in the overall condensation. This is preferably achieved by the action of trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine, as described by Movasssaghi (J.Am.chem.Soc., 129(33), 10096-10097), but can also be achieved in other ways. Amides VId are generally commercially available, although those skilled in the art will appreciate that they are also readily available from commercially available aniline or nitro aromatic ring precursors. The cyclic diketal is then hydrolyzed under acidic conditions to give the diol VIf. The terminal alcohol is then protected to give VIg, where P can be a number of different protecting groups including, but not limited to, pivaloyl. The secondary alcohol is then derivatized with a t-butyl group to give compound VIh. Those skilled in the art will appreciate that this can be achieved in more than one way, including SN₁Reaction or acid catalyzed addition to isobutylene. Next, the protecting group is removed to give primary alcohol VIj, which is then oxidized to carboxylic acid VIk. It is apparent that the oxidation of VIj to VIk can be achieved in one or two synthesis steps. In a preferred method, oxidation is carried out to the intermediate aldehyde using Dess-Martin, followed by Lindgren oxidation.

Reaction equation 5: alternative synthesis of thienopyridine frameworks

In another approach to obtain compounds of formula I, the synthesis of intermediate VIh can also be achieved by starting with an acid-catalyzed hydrolysis of a cyclic diketal of a terminal alkyne VIb to give diol VIIa. Then, the terminal alcohol is protected to give VIIb, whereinP may be a variety of different protecting groups including, but not limited to, pivaloyl. The secondary alcohol is then derivatized with a t-butyl group to provide compound VIIc. Those skilled in the art will appreciate that this can be achieved in more than one way, including SN₁Reaction or acid catalyzed addition to isobutylene. Then, R is added⁴The group is linked to the alkyne using conditions known to those skilled in the art, preferably through alkyne and R⁴Sonogashira coupling between aryl iodide derivatives of the group gives the intermediate alkyne VIId. Followed by cyclocondensation of the intermediate alkyne VIId with the amide VId to give quinoline VIh, preferably by triflic anhydride, in the presence of 2-chloropyridine, as described in step 3 of equation 4. The synthesis of the compound of formula (I) is then completed from intermediate VIh according to steps 7 and 8 of reaction equation 4.

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. It will be apparent to those skilled in the art that the procedures exemplified below may be used with appropriate modifications to prepare other compounds of the invention as described herein.

As is well known to those skilled in the art, the reaction is carried out in an inert atmosphere (including but not limited to nitrogen or argon) if desired to avoid exposure of the reaction components to air or moisture. Temperatures are expressed in degrees Celsius (. degree. C.). Solution percentages and ratios refer to volume ratios 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 spectrometry analysis was recorded using electrospray mass spectrometry. Many of the intermediates and final products were obtained using a commercial product from Teledyne Isco IncThe company device, using a pre-filled silica gel cartridge, and EtOAc and hexane as the solvent was purified. These cartridges are available from silicon Inc (SiliaFlash, 40-63 micron silica gel) or from Teledyne Isco (RediSep, 40-63 micron silica gel). Preparative HPLC was performed under standard conditions using SunAire^TMPrep C18 OBD 5 μ M reverse phase column, 19 × 50 mm, and linear gradient using 0.1% TFA/acetonitrile and 0.1% TFA/water as solvents. When appropriate, the compound was isolated as a TFA salt. Analytical HPLC was performed under standard conditions using a CombioscreenODS-AQ C18 reverse phase column, YMC, 50X4.6 mm ID, 5. mu.M,at 220nM, with a linear gradient as described in the following table (solvent A is H in 0.06% TFA)₂O solution; solvent B is CH of 0.06% TFA₃CN in solution) elution:

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:

ac: acetyl;

AcOH: acetic acid;

Ac₂o: acetic anhydride;

BOC or BOC: a tert-butoxycarbonyl group;

bu: a butyl group;

CD: circular dichroism spectroscopy;

DABCO: 1, 4-diazabicyclo [2.2.2] octane

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

DCE: ethylene dichloride;

DCM: dichloromethane;

DEAD: diethyl azodicarboxylate;

the DIAD: diisopropyl azodicarboxylate;

DIBAL: diisobutylaluminum hydride;

DMAP: n, N-dimethyl-4-aminopyridine;

DME: 1, 2-dimethoxyethane;

DMF: n, N-dimethylformamide;

DMSO, DMSO: dimethyl sulfoxide;

dppf: 1, 1' -bis (diphenylphosphino) ferrocene;

EC₅₀: 50% effective concentration;

eq: equivalent weight;

et: an ethyl group;

Et₃n: triethylamine;

Et₂o: diethyl ether;

EtOAc: ethyl acetate;

EtOH: ethanol;

HPLC: high performance liquid chromatography;

IC₅₀: 50% inhibitory concentration;

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

LiHMDS: lithium hexamethyldisilazide (lithium hexamethyldisilazide);

me: a methyl group;

MeCN: acetonitrile;

MeOH: methanol;

MOI: how severe the infection is;

MS: mass spectrometry (ES: electrospray);

n-BuONa: n-Butanol sodium salt

n-BuOH: n-butanol;

n-BuLi: n-butyl lithium;

NMR: nuclear magnetic resonance spectroscopy;

ORD: optical dispersion;

ph: a phenyl group;

PhMe: toluene;

PG: a protecting group;

pr: propyl;

RPMI: roswell Park mental institute (cell culture media);

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

SM: starting materials;

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

tf: a trifluoromethanesulfonyl group;

Tf₂o: trifluoromethanesulfonic anhydride;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: thin layer chromatography;

TsOH: p-toluenesulfonic acid; and

TMSCN: trimethylsilyl cyanide

Example 1: synthesis of thienopyridine framework IA

Step 1:

thiophene 1a (11.2 g, 65.3 mmol) was dissolved in anhydrous xylene (250 ml) and then treated with ethyl 3-ethoxybut-2-enoate (10.84 g, 68.5 mmol) and catalyst TsOH (30 mg, 0.16 mmol). The resulting solution was heated under reflux (bath temperature: 158 ℃ C.) and fitted with a Dean-Stark column and a condenser to collect ethanol. After 5 hours, the solution was cooled (cold water bath), transferred to a dropping funnel, and then added dropwise (over about 15 minutes) to a stirred solution of sodium ethoxide in ethanol (25.6 ml, 21 wt% NaOEt in ethanol (68.5 mmol diluted to 150 ml absolute ethanol)). The resulting solution was heated to reflux under nitrogen. After 16 hours, the reaction was cooled and the ethanol and xylene were removed under reduced pressure to give an earthy yellow semi-solid. The material was dissolved/suspended in water (500 ml) and washed with diethyl ether (2 × 500 ml). The aqueous phase was separated, cooled to 0 ℃, and slowly acidified to pH-4 with 1N HCl (65 ml) and stirred rapidly. The precipitate formed was filtered, washed with dilute HCl (pH 4, 50 ml) and air dried to give 1b (11.85 g, 72% yield) as an orange powder, which was used as such in the following step.

Step 2:

thienopyridine 1b (11.85 g, 47.15 mmol) was suspended in POCl₃(100 ml) and the mixture was heated to 100 ℃ for 20 minutes and then concentrated under vacuum. The residue was diluted with EtOAc and saturated NaHCO₃Washing with aqueous solution, water and brine, followed by drying(MgSO₄) Filtered and concentrated under vacuum. The crude product was purified by flash chromatography using hexanes/EtOAc 8/2 to give 4-chloro analog 1c as a yellow oil (10.50 g, 82.5% yield).

And step 3:

to a solution of 4-chloro analog 1c (10.5 g, 38.9 mmol) in THF (100 ml) was slowly added a 4M solution of HCl in dioxane (97 ml, 389 mmol) at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, and then the solvent was evaporated. Suspending the pellet in CH₃CN (300 ml) and treated with NaI (46.7 g, 311 mmol). The resulting mixture was heated to reflux for 16 hours. The mixture was then concentrated and then dissolved in EtOAc (300 ml) followed by 1.0N NaOH (100 ml), water (2 ×), 10% Na₂S₂O₃(2X), water and saturated brine. The organic phase was dried (MgSO)₄) Filtered, and concentrated in vacuo to afford 1d as a yellow solid (12.88 g, 91.6% yield).

And 4, step 4:

to a solution of 4-iodo intermediate 1d (12.88 g, 35.66 mmol) in DCM (100 ml) was added DIBAL/DCM solution (1M in DCM, 82 ml, 82 mmol) dropwise over 5 min at-78 ℃. The resulting solution was stirred for 1.5 hours and then at 0 ℃ for 30 minutes. The reaction was quenched by slow addition with 100 ml of 1N HCl and the resulting mixture was stirred for 1 hour. The mixture was extracted with DCM and the combined organic extracts were washed with Rochelle's solution, water and brine, followed by drying (MgSO)₄). The organic phase was filtered and concentrated in vacuo to afford 1e as a pale beige solid (10 g, 88% yield).

And 5:

to a cold (15 ℃) solution of alcohol 1e (10.05 g, 31.5 mmol) in DMSO (50 mL) was added Et₃N (13.2 ml, 94.5 mmol) followed by py₃Complex (12.5 g, 78.7 mmol). The reaction mixture was stirred at room temperature for 1 hour and then pouredInto water (200 ml). The mixture was filtered and dried under vacuum to give compound 1f (8.8 g, 88% yield) as an off-white solid.

Step 6:

to a cold (0 ℃) mixture of aldehyde 1f (8.8 g, 27.8 mmol) in DCM (150 mL) was added ZnI₂(4.43 g, 13.9 mmol, 0.5 eq) followed by the addition of TMSCN (11.1 ml, 83.3 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM (150 ml) and quenched with water (200 ml). The aqueous phase was extracted with DCM and the combined organic extracts were washed with water and brine and then dried (MgSO)₄) And filtering. The extract was concentrated in vacuo to afford compound 1g as an off-white solid (11.02 g, 95% yield).

And 7:

adding concentrated H₂SO₄(20 ml, 375 mmol) was carefully added to cold (0 ℃) MeOH (104 ml) and then the warm solution formed was added to TMS protected cyanohydrin 1g (5.52 g, 13.7 mmol). The reaction mixture was stirred at 100 ℃ for 5 hours, cooled to 0 ℃, diluted with water (200 ml) and neutralized with solid NaOH. The precipitate formed was filtered and dried under vacuum overnight to give compound 1h as an off-white solid (7.97 g, 85% yield).

And 8:

to a mixture of alpha hydroxy ester 1h (7.97 g, 21.1 mmol) in tert-butyl acetate (100 ml) was added perchloric acid (70%, 3.33 ml, 23.2 mmol) at room temperature. The resulting solution was stirred at room temperature for 4 hours. Addition of saturated NaHCO₃Solution until pH 8 is reached, then the solution is extracted with DCM (3X), over MgSO₄Dried, filtered, and concentrated under vacuum. The residue was purified by flash chromatography using hexanes/EtOAc 8/2 to give compound 1i (7.34 g, 80% yield) as a white solid.

And step 9:

to a solution of tert-butyl ether 1i (5.34 g, 12.3 mmol) in THF (150 ml) and MeOH (75 ml) was added 5N NaOH (12.3 ml, 61.6 mmol) at room temperature and the reaction mixture was stirred overnight. The mixture was then treated with 1.0N HCl (aq) (to make it slightly acidic) and the mixture was extracted with DCM. The combined extracts were washed with water, brine and dried (MgSO)₄) Filtered and concentrated under vacuum. The crude product 1j was used as such in the next reaction step (5.1 g, 98% yield).

Step 10:

the acid 1j (5.1 g) was dissolved in anhydrous DCM (100 ml) at 0 ℃ and then anhydrous DMF (50 μ l) was added. To this solution, oxalyl chloride (1.62 ml, 17 mmol) was slowly added. The solution was warmed to room temperature and after 20 minutes; the reaction mixture was concentrated to give a foamy solid which was used directly in the subsequent step.

A solution of (R- (+) -4-benzyl-2-oxazolidinone (6.46 g, 36.4 mmol) in 75 mL anhydrous THF was cooled to-78 deg.C, followed by the dropwise addition of n-BuLi (2.5M in hexanes, 13.6 mL, 34 mmol.) the resulting solution was stirred for 20 minutes, then treated with the acid chloride (prepared above) in THF (75 mL.) the mixture was stirred at-78 deg.C for 15 minutes, then allowed to warm slowly to room temperature, then stirred for an additional 30 minutes, with saturated NH₄Cl solution, followed by quenching the reaction mixture with water. The mixture was extracted with DCM (3 ×), and MgSO₄Dried, filtered, and concentrated under vacuum. The mixture of diastereomers was separated by flash column chromatography using benzene/EtOAc 95/5 to give the desired compound 1k (2.99 g, 43% yield, 2nd eluate), plus the diastereomer (2.88 g, 41% yield, 1 st eluate).

Step 11:

to a solution of compound 1k (2.99 g, 5.18 mmol) in THF (50 ml)/water (15 ml) was added water (10 ml) of premixed H at 0 ℃₂O₂(1.6 mL, 15.5 mmol)/LiOH-H₂O (261 mg, 6.21 mmol). The reaction was stirred at 0 ℃ for 20 minutes. Saturated Na at 0 deg.C₂SO₃(10 ml) the reaction mixture was quenched and stirred for 10 minutes. The pH was adjusted to pH 4-5 using 1N HCl (aq) and then extracted with DCM (3X). The organic phase was washed with MgSO₄Dried, filtered, and concentrated under vacuum. The crude product was diluted with EtOAc (100 ml) and treated with diazomethane/diethyl ether solution at room temperature until complete conversion to the ester. The reaction mixture was quenched with silica gel and then carefully concentrated in vacuo. This material was dry-loaded and purified by flash column chromatography using DCM/acetone 9/1 to give the key thienopyridine fragment IA as a white solid (2.13 g, 95% yield).

Example 2: synthesis of thienopyridine skeleton IB

The key thienopyridine fragment IB was prepared starting from commercially available thiophene 2a using the same synthetic scheme as shown for example 1.

Example 3: synthesis of fragment 3f

Step 1:

aldehyde 3a (5.85 g, 28.6 mmol, see for preparation: Michel, P. and Ley, S.VSynthesis 2003, 10, 1598-₂CO₃(8.8 g, 64 mmol) was mixed in MeOH (125 ml) and the reaction was stirred at rt overnight. The reaction was almost evaporated to dryness and the residue was taken up in H₂Partition between O (250 ml) and EtOAc (500 ml). Applying the aqueous layerEtOAc (2 × 250 ml) was washed, and the combined organic layers were washed with anhydrous Na₂SO₄Drying and concentration gave alkyne 3c (5.55 g, 97% yield).

Step 2:

alkyne 3c (5.0 g, 25 mmol) was dissolved in TFA (35 ml) and water (3.6 ml) and the solution was stirred at room temperature. After 30 minutes, the reaction was concentrated under reduced pressure and the residue was passed throughPurification by company gave diol 3d (1.8 g, 84% yield).

And step 3:

in N₂Next, a solution of diol 3d (1.2 g, 14 mmol) and triethylamine (1.7 ml, 12 mmol) in DCM (80 ml) was cooled to 0 ℃. Trimethylacetyl chloride was added dropwise and the resulting mixture was brought to room temperature and stirred overnight. The reaction was then quenched with MeOH (100 ml) and stirring continued for 20 minutes. The mixture was then concentrated under reduced pressure and the residue was passed throughPurification by company afforded the desired monoester 3e (550 mg, 40% yield) along with the undesired regioisomeric monoester (378 mg, 27% yield).

And 4, step 4:

propargyl alcohol 3e (375 mg, 2.20 mmol) was reacted withA solution of H-15 resin (150 mg) in hexane (3 mL) was cooled to-78 ℃. Next, isobutylene was bubbled through the solution until approximately twice the volume. The tube was then sealed, brought to room temperature, and stirred overnight. The tube was then cooled to-78 ℃, opened, and returned to room temperature. Then, the mixture was passed through SiO₂Plug filtration (EtOAc wash) and concentration under reduced pressurePure tert-butyl ether 3f (390 mg, 78% yield) was obtained.

Example 4: synthesis of Borate fragment 4f (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

to a solution of 4a (6 g, 37 mmol) in nitrobenzene (12 ml) was added chloroacetyl chloride (4.6 ml, 57.5 mmol) followed by AlCl₃(20.4 g, 152 mmol). When AlCl is added₃At this time, the mixture became viscous and gas evolution was observed. The resulting brown slurry mixture was stirred at room temperature overnight (ref: Y. Takeuchi et al, chem. pharm. Bull.1997, 45(12), 2011-2015). The thick reaction mixture was cooled and several drops of ice water were added at the same time with minimal care (exotherm). Once gas evolution and bubbling subsided, further cold water was added followed by EtOAc. The mixture was stirred for 5 min and the product was extracted with EtOAc (3 ×). The combined organic layers were washed with brine (1 ×), washed with Na₂SO₄Drying, filtration and concentration gave the uncyclized chloroketone (24 g crude; contaminated with some parts nitrobenzene) as a pale yellow solid. This intermediate was then dissolved in EtOH (100 ml), NaOAc (20.4 g, 248 mmol) was added, and the reaction was brought to reflux for 40 min. EtOH was evaporated, the residue dissolved in EtOAc (. about.300 mL) and washed with 5% K₂CO₃Washed (2 × 200 ml) and the aqueous layer was acidified with aqueous HCl (1N; pH ═ 5). The acidic layer was extracted with EtOAc (2 × 250 ml), washed with brine (1 ×), and Na₂SO₄Dried, filtered, and concentrated to give the crude product. Passing the substance throughPurification by company (120 g) gave intermediate 4b as a yellow solid (4.7 g).

Step 2:

ketone 4b (127 mg, 0.64 mmol) was dissolved in EtOH (2 ml) and treated with hydrazine hydrate (500 μ l, 16 mmol). The mixture was heated to reflux for 45 minutes and then cooled to room temperature. The solvent was removed by evaporation and the residue was dissolved in diethylene glycol (1 ml) followed by treatment with KOH (108 mg, 1.92 mmol) and then heated to 110-. The reaction mixture was diluted with EtOAc and the pH was adjusted to pH < 4 with 1N HCl. The organic phase was separated, washed with saturated brine, and anhydrous MgSO₄Dried, filtered, and concentrated. Crude material is passed throughPurification by company (eluent: 0-50% EtOAc/hexanes) provided intermediate 4c as a yellow oil (62 mg).

And step 3:

a solution of 4c (61 mg, 0.33 mmol) in DCM (2 mL) was cooled to-78 deg.C and then BBr was used₃(1M in DCM, 825. mu.l, 0.82 mmol). After 15 minutes, the bath was removed and the reaction was brought to room temperature. The reaction was then stirred for 1.5 hours. The reaction was cooled to 0 ℃ and then quenched by careful dropwise addition of water. The mixture was washed with saturated NaHCO₃(to about pH 8) and the phases are separated. The organic phase was washed with saturated brine and MgSO₄Dried, filtered, and concentrated to dryness. Product passingPurification by company (0-50% EtOAc/hexanes) provided intermediate 4d as a colorless oil that solidified upon standing (40 mg, 71% yield).

And 4, step 4:

phenol 4d (40 mg, 0.23 mmol) was dissolved in DCM (2 ml), cooled to 0 ℃ and washed with pyridine (95 μ l, 1.17 mmol) followed by Tf₂O(44 μ l, 0.26 mmol). The reaction was stirred at this temperature for 10 minutes and then allowed to warm to room temperature over 1 hour. The reaction mixture was diluted with DCM and the organic phase was washed with 10% citric acid followed by brine. The organic phase was extracted with anhydrous MgSO₄Drying, filtering, concentrating, and passingPurification by company (0-50% EtOAc/hexanes) afforded 4e as a yellow oil (67 mg, 94% yield).

And 5:

to a solution of triflate 4e (66 mg, 0.22 mmol) in DMF (2 ml) was added bis pinacolatodiborane (72 mg, 0.28 mmol) and potassium acetate (64 mg, 0.65 mmol). The solution was degassed (using bubbled Ar) for 10 minutes, then PdCl was added₂(dppf)-CH₂Cl₂(27 mg, 0.03 mmol). The mixture was degassed for an additional 5 minutes, then heated to 90 ℃ for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc/water. The organic phase was washed with saturated brine (3 ×), anhydrous MgSO₄Dried, filtered, and concentrated. Crude material is passed throughPurification by company (0-70% EtOAc in hexanes) gave boronic ester 4f as a white solid (41 mg, 67% yield).

Example 5: synthesis of boronic ester fragment 5f (for preparation of 1037, 1041, 1042, 2020, 2021)

Step 1:

nitrophenol 5a (5.23 g, 34.1 mmol) was dissolved in acetic acid (20 ml) and the solution was cooled in an ice bath. Bromine (1.75 mm) was added dropwiseL, 34.15 mmol, dissolved in 5 ml of acetic acid) and stirred. The mixture was stirred at 0 ℃ for 1 hour and then poured into ice water (250 ml). The mixture was extracted with EtOAc (2 × 100 ml) followed by 5% NaHCO₃(2X50 mL) and then over anhydrous MgSO₄Drying, filtration, and concentration gave the desired crude product 5b as an orange solid (8.2 g, quantitative yield). This material was used in the next step without further purification.

Step 2:

to a well stirred solution of 5b (8.1 g, 34.9 mmol) in ethanol (75 ml) was added SnCl₂(20 g, 105 mmol). The reaction mixture was stirred at reflux for 2.5 hours. After this time, the transition was not complete, so more SnCl was added₂(2 g, 10 mmol), reflux was continued for 1 hour, then cooled to room temperature. The mixture was poured onto 250 g of ice and washed with 5% NaHCO₃The pH was adjusted to about 7.5 with aqueous solution and the product was extracted with EtOAc (3 × 100 ml) followed by washing with brine (2 × 100 ml). The organic phase was extracted with anhydrous MgSO₄Drying, filtration, and concentration to dryness gave aniline intermediate 5c as a grey solid (8.25 g, 100% yield, this material contained some tin residue, however, it was used as such in the following step.

And step 3:

to a stirred and ice-cold suspension of potassium carbonate (2.05 g, 14.8 mmol) and aniline 5c (750 mg, 3.71 mmol) in DMF (5 ml) under nitrogen was added chloroacetyl chloride (355 μ l, 4.45 mmol) dropwise. The mixture was warmed to room temperature over 15 minutes and then heated to 60 ℃ for 1 hour. The mixture was cooled to room temperature, poured into an ice/water mixture (250 ml) and stirred for about 15 minutes. The suspension was centrifuged and the supernatant discarded. The solid material was suction dried overnight to afford intermediate 5d (280 mg, 31% yield).

And 4, step 4:

in cyclic amide 5d (280 mg, 1.16 mmol) in ice-cold THF (6 mL)) To the solution, borane-THF solution (1M in THF, 1.74 ml, 1.74 mmol) was slowly added under nitrogen. The reaction mixture was slowly warmed to room temperature, followed by stirring at room temperature for about 1.5 hours, then gently heated to reflux for 1 hour to complete conversion. The mixture was cooled in an ice bath and the reaction was carefully quenched with 1M aqueous NaOH (4 ml) over 10 minutes. The reaction mixture was partitioned between EtOAc (150 ml) and water (25 ml). The organic layer was washed with 1N aqueous NaOH (20 mL) and brine, anhydrous MgSO₄Dried, filtered, and concentrated to give crude 5e as an amber oil (212 mg, 81% yield). This product was used as such for the next conversion.

And 5:

a well-stirred DMF (15 ml) solution of aryl bromide 5e (0.50 g, 2.19 mmol), potassium acetate (0.728 g, 7.67 mmol) and bis (pinacolato) diborane (0.83 g, 3.3 mmol) was degassed by bubbling Ar through the solution for 20 min. Addition of PdCl₂(dppf) -DCM (320 mg, 0.44 mmol) and degassing was continued for 15 min. The system was sealed under Ar (teflon screw cap container) and heated to 90 ℃ for 5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 ml), washed with brine (3 × 100 ml) and water (2 × 100 ml), over anhydrous MgSO₄Dried, filtered, and concentrated to dryness. Passing the residue throughPurification by company (EtOAc/hexanes) gave the desired boronic ester 5f (389 mg, 65% yield) as a light yellow waxy solid.

Example 6: synthesis of boronic ester fragment 6i (for preparation of 1027, 1028, 2007, 2008)

Step 1:

sodium hydride (60%, 7.78 g, 194 mmol) was added to a well-stirred suspension of 6a (12.5 g, 97.2 mmol) in THF (100 ml). After the reaction mixture was stirred for 1 hour, N-diethylcarbamoyl chloride (24.64 ml, 194 mmol) was added at room temperature. After stirring the reaction overnight, the reaction mixture was quenched with water (100 ml), extracted with EtOAc (3 × 50 ml), and extracted with anhydrous MgSO₄Drying, filtration and evaporation under reduced pressure gave 6b (33 g, 75% yield) in high purity.

Step 2:

diisopropylamine (21.0 ml, 121 mmol) in THF (330 ml) was treated with a solution of n-BuLi (2.5M in hexane, 48.2 ml, 121 mmol) at 0 ℃. After 30 minutes at this temperature, the solution was cooled to-78 ℃ and carbamate 6b (33.29 g, 109.7 mmol, 75% pure) was added. The reaction was stirred at this temperature for 30 minutes, then iodine (33.4 g, 132 mmol) was added. The solution was stirred at 0 ℃ for 30 minutes, then warmed to room temperature. After 2 hours, the reaction mixture was quenched with water (250 ml) and the volatile organic solvent was removed under reduced pressure. The aqueous phase was then extracted with EtOAc (3 × 100 ml), washed with 1N HCl (1 × 200 ml), and MgSO₄Drying, filtration, and evaporation under reduced pressure gave 6c (18.6 g, 39% yield).

And step 3:

in a sealable tube, under Ar, iodocarbamate 6c (10 g, 28 mmol), propargyl alcohol (3.3 mL, 56 mmol), Pd (PPh)₃)₄(3.27 g, 2.83 mmol) and copper iodide (1.08 g, 5.66 mmol) were mixed in diisopropylamine (39 ml, 39 mmol) and heated at 100 ℃. After 1h, the reaction was cooled to room temperature and poured into EtOAc (100 ml) and the mixture was extracted with 10% HCl (2 × 100 ml). The organic layer was washed with MgSO₄Dried and concentrated to dryness. The crude product is passed throughCompanPurification by ion gave alcohol 6d (3.65 g, 46% yield).

And 4, step 4:

alkyne 6d (3.63 g, 12.9 mmol) was dissolved in EtOAc (81 mL) and treated with Rh-Al₂O₃(5% w/w, 3.45 g, 1.68 mmol). The flask was evacuated and charged with 1 atmosphere of H₂(balloon) and the reaction was stirred at rt overnight. Passing the reaction mixture throughFiltration (EtOAc wash) and concentration of the filtrate under reduced pressure. Then, the residue is passed throughPurification by company gave alcohol 6e (3.7 g, 71% yield).

And 5:

solid NaOH (920 mg, 23 mmol) was added to a solution of carbamate 6e (2.63 g, 9.20 mmol) in EtOH (93 ml) and the mixture was heated to reflux and stirred overnight. Then, the mixture was cooled to room temperature, and the organic solvent was removed under reduced pressure. Water (100 mL) was added and the mixture was taken up in Et₂O (3X100 ml) extraction with MgSO₄Drying, filtration and evaporation under reduced pressure gave phenol 6f (869 mg, 51% yield).

Step 6:

diethyl azodicarboxylate (953. mu.l, 6.05 mmol) was added dropwise to phenol 6f (869 mg, 4.66 mmol) and PPh₃(1.59 g, 6.05 mmol) in THF (65 ml) and the reaction was stirred at rt. After 4 hours, the reaction mixture was evaporated under reduced pressure. Then, the residue is passed throughPurification by company gave 6g (387 mg, 49% yield) of chroman intermediate.

And 7:

iodine (583 mg, 2.29 mmol) was added to chroman 6g (387 mg, 2.29 mmol) and AgNO₃(429 mg, 2.52 mmol) in MeOH (23 ml). After 20 min, 0.5M sodium thiosulfate solution (10 ml) was added and the aqueous phase was extracted with EtOAc (3 × 25 ml). The combined organic phases were washed with brine and then dried (MgSO)₄) Filtered and evaporated to give the aryl iodide over 6h (647 mg, 96% yield).

And 8:

a solution of iodo intermediate 6h (647 mg, 2.20 mmol), bis (pinacolato) diborane (0.725 g, 2.86 mmol) and potassium acetate (0.626 g, 6.59 mmol) in DMF (17 ml) was degassed with Ar for 10 min. Then PdCl is added₂(dppf) -DCM complex (179 mg, 0.22 mmol) and the mixture degassed with Ar for an additional 5 minutes. The reaction was then heated to 95 ℃ in a sealable tube and stirred overnight. The reaction was cooled to rt and EtOAc (100 ml) was added. The solution was washed with brine (3 × 150 ml), water (1 × 150 ml), over MgSO₄Dry, filter, and remove solvent under reduced pressure. Passing the residue throughPurification by company gave boronic ester 6i (260 mg, 40% yield).

Example 7: synthesis of boronic acid ester fragment 7d (for preparation of 1038, 1039, 1043, 1044, 2026, 2027)

Step 1:

a solution of phenol 7a (0.91 g, 5.74 mmol) in anhydrous DMF (1 mL) was added dropwise to a solution of NaH (60% in oil, 0.60 g, 15 mmol) in water cooled to 10-15 deg.C (cold water bath)Slurry in anhydrous DMF (1 ml) and the mixture was stirred for 20 min. This resulted in a thick bubbling white mixture. Then, a solution of 3-bromopropionic acid (1.1 g, 6.9 mmol) in anhydrous DMF (0.5 ml) was added dropwise and the reaction was stirred at room temperature overnight. After 16 h, methanol (1.2 ml) was added to help break up the thick paste reaction mixture, which was then added to dilute HCl (12 ml, 1N HCl in 100 ml water) and extracted with EtOAc (80 ml; adjusting the pH of the aqueous phase to pH < 3). The organic layer was washed with anhydrous Na₂SO₄Dried and evaporated to give 7b, a white solid material (1.29 g crude material) contaminated with some unreacted SM. This material was used in the next step without purification.

Step 2:

crude compound 7b (1.53 g, 6.63 mmol) was mixed with polyphosphoric acid (approximately 7 g) and heated to 75 ℃ to give a cherry red solution. During the reaction time, the reaction mixture became viscous and stirring became difficult. After 4 hours, ice and water were slowly added with rapid stirring to give a thick suspension. The mixture was transferred to a separatory funnel where the product was extracted with EtOAc (100 ml) and water (100 ml), saturated NaHCO₃(2 × 100 ml) and brine (75 ml). The organic phase was extracted with anhydrous MgSO₄Dried and evaporated to give 7c as a viscous purple solid, which was used as such (1.29 g crude).

And step 3:

intermediate 7c is analogous to intermediate 4b in example 4; those skilled in the art will recognize that the same synthetic methods used to convert 4b to the boronic ester 4f can be applied to the conversion of 7c to its corresponding boronic ester 7 d.

Example 8: synthesis of Borate fragment 8h (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1

2-amino-m-methylphenol 8a (5.7 g, 46.3 mmol) was dissolved in H₂O (30 ml) and 1, 4-dioxane (15 ml). The mixture was heated to reflux and HBr (48%, 17 ml, 0.31 mol) was then added dropwise over 20 minutes. After the addition was complete, reflux was continued for a further 15 minutes. The reaction was cooled to 0 ℃ and NaNO was added over 30 minutes₂H of (A) to (B)₂O solution (20 ml). Stirring was continued at 0 ℃ for 15 minutes, then at 0 ℃ the mixture was transferred in one shot to Cu (I) Br (7.64 g, 53.2 mmol) in H₂O (20 ml) and HBr (48%, 17 ml, 0.31 mol) were stirring (protected from light). The reaction was stirred at 0 ℃ for 15 minutes, warmed to 60 ℃, stirred for an additional 15 minutes, cooled to room temperature, and then stirred overnight. Next, the reaction mixture was transferred to a separatory funnel and extracted with EtOAc (3 ×). The combined organic layers were washed with brine, anhydrous MgSO₄Drying, filtering and concentrating on silica gel to give a mixture, which is usedPurification by company (20% EtOAc/hexanes) provided the desired bromide 8b (1.46 g, 17% yield) as a reddish brown oil.

Step 2:

in the presence of bromide 8b (1.36 g, 7.27 mmol) and (PPh)₃)₂PdCl₂(766 mg, 1.09 mmol) to a solution in DMF (12 mL) was added 1-ethoxyvinyl-tri-n-butyltin (2.7 mL, 8.0 mmol). The mixture was capped and heated in a microwave at 160 ℃ for 15 minutes. HPLC and LC-MS analysis showed approximately 70% conversion. More 1-ethoxyvinyl-tri-n-butyltin (2.7 ml; 8.0 mmol) and catalyst (PPh) were added₃)₂PdCl₂(380 mg, 0.05 mol%) and the solution was again subjected to the same microwave conditions. The reaction was quenched with 6N HCl (1.5 ml) and stirred at room temperature for 1 hour until hydrolysis of the intermediate was achieved. Pouring the mixture intoEtOAc (150 ml), washed with brine (3 ×), and MgSO₄Drying, filtering and concentrating on silica gel to give a mixture, which is usedPurification by company afforded the desired ketone 8c (947 mg, 87% yield) as an orange oil.

And step 3:

methyl ketone 8c (1.02 g, 6.8 mmol) was dissolved in EtOAc (15 ml) and CHCl₃(15 ml), then with Cu (II) Br₂(3.03 g, 13.6 mmol). The mixture was heated to reflux for 16 hours. The mixture was cooled to rt, the product was filtered and washed with EtOAc (1 ×). Concentrating the solution on silica gel to obtain a mixture, which is usedPurification by company (10% EtOAc/hexanes) afforded α -bromoketone 8d (710 mg, 46% yield) as an orange oil. This material was used as such in the next step without purification.

And 4, step 4:

to a solution of bromoketone 8d (710 mg, 3.1 mmol) in anhydrous DMF (12 ml) was added KF (400 mg, 6.95 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was dissolved in EtOAc (150 ml), washed with brine (3 ×), and anhydrous MgSO₄Drying, filtering and concentrating on silica gel to give a mixture, which is usedPurification by company (20% EtOAc/hexanes) provided cyclic ketone 8e (280 mg, 61% yield) as a light orange solid.

And 5:

the pre-activation method of Zn powder comprises the following steps: zinc powder (20 g, 350 mesh) was placed in a round bottom flask and 1N HCl (50 ml) was added. The suspension was sonicated for 1 minute, then the liquid was decanted. Repetition ofThis step was performed twice, and then the solid was washed with EtOH (2X), Et₂O (2 ×) washed and dried under high vacuum. To a solution of ketone 8e (280 mg, 1.89 mmol) in AcOH (10 ml) was added preactivated Zn powder (1.24 g, 18.9 mmol). The reaction mixture was then heated to 75 ℃ for 2 hours. The reaction mixture was filtered (the solid was washed with EtOAc). Evaporating the solvent on silica gel, and using the mixtureDirect purification (10% EtOAc/hexanes) from company afforded the desired dihydrobenzofuran 8f (174 mg, 69% yield) as a colorless oil.

Step 6:

to a solution of dihydrobenzofuran 8f (240 mg, 1.8 mmol) in MeOH (5 ml) was added AgNO₃(304 mg, 1.79 mmol) followed by iodine (453 mg, 1.79 mmol) addition. The yellow mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% Na₂S₂O₃The solution was dissolved and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc (100 ml) and the organic layer was washed with brine (3 ×) and 10% Na₂S₂O₃(2x) washing. The organic phase was extracted with anhydrous MgSO₄Dried, filtered, and concentrated on silica gel to give a mixture. Using the mixturePurification by company (10% EtOAc/hexanes) provided 8g (400 mg, 86% yield) of the iodo derivative as a white amorphous solid.

And 7:

a mixture of 8g (400 mg, 1.54 mmol) of the iodo derivative, bis (pinacolato) diborane (585 mg, 2.31 mmol), potassium acetate (511 mg, 5.4 mmol) in DMF (20 ml) was deoxygenated (Ar balloon and sonicated for 5 min); then the catalyst (PdCl) is added₂dppf, 188 mg, 0.23 mmol) with re-degassing (Ar balloon and sonication for 2 min).The mixture was then heated to about 95 ℃ for 4 hours. The mixture was cooled, EtOAc (200 ml) was added, washed with brine (3 ×), water (2 ×), and anhydrous MgSO₄Drying, filtering and evaporating the solvent on silica gel to obtain a mixture, which is usedPurification by company (10% EtOAc/hexanes) provided the desired boronic ester 8h (315 mg, 79% yield) as a yellow oil.

Example 9: synthesis of Borate fragment 9b (for preparation of 1053, 1054)

Anhydrous DMF (60 ml) was added to a flask charged with bromide 9a (5.00 g, 22.2 mmol), bis- (pinacolato) diborane (8.48 g, 33.4 mmol) and potassium acetate (6.35 g, 66.8 mmol) and the resulting suspension was passed through N₂The gas stream was deoxygenated by bubbling through the mixture for 45 minutes. 1, 1' -bis (diphenylphosphino) ferrocene (2.73 g, 3.34 mmol) was then added and the mixture was deoxygenated for an additional 5 minutes, followed by heating to 95 ℃. After 16 h, the dark reaction mixture was cooled, extracted with EtOAc (500 ml to 300 ml) and washed with 1: 1 water/brine (600 ml) and brine (600 ml). The combined extracts were over anhydrous MgSO₄Dried, filtered, and evaporated to a black slurry which was purified by flash column chromatography (EtOAc/hexanes) to give the boronic ester 9b as a white solid contaminated with < 25% diborane reagent (4.24 g, 62% yield).

Example 10: synthesis of Borate fragment 10g (for preparation of 1045, 1046, 1051, 1052, 2024, 2025)

Step 1:

2-chloro-6-fluoronitrobenzene 10a (6.62 g, 37.7 mmol) and LiOH monohydrate (6.33 g, 151 mmol) were dissolved in THF (45 mL) and water (65 mL) and H was added₂O₂Aqueous solution (30%, 8.60 ml, 80.0 mmol). The resulting cloudy solution was sealed and heated to 60 ℃ and stirred rapidly. After 3 days, the dark orange mixture was cooled and added to half-saturated aqueous sodium thiosulfate solution (200 ml) and shaken vigorously in a separatory funnel. The mixture was then acidified to pH < 3 with 1N HCl, extracted with EtOAc (400 ml +100 ml) and washed with brine (400 ml). The combined extracts were washed with MgSO₄Dried, filtered and evaporated to give 10b as a dark yellow oil containing some solid particles (residual starting material) which was used as such (6.37 g, 97% yield).

Step 2:

crude aminophenol 10b (6.37 g, 36.7 mmol) was dissolved in THF (100 ml) and tin powder (17.4 g, 147 mmol) was added followed by 1N HCl (220 ml, 220 mmol). The resulting mixture was stirred vigorously at room temperature. After 16 h, the reaction was cooled to 0 ℃, the acid was neutralized with 10n naoh (22 ml), and the resulting milky white suspension was vigorously stirred for 15 min. Then, the mixture is passed throughThe pad was filtered and the solid was washed well with EtOAc (4 × 200 ml). The filtrate was transferred to a separatory funnel and the aqueous phase was acidified with 1N HCl (4 ml), diluted with brine (400 ml) and the organic phase was washed with brine (400 ml). The extract was then dried over sodium sulfate, filtered, and evaporated to give aminophenol 10c as a waxy light brown solid (2.91 g, 55% yield).

And step 3:

in N₂Chloroacetyl chloride (1.94 ml, 24.3 mmol) was added to the flask under airAminophenol 10c (2.91 g, 20.3 mmol) and potassium carbonate (8.40 g, 60.8 mmol) in dry DMF (200 ml) in ice-cold mixture. After 5 minutes, the reaction was warmed to room temperature and after an additional 45 minutes, heated to 50 ℃. After 15h, the reaction was cooled and extracted with EtOAc (600 ml) and washed with water/brine (1 l), half saturated sodium bicarbonate (1 l) and brine (600 ml). The organic phase is then MgSO₄Drying, filtration and evaporation gave lactam 10d as a fibrous pale olive solid (3.15 g, 85% yield).

And 4, step 4:

bromine (1.8 ml; 35 mmol) was slowly added dropwise to a stirred solution of lactam 10d (3.15 g; 17.1 mmol) in anhydrous DCM (40 ml) at room temperature. After 3 hours, the resulting suspension was slowly added to saturated aqueous sodium thiosulfate (200 ml) and extracted with DCM (4 × 100 ml). The combined extracts were then washed with brine (200 ml) and MgSO₄Drying, filtration, and evaporation gave bromide 10e as a pale beige powder (4.00 g, 89% yield).

And 5:

a THF solution of borane (1.0M, 18.5 ml, 18.5 mmol) was added dropwise to an ice-cold solution of lactam 10e (4.00 g, 15.2 mmol) in anhydrous THF (75 ml) and the reaction was warmed to room temperature. After 30 minutes, the solution was taken up in N₂Heated to gentle reflux under gas. After 2 hours, the reaction was cooled to 0 ℃, carefully quenched with 1N NaOH (19 ml), and stirred for 15 minutes. The mixture was then diluted with water (30 ml) and THF was evaporated. The aqueous residue was then extracted with EtOAc (400 ml +50 ml) and washed with water/brine (200 ml), 0.5N NaOH (200 ml) and brine (100 ml). The combined extracts were washed with MgSO₄Drying, filtration and evaporation gave morpholine derivative 10f as a yellow slurry (3.90 g, quantitative yield).

Step 6:

anhydrous DMF (30 ml) was added toIn a flask charged with aryl bromide 10f (1.84 g, 7.42 mmol), bis (pinacolato) diborane (2.83 g, 11.1 mmol) and potassium acetate (2.47 g, 26.0 mmol), the resulting suspension was then formed by passing N₂The gas stream was bubbled through the mixture for 15 minutes to deoxygenate. 1, 1' -bis (diphenylphosphino) ferrocene (909 mg, 1.11 mmol) was then added, and the mixture was deoxygenated for another 5 minutes, followed by heating to 95 ℃. After 16 h, the dark reaction mixture was cooled, diluted with EtOAc (300 ml) and washed with 1: 1 water/brine (500 ml) and brine (200 ml). Then, the extract was extracted with MgSO₄Dried, filtered, and evaporated to a brown slurry which was chromatographed on silica gel (EtOAc/hexanes) to give the boronic ester 10g as a white solid contaminated with 0.8 equivalents of diborane reagent (1.52 g, 69% yield).

Example 11: synthesis of boronic ester fragment 11d (for preparation of 1009, 1011, 1013, 2001, 2014, 2015, 2028, 2033, 2034)

Step 1:

commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 ml) was added to a suspension of zinc powder (108 g, 1.65 mol) in AcOH (150 ml). The mixture was heated to 100 ℃ and mechanically stirred overnight. Subsequently, the mixture is passed throughFiltration (washing with EtOAc, 100 ml), dilution with PhMe (300 ml) and evaporation of the solution gave chroman intermediate 11b (8.45 g, 95% yield).

Step 2:

mixing AgNO₃(12.0 g, 70.6 mmol) with I₂(15.8 g, 62.3 mmol) were added in succession to the solution dissolved in MeOH (225 ml)11b (8.45 g, 63.0 mmol). The reaction was stirred for 1 hour atFiltered and the filtrate concentrated under reduced pressure. The crude mixture was diluted with EtOAc (250 ml) and washed with saturated sodium thiosulfate (250 ml). The organic layer was washed with water (200 ml), followed by Na₂SO₄Dried, filtered, and concentrated. The crude mixture is further passedPurification by company gave 6-iodochroman 11c (12.1 g, 74% yield).

And step 3:

6-iodo-chroman 11c (1.0 g, 3.85 mmol), bis [ pinacol]A solution of diborane (1.22 g, 4.81 mmol) and potassium acetate (1.10 g, 11.5 mmol) in DMF (36 mL) was degassed with Ar for 5 minutes and then PdCl was added₂dppf-DCM complex (314 mg, 0.38 mmol). Subsequently, the reaction mixture was degassed for a further 5 minutes and then heated to 95 ℃ for 5 hours. The reaction was then cooled to room temperature. The crude reaction mixture was diluted with water and the product was extracted with EtOAc (3 × 100 ml). The combined organic material was washed with water (100 ml) and brine (100 ml). The organic phase is then washed with MgSO₄Dried, filtered and concentrated. The crude mixture is further passedPurification by company using a gradient of EtOAc/hexanes provided borane fragment 11d (840 mg, 84% yield).

Example 12: synthesis of boronic ester fragment 12g (for preparation of 1029, 2009, 2010)

Step 1:

phenol 12a (6.75 g, 47.3 mmol) was dissolved in DMF (270 ml) and treated with allyl bromide (6.55 ml, 75.7 mmol). To this solution, NaH (60%, 4g, 99.4 mmol) was added portionwise and stirring continued overnight. The reaction mixture was diluted with EtOAc (500 ml) and washed with H₂O (3 × 500 ml) wash. The organic layer was washed with MgSO₄Drying, filtration and concentration to dryness gave the desired product 12b, which was used as such in the next step.

Step 2:

ether 12b (9.67 g) was placed in a clean microwave vial with stir bar and heated to 240 ℃ for 20 minutes at which time the Claisen rearrangement reaction was complete. The crude product 12c (9.3 g) was used in the following step without further purification.

And step 3:

to a solution of allyl intermediate 12c (9.3 g, 45.8 mmol) in anhydrous THF (300 ml) was added borane (1M in THF, 96 ml, 96 mmol) at 0 ℃. The solution was warmed to room temperature and then stirred for 2.5 hours. The solution was then cooled to 0 ℃ and treated dropwise with 10N NaOH, followed by slow addition of 30% H₂O₂(104 ml, 916 mmol). The resulting mixture was warmed to room temperature and then stirred at room temperature for 1 hour. The reaction mixture was diluted with HCl (10%, 100 ml) and extracted with EtOAc (3 × 200 ml). The combined organic phases were washed with MgSO₄Dried and concentrated. The crude product is passed throughPurification by company gave 12d (7.1 g, 77% yield).

And 4, step 4:

to a solution of diol 12d (7.1 g, 35.3 mmol) in THF (500 ml) was added PPh₃(12 g, 45.9 mmol) followed by the addition of DEAD (7.2 mL, 45.9 mmol). The solution was stirred at room temperature for 4 hours. The reaction mixture is evaporated under reduced pressure and passed throughPurification by company afforded the desired product 12e (5.26 g, 82% yield).

And 5:

chroman derivative 12e (5.26 g, 28.8 mmol) is dissolved in AcOH (70 ml) followed by Br₂AcOH solution (40 ml). The reaction was stirred at room temperature for 15 minutes, then diluted with toluene and concentrated to dryness. The residue was dissolved in EtOAc (25 ml) and saturated Na₂S₂O₃(25 mL) with saturated NaHCO₃(25 ml) wash. The organic layer was washed with MgSO₄Drying, concentrating, and passingPurification by company gave the desired product 12f (2.7 g, 36% yield).

Step 6:

bromide 12f (2.71 g, 10.4 mmol) was dissolved in DMF (120 mL) and bis [ pinacol ] was used]Diborane (4 g, 15.5 mmol) was treated with potassium acetate (3.45 g, 36.3 mmol). The mixture was degassed (using an Ar balloon) and then the catalyst (PdCl) was added₂dppf, 845 mg, 1.04 mmol). Next, the mixture was degassed again (using an Ar balloon) and heated to 95 ℃ for 16 hours. The mixture was cooled to room temperature and washed with H₂O (300 ml) was diluted and extracted with EtOAc (2 × 300 ml). The combined organic layers were washed with water (3 × 300 ml) and MgSO₄Dried, filtered, and concentrated. Then, the product is passed throughAnd (5) purifying by company. The semi-purified product was then triturated with hexane (3 × 50 ml) to remove excess diborane to afford the pure compound 12g (1.74 g, 54% yield).

Example 13: synthesis of boronic ester fragment 13a (for preparation of 1030, 1031, 1040, 2011)

Step 1:

palladium on activated carbon (10 wt% Pd, 0.63 mg, 0.59 mmol) was added to a solution of 12g (0.91 g, 2.95 mmol) of aryl chloride and ammonium formate (1.92 g, 30.4 mmol) dissolved in MeOH (10 ml) and the mixture was heated to reflux. After 15 minutes, the reaction was cooled to room temperature and passed(MeOH rinse) filtration. The filtrate was evaporated to dryness and the residue was partitioned between water and EtOAc (10 ml each). The organic layer was washed with anhydrous MgSO₄Dried and concentrated to give boronic ester 13a (0.78 g, 97% yield).

Example 14: synthesis of boronic ester fragment 14g (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

allyl bromide (9.3 ml, 110 mmol) followed by potassium carbonate (20 g, 150 mmol) is added to a solution of 14a (10 g, 73 mmol) dissolved in DMF (110 ml). The reaction was stirred at room temperature overnight under Ar. The reaction was diluted with water (400 ml) and extracted with EtOAc (400 ml). The organic layer was washed with water (2 × 400 ml) and Na₂SO₄Dried and concentrated. Then, the product is passed throughThe company was purified in two portions (120 g column) to afford allyl ether 14b (12 g, 92% yield).

Step 2:

a solution of n-BuLi in hexane (2.5M, 6.4 ml, 16 mmol) was added dropwise to a pre-cooled (-78 ℃ C.) suspension of methyltriphenylphosphonium bromide (6.6 g, 19 mmol) in THF (90 ml). The resulting bright yellow mixture was stirred at-78 ℃ for 5 minutes, warmed to room temperature over about 5 minutes, and then cooled to-78 ℃. Aldehyde 14b (2.4 g, 14 mmol) dissolved in THF (10 ml) was added dropwise and the reaction was allowed to proceed at-78 ℃ for 10 min, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with brine (100 ml), diluted with water (100 ml) and extracted with EtOAc (100 ml). The organic layer was then washed with water (2 × 100 ml) and Na₂SO₄Dried and concentrated. The crude yellow liquid was then dissolved in 1 ml EtOAc and diluted with hexane (about 20 ml) followed by Ph₃PO precipitated as a white solid. The solid was removed by filtration, washed with 1: 9 EtOAc: hexane (ca. 50 mL) and the filtrate was evaporated to dryness. Product passingPurification by company gave diene 14c (1.3 g, 54% yield).

And step 3:

grubb's second generation catalyst (50 mg, 0.075 mmol) was added to a degassed solution of diene 14c (1.3 g, 7.5 mmol). After stirring for 2.5 hours under Ar, the reaction was concentrated to SiO₂(about 2 g) of the product obtained byPurification by company gave benzopyran 14d (940 mg, 86% yield) as a clear oil.

And 4, step 4:

solid Pd-C (10% w/w, 680 mg, 0.64 mmol) was added to benzopyran 14d (940 mg, 6.4 mmol) in EtOH (8.5 mL) and the flask evacuated and treated with H₂(balloon) backfill. The reaction was stirred at room temperature for 2.5 hours, thenThe mixture was filtered (EtOAc wash) and then the filtrate was concentrated to dryness. Product passingPurification by company gave chroman 14e (800 mg, 84% yield).

And 5:

pure Br is added₂(275 μ l, 5.4 mmol) was added dropwise to a solution of chroman 14e (800 mg, 5.4 mmol) dissolved in AcOH (25 mL). The reaction was then diluted with water (50 ml) and EtOAc (50 ml). Water (2 × 50 ml) and saturated NaHCO₃The organic layer was washed (2 × 50 ml). The organic layer was washed with Na₂SO₄Dried and concentrated to dryness. Product passingPurification by company gave bromide 14f as a mixture with dibromide (1.3 g, 68 mass% 14f, 51% yield).

Step 6:

bromide 14f (950 mg, 2.8 mmol), bis [ pinacol]A solution of diborane (840 mg, 3.3 mmol) and potassium acetate (920 g, 9.6 mmol) in DMF (30 mL) was degassed with Ar for 5 minutes followed by the addition of PdCl₂dppf-DCM complex (290 mg, 0.36 mmol). The reaction mixture was then degassed for a further 5 minutes, followed by heating to 95 ℃ for 3 hours. Then, the reaction was cooled to room temperature. The crude reaction mixture was diluted with water and the product was extracted 3 times with EtOAc (3 × 20 ml). The combined organic material was washed with water (2 × 20 ml). Then, the organic phase was treated with Na₂SO₄Dried, filtered, and concentrated. The crude mixture is further passedPurification by company gave 14g of the boronic ester (403 mg, 53% yield) as a pale yellow solid.

Example 15: synthesis of Borate fragment 15l (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

an ethereal solution of diazomethane (0.7M, 100 ml) was added to a solution of 15a (5.0 g, 30 mmol) in ether (20 ml). After SM consumption (TLC monitoring), the reaction was concentrated to SiO₂(about 10 g) of the product obtained byPurification by company gave the crude ester 15b (5.2 g, 95% yield).

Step 2:

adding NaNO at 0 deg.C₂A solution of (2.1 g, 30 mmol) in water (10 ml) was slowly added to a solution of aniline 15b (5.0 g, 28 mmol) dissolved in AcOH (50 ml) and 2M HCl (75 ml). The resulting mixture was stirred at this temperature for 1 hour. Solid CuCl (8.4 g, 85 mmol) was added portionwise (over 2 min). The reaction was brought to room temperature, stirred for 30 minutes, then warmed to 60 ℃ for 40 minutes. The mixture was poured into water (200 ml) and extracted with EtOAc (2 × 200 ml). The organic layer was washed with MgSO₄Dried, filtered and evaporated to dryness. Product passingPurification by company gave the aryl chloride 15c (3.8 g, 68% yield).

And step 3:

DIBAL in DCM (1M, 42 mL, 42 mmol) was added dropwise over 25 min to the ester 15c (3.8 g, 19 mmol) in dry CH₂Cl₂(100 ml) in a pre-cooled (-78 ℃ C.) solution. The reaction was stirred at-78 ℃ for 2 hours. The reaction was terminated by dropwise addition of 1N HCl (8 mL) at-78 ℃. The reaction was warmed to room temperature and the organic phase was washed with 5% Rochelle's salt solution (100 mL) over MgSO₄Drying, filtration and concentration under reduced pressure gave crude benzyl alcohol 15d (3.2 g, 99% yield), which was used in the next step without any further purification.

And 4, step 4:

solid Dess Martin reagent (8.7 g, 20 mmol) was added to alcohol 15d in anhydrous CH₂Cl₂Pre-cooled (0 ℃) solution in (100 ml). The reaction was stirred for 2 hours while slowly warming to room temperature. At this point, another 0.5 grams of Dess Martin periodinane was added and the reaction was continued for an additional 1 hour. Addition of saturated NaHCO₃With 0.5M Na₂S₂O₃1: 1 mixture (100 ml) and the mixture is stirred vigorously until the liquid phase becomes clear (about 30 minutes). The organic phase was separated and the aqueous phase was extracted with DCM (100 ml) and saturated NaHCO₃(100 ml) washing. The combined organic phases were then over MgSO₄Dried and evaporated. Product passingPurification by company gave aldehyde 15e (2.9 g, 90% yield).

And 5:

methyl ether 15e (720 mg, 4.2 mmol) in dry CH₂Cl₂(20 ml) solution was slowly added to BBr₃(1M, 8.4 ml, 8.4 mmol) in a pre-cooled (-30 ℃ C.) solution. The solution was warmed to 0 ℃ and stirred for 3 hours. The reaction was carefully quenched with methanol (1 ml) and saturated NaHCO₃Followed by washing with brine (25 ml each). The organic layer is MgSO₄Drying, filtering, and concentrating the product byPurification by company gave phenol 15f (530 mg, 80% yield).

Step 6:

a mixture of aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 ml, 36 mmol) and DABCO (190 mg, 1.7 mmol) was refluxed for 5 hours. The reaction mixture was cooled to rt, diluted with EtOAc (50 ml), and diluted with 1N NaOH (20 ml), followed by 1N HCl (20 ml). Washing, and using MgSO 2 as organic phase₄Dried and concentrated to dryness. Product passingPurification by company gave 15g of nitrile (650 mg, 47% yield).

And 7:

a mixture of nitrile 15g (650 mg, 3.4 mmol), 10% NaOH (10 ml, 25 mmol) and EtOH (95%, 0.5 ml) was heated to reflux for 5 days. The reaction was then cooled to room temperature and 1N HCl was added until pH 4. The precipitate was then collected by filtration, washed with water, and dried in vacuo to give the acid 15h (740 mg, > 99% yield).

And 8:

triethylamine (0.56 ml, 4.0 mmol) and diphenylphosphonyl azide (0.75 ml, 3.5 mmol) were added sequentially to a solution of the acid 15h (714 mg, 3.4 mmol) in dry toluene (40 ml). The mixture was heated to 85 ℃ for 2 hours, then cooled to room temperature and treated with 6N HCl (6 ml). The mixture was brought to reflux and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (100 ml), and saturated NaHCO₃(2x100 ml), water (2x100 ml) and brine (100 ml). The organic layer was washed with MgSO₄Drying and passing throughFiltered and evaporated to dryness. Then, the product is passed throughPurification by company gave ketone 15i (269 mg, 44% yield).

And step 9:

in a sealed tube, a(0.54 mL, 2.9 mmol) was added to ketone 15i (270 mg, 1.5 mmol) in CH₂Cl₂(0.6 ml) in EtOH (17. mu.l). The sealed tube was heated to 40 ℃ for 24 hours. The tube was then opened, cooled to 0 ℃ and quenched by slow addition of saturated NaHCO₃(1 ml) (exothermic) the reaction was terminated. The crude reaction mixture was diluted with water (20 ml) and extracted with DCM (3 × 20 ml). The combined organic material was washed with water (20 ml) and the organic phase was MgSO₄Dried, filtered, and concentrated. Product passingPurification by company gave difluorochroman 15j (225 mg, 71% yield).

Step 10:

solid silver nitrate (187 mg, 1.1 mmol) and iodine (279 mg, 1.1 mmol) were added sequentially to a solution of difluorochroman 15j (225 mg, 1.1 mmol) dissolved in MeOH (7.8 ml). The reaction was stirred at room temperature for 90 minutes and then passedThe pad is filtered. The filtrate was washed with one drop of 0.5N Na₂S₂O₃Treated (orange dissipate) and then concentrated under reduced pressure. Adding the residue to H₂O、0.5N Na₂S₂O₃And EtOAc (20 ml each). The aqueous layer was extracted with EtOAc (3 × 20 ml) and the combined organics were extracted with brine (20 mm)Liter) washing with MgSO 2₄Dried, filtered, and concentrated. Product passingPurification by company gave aryl iodide 15k (158 mg, 44% yield).

Step 11:

aryl iodide 15k (150 mg, 0.45 mmol), bis [ pinacol]A solution of diborane (150 mg, 0.59 mmol) and potassium acetate (130 mg, 1.4 mmol) in DMF (5 mL) was degassed with Ar for 5 minutes followed by the addition of PdCl₂dppf-DCM complex (44 mg, 0.054 mmol). The reaction mixture was then degassed for a further 5 minutes, followed by heating to 85 ℃ for 9 hours. Then, the reaction was cooled to room temperature. The crude reaction mixture was diluted with water and the product was extracted with EtOAc (3 × 10 ml). The combined organic material was washed with water (10 ml) and brine (10 ml). The organic phase is then MgSO₄Dried, filtered, and concentrated. The crude mixture is further passedPurification by company gave 15l of boronic ester (123 mg, 70% pure by NMR, 57% yield).

Example 16: synthesis of Borate fragment 16c (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

mixing solid NaBH₄(342 mg, 9.0 mmol) was added to a solution of ketone 4b (1.5 g, 7.5 mmol) dissolved in MeOH (10 ml) followed by addition of THF (25 ml) at 0 ℃. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched with aqueous HCl (1N, 5 ml), MeOH was removed by concentration,and the product extracted with EtOAc (2 × 50 ml). The organic layer was washed with brine (50 ml) and Na₂SO₄Drying, filtration, and concentration gave alcohol 16a (1.52 g, > 99% yield). This material was used as such in the next step.

Step 2:

TFA (2.9 mL) was added dropwise to the crude alcohol 16a (1.5 g; 7.47 mmol) in CH at 0 deg.C₂Cl₂(28 ml) in solution. The solution was stirred for 30 minutes and then concentrated to dryness. The residue was dissolved in EtOAc and washed with NaHCO₃(saturated), washed with brine, and Na₂SO₄Dried, filtered, and concentrated to a pale yellow gum. Product passingPurification by company gave benzofuran 16b (0.30 g, 22% yield) as a white solid.

And step 3:

compound 16c was prepared from 16b following the same synthetic sequence as steps 3 to 5 of example 4.

Example 17: synthesis of boronic ester fragment 17g (for preparation of 2016, 2017)

Step 1:

zn powder (7.89 g, 121 mmol) was added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 ml). The reaction mixture was then heated to 100 ℃ and stirred overnight. The reaction was cooled to room temperature and the mixture was filtered (EtOAc wash), the solvent was evaporated and the residue was passed throughPurification by company gave aniline 17b (3.06 g, 72% yield) as a yellow solid。

Step 2:

adding NaNO at 0 deg.C₂A solution of (640 mg, 9.3 mmol) in water (3 ml) was slowly added to a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 ml) and 2M HCl (25 ml). The resulting mixture was stirred at this temperature for 1 hour. Solid CuCl (2.6 g, 26 mmol) was added portionwise (over 2 min) and the reaction was brought to room temperature followed by stirring for 30 min, then warming to 60 ℃ for 40 min. The mixture was poured into water (100 ml) and extracted with EtOAc (2 × 100 ml). The organic layer was washed with MgSO₄Dried, filtered and evaporated to dryness. Product passingPurification by company gave the aryl chloride 17c (1.11 g, 99% yield) as a light yellow solid.

And step 3:

solid preactivated Zn powder was added to a solution of ketone 17c in AcOH. The reaction mixture was then heated to 100 ℃ and stirred at this temperature for 4 hours. The reaction mixture was filtered (EtOAc wash), the filtrate was evaporated to dryness and the product was passed throughPurification by company gave indane 17d (902 mg, 88% yield) as a white crystalline solid.

And 4, step 4:

will BBr₃To a pre-cooled (-78 ℃) solution of methyl ether 17d (902 mg, 4.9 mmol) dissolved in DCM (20 ml) was added dropwise a solution of DCM (1M, 9.9 ml, 9.9 mmol). The reaction solution was stirred at this temperature for 10 minutes and allowed to warm to room temperature. After stirring for 1.5 h, water (50 ml) (exothermic) was added and the mixture was extracted with DCM (3 × 50 ml). The combined organic layers were washed with MgSO₄Dried, filtered and evaporated to dryness. Product passingPurification by company gave phenol 17e (700 mg, 84% yield) as an off-white solid.

And 5:

will Tf₂O (1.05 mL, 12 mmol) was added to phenol 17e (700 mg, 4.1 mmol) and Et₃N (1.7 ml, 12 mmol) in DCM (20 ml) in a pre-cooled (0 ℃). The resulting dark solution was warmed to room temperature. After 25 minutes, saturated NaHCO was used₃(10 mL) the reaction was quenched, diluted with DCM, and the organic layer was washed with water, brine, MgSO₄Dried and evaporated to dryness. Product passingPurification by company gave triflate 17f (1.21 g, 97% yield) as a yellow oil.

Step 6:

triflate 17f (1.2 g, 4.0 mmol), bis [ pinacol]A solution of diborane (1.5 g, 6.0 mmol) and potassium acetate (1.3 g, 14 mmol) in DMF (20 mL) was degassed with Ar for 5 minutes followed by the addition of PdCl₂dppf-DCM complex (490 mg, 0.60 mmol). The reaction mixture was then degassed for a further 5 minutes, followed by heating to 95 ℃ for 5 hours. Then, the reaction was cooled to room temperature. The crude reaction mixture was diluted with water and the product was extracted with EtOAc (3 × 100 ml). The combined organic material was washed with water (100 ml) and brine (100 ml). The organic phase is then MgSO₄Dried, filtered and concentrated. The crude mixture is further passedPurification by company gave 17g (593 mg, 53% yield) of the boronic ester as a pale yellow solid.

Example 18: synthesis of Borate fragment 18d (for preparation of 1033)

Step 1:

will be pure Tf₂O (0.83 ml, 4.9 mmol) is added dropwise to a cooled (0 ℃) solution of phenol 18a (0.50 g, 3.1 mmol) and pyridine (1.3 ml, 17 mmol) in DCM (15 ml). The reaction was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of 10% citric acid solution (50 ml) and the mixture was extracted with DCM (3 × 50 ml). The combined organic material was washed with water (50 ml) and MgSO₄Dried, filtered, and concentrated. Product passingPurification by company gave triflate 18b (500 mg, 94% yield).

Step 2:

in a sealable test tube, will(0.83 ml, 4.2 mmol), followed by EtOH (10 μ l, 0.2 mmol) was added to pure triflate 18b (500 mg, 1.7 mmol). The tube was sealed and the reaction was heated in an oil bath at 85 ℃ and stirred overnight. The reaction was then cooled to 0 ℃ and quenched by slow addition of NaHCO₃(100. mu.l, exothermic) the reaction was terminated. The mixture was diluted with water (50 ml) and extracted with DCM (3 × 50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The organic phase is then MgSO₄Dried, filtered, and concentrated. The crude product is passed throughPurification by company gave difluoromethane sulfonate tetrahydronaphthyl ester 18c (175 mg, 33% yield).

And step 3:

step 3 was performed exactly as in step 6 of example 17 to give boronic ester 18 d.

Example 19: synthesis of boronic ester fragment 19d (for preparation of 1063, 1064, 2044, 2045)

Step 1:

over 5 minutes, solid N-chlorosuccinimide (2.2 g, 16 mmol) was added portionwise to the solution which had been dissolved in CCl₄(150 ml) of naphthylamine 19a (2.3 g, 16 mmol). The reaction was then heated to 50 ℃ and stirred for 40 minutes. The reaction was then cooled to room temperature, the solids removed by filtration, and the filtrate washed with water (100 ml), over MgSO₄Dried and evaporated to dryness to give chloroaniline 19b (2.8 g, 96% yield).

Step 2:

adding NaNO₂A solution of (1.2 g, 17 mmol) in water (5 ml) was slowly added to a pre-cooled (0 ℃) suspension of aniline 19b (2.8 g, 15 mmol) in 12N HCl (7 ml) and ice (9.7 g) to maintain the temperature below 5 ℃. The mixture was stirred for 15 minutes, then transferred to a solution of KI (8.7 g, 52 mmol) in water (30 ml) and the resulting mixture was stirred for 2 hours. With Et₂The mixture was O (3X100 mL) extracted and the combined organic layers were successively washed with 3N NaOH (2X50 mL), 5% NaHSO₃(50 ml) and brine (100 ml). The organic phase was washed with MgSO₄Dried, filtered, and concentrated to dryness. The crude product was purified by flash chromatography (EtOAc/hexanes) to give aryl iodide 19c (2.4 g, 54% yield).

And step 3:

step 3 was performed exactly as described in example 15, step 11 to give boronic ester 19 d.

Example 20: synthesis of Borate fragment 20d (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

allyl bromide (2.1 ml, 25 mmol), followed by potassium carbonate (7.2 g, 52 mmol) is added to a solution of 6-chlororesorcinol 20a (10 g, 69 mmol) dissolved in DMF (120 ml). The reaction was stirred overnight, diluted with EtOAc (500 ml) and washed with water (3 × 500 ml). The organic layer was washed with MgSO₄Dried and concentrated to dryness. The crude product is passed throughPurification by company gave allyl ether 20b (1.8 g, 40% yield).

Step 2:

methyl iodide (1.2 ml, 20 mmol) followed by potassium carbonate (3.8 g, 27 mmol) was added to a solution of phenol 20b (1.8 g, 9.8 mmol) dissolved in DMF (12 ml). The reaction was stirred for 2 h, diluted with EtOAc (50 ml) and washed with water (3 × 50 ml). The organic layer was washed with MgSO₄Dried and concentrated to dryness. The crude product is passed throughPurification by company gave methyl ether 20c (1.8 g, 40% yield).

And step 3:

step 3 comprises the same sequence of steps 2 through 6 as example 12, followed by step 1 of example 13 to provide boronic ester 20 d.

Example 21: synthesis of boronic ester fragment 21g (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

adding solid CuBr₂(7.9 g; 35 mmol) was added to the solution dissolved in EtOAc (32 mL) and CHCl₃(32 ml) of 21a (4.0 g, 23 mmol). The mixture was heated to reflux and stirred for 8 hours. Then adding CuBr₂(3.9 g) and the mixture was stirred under reflux for a further 15 hours. The mixture was cooled to rt and the solid was removed by filtration (EtOAc washing). The filtrate was concentrated to give crude bromoketone 21b (6.3 g), which was used directly in the next step.

Step 2:

solid KF (2.5 g, 43 mmol) was added to a solution of crude bromoketone 21b (6.3 g, 23 mmol) dissolved in DMF (21 ml). The reaction was stirred at room temperature for 3 hours, then dissolved in ether (300 ml), washed with brine (3 × 100 ml), and MgSO₄Dried, filtered, and concentrated to dryness. The crude product is passed throughPurification by company gave ether 21c (2.1 g, 49% yield, two steps).

And step 3:

mixing solid NaBH₄(270 mg, 7.1 mmol) was added to a pre-cooled (0 ℃ C.) solution of ketone 21c (1.0 g, 5.9 mmol) dissolved in MeOH (20 mL). The reaction was stirred for 1 hour, then quenched with aqueous HCl (1N, 1 ml). The volatiles were removed in vacuo and the product was extracted with EtOAc (1 × 20 ml). The organic layer was washed with brine (20 ml) and dried (Na)₂SO₄) Filtered and concentrated to give crude alcohol 21d (1.0 g), which was used directly in the next step.

And 4, step 4:

mixing solid AgNO₃(1.0 g, 6.1 mmol) followed by I₂(1.6 g, 6.2 mmol) was added to a solution of alcohol 21d (1.0 g, 6.2 mmol) dissolved in MeOH (58 ml). The mixture was stirred at room temperature for 1 hour, then Na was added₂S₂O₄Solution (0.5M, 10 ml) and the mixture was stirred for 30 minutes. MeOH was removed in vacuo and the residue was dissolved in EtOAc (50 ml), washed with water (1x50 ml), brine (1x50 ml), dried (Na)₂SO₄) Filtered and concentrated to give the aryl iodide 21e (1.6 g), which was used directly in the next step.

And 5:

crude alcohol 21e (1.6 g,. about.5 mmol) was dissolved in a mixture of DCM (20 ml) and TFA (2.2 ml). The reaction was stirred for 45 minutes and then concentrated to dryness. The residue was dissolved in EtOAc (50 ml) and saturated NaHCO₃(50 ml) washed with brine (50 ml). The organic layer was washed with Na₂SO₄Dried, filtered, and concentrated to dryness. The crude product is passed throughPurification by company gave benzofuran 21f (978 mg, 65% yield, 3 steps).

Step 6:

step 6 was performed exactly as described for example 15, step 11 to give 21g of the boronic ester.

Example 22: synthesis of Borate fragment 22d (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

pure 3-bromo-2-methylpropene (1.7 ml, 16 mmol) was added to a suspension of phenol 22a (3.0 g, 14 mmol) and potassium carbonate (5.6 g, 41 mmol) in DMF (35 ml). The reaction was stirred for 2 hours, then quenched with water (100 ml) and extracted with hexane (2 × 100 ml). The organic phase was washed with brine (2 × 100 ml) and concentrated to give ether 22b (3.3 g, 87% yield).

Step 2:

pure tributyltin hydride (2.3 ml, 8.8 mmol) was added to a solution of aryl iodide 22b (2.0 g, 7.3 mmol) and AIBN (120 mg, 0.73 mmol) in PhMe (40 ml) and the reaction was then brought to reflux and N₂Stirring the mixture. After 1 hour, the reaction was concentrated to dryness and the crude product was passed throughPurification by company gave dihydrobenzofuran 22c (785 mg, 73% yield).

And step 3:

step 3 comprises the same sequence of synthetic steps as steps 10 and 11 of example 15 to give boronic ester 22 d.

Example 23: synthesis of boronic ester fragment 23c (for preparation of 1025, 1026, 2005, 2006)

Step 1:

under Ar gas, pure Tf₂O (0.56 ml, 3.3 mmol) is added dropwise to a cooled (0 ℃ C.) solution of phenol 23a (350 mg, 2.1 mmol; prepared according to Doi et al, Bull. chem. Soc. Jpn.200477, 2257-2263) and pyridine (0.91 ml, 11 mmol) in DCM (10 ml). The reaction was warmed to room temperature and then stirred for 2 hours. The reaction was quenched by the addition of 10% citric acid solution (20 ml) and extracted with DCM (3 × 20 ml). The combined organic layers are washed withWashed with water (20 ml) and MgSO₄Dried, filtered, and concentrated to dryness. The crude product is passed throughPurification by company gave triflate 23b (512 mg, 82% yield).

Step 2:

triflate 23b (510 mg, 1.7 mmol), bis [ pinacol ] was added]A solution of diborane (560 mg, 2.2 mmol) and potassium acetate (500 mg, 5.1 mmol) in DMF (18 mL) was degassed with Ar for 5 minutes followed by the addition of PdCl₂dppf-DCM complex (140 mg, 0.17 mmol). The reaction mixture was then degassed for a further 5 minutes, and subsequently heated to 100 ℃ by microwave radiation for 10 minutes. Then, the reaction was cooled to room temperature. The crude reaction mixture was diluted with EtOAc (60 ml) and washed with brine (3 × 60 ml). The organic layer was washed with MgSO₄Dried, filtered and concentrated. The crude mixture is further passedPurification by company gave boronic ester 23c (200 mg, 42% yield).

Example 24: synthesis of Borate fragment 24b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 24b was prepared from 24a following the same synthetic sequence as steps 1 to 6 of example 12.

Example 25: synthesis of Borate fragment 25b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 25b was prepared from 25a following the same synthetic sequence as steps 1 to 6 of example 12.

Example 26: synthesis of boronic ester fragment 26b (for preparation of 1049, 1050)

Step 1:

compound 26b was prepared from 26a following the same synthetic sequence as steps 1 to 6 of example 12.

Example 27: synthesis of boronic ester fragment 27b (for preparation of 1023, 1024)

Step 1:

compound 27b was prepared from 27a following the same synthetic sequence as steps 1 to 6 of example 14.

Example 28: synthesis of Borate fragment 28b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 28b was prepared from 28a following the same synthetic sequence as steps 1 to 8 of example 6.

Example 29: synthesis of Borate fragment 29b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 29b was prepared from 29a following the same synthetic sequence as steps 1 to 6 of example 14.

Example 30: synthesis of Borate fragment 30b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 30b was prepared from 30a following the same synthetic sequence as steps 2 and 3 of example 18.

Example 31: synthesis of Borate fragment 31b (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

compound 31b was prepared from 31a following the same synthetic sequence as example 15, steps 9 to 11.

Example 32: synthesis of boronic ester fragment 32b (for preparation of 1020)

Step 1:

compound 32b was prepared from 32a following the same synthetic sequence as steps 5 to 6 of example 17.

Example 33: synthesis of boronic ester fragment 33b (for preparation of 1021)

Step 1:

compound 33b was prepared from 33a following the same synthetic sequence as steps 1 and 3 of example 11.

Example 34: synthesis of Borate fragment 34f (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

benzyl bromide (25 ml, 210 mmol) followed by potassium carbonate (44 g, 320 mmol) was added to a solution of 2-methylresorcinol 34a (38 g, 310 mmol) dissolved in DMF (1 l). The reaction was stirred overnight, diluted with EtOAc (2 l) and washed with water (3 × 2 l). The organic layer was washed with Na₂SO₄Dried and concentrated to dryness. The crude product is passed throughPurification by company gave benzyl ether 34b (18.6 g, 39% yield).

Step 2:

allyl bromide (3.0 ml, 35 mmol) followed by potassium carbonate (6.5 g, 47 mmol) was addedTo a solution of phenol 34b (5 g, 23 mmol) dissolved in DMF (100 ml). The reaction was stirred overnight, diluted with EtOAc (500 ml) and washed with water (3 × 500 ml). The organic layer was washed with Na₂SO₄Dried and concentrated to dryness. The crude product is passed throughPurification by company gave benzyl ether 34c (4.4 g, 75% yield).

And step 3:

compound 34d was prepared from 34c following the same synthetic sequence as steps 2 through 4 of example 12.

And 4, step 4:

benzyl ether 34d was mixed with Pd-C (10% w/w, 100 mg, 0.094 mmol) in EtOAc (5 mL) and the flask was evacuated and charged with H₂And (5) backfilling with air (balloon). After stirring for 3 hours, the reaction was passedFiltration (EtOAc wash) and concentration of the filtrate yielded phenol 34e (145 mg, 95% yield).

And 5:

compound 34f was prepared from 34e following the same synthetic sequence as steps 5 to 6 of example 17.

Example 35: synthesis of Borate fragment 35e (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Steps 1 to 4 were carried out analogously to steps 3 to 6 of example 17.

Example 36: synthesis of Borate fragment 36d (for preparation of 1034, 1035, 2018, 2022)

Step 1:

4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) was dissolved in ethyl acetate (50 ml) and solid tin (II) chloride dihydrate (20.0 g, 86.9 mmol) was added. The mixture was heated under nitrogen at 70 ℃ for 2 hours (note: temporary superheating to 100 ℃ C. was found). The mixture was cooled down and poured into ice water (200 ml). Add 5% NaHCO₃Aqueous (50 ml) solution (quick bubble) followed by the addition of 10N aqueous NaOH to give pH 7-8. A large amount of a gummy yellowish precipitate formed. The heterogeneous mixture was shaken with EtOAc (200 ml) and the mixture was centrifuged in portions of 50 ml resulting in good separation of a pale yellow solid. The clear supernatant was decanted and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange oily residue. The residue was redissolved in 100 ml of ether and the solution was taken up in 10% Na₂CO₃(20 ml) and then washed with 2.5M aqueous NaOH (20 ml). Next, the dark brown organic solution was mixed with MgSO₄Stirred with activated carbon and filtered to give a pale yellow solution which darkened rapidly on standing in an open flask. The solvent was removed in vacuo to afford the desired compound 36b as a brownish red oil, which was used in the next step without further purification (3.31 g, 78% yield).

Step 2:

a mixture of compound 36b (3.3 g, 17.7 mmol), glycerol (3.3 g, 35.5 mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10 ml, 138 mmol) was stirred at 150 ℃ for 3 hours (the mixture turned black and viscous). The reaction mixture was cooled down, poured into ice water (200 ml) and aqueous 10N NaOH (30 ml, 300 mmol) was added. Then, mixing the black mixture withEtOAc (100 ml) was shaken together and centrifuged with several 50 ml portions. The upper EtOAc layers were combined and the bottom aqueous layer containing black tar was shaken with EtOAc and centrifuged. Combine all EtOAc extracts, wash with brine, and wash with Na₂SO₄Dried, filtered, and concentrated in vacuo to give 4.8 g of a brownish red oil. Chromatography of this material on a 80 g silica gel column (Company apparatus, hexanes/EtOAc gradient). The fractions containing compound were concentrated in vacuo to afford compound 36c as a white solid (3.26 g, 83% yield).

And step 3:

in compound 36c (500 mg, 2.25 mmol) in anhydrous Et₂To a cooled (-78 ℃ C.) solution in O (20 mL) was added a 1.6M solution of n-BuLi in hexane (3.5 mL, 5.60 mmol) over 5 minutes under Ar atmosphere. The mixture was stirred at-78 ℃ for 50 minutes, then triisopropyl borate (2.00 ml, 8.55 mmol) was added dropwise and the mixture was stirred at this temperature for about 2 hours. The mixture was slowly brought to room temperature over 2 hours and poured into 1M aqueous HCl (30 ml). The mixture was transferred to a separatory funnel, the organic layer was separated, and Et was used₂O wash the aqueous layer. The aqueous layer was then transferred to a 500 ml conical flask and purified by slowly adding NaHCO₃Saturated solution in water (-25 ml, caution: bubbling) the pH of the solution was adjusted to about 6.3 (measured as pH). The suspension is filtered off and the separated pale beige solid is washed with water and dried under high vacuum. The crude product (383 mg) was taken up in Et₂Trituration with O/hexane afforded the first desired compound 36d as the free base (120 mg, 28% yield). The mother liquor was concentrated in vacuo and subjected to reverse phase HPLC using CH with 0.06% TFA₃CN/H₂O gradient purification (ODS-AQ, C-18 column, 75X30 mm, 5 μm particle size). After lyophilization, a second crop of compound 36d was obtained as the TFA salt (102 mg, 15% yield) (total yield: 43%).

Example 37: synthesis of Borate fragment 37d (for preparation of 1036, 2019, 2023)

Step 1:

1-bromo-4-chloro-2-nitrobenzene 37a is converted to compound 37b using the method of example 36b, except Et is used₂O instead of EtOAc for extraction.

Step 2:

in a 100 ml round bottom flask with a stir bar, compound 37b (4.2 g, 20.3 mmol) was melted at 50 ℃ and immersed in an oil bath. A solution of zinc chloride (700 mg, 5.03 mmol) and ferric chloride (540 mg, 3.25 mmol) in 3.3 ml of water was added in one portion followed by 20 ml of anhydrous EtOH. The flask was plugged with a rubber stopper and a needle was inserted to avoid any pressure build-up. The mixture was warmed to 80 ℃ and acrolein (1.68 ml, 24.4 mmol) was added via syringe pump over 2 hours. After addition, the mixture was stirred at 80 ℃ for 1 hour and an additional amount of solid ferric chloride (4.1 g, 25.3 mmol) was added. The mixture was stirred at 80 ℃ for about 24 hours and then concentrated under vacuum to give a semi-solid residue. 200 ml of water were added, followed by 10N aqueous NaOH (20 ml) and 200 ml of DCM. After shaking the mixture for a few minutesThe solid was filtered over a pad and the filtrate was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give 3.69 g of a brown solid. Subjecting the solid to hot CH₃Triturated in CN and filtered. The solid was discarded and the filtrate was concentrated in vacuo to give 2.3 g of a brown semi-solid. The substance is inOn a company unit, on a 40 g silica gel column, eluting with a gradient of EtOAc/hexane. After evaporation of the solvent under vacuum, the desired compound 37c was isolated as a yellow solid (390 mg, 8% yield).

And step 3:

compound 37c was converted to compound 37d using the procedure of example 36 d.

Example 38: synthesis of Borate fragment 38c (which can be coupled to a thienopyridine backbone to give the compounds of the invention)

Step 1:

2-Bromophenylamine 38a is converted to compound 39b using the method of example 37c, except that methyl vinyl ketone is used instead of acrolein.

Step 2:

compound 38b was converted to compound 38c using the procedure of example 36 d.

Example 39: synthesis of boronic ester fragment 39k (for preparation of 1059, 1060, 2035, 2036)

Reference: feliu, l.; ajana, w.; alvarez, m.; joule, j.a. tetrahedron 1997, 53, 4511.

Step 1:

meldrum's acid 39b (47.04 g, 326 mmol) was dissolved in trimethyl orthoformate (360 ml) and refluxed for 2 hours. 2, 5-dimethoxyaniline 39a (50 g, 326 mmol) was then added and the mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and, while cooling, the solid formed was collected by filtration. It was further crystallized from MeOH to give compound 39c as a yellow solid (63 g, 63% yield).

Step 2:

compound 39c (62.00 g, 202 mmol) was dissolved in diphenyl ether (310 ml) and refluxed at 240 ℃ for 30 min. The mixture was then cooled to room temperature and n-hexane was added, which caused a brown precipitate to form. This solid was isolated by filtration and washed with n-pentane and n-hexane to remove non-polar impurities and the remaining dark brown solid (compound 39d) was used as such in the next step (27 g, 65% yield).

And step 3:

a mixture of compound 39d (30.0 g, 146 mmol), DMAP (3.75 g, 30.7 mmol) and 2, 6-lutidine (24.4 mL; 208 mmol) in DCM (1.4L) was cooled to 0 deg.C and Tf was slowly added at 0 deg.C₂O (29.6 ml, 175 mmol). The resulting mixture was stirred at 0 ℃ for 2 hours and at room temperature for 1 hour. Then, it is treated with CH₂Cl₂Diluting with H₂O was washed with brine and dried (Na)₂SO₄). The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (20% EtOAc/petroleum ether). The desired compound 39e was isolated as a yellow solid (35 g, 70% yield).

And 4, step 4:

a mixture of diisopropylethylamine (46.5 ml, 267 mmol) in anhydrous DMF (250 ml) was degassed with argon for 30 min and added to a mixture of compound 39e (30.0 g, 89.0 mmol), triphenylphosphine (7.70 g, 29.4 mmol), tris (dibenzylideneacetone) bis-palladium (0) -chloroform adduct (9.21 g, 8.9 mmol). The resulting mixture was stirred at 0 ℃ for 5 minutes and TMS-acetylene (13.4 g, 136 mmol) was added dropwise. The temperature was raised to room temperature and the mixture was stirred for 4 hours. Ether and water were added, and the aqueous layer was separated and washed with ether. The combined organic layers were washed with H₂The O was washed with brine. With Na₂SO₄After drying, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (30% EtOAc/petroleum ether). Compound 39f was isolated as a yellow solid (18 g, 70% yield).

And 5:

cerium ammonium nitrate (42.3 g, 77.2 mmol) in H under argon₂A solution in O (47 ml) was added to a solution of compound 39f (11.0 g, 38.3 mmol) in acetonitrile (366 ml). The reaction mixture was degassed with argon for 10 minutes and the mixture was stirred at room temperature for 20 minutes. Then water is added and CH is used₂Cl₂And (4) extracting the solution. Combining the organic extracts with H₂O, brine wash, and dry (Na)₂SO₄). The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (40% EtOAc/petroleum ether). The desired compound, 39g, was isolated as a yellow solid (5.0 g, 52% yield).

Step 6:

compound 39g (1.80 g, 7.1 mmol) was dissolved in distilled acetic acid (72 ml) under argon. Ammonium chloride (7.55 g, 141 mmol) was added and the reaction refluxed for 45 min. The reaction mixture was cooled to room temperature and H was added₂O, and the solution was washed with EtOAc. With saturated NaHCO₃The aqueous layer was neutralized and extracted with EtOAc. The combined organic extracts are washed with H₂O, brine wash, and dry (Na)₂SO₄). Removal of the solvent under reduced pressure gave compound 39h as a brown solid (250 mg, 20% yield).

And 7:

compound 39h (230 mg, 1.24 mmol) was dissolved in anhydrous EtOH (11 ml) and 10% palladium on carbon (46 mg) was added under nitrogen. The mixture was stirred under hydrogen at one atmosphere for 15 hours. The reaction is degassed with nitrogen and passedFiltering, and mixingPad with EtOH-CHCl₃The mixture is washed. Removal of the solvent under reduced pressure gave compound 39i as a brown viscous solid (200 mg, 86% yield).

And 8:

compound 39i (600 mg, 3.21 mmol) was dissolved in anhydrous CH under nitrogen₂Cl₂(30 ml). The solution was cooled to 0 ℃ and triethylamine (0.89 ml, 6.42 mmol) was added dropwise followed by Tf₂O (0.65 ml, 3.87 mmol). The temperature was raised to room temperature and the reaction mixture was stirred for 2 hours. By CH₂Cl₂Diluting the mixture with H₂O, brine wash, and dry (Na)₂SO₄). The solvent was removed under reduced pressure to give a residue which was purified by flash chromatography (10% EtOAc/hexanes). Compound 39j was isolated as a brown solid (630 mg, 61% yield).

And step 9:

in a 5 ml glass microwave vessel dried (oven dried for 30 minutes) with a magnetic stir bar, compound 39j (250 mg, 0.078 mmol), bis (pinacolato) diborane (250 mg, 0.098 mmol), anhydrous potassium acetate (150 mg, 1.51 mmol), Pd (PCy) were added₃)₂(62.0 mg, 0.091 mmol) and anhydrous deoxygenated (argon bubbling for 30 min) 1, 4-dioxane (4 ml). The vial was capped tightly with a rubber stopper and the container was flushed with argon. The mixture was stirred at 95 ℃ (oil bath temperature) under argon for 16 hours. The reaction mixture was then concentrated in vacuo and the brown oily residue was dissolved in 7 ml of glacial AcOH and filtered through a 45 μm membrane filter. The dark brown solution was divided into several 5X 1.5 ml portions and injected into an automated preparative reverse phase HPLC-MS apparatus (CH)₃CN/H₂O gradient containing 0.06% TFA, ODS-AQ, C-18 column50x19 mm, 5 micron particle size). The combined fractions were lyophilized to give the desired compound 39k as a yellow amorphous solid (115 mg, 45% yield for TFA salt).

Example 40: synthesis of compounds 1030 and 1031

In a microwavable container, the thienopyridine backbone 1A (69 mg, 0.16 mmol), potassium carbonate (66 mg, 0.47 mmol), and the borate ester 13a (52 mg, 0.19 mmol) in DMF (2.2 ml) and water (0.22 ml) were added. To this mixture, the catalyst Pd (PPh) was added₃)₄(18.3 mg, 0.02 mmol), and then the vessel was sealed and heated at 120 ℃ for 8 minutes. The cooled reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, over anhydrous MgSO₄Dried, filtered, and concentrated to dryness. Adsorbing the crude material to SiO₂Purified by Combi-flash (EtOAc/hexanes) to give a mixture of atropisomers (62.4 mg, 0.14 mmol, 87% yield). To a solution of this mixture (62.4 mg, 0.14 mmol) in THF (3 ml) and MeOH (2 ml) was added aqueous LiOH (1N solution, 0.69 mmol) at room temperature. The reaction was heated to 50 ℃ for 4 hours. The mixture was quenched by addition of AcOH and then concentrated in vacuo. The two compounds (1030 and 1031) were separated by preparative reverse phase HPLC followed by lyophilization to give inhibitor 1031(12.9 mg, 21% yield) and 1030(1.7 mg, 3% yield) as white solids.

Example 41: synthesis of Compounds 1053 and 1054

Mixing N, N-dimethyl methylAmide (10 ml) and distilled water (2.0 ml) were added to each of borate 9b (614 mg; 2.26 mmol), thienopyridine skeleton 1a (700 mg; 1.61 mmol), potassium carbonate (669 mg; 4.84 mmol) and Pd (PPh)₃)₄(280 mg; 0.243 mmol) in a microwave vial, the vial is then sealed and heated in a microwave reactor (10 min, 140 ℃). The resulting mixture was cooled and extracted with EtOAc (200 ml) and washed with half-saturated aqueous sodium bicarbonate (200 ml) and brine (200 ml). Extracting with anhydrous MgSO₄Dried, filtered and evaporated to a red slurry which was chromatographed on silica gel (EtOAc/hexane) to give a mixture of atropisomeric esters 41a and 41b (504 mg; 69% yield) as a light yellow amorphous solid. Some of this mixture (120 mg; 0.266 mmol) was dissolved in THF (3.0 ml) and MeOH (1.5 ml), 1.0n naoh solution (1.0 ml; 1.0 mmol) was added, and then the reaction was heated to 50 ℃. After 16 h, the reaction was cooled, acidified to pH-5 using 1.0N HCl, and extracted with DCM. The extract was washed with MgSO₄Dried, filtered and evaporated. The residue was purified by reverse phase preparative HPLC and lyophilized to give the final compounds 1053(26 mg; 46% yield) and 1054(11 mg; 19% yield) as light yellow powders.

Example 42: synthesis of alkyne 42a

Step 1:

solid Pd (PPh)₃)₄(444 mg, 0.385 mmol) and CuI (146 mg, 0.769 mmol) are added successively to a solution of 11c (10 g, 34 mmol) and alkyne 3c (11 g, 55 mmol) dissolved in DMF (23 ml) and diethylamine (115 ml). The reaction mixture was stirred at rt overnight, then concentrated, diluted with EtOAc (300 ml) and washed successively with brine, 1N aqueous HCl and water (300 ml each). The organic layer was washed with Na₂SO₄Drying and passing the residue throughPurification by company yielded alkyne 42a (10.8 g, 84% yield).

Example 43: synthesis of Compound 2028

Step 1:

LiBH in THF₄(2M, 8.7 ml, 17 mmol) was added to a solution of 43a (379 mg, 1.78 mmol) dissolved in THF (7.6 ml) and the reaction was stirred at rt. After 3h, the excess was quenched with HCl (slowly added (note, bubbling), 10 ml) and the mixture was partitioned between brine (50 ml) and EtOAc (50 ml). The aqueous layer was washed with EtOAc (2 × 50 ml) and the combined organic layers were washed with Na₂SO₄Dried and concentrated. The residue is passed throughPurification by company gave alcohol 43b (164 mg, 50% yield).

Step 2:

solid Dess-Martin periodinane (434 mg, 1.03 mmol) was added to a solution of alcohol 43b (145 mg, 0.78 mmol) dissolved in DCM (6 ml). After stirring for 20 minutes, 20 ml of saturated NaHCO were used₃With saturated NaS₂O₃The reaction was terminated with the 1: 1 mixture, and then the mixture was stirred for about 15 minutes (until both liquid phases were clear). The mixture was extracted with EtOAc (2 × 50 ml) and the organic layer was taken over Na₂SO₄Drying and concentration gave aldehyde 43c (125 mg, 87% yield).

And step 3:

phenylmagnesium bromide (1M, 1.3 ml, 1.3 mmol) is added dropwise to a solution of aldehyde 43c (125 mg, 0.68 mmol) dissolved in THF (12 ml) at room temperature. After 5 min, the reaction was quenched by addition of HCl (1 ml, 10%) and water (50 ml) and extracted with EtOAc (3 × 50 ml). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give alcohol 43d (180 mg, quantitative yield).

And 4, step 4:

zn powder (875 mg, 13.4 mmol) was added to a solution of alcohol 43d (140 mg, 0.54 mmol) dissolved in AcOH (2.1 ml) and the reaction was sealed in a Schlenck tube, heated to 100 ℃ and stirred vigorously at this temperature. After stirring overnight, the reaction was filtered, cooled to room temperature and filteredFiltration (AcOH wash), dilution with 4 volumes of PhMe and evaporation to dryness. The residue is passed throughPurification by company gave thiophene 43e (69 mg, 53% yield).

And 5:

at-78 ℃ over 1 min, Tf was added₂O (52 μ l, 0.31 mmol) was added by syringe to a stirred mixture of amide 43e (69 mg, 0.28 mmol) and 2-chloropyridine (32 μ l, 0.34 mmol) in DCM (0.75 ml). After 5 minutes, the reaction flask was placed in an ice-water bath and warmed to 0 ℃. Alkyne 42a (187 mg, 0.56 mmol) in DCM (1 ml) was added by syringe. The resulting solution was warmed to room temperature. After stirring for 30 min, Et was added₃N (1 ml) and the mixture was partitioned between DCM (50 ml) and brine (50 ml). The organic layer was washed with brine (50 ml) and Na₂SO₄Dried and concentrated. Then, the residue is passedPurification by company gave thienopyridine 43f (105 mg, 87% pure, 59% yield).

Step 6:

thienopyridine 43f (40 mg, 0.071 mmol) was dissolved in TFA/water (10: 1, 1.1 ml) and the reaction was stirred at room temperature. After 30 min, the reaction was concentrated under reduced pressure and taken up with saturated NaHCO₃Diluted (5 ml) and extracted with DCM (3 × 10 ml). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give 43g of diol (30 mg, 94% yield).

And 7:

trimethylacetyl chloride (24. mu.l, 0.19 mmol) was added to 43g of diol (30 mg, 0.067 mmol) and Et₃N (59. mu.l, 0.43 mmol) in DCM (240. mu.l) at 0 ℃. The reaction was brought to room temperature and stirred overnight. The reaction was quenched with water (10 ml) and washed with EtOAc (10 ml). The organic layer was washed with Na₂SO₄Dried and concentrated. The mixture is passed throughPurification by company gave the ester 43h (16 mg, 45% yield).

And 8:

a drop of 70% perchloric acid was added to a stirred solution of alcohol 43h (46 mg, 0.087 mmol) dissolved in tert-butyl acetate (1 ml) at room temperature, and the mixture was stirred overnight. By addition of saturated NaHCO₃The reaction was quenched (5 ml) and the mixture was extracted with EtOAc (5 ml). The organic layer was washed with Na₂SO₄Dried, filtered and the solvent evaporated. The residue is passed throughPurification by company gave tert-butyl ether 43i (27 mg, 53% yield).

And step 9:

reacting LiBH₄To a solution of ester 43i (27 mg, 0.046 mmol) dissolved in THF (250 μ l) was added THF solution (2M, 69 μ l, 0.14 mmol) and the reaction was stirred at rt overnight. Excess reagent was quenched with HCl (three drops, copious sparge) and NaHCO₃The mixture was neutralized (10 ml) and extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give alcohol 43j (21 mg, 91% yield).

Step 10:

Dess-Martin periodinane (120 mg, 0.28 mmol) was added in 5 parts at 20 minute intervals to a solution of alcohol 43j (21 mg, 0.042 mmol) dissolved in DCM (1 ml). Next, a reaction is applied to the SiO₂Plug (1.5X1 cm) and product eluted with 1: 1 hexane/EtOAc (20 mL). The filtrate was evaporated to give crude aldehyde (17 mg). The aldehyde was then dissolved in 1: 1THF/tBuOH (1 mL) and a drop of methylcyclohexene was added. Adding NaClO₂(31 mg, 0.34 mmol) with NaH₂PO₄A single solution of (25 mg, 0.21 mmol) in water (0.5 ml) was added to the initial solution and the reaction was stirred at room temperature. After 20 min, the reaction was diluted with water (5 ml) and extracted with EtOAc (3 × 10 ml). The organic layer was washed with Na₂SO₄Dried and concentrated. The residue was purified by preparative HPLC to give carboxylic acid 2028(3 mg, 14% yield).

It will be apparent to those skilled in the art that the above synthetic schemes may also be used for the synthesis of other inhibitors, 11c being replaced by another aromatic halide in step 1 of example 42, and/or acetanilide being replaced by another aryl-NH-CO-R in step 5 of example 43²Or heteroaryl-NH-CO-R²And (4) replacement.

Example 44: synthesis of intermediate 44b

Step 1:

a solution of ester 44a (1.0 g, 4.3 mmol) in 1.0M NaOH (8.5 ml, 8.5 mmol), THF (8.6 ml) and MeOH (8.6 ml) was stirred at rt for 72 h, then at reflux for 3 h. The volatile solvent was concentrated under reduced pressure and 10% HCl (25 ml) was added. The white solid was collected by filtration, suspended in isopropanol (9.1 ml) and solid oxalic acid (470 mg, 5.2 mmol) was added. The suspension was gently warmed to 40 ℃ for 1 hour, then cooled to room temperature and treated with Et₂And (4) diluting with oxygen. The precipitate formed was collected by filtration and air dried. The white solid was reacted with Et₃N (1.8 ml, 13 mmol) was dissolved in DCM (5 ml) and acetyl chloride (0.37 ml, 5.3 mmol) was added very slowly. The reaction was stirred for 3 hours, and then quenched with water (50 ml). The mixture was extracted with EtOAc (2 × 50 ml) and the combined organic layers were extracted with Na₂SO₄Dried and concentrated to give pure amide 44b (473 mg, 83% yield).

Example 45: synthesis of Compound 2034

Step 1:

solid Pd (PPh)₃)₄(9 mg, 0.008 mmol) and CuI (3 mg, 0.015 mmol) are added sequentially to a solution of 11c (200 mg, 0.75 mmol) and alkyne 3f (190 mg, 1.1 mmol) dissolved in DMF (0.46 ml) and diethylamine (2.3 ml). The reaction mixture was stirred at rt overnight, then concentrated, diluted with EtOAc (10 ml) and washed successively with brine, 1N aqueous HCl and water (10 ml each). The organic layer was washed with Na₂SO₄Drying, concentrating under reduced pressure, passing the residue throughPurification by company yielded alkyne 45a (126 mg, 46% yield).

Step 2:

at-78 ℃ over 1 min, Tf was added₂O (75 μ l, 0.45 mmol) was added by syringe to a stirred mixture of amide 44b (91 mg, 0.42 mmol) and 2-chloropyridine (53 μ l 0.56 mmol) in DCM (0.8 ml). After 5 minutes, the reaction flask was placed in an ice-water bath and warmed to 0 ℃. Alkyne 45a (100 mg, 0.28 mmol) in DCM (1 ml) was added by syringe. The resulting solution was warmed to room temperature. After stirring for 30 min, triethylamine (1 ml) was added and the mixture was partitioned between DCM (50 ml) and brine (50 ml). The organic layer was washed with brine (50 ml) and anhydrous Na₂SO₄Dried and concentrated. Then, the residue is passedPurification by company afforded quinoline 45b (25 mg, 16% yield).

And step 3:

reacting LiBH₄To a solution of ester 45b (25 mg, 0.05 mmol) dissolved in THF (180 μ l) was added THF solution (2M, 225 μ l, 0.45 mmol) and the reaction was stirred at rt overnight. Excess reagent was quenched with HCl (one drop, copious bubbles) and saturated NaHCO₃The mixture was neutralized (10 ml) and extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with anhydrous Na₂SO₄Dried and concentrated to give alcohol 45c (21 mg, > 99% yield).

And 4, step 4:

Dess-Martin periodinane (34 mg, 0.08 mmol) was added to a solution of alcohol 45c (21 mg, 0.061 mmol) dissolved in DCM (0.5 ml). After 2 hours, the reaction was applied to SiO₂Pad (1.5X1 cm) and product eluted with 1: 1 hexane/EtOAc (20 mL). The filtrate was evaporated to give crude aldehyde. Next, the aldehyde was dissolved in 2: 1THF/H₂O/tBuOH (3 mL) and 2, 3-dimethyl-2-butene (0.3 mL of 1M solution in THF) was added. Adding NaClO₂(45 mg, 0.50 mmol) with NaH₂PO₄(37 mg, 0.31 mmol) was added as a solid to the solution and the reaction was stirred at room temperature. After 30 minutes, use H₂The reaction was diluted with O (5 ml) and extracted with EtOAc (3 × 10 ml). The organic layer was washed with anhydrous MgSO₄Dried and concentrated. The residue was purified by preparative HPLC to give compound 2034(3 mg, 10% yield).

It will be apparent to those skilled in the art that the above synthetic protocol may also be used for the synthesis of other inhibitors, 11c being replaced by another aromatic halide in step 1, and/or amide 44b being replaced by another thienyl-NH-CO-R in step 2²And (4) replacement.

Example 46: synthesis of boronic ester fragment 46b (for preparation of 2046)

Step 1:

a stirred DMF (5 ml) solution of aryl bromide 46e (0.152 g, 0.71 mmol), potassium acetate (0.209 g, 2.1 mmol) and bis (pinacolato) diborane (0.234 g, 0.92 mmol) was degassed by bubbling Ar through the solution for 20 min. Addition of PdCl₂(dppf) -DCM (87 mg, 0.11 mmol) and degassing was continued for 15 min. The system was sealed under Ar (Teflon screw cap container) and heated to 90 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 ml), washed with brine (3 × 100 ml) and water (2 × 100 ml), over anhydrous MgSO₄Dried, filtered, and concentrated to dryness. The residue is passed throughPurification by company (EtOAc/hexanes) gave the desired boronic ester 46b (144 mg, 77% yield) as a light yellow solid.

Example 47: synthesis of boronic ester fragment 47a (for preparation of 2047)

Step 1:

the reaction was carried out completely as in step 1 of example 13, starting from 10g to give the boronic ester 47 a.

Example 48: synthesis of boronic ester fragment 48c (for preparation of 1010)

Step 1:

solid NaBH is added at 0 DEG C₄(603 mg, 15.9 mmol) is added to a solution of aldehyde 48a (4.11 g, 19.92 mmol) dissolved in MeOH (62 ml). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with aqueous HCl (1N, 20 ml), MeOH was removed by concentration, and the product was extracted with EtOAc (2 × 50 ml). The organic layer was washed with brine (50 ml) and MgSO₄Drying, filtration, and concentration gave alcohol 48b (4.1 g, 97% yield). This material was used as such in the next step.

Step 2:

to a cold solution (0 ℃) of 48b (3.96 g, 19.31 mmol) in DCM (12 ml) was added diethylaminosulfur trifluoride (2.78 ml, 21.25 mmol). The reaction was warmed to room temperature and stirred for 2 hours. With NaHCO₃The reaction was quenched with aqueous solution and extracted with DCM. The organic layer was washed with MgSO₄Dried, filtered and evaporated to dryness. Product passingPurification by company gave 48c (2.1 g, 52% yield) as a colorless oil.

And step 3:

step 3 was performed exactly as in step 1 of example 46 to give boronic ester 48 d.

Example 49: synthesis of boronic ester fragment 49f (for preparation of 1047, 1048)

Step 1:

to a solution of 3-bromo-2-methylaniline 49a (2.44 g, 13.11 mmol) in MeCN (50 ml) was added β -propiolactone 49b (1.8 ml, 26.2 mmol, content 90%). The reaction was heated to reflux for 48 hours, followed by removal of the solvent. The residue was dissolved in EtOAc, then washed with 1N HCl, followed by brine. Over MgSO₄After drying, the solution is concentrated to dryness and passed throughPurification by company (EtOAc/hexanes) afforded the desired acid 49c (1.1 g, 33%) as a white solid.

Step 2:

acid 49c (1.1 g, 4.26 mmol) was mixed in polyphosphoric acid (40 g) and heated at 100 ℃ for 22 hours, then cooled to room temperature. The residue was dissolved in EtOAc and ice, followed by dropwise addition of 10N NaOH until pH 8. The aqueous phase was extracted with EtOAc (3 ×), and the combined organic phases were extracted with MgSO₄Dried, filtered, and concentrated to dryness. The residue is passed throughPurification by company (EtOAc/hexanes) afforded the desired ketone 49d (0.535 g, 52%) as a yellow solid。

And step 3:

ketone 49d (0.49 g, 2.04 mmol) was dissolved in dichloroethane (20 mL) and washed with ZnI₂(0.97 g, 3.06 mmol), followed by NaBH₃CN (0.96 g, 15.3 mmol). The mixture was heated to reflux for 1.5 hours, then cooled to room temperature. The mixture was diluted with EtOAc and washed with NH₄Washed with an acidified solution of Cl. The mixture was stirred for 30 minutes, then the phases were separated and the organic phase was washed with brine. Over (MgSO)₄) After drying, the mixture was filtered and concentrated to dryness. By passingPurification by company (EtOAc/hexanes) afforded the desired bromide 49e (232 mg, 50%) as a white solid.

And 4, step 4:

a well-stirred DMF (10 ml) solution of aryl bromide 49e (0.26 g, 1.15 mmol), potassium acetate (0.339 g, 3.45 mmol) and bis (pinacolato) diborane (0.38 g, 1.5 mmol) was degassed by bubbling Ar through the solution for 20 min. Addition of PdCl₂(dppf) -DCM (141 mg, 0.17 mmol) and degassing was continued for 15 min. The system was sealed under Ar (Teflon screw cap container) and heated to-90 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 ml), washed with brine (3 × 100 ml) and water (2 × 100 ml), over anhydrous MgSO₄Dried, filtered, and concentrated to dryness. The residue is passed throughPurification by company (EtOAc/hexanes) gave the desired boronic ester 49f (252 mg, 80% yield) as a light yellow solid.

Example 50: synthesis of boronic ester fragment 50a (for preparation of 2041)

Step 1:

to a cooled solution (0 ℃) of the boronic ester 5f (400 mg, 1.45 mmol) in anhydrous DMF (8 ml) was added NaH (87.4 mg, 2.18 mmol, 60% dispersion in oil). The mixture was stirred for 30 minutes and then treated with iodoethane (233 μ l, 2.9 mmol). The resulting mixture was stirred for 18 hours, then the reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine and MgSO₄Dried, filtered, and concentrated. The residue is passed throughPurification by company (EtOAc/hexanes) provided 50a as a colorless oil (317 mg, 72%).

Example 51: synthesis of boronic ester fragment 51b (for preparation of 1032)

Step 1:

to a solution of 51a (500 mg, 2.15 mmol) in DCM (1.4 ml) was added bis (2-methoxyethyl) aminosulfur trifluoride (0.84 ml, 4.31 mmol) and EtOH (12.2 μ l, 0.22 mmol). The reaction was sealed in a vial and stirred at room temperature overnight. With NaHCO₃The reaction was quenched with aqueous solution and extracted with DCM. The organic layer was washed with MgSO₄Dried, filtered and evaporated to dryness. The crude product 51b (210 mg, 39% yield) was used as such in the next step.

Step 2:

the reaction was carried out completely as described in example 46, step 1, using 51b as starting material to give 51 c.

Example 52: synthesis of boronic ester fragment 52f (for preparation of 1018, 1019)

Step 1:

lithium diisopropylamide (43.6 g, 245 mmol) was made up in THF (400 ml), cyclohexanone 52a (21.0 ml, 204 mmol) was added dropwise at-78 ℃ and stirred for 1 hour. This solution was added to a solution of diphenyl disulfide (53.4 g, 244 mmol) in hexamethylphosphoramide (60 ml) and stirred at room temperature for 2 hours. By NH₄The reaction mixture was quenched with Cl solution and THF was distilled off. The crude compound was extracted in EtOAc (3 ×), and the organic layer was washed with water and brine, Na₂SO₄Dried and concentrated under vacuum. The yellow oily liquid was purified by column chromatography on silica gel eluting with 5% ether/hexanes to give 52b (25.0 g, 59% yield) as a viscous oil.

Step 2:

NaIO was added dropwise to a solution of 52b (25 g, 12 mmol) in MeOH (500 mL) at 0 deg.C₄Aqueous solution (31 g, 151 mmol) (in a minimum amount of water) and stirred at room temperature overnight. Passing the reaction mixture throughFilter and wash the precipitate with MeOH. The filtrate was concentrated in vacuo and extracted with DCM; the organic layer was washed with water and brine, and Na was added₂SO₄Dried and concentrated under vacuum. The yellow solid formed was crystallized from an ether/hexane system (50: 50) to give 52c (17.0 g, 63%) as a yellow solid.

And step 3:

to a stirred solution of 52c (5.0 g, 2.25 mmol) in MeOH (30 ml) was added MeOH (5 ml) dropwise at 0 ℃) NaOMe (1.33 g, 2.5 mmol) in (b), and 3-methyl-3-buten-2-one (2.45 g, 2.9 mmol) was added dropwise. The reaction mixture was stirred at 0 ℃ overnight. Additional NaOMe (1.33 g, 2.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. MeOH was distilled off, and the resulting solution was poured onto 5% HCl solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine and Na₂SO₄Dried and concentrated under vacuum. The crude compound was chromatographed (5-10% ether/hexanes gradient elution) to give 52d (506 mg, 14% yield) as a white solid.

And step 3:

the reaction was carried out completely as described in example 17, step 5, using 52d as starting material to give 52 e.

And 4, step 4:

the reaction was carried out completely as described in example 17, step 6, using 52e as starting material to afford the boronic ester 52 f.

Example 53: synthesis of boronic ester fragment 53c (for preparation of 1061, 1062, 2042, 2043)

Step 1

To a solution of 3-chloro-2-methylanisole 53a in AcOH (100 ml) was added bromine (1.7 ml, 33.5 mmol) dropwise. After 2 hours at room temperature, the reaction mixture was concentrated in vacuo, then diluted with EtOAc, 1.0N NaOH, saturated Na₂S₂O₃Washed with water and brine, dried (MgSO)₄) Filtered and concentrated in vacuo to give the bromide 53b as a colorless oil (5.97 g, 79% yield).

Step 2:

the reaction was carried out completely as described in example 46, step 1, using 53b as starting material to give 53 c.

Example 54: synthesis of Compounds 1055 and 1056

Step 1:

CuBr in anhydrous MeCN (600. mu.l)₂(37.15 mg, 0.166 mmol) and tert-butyl nitrite (0.253 mmol) at room temperature under argon, a mixture of anilines 41a and 41b (60.0 mg, 0.133 mmol) in MeCN (400. mu.L) was slowly added. The reaction was stirred for 1 hour, then quenched with 1.0N HCl and extracted with EtOAc (3 ×). The combined organic extracts were washed with water and brine, dried (MgSO)₄) Filtered and concentrated in vacuo to give crude 54a as a mixture of atropisomers (76.1 mg, 68% yield) which was used as such in the next step.

Step 2:

a solution of 54a (68.5 mg, 0.133 mmol) in THF (3 ml)/MeOH (1.5 ml) was treated with 1.0N NaOH (1 ml) at rt. The reaction mixture was stirred at 50 ℃ overnight. The cooled reaction mixture was acidified (pH 4-5) with 1.0N HCl, extracted with DCM, and dried (MgSO 4)₄) Filtered and concentrated under vacuum. The mixture was purified by preparative reverse phase HPLC and the pure fractions were combined and lyophilized to give inhibitor 1055(16.7 mg, 25% yield) and 1056(4.3 mg, 6.5% yield) as white solids.

Example 55: synthesis of Compounds 1057 and 1058

Step 1:

the reaction was carried out completely as described in example 54, step 1, except that CuCl was used₂Replace CuBr₂This gave 55a as a mixture of atropisomers.

Step 2:

the reaction was carried out completely as described in example 54, step 2, using 55a as starting material and, after isolation, compounds 1057 and 1058 were obtained as white solids.

It will be apparent to those skilled in the art that the synthetic schemes described above for examples 54 and 55 can also be used for the synthesis of other inhibitors for table 2, starting from iodo intermediate 1B.

Example 56: c8166HIV-1 luciferase assay (EC)₅₀)

The C8166 cells are derived from a human T-lymphophagous lymphotropic virus type 1 immortalized but non-expressing cell line from cord blood lymphocytes (J.Sullivan), and are highly permissive to HIV-1 infection. pGL3Basic LTR/TAR plasmid was made in such a way that HIV-1HxB2 LTR sequence of nucleotides-138 to +80(Scal-HindIII) was introduced upstream of the luciferase gene in pGL3Basic vector (promoterless luciferase expression vector from Promega catalog # E1751) in which blasticidin (blastcidine) resistance gene was cloned. Reporter cells were made by electroporating C8166 cells in the presence of pGL3Basic LTR/TAR and selecting positive clones with blasticidin. Clone C8166-LTLUC # A8-F5-G7 was selected by limiting dilution in 3 consecutive rounds under blasticidin selection. The cultures were maintained in complete medium (consisting of Rosswellpark Medium Institute (RPMI)1640+ 10% FBS + 10) with 5. mu.g/ml blasticidin^-5M β -mercaptoethanol +10 μ g/ml gentamicin), however, blasticidin was selectively removed from the cells prior to performing the virus replication assay.

Luciferase assay protocol

Preparation of the Compounds

Serial dilutions of HIV-1 inhibitor compounds were made in complete medium from 10mM DMSO stock. 2.5X 11 serial dilutions were made in 1 ml deep well titer plates (96 wells) at the final concentration required at 8X. Well 12 contained complete medium, no inhibitor, and served as a positive control. All samples contained the same concentration of DMSO (< 0.1% DMSO). A 25 microliter aliquot of the inhibitor was added to triplicate wells of a 96-well tissue culture treated clear black microtiter plate (Corning Costar catalog # 3904). The total volume per well was 200 microliters of medium containing cells and inhibitors. The last row was reserved for uninfected C8166LTRluc cells as a background blank, while the first row was media alone.

Infection of cells

C8166 LTLUC cells were counted and placed in a minimal volume of complete RPMI 1640 (e.g., 30X 10) in tissue culture flasks⁶Cell, 10 ml medium/25 cm²A flask). Cells were infected with HIV-1 or a virus with a variant integrase as described below at a multiplicity of infection of 0.005. Cells were plated on a rotating rack at 37 ℃ in 5% CO₂Incubate for 1.5 hours and resuspend in complete RPMI to give a final concentration of 25,000 cells/175 microliters. 175 microliters of the cell mixture was added to the wells of a 96-well microtiter plate containing 25 microliters of the 8X inhibitor. 200 microliters of 25,000 uninfected C8166-LTLuc cells/well in complete RPMI were added to the last row for background control. Cells were incubated at 37 ℃ in 5% CO₂The medium incubator is used for 3 days.

Luciferase assay

50 microliters of Steady Glo (luciferase substrate T)_1/25 hour Promega catalog # E2520) were added to each well of a 96-well plate. Relative Light Units (RLU) of luciferase were determined using a LUMIstar Galaxy luminometer (BMG Labtechnologies). Read plate from bottom 2 seconds per well with magnification factor of 240.

The degree of inhibition (% inhibition) of each well containing inhibitor was calculated as follows:

calculated% inhibition value for determining EC₅₀Slope factor (n) and maximum inhibition (I)_max) The following equation is used by the nonlinear regression procedure NLIN method of SAS:

list of compounds

The compounds of the present invention shown in tables 1 to 4 are integrase inhibitors. Representative compounds of tables 1 to 2 below have EC's when tested in the HIV-1 luciferase assay of example 46₅₀The value is not more than 20. mu.M.

Retention time (t) for each compound_R) Measured using standard analytical HPLC conditions as described in the examples. As is known to those skilled in the art, retention time values are sensitive to a particular measurement. Thus, even if the same conditions of solvent, flow rate, linear gradient, etc. are used, the retention time values may vary when measured, for example, on different HPLC instruments. This value may change even when measured on the same instrument, when measured, for example, using different individual HPLC columns, or when measured on the same instrument and the same individual column, the value may change, for example, between individual measurements taken at different times.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety as if each had been individually incorporated by reference. Furthermore, it should be understood that within the above summary of the invention, certain changes or modifications may be made to the invention by those skilled in the art, and such equivalents may still fall within the scope of the invention as defined by the appended claims.

Claims

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

wherein

Represents a single bond or a double bond;

x is S or CR⁵；

Y is S or CR⁷；

Wherein one of X or Y is S;

R²、R⁵、R⁶and R⁷Each independently selected from:

a) halogen;

and is

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

and

Wherein

R⁹Independently selected from H, (C) at each occurrence_1-6) Alkyl and (C)_3-7) A cycloalkyl group; and R is¹⁰Independently at each occurrence selected from R⁸、-(C_1-6) alkylene-R⁸、-SO₂-R⁸、-C(＝O)-R⁸、-C(＝O)OR⁸and-C (═ O) N (R)⁹)R⁸(ii) a Wherein R is⁸And R⁹As defined above;

R³Is (C)_1-6) Alkylidene, and bond c is a double bond;

R⁴is aryl or Het, wherein each aryl and Het is optionally substituted by 1 to 5 substituents each independently selected from

Substituted by the following groups: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy, -O (C)_1-6) Alkyl, cyano or oxo;

and is

Or a salt or ester thereof.

2. The compound of claim 1, which is a compound of formula (Ie):

wherein R is²、R³、R⁴、R⁵And R⁶Are as defined in claim 1.

3. The compound of claim 1, which is a compound of formula (Ih):

wherein R is²、R³、R⁴、R⁶And R⁷Are as defined in claim 1.

4. A compound according to any one of claims 1 to 3, wherein R²Is (C)_1-6) Alkyl or-O (C)_1-6) An alkyl group.

5. The compound of claim 4, wherein R²is-CH₃、-CH₂CH₃、-CH(CH₃)₂or-OCH₃。

6. The compound of claim 5, wherein R²is-CH₃。

7. The compound of any one of claims 1 to 6, wherein R³is-O (C)_1-6) Alkyl, -O- (C)_1-6) Haloalkyl, -O (C)_2-6) Alkenyl, -O (C)_2-6) Alkynyl or-O- (C)_3-7) A cycloalkyl group;

The bond c is a single bond.

8. The compound of claim 7, wherein R³is-O (C)_1-4) An alkyl group; wherein the-O (C)_1-4) Alkyl is optionally substituted with 1 to 2 substituents each independently selected from cyano, oxo and-O (C)_1-6) Alkyl is substituted by a substituent; and is

The bond c is a single bond.

9. The compound of claim 8, wherein R³is-OC (CH)₃)₃(ii) a And the bond c is a single bond.

10. The compound of any one of claims 1 to 9, wherein R⁴Is aryl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl group, (C)_3-7) Cycloalkyl- (C)_1-6) Alkyl-, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy, -O (C)_1-6) Alkyl, cyano or oxo groups.

11. The compound of claim 10, wherein R⁴Is phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: F. cl, Br, NH₂、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、CH₂F、CF₃and-CH₂CH₂F。

12. The compound of any one of claims 1 to 9, wherein R⁴Is Het, optionally substituted with 1 to 3 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_1-6) Haloalkyl, (C)_3-7) Cycloalkyl, -OH, -O (C)_1-6) Alkyl, -SH, -S (C)_1-6) Alkyl, -NH₂、-NH(C_1-6) Alkyl and-N ((C)_1-6) Alkyl radical)₂(ii) a Wherein (C) is_1-6) Alkyl optionally substituted by hydroxy or-O (C)_1-6) Alkyl substitution.

13. The compound of claim 12, wherein R⁴Is Het, optionally substituted by 1 or 2 substituents each independently selected from halogen, (C)_1-6) Alkyl and-O (C)_1-6) Alkyl is substituted by a substituent;

wherein the Het is a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9-or 10-membered heteropolycyclic ring having 1 to 3 heteroatoms each independently selected from N, O and S.

14. The compound of any one of claims 1 to 9, wherein R⁴Is aryl or Het, optionally substituted with 1 to 3 substituents each independently selected from: halogen, (C)_1-6) Alkyl, (C)_1-6) Haloalkyl, NH₂and-O (C)_1-6) An alkyl group;

wherein aryl is selected from:

and is

Wherein Het is selected from:

15. the compound of any one of claims 1, 2, or 4-14, wherein R⁵Is H or (C)_1-4) An alkyl group.

16. The compound of claim 15, wherein R⁵Is (C)_1-4) An alkyl group.

17. The compound of claim 16, wherein R⁵Is H or CH₃。

18. The compound of any one of claims 1 to 17, wherein R⁶Is H, (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or-O (C)_1-6) An alkyl group.

19. The compound of claim 18, wherein R⁶Is H or (C)_1-4) An alkyl group.

20. The compound of claim 19, wherein R⁶Is (C)_1-4) An alkyl group.

21. The compound of claim 19, wherein R⁶Is H or CH₃。

22. The compound of any one of claims 1, 3-14, or 18-21, wherein R⁷Is H, (C)_1-6) Alkyl, (C)_3-7) Cycloalkyl or-O (C)_1-6) An alkyl group.

23. The compound of claim 22, wherein R⁷Is H or (C)_1-4) An alkyl group.

24. The compound of claim 23, wherein R⁷Is (C)_1-4) An alkyl group.

25. The compound of claim 23, wherein R⁷Is H or CH₃。

26. The compound of claim 1 having the formula

Wherein R is³、R⁴、R⁵And R⁶As defined below:

27. the compound of claim 1 having the formula

Wherein R is³、R⁴、R⁵And R⁶As defined below:

28. the compound of claim 1 having the formula

Wherein R is³、R⁴、R⁶And R⁷As defined below:

29. the compound of claim 1 having the formula

Wherein R is³、R⁴、R⁶And R⁷As defined below:

30. a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as claimed in any one of claims 1-29, for use as a medicament.

31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable carriers.

32. The pharmaceutical composition of claim 31, further comprising at least one additional antiviral agent.

33. The pharmaceutical composition of claim 32, wherein the at least one other antiviral agent comprises at least one NNRTI.

34. The pharmaceutical composition of claim 32, wherein the at least one other antiviral agent comprises at least one NRTI.

35. The pharmaceutical composition of claim 32, wherein the at least one additional antiviral agent comprises at least one protease inhibitor.

36. The pharmaceutical composition of claim 32, wherein said at least one other antiviral agent comprises at least one entry inhibitor.

37. The pharmaceutical composition of claim 32, wherein said at least one additional antiviral agent comprises at least one integrase inhibitor.

38. Use of the pharmaceutical composition of any one of claims 31-37 for treating HIV infection in a mammal having or at risk of having the infection.

39. A method of treating HIV infection in a mammal having or at risk of having the infection, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 29, a pharmaceutically acceptable salt or ester thereof, or a composition as claimed in any one of claims 31 to 37.

40. A method of treating HIV infection in a mammal having or at risk of having the infection, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as claimed in any one of claims 1-29, in combination with at least one other antiviral agent; or the composition of any one of claims 31-37.

41. Use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as claimed in any one of claims 1-29, for the treatment of HIV infection in a mammal having or at risk of having the infection.

42. Use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as claimed in any one of claims 1-29, in the manufacture of a medicament for the treatment of HIV infection in a mammal having or at risk of having the infection.

43. An article of manufacture comprising a composition effective in treating HIV infection; and a packaging material comprising a label indicating that the composition is useful for treating HIV infection; wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof as claimed in any one of claims 1 to 29.

44. A method of inhibiting HIV replication comprising exposing the virus to an effective amount of a compound of formula (I), or a salt or ester thereof, as claimed in any one of claims 1-29, under conditions which inhibit HIV replication.

45. Use of a compound of formula (I), or a salt or ester thereof, as claimed in any one of claims 1-29, for inhibiting HIV integrase activity.

46. Use of a compound of formula (I), or a salt or ester thereof, as claimed in any one of claims 1-29, for inhibiting HIV replication.