阅读说明：本技术 用于制备苯二氮*衍生物的方法 (Process for the preparation of benzodiazepine derivatives ) 是由 金寅锺 于建明 T·P·布莱斯德尔 J·帕那斯 B·C·舒克 柯日新 于 2018-02-16 设计创作，主要内容包括：本发明涉及用于制备生物活性分子,尤其是合成呼吸道合胞病毒(RSV)抑制剂的方法和中间体。本发明还涉及用于制备式(I)的化合物的方法和中间体。特别地,本发明还涉及用于制备化合物(I-a)的方法和中间体。<Image he="173" wi="700" file="DDA0002230661590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to processes and intermediates for the preparation of biologically active molecules, in particular synthetic Respiratory Syncytial Virus (RSV) inhibitors. The invention also relates to processes and intermediates for preparing compounds of formula (I). In particular, the present invention also relates to processes and intermediates for preparing compound (I-a).)

1. A process for the preparation of a compound of formula (I),

wherein

m is 0,1, 2,3 or 4; and

R₁selected from:

1) optionally substituted-C₁-C₈An alkyl group;

2) optionally substituted-C₃-C₈A cycloalkyl group;

3) an optionally substituted 3-to 12-membered heterocyclic ring;

alternatively, two adjacent R₁The groups together with the carbon atoms to which they are attached form a fused ring; two geminal R₁The groups together with the carbon atom to which they are attached form a spiro ring; or two R on non-adjacent carbon atoms₁The radicals together forming a bridging group, e.g. -CH₂-or-CH₂CH₂-；

The method comprises the following steps:

(a) reacting a compound of the formula (VII),

wherein R is₇Selected from hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkenyl, 3-to 8-membered heterocycles, aryl and heteroaryl; and X is a leaving group;

with a compound of formula (VII-X),

wherein PG is hydrogen or an amine protecting group;

to prepare a compound of formula (VIII):

(b) reacting a compound of formula (VIII) with a compound of formula (IX):

to prepare a compound of formula (X):

(c) reacting a compound of formula (X) with a compound of formula (III)

Wherein R is₅Selected from-O (CO) O-R₆Optionally substituted aryl and optionally substituted heteroaryl; and R is₆Selected from optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₃-C₈Cycloalkenyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl and optionally substituted heteroaryl;

to prepare a compound of formula (V),

(d) reacting a compound of formula (V) with a cyclising agent to form a compound of formula (I).

2. The method of claim 1, wherein

3. The process of claim 1, wherein step (a) is carried out in a protic solvent at a temperature of about 10 ℃ to about 70 ℃.

4. The method of any one of claims 1 to 3, wherein R₇Is hydrogen and step (a) is carried out in the presence of an amide coupling agent.

5. The process of claim 4 wherein the amide coupling agent is HATU or EDU.

6. The process of claim 4 or 5, wherein step (a) is carried out in a solvent selected from the group consisting of: isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, NMP, 2-methyltetrahydrofuran and acetonitrile.

7. The method of any one of claims 1 to 3, wherein R₇Is C₁-C₈Alkyl and step (a) is carried out in the presence of a protic solvent.

8. The method of claim 7, wherein the protic solvent is methanol, ethanol, or isopropanol.

9. The method of claim 8, wherein step (a) is performed at a temperature of about 10 ℃ to about 70 ℃ for about 3 to 12 hours.

10. The process of any one of claims 1 to 9, wherein step (b) is carried out under the following conditions: (i) no solvent, or (ii) in an aprotic solvent; at a temperature of from about 10 ℃ to about 100 ℃.

11. The method of any one of claims 1 to 10, further comprising the steps of:

the reaction of the compound (IV),

and a compound of the formula Y-C (O) R₅To prepare a compound of formula (III) wherein Y is a leaving group.

12. The method of claim 11, wherein formula Y-C (O) R₅The compound of (1) is 1, 1' -carbonyldiimidazole or nitrophenylchloroformate.

13. The method of claim 12, wherein the compound of formula IV is reacted with an amine activator in a solvent selected from the group consisting of: acetonitrile, THF, DMSO and dichloromethane.

14. The process of any one of claims 1 to 13, wherein step (c) is carried out in acetonitrile, THF, DMSO, DMF, sulfolane, or 1-methyl-2-pyrrolidone.

15. The method of claim 14, wherein step (c) is performed at a temperature of about 10 to 50 ℃ for 6 to 48 hours.

16. The process of any one of claims 1 to 15, wherein the cyclizing agent of step (d) is p-toluenesulfonyl chloride.

17. The method of claim 16, wherein step (d) is performed under the following conditions: (i) in the presence of triethylamine or diisopropylethylamine; (ii) in a solvent selected from acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethyl acetate and isopropyl acetate; (iii) (iii) at a temperature of about 0 ℃ to about 30 ℃ (iv) for about 3 to 15 hours; (v) (III) the concentration of the compound of formula (III) is about 1M to 3M, and (vi) the ratio of the concentration of the compound of formula (III) to the concentration of the compound of formula (V) is about 1: 1.

18. The method of any one of claims 1 to 17, wherein the compound of formula I is compound I-a:

Technical Field

The present invention relates to processes and intermediates for the preparation of biologically active molecules, particularly for the synthesis of inhibitors of Respiratory Syncytial Virus (RSV).

Background

Human Respiratory Syncytial Virus (HRSV) is an antisense single-stranded RNA paramyxovirus (KM. Empey et al, Rev. anti-infectious Agents,2010,50 (1.5 months), 1258-1267). RSV is a major cause of acute lower respiratory tract infections (ALRI) and affects patients of all ages. The symptoms in adults are usually not severe and often resemble mild colds. However, in infants and young children, the virus can cause lower respiratory tract infections, including bronchiolitis or pneumonia, many of which require hospitalization. Almost all children have been infected by the age of 3. It is known that RSV infection is more likely to develop into a high risk group of ALRI. Preterm and/or infant with lung or heart disease are at the highest risk of developing ALRI. Other high risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant patients, and immunosuppressors.

Currently, there is no vaccine available to prevent HRSV infection. Palivizumab is a monoclonal antibody that can be used prophylactically to prevent HRSV infection in high risk infants, such as preterm infants and infants with heart and/or lung disease. The high cost of palivizumab therapy limits its use for general purposes. Ribavirin has also been used to treat HRSV infections, but has limited effectiveness. There is a significant medical need for new and effective HRSV treatments that are widely available for all population types and ages.

There have been several RSV fusion inhibitors disclosed in the following publications: WO2010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO2013/186332, WO2012/080451, WO2012/080450, WO2012/080449, WO2012/080447, WO2012/080446 and j.med.chem.2015,58, 1630-. Examples of other N-protein inhibitors for the treatment of HRSV have been disclosed in the following publications: WO2004/026843, J.Med.chem.2006,49, 2311-. Examples of L-protein inhibitors for HRSV have been disclosed in the following publications: WO2011/005842, WO2005/042530, Antiviral Res.2005,65,125-. Examples of nucleoside/polymerase inhibitors are disclosed in the following publications: WO2013/242525 and J.Med.chem.2015,58, 1862-1878.

There is a need to develop effective treatments for HRSV. The present inventors have identified benzodiazepines substituted as aminoheteroaryl groups

And HRSV inhibiting compounds. The invention includes methods of making the compounds and methods of using the compounds to treat diseases.

Summary of The Invention

The present invention provides a process for the preparation of a compound of formula (I):

wherein

Is an optionally substituted aryl or an optionally substituted heteroaryl group, preferably,

is optionally substituted pyridyl; each n is independently selected from 1 and 2; preferably, each n is 1; m is 0,1, 2,3 or 4; preferably, m is 0;

R₁selected from:

1) optionally substituted-C₁-C₈An alkyl group;

2) optionally substituted-C₃-C₈A cycloalkyl group; and

3) an optionally substituted 3-to 12-membered heterocycle;

alternatively, two adjacent R₁The groups together with the carbon atoms to which they are attached form a fused ring; two geminal R₁The groups together with the carbon atom to which they are attached form a spiro ring; or two R on non-adjacent carbon atoms₁The radicals together forming a bridging group, e.g. -CH₂-or-CH₂CH₂-。

Preferably, when m is not 0, each R₁Is methyl.

Preferred compounds of formula (I) are compounds (I-a):

the invention also relates to process steps for increasing product yield and reducing intermediates and to large scale processes for preparing compounds of formula (I), such as compound (I-a). These compounds are useful as RSV inhibitors.

Detailed Description

In its main embodiment, the present invention provides a process for the preparation of a compound of formula (I):

wherein

R₁M andn is as previously defined. In some embodiments of the present invention, the substrate is,

selected from the group listed below:

the method comprises the following steps:

1) reacting a compound of the formula (VII),

wherein R is₇Selected from hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkenyl, 3-to 8-membered heterocycles, aryl and heteroaryl; x is a leaving group such as, but not limited to, halogen or-ortho-triflate;

with a compound of formula (VII-X),

wherein PG is hydrogen or an amino protecting group such as, but not limited to, cbz, Boc, methoxycarbonyl, or 9-fluorenyl-methoxycarbonyl;

to prepare a compound of formula (VIII),

2) reacting a compound of formula (VIII) with a compound of formula (IX):

wherein R is₁M and n are as previously defined; to prepare a compound of formula (X):

3) reacting a compound of formula (X) with a compound of formula (III),

wherein R is₅Selected from-O (CO) O-R₆Optionally substituted aryl and optionally substituted heteroaryl; and R is₆Selected from optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₃-C₈Cycloalkenyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl and optionally substituted heteroaryl;

to form a compound of formula (V),

and

4) reacting a compound of formula (V) with a cyclising agent to form a compound of formula (I).

Preferred embodiments of compounds of formula (VIII) are compounds of formula (VIII-a), formula (VIII-b) or formula (VIII-c):

wherein R is₄Selected from halogen, methyl, CF₃And CN. A more preferred embodiment of the compound of formula (VIII) is a compound of formula (VIII-d),

preferred embodiments of the compound of formula (X) are compounds of formula (X-a), formula (X-b) or formula (X-c):

a more preferred embodiment of the compound of formula (X) is a compound of formula (X-d):

in a preferred embodiment, the compound of formula (III) is compound (III-a):

a preferred embodiment of the compound of formula (V) is compound (V-a).

The compound of formula (III) can be prepared by reacting compound (IV),

and a compound of the formula Y-C (O) R₅Wherein Y is a leaving group, such as halogen or 1-imidazolyl.

Compound (IV) can be prepared, for example, by resolution of a racemic mixture of compound (IV) and its enantiomer.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof in amorphous solid form. In this embodiment, the compound of formula I is preferably compound (I-a) or a pharmaceutically acceptable salt thereof, and more preferably, the compound of formula (I) is compound (I-a) free base.

In another embodiment, the present invention provides a composition comprising an amorphous solid form of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable hydrophilic polymer for enhancing activity.

In one embodiment of this aspect of the invention, the hydrophilic polymer is selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, vinyl acetate polymers, oligosaccharides and polysaccharides. Non-limiting examples of suitable hydrophilic polymers include homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcellulose, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, copolymers of ethylene oxide and propylene oxide, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylpyrrolidone and vinyl propionate, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of propylene oxide, Butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly (hydroxyalkyl acrylate), poly (hydroxyalkyl methacrylate), copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, or xanthan gum.

In yet another embodiment of this aspect of the invention, the hydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone. Preferably, the hydrophilic polymer is copovidone.

Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt in amorphous solid form and a pharmaceutically acceptable hydrophilic polymer may be prepared by a variety of techniques such as, but not limited to, melt extrusion, spray drying, co-precipitation, freeze drying or other solvent evaporation techniques, preferably melt extrusion and spray drying. Melt extrusion processes generally comprise the following steps: a melt is prepared comprising the active ingredient(s), hydrophilic polymer(s) and preferably surfactant(s), and the melt is then cooled until it solidifies. By "molten" is meant a transition to a liquid or rubbery state in which one component may be embedded, preferably homogeneously embedded, in the other component or components. In many cases, the polymer component(s) will melt and other components, including the active ingredient(s), will dissolve in the melt, forming a solution. Melting typically involves heating above the softening point of the polymer(s). The preparation of the melt can be carried out in various ways. The mixing of the components can be carried out before, during or after the melt is formed. For example, the components may be mixed first and then melted or mixed and melted simultaneously. The melt may also be homogenized to effectively disperse the active ingredient(s). In addition, it may be convenient to first melt the polymer(s) and then mix and homogenize the active ingredient(s). In one example, all materials except the surfactant(s) are blended and fed into the extruder while the surfactant(s) are melted externally and pumped in the extrusion process.

Synthetic schemes

The invention will be better understood in connection with schemes 1-2, wherein

R₁PG, X, m, n and R₅As previously defined, unless otherwise indicated.

It will be apparent to one of ordinary skill in the art that the method of the present invention may be practiced by substituting the appropriate reactants, and that the order of the steps themselves may be varied.

The chemical route for the synthesis of hydrazides, compounds of formula (X) is summarized in scheme 1.

Scheme 1

R₇Selected from hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkenyl, 3-to 8-membered heterocyclic, aryl and heteroaryl. Preferably, the compound of formula (VII) is 3-halo-5- (trifluoromethyl) -2-pyridinecarboxylic acid or an alkyl 3-halo-5- (trifluoromethyl) picolinate, and more preferably is commercially available ethyl 3-chloro-5- (trifluoromethyl) -picolinate. Preferred compounds of formula (VII-X) include hydrazine monohydrate, Boc-hydrazine or Cbz-hydrazine.

In one embodiment, R₇Is C₁-C₈Alkyl, preferably methyl or ethyl. In this embodiment, the reaction of the compound of formula (VII) and hydrazine monohydrate is typically carried out in a protic solvent such as, but not limited to, methanol, ethanol or isopropanol or a mixture of two or more thereof. The reaction temperature is generally from about 10 ℃ to about 70 ℃, and the reaction time is generally from about 3 to 12 hours.

In another embodiment, R₇Is hydrogen and the compound of formula (VII) is converted into a compound of formula (VIII) by coupling with a compound of formula (VII-X) in the presence of an amide coupling agent such as 1, 1' -carbonyldiimidazole, bis (2-oxo-3-oxazolidinyl) -phosphinic acid chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3-hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-nitrophenol, pentafluorophenol, 2-hydroxypyridine, N-hydroxysuccinimide, N-hydroxyphthalimide, 2-mercaptobenzoxazole, trimethylacetyl chloride, isobutyl chloroformate, chlorodimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide, 5-nitro-2-hydroxypyridine, Boc-L-valine anhydride or mixtures thereof. Examples of solvents suitable for this reaction include, but are not limited to, isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, NMP, 2-methyltetrahydrofuran, and acetonitrile. The specific reaction conditions will vary depending on the nature of the coupling reagent and are known to those of ordinary skill in the art.

The compound of formula (VIII) may be converted to the compound of formula (X) by amination with a compound of formula (IX). The compound of formula (IX) may be, but is not limited to, morpholine, 2-methylmorpholine and its stereoisomers, 3, 5-dimethylmorphine and its stereoisomers, 2, 6-dimethylmorphine and its stereoisomers, 3-oxa-8-azabicyclo [3.2.1] octane, 2-oxa-5-azabicyclo [2.2.1] heptane, 8-oxa-3-azabicyclo [3.2.1] octane. The reaction is typically carried out in the absence of a solvent or in an aprotic solvent such as, but not limited to, toluene, THF or dichloromethane. The reaction temperature is generally from about 10 ℃ to about 100 ℃ and the reaction time is generally from 3 to 12 hours.

In one embodiment, wherein PG is not hydrogen, the compound of formula (X) is deprotected by removal of PG. Suitable deprotection conditions depend on the nature of the PG and are known to those skilled in the art, for example as commonly described in t.h.greene and p.g.m.wuts,Protective Groups in Organic Synthesis3 rd edition, John Wiley&Sons, New York (1999).

Scheme 2 illustrates the synthesis of compounds of formula (I).

Scheme 2

Compound (XI) is commercially available or can be synthesized by methods known to those of ordinary skill in the art. Chiral separation of racemic compound (XI) can be carried out using methods such as, but not limited to, treatment with a chiral acid and separation of diastereomeric salts by crystallization or chromatography, Capillary Electrophoresis (CE), Supercritical Fluid Chromatography (SFC), Capillary Electrochromatography (CEC), Gas Chromatography (GC), High Performance Liquid Chromatography (HPLC), and crystallization with a chiral salt followed by separation of the diastereomeric analogs, to provide chiral compound (IV), S-isomer. In one embodiment, compound (IV) is prepared from racemic compound (XI) using the method disclosed in U.S. provisional application No. 62/585,192.

In one embodiment, the chiral compound (IV) is obtained using SFC and the mobile phase is carbon dioxide (CO)₂) Or a mixture of carbon dioxide and a polar organic co-solvent such as, but not limited to, methanol, ethanol, or 2-propanol; the temperature range is limited to 5 to 40-50 c, preferably the temperature is room temperature (about 25 c). The procedure and conditions for SFC will vary and depend on the nature of the racemic compound and are known to those of ordinary skill in the art.

In one aspect, chiral compound (IV) is obtained after separation of the SFC with greater than about 90% enantiomeric excess purity (ee). In one aspect, chiral compound (IV) is obtained after separation of the SFC with greater than about 95% enantiomeric excess purity (ee). In one aspect, chiral compound (IV) is obtained after SFC separation with an enantiomeric excess purity (ee) of greater than about 98%.

In one embodiment, after chiral separation, in addition to the chiral compound (IV), another epimer is obtained, namely chiral compound (IV-a), the R-isomer:

in one embodiment, chiral compound (IV-a) is racemized under basic conditions to obtain racemic compound (XI). Racemization is carried out in the presence of a base in a protic solvent such as, but not limited to, methanol, ethanol,^tBuOH or isopropanol, with bases such as, but not limited to, NaOMe or^tBuOK. The reaction temperature is generally from about 10 ℃ to about 70 ℃, and the reaction time is generally from about 3 to 24 hours.

In one embodiment, the chiral compound (IV) is converted to the compound of formula (III) by reaction with an amino activator such as, but not limited to, 1' -carbonyldiimidazole, nitrophenylchloroformate, triphosgene, or phosgene. The process is typically carried out in a protic or aprotic solvent, such as, but not limited to, acetonitrile, THF, DMSO, or dichloromethane. Typical reaction temperatures are about 0 ℃ to 30 ℃ and reaction times are usually about 6 to 15 hours. In one aspect, the molar ratio of compound (IV) to amino activator is about 1: 1. In one aspect, the molar ratio of compound (IV) to amino activator is about 1: 2. In one aspect, the molar ratio of chiral compound (IV) to amino activator is about 1: 3. Preferably, the molar ratio of chiral compound (IV) to amino activator is about 1: 3.

In one embodiment, PG is hydrogen and the reaction of the compound of formula (III) with the compound of formula (X) is carried out in a protic solvent such as, but not limited to, acetonitrile, THF, DMSO, DMF, sulfolane or 1-methyl-2-pyrrolidone. Typical reaction temperatures are about 10 to 50 ℃ and reaction times are usually 6 to 48 hours. The reaction is generally carried out at a concentration of the compound of formula (III) of about 1M to 3M, preferably at a concentration of the compound of formula (III) of 1.5M. The molar ratio of the compound of formula (III) to the compound of formula (X) is 1: 1.

The compound of formula (V) may be cyclized to the compound of formula (I) by reaction with a cyclizing agent such as, but not limited to, p-toluenesulfonyl chloride, thionyl chloride, phosphorus oxychloride or HATU in the presence of an organic base. Suitable organic bases include, but are not limited to, triethylamine and diisopropylethylamine. The process is carried out in an aprotic solvent such as, but not limited to, acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethyl acetate, or isopropyl acetate. The reaction temperature is about 0 ℃ to about 30 ℃, and the reaction time is usually 3 to 15 hours.

Definition of

Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout the specification and claims, unless otherwise defined in specific instances either individually or as part of a larger group.

The term "aryl" as used herein refers to a monocyclic or polycyclic carbocyclic ring system comprising at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. Polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. Polycyclic aryl groups can include fused rings, covalently linked rings, or combinations thereof.

As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic group having one or more ring atoms selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may optionally be oxidized. Heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. The polycyclic heteroaryl group can include fused rings, covalently linked rings, or combinations thereof.

According to the invention, the aromatic group may be substituted or unsubstituted.

The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic; and the two rings may be fused or covalently linked.

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon group. "C₁-C₄Alkyl group "," C₁-C₆Alkyl group "," C₁-C₈Alkyl group "," C₁-C₁₂Alkyl group "," C₂-C₄Alkyl "or" C₃-C₆Alkyl "refers to alkyl groups containing 1 to 4, 1 to 6, 1 to 8,1 to 12, 2 to 4, and 3 to 6 carbon atoms, respectively. C₁-C₈Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, and octyl.

The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond by removal of a single hydrogen atom. "C₂-C₈Alkenyl group "," C₂-C₁₂Alkenyl group "," C₂-C₄Alkenyl group "," C₃-C₄Alkenyl "or" C₃-C₆Alkenyl "refers to alkenyl groups containing 2 to 8, 2 to 12, 2 to 4, 3 to 4, or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, for example, vinyl,Propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond by removal of a single hydrogen atom. "C₂-C₈Alkynyl group "," C₂-C₁₂Alkynyl group "," C₂-C₄Alkynyl group "," C₃-C₄Alkynyl "or" C₃-C₆Alkynyl "refers to alkynyl groups containing 2 to 8, 2 to 12, 2 to 4, 3 to 4, or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "cycloalkyl" as used herein refers to a fused, bridged or spiro ring system of monocyclic or polycyclic saturated carbocyclic or bicyclic or tricyclic groups, and carbon atoms may be optionally substituted by oxo or optionally by an exocyclic olefinic double bond. Examples of preferred cycloalkyl groups include C₃-C₁₂Cycloalkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₈Cycloalkyl and C₄-C₇A cycloalkyl group. C₃-C₁₂Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo [2.2.1]Heptyl, bicyclo [3.1.0]Hexyl, spiro [2.5]]Octyl, 3-methylenebicyclo [3.2.1]]Octyl, spiro [4.4]]Nonyl, and the like.

The term "cycloalkenyl" as used herein refers to a fused, bridged or spiro ring system of monocyclic or polycyclic carbocyclic or bicyclic or tricyclic groups having at least one carbon-carbon double bond, and carbon atoms may be optionally substituted by oxo or optionally by an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C₃-C₁₂Cycloalkenyl radical, C₃-C₈Cycloalkenyl or C₅-C₇A cycloalkenyl group. C₃-C₁₂Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] alkenyl]Hept-2-enyl, bicyclo [3.1.0]Hex-2-enyl, spiro [2.5]]Oct-4-enyl, spiro [4.4]]Non-1-alkenyl, bicyclo [ 4].2.1]Non-3-en-9-yl, and the like.

The term "aralkyl" as used herein means a functional group in which an alkylene chain is attached to an aryl group, for example-CH₂CH₂-phenyl. The term "substituted aralkyl" means an aralkyl functional group in which the aryl group is substituted. Similarly, the term "heteroaralkyl" means a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroaralkyl" means a heteroaralkyl functional group in which a heteroaryl group is substituted.

As used herein, unless otherwise specified, the term "alkoxy" used alone or in combination with other terms means an alkyl group having the specified number of carbon atoms attached to the remainder of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. Preferred alkoxy is (C)₁-C₃) An alkoxy group.

It is to be understood that any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and cycloalkenyl moieties described herein can also be an aliphatic or alicyclic radical.

An "aliphatic" group is a non-aromatic moiety consisting of any combination of carbon, hydrogen, halogen, oxygen, nitrogen, or other atoms, and optionally contains one or more units of unsaturation, such as double and/or triple bonds. Examples of aliphatic radicals are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH₂、C(O)、S(O)₂、C(O)O、C(O)NH、OC(O)O、OC(O)NH、OC(O)NH₂、S(O)₂NH、S(O)₂NH₂、NHC(O)NH₂、NHC(O)C(O)NH、NHS(O)₂NH、NHS(O)₂NH₂、C(O)NHS(O)₂、C(O)NHS(O)₂NH or C (O) NHS (O)₂NH₂Etc.; a group comprising one or more functional groups, a non-aromatic hydrocarbyl group (optionally substituted), and a group in which one or more carbon atoms of the non-aromatic hydrocarbyl group (optionally substituted) are replaced with a functional group. The carbon atoms of the aliphatic group may be optionally substituted by oxo. The aliphatic radical may be linear, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24And more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyl groups, polyalkoxyalkyl groups such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group may be optionally substituted.

The terms "heterocycle" or "heterocycloalkyl" are used interchangeably and refer to a non-aromatic ring or a bicyclic or tricyclic group fused, bridged or spiro ring system in which (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms, which may be optionally substituted by oxo or optionally substituted by an exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinone (pyridazizinonyl), 2-azabicyclo [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1-oxa-7-azaspiro [4.4] nonyl, 7-oxooxepin-4-yl, and tetrahydrofuranyl. These heterocyclic groups may be further substituted. The heteroaryl or heterocyclyl group may be C-linked or N-linked (if possible).

It is to be understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc., described herein, when used as a bond that can join two or more groups or substituents at the same or different atoms, can also be a divalent or multivalent group. The valency of any such group can be readily determined by those skilled in the art from the context in which it occurs.

The term "substituted" refers to substitution by independently replacing one, two, or three or more hydrogen atoms with a substituent including, but not limited to, -F, -Cl, -Br, -I, -OH, C₁-C₁₂-an alkyl group; c₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, -C₃-C₁₂-cycloalkyl, protected hydroxy, -NO₂、-N₃、-CN、-NH₂Protected amino, oxo, thio, -NH-C₁-C₁₂-alkyl, -NH-C₂-C₈-alkenyl, -NH-C₂-C₈-alkynyl, -NH-C₃-C₁₂-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C₁-C₁₂-alkyl, -O-C₂-C₈-alkenyl, -O-C₂-C₈-alkynyl, -O-C₃-C₁₂-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C₁-C₁₂Alkyl, -C (O) -C₂-C₈-alkenyl, -C (O) -C₂-C₈-alkynyl, -C (O) -C₃-C₁₂-cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) -heterocycloalkyl, -CONH₂、-CONH-C₁-C₁₂-alkyl, -CONH-C₂-C₈-alkenyl, -CONH-C₂-C₈-alkynyl, -CONH-C₃-C₁₂-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO₂-C₁-C₁₂-alkyl, -OCO₂-C₂-C₈-alkenyl, -OCO₂-C₂-C₈-alkynyl, -OCO₂-C₃-C₁₂-cycloalkyl, -OCO₂-aryl, -OCO₂-heteroaryl, -OCO₂-heterocycloalkyl, -CO₂-C₁-C₁₂Alkyl, -CO₂-C₂-C₈Alkenyl, -CO₂-C₂-C₈Alkynyl, CO₂-C₃-C₁₂-cycloalkyl, -CO₂Aryl, CO₂-heteroaryl, CO₂-heterocycloalkyl, -OCONH₂、-OCONH-C₁-C₁₂-alkyl, -OCONH-C₂-C₈-alkenyl, -OCONH-C₂-C₈-alkynyl, -OCONH-C₃-C₁₂-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC (O) H, -NHC (O) -C₁-C₁₂-alkyl, -NHC (O) -C₂-C₈-alkenyl, -NHC (O) -C₂-C₈-alkynyl, -NHC (O) -C₃-C₁₂-cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -heterocycloalkyl, -NHCO₂-C₁-C₁₂-alkyl, -NHCO₂-C₂-C₈-alkenyl, -NHCO₂-C₂-C₈-alkynyl, -NHCO₂-C₃-C₁₂-cycloalkyl, -NHCO₂-aryl, -NHCO₂-heteroaryl, -NHCO₂-heterocycloalkyl, -NHC (O) NH₂、-NHC(O)NH-C₁-C₁₂Alkyl, -NHC (O) NH-C₂-C₈-alkenyl, -NHC (O) NH-C₂-C₈-alkynyl, -NHC (O) NH-C₃-C₁₂-cycloalkyl, -NHC (O) NH-aryl, -NHC (O) NH-heteroaryl, -NHC (O) NH-heterocycloalkyl, NHC (S) NH₂、-NHC(S)NH-C₁-C₁₂Alkyl, -NHC (S) NH-C₂-C₈-alkenyl, -NHC (S) NH-C₂-C₈-alkynyl, -NHC (S) NH-C₃-C₁₂-cycloalkyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, -NHC (NH) NH₂、-NHC(NH)NH-C₁-C₁₂Alkyl, -NHC (NH) NH-C₂-C₈-alkenyl, -NHC (NH) NH-C₂-C₈-alkynyl, -NHC (NH) NH-C₃-C₁₂-cycloalkyl, -NHC (NH) NH-aryl, -NHC (NH) NH-heteroaryl, -NHC (NH) NH-heterocycloalkyl, -NHC (NH) -C₁-C₁₂-alkyl, -NHC (NH) -C₂-C₈-alkenyl, -NHC (NH) -C₂-C₈-alkynyl, -NHC (NH) -C₃-C₁₂-cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C₁-C₁₂Alkyl, -C (NH) NH-C₂-C₈-alkenyl, -C (NH) NH-C₂-C₈-alkynyl, -C (NH) NH-C₃-C₁₂-cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocycloalkyl, -S (O) -C₁-C₁₂-alkyl, -S (O) -C₂-C₈-alkenesRadical, -S (O) -C₂-C₈-alkynyl, -S (O) -C₃-C₁₂-cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO₂NH₂、-SO₂NH-C₁-C₁₂-alkyl, -SO₂NH-C₂-C₈-alkenyl, -SO₂NH-C₂-C₈-alkynyl, -SO₂NH-C₃-C₁₂-cycloalkyl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -SO₂NH-heterocycloalkyl, -NHSO₂-C₁-C₁₂-alkyl, -NHSO₂-C₂-C₈-alkenyl, -NHSO₂-C₂-C₈-alkynyl, -NHSO₂-C₃-C₁₂-cycloalkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHSO₂-heterocycloalkyl, -CH₂NH₂、-CH₂SO₂CH₃-aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C₃-C₁₂Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C₁-C₁₂-alkyl, -S-C₂-C₈-alkenyl, -S-C₂-C₈-alkynyl, -S-C₃-C₁₂-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthiomethyl. It is understood that aryl, heteroaryl, alkyl, cycloalkyl, and the like may be further substituted.

As used herein, the term "halo" or "halogen" alone or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

As used herein, the term "optionally substituted" means that the group referred to may be substituted or unsubstituted. In one embodiment, the mentioned groups are optionally substituted with 0 substituents, i.e. the mentioned groups are unsubstituted. In another embodiment, the mentioned groups are optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

The term "hydrogen" includes hydrogen and deuterium. Furthermore, recitation of an atom includes other isotopes of that atom, provided that the resulting compound is pharmaceutically acceptable.

As used herein, the term "hydroxyl activating group" refers to a labile chemical moiety known in the art that activates a hydroxyl group to be liberated during synthesis, for example, in a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylate, tosylate, triflate, paranitrobenzoate, phosphonate, and the like.

As used herein, the term "activated hydroxyl group" refers to a hydroxyl group activated with a hydroxyl activating group as defined above, including, for example, mesylate, tosylate, triflate, paranitrobenzoate, phosphonate.

As used herein, the term "hydroxyl protecting group" refers to a labile chemical moiety known in the art that protects a hydroxyl group from undesired reactions during synthesis. Following the synthetic procedure(s), the hydroxyl protecting group, as described herein, may be selectively removed. Hydroxyl protecting groups known in the art are generally described in t.h.greene and p.g.m.wuts,Protective Groups in Organic Synthesis3 rd edition, John Wiley&Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, isopropyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- (trimethylsilyl) -ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl and the like.

As used herein, the term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl.

As used herein, the term "hydroxy prodrug group" refers to a precursor moiety (promoity) group known in the art that alters the physicochemical properties of the parent drug, thereby altering its biological properties, in a transient manner by covering or masking the hydroxy group. After the synthetic process (es), the hydroxy prodrug group as described herein must be able to revert back to the hydroxy group in vivo. Hydroxy prodrug groups known in the art are generally described in Kenneth b.sloan,Prodrugs,Topical and Ocular Drug Delivery(Drugs and the Pharmaceutical Sciences; Vol. 53), Marcel Dekker, Inc., New York (1992).

As used herein, the term "amino protecting group" refers to a labile chemical moiety known in the art that protects an amino group from undesired reactions during synthesis. Following the synthetic procedure(s), the amino protecting groups described herein may be selectively removed. Amino protecting groups known in the art are generally described in t.h.greene and p.g.m.wuts,Protective Groups in Organic Synthesis3 rd edition, John Wiley&Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

As used herein, the term "protected amino" refers to an amino group that is protected with an amino protecting group as defined above.

The term "leaving group" means a functional group or atom that can be replaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. Representative leaving groups include, for example, chloro, bromo, and iodo groups; sulfonate groups such as mesylate, tosylate, bromobenzenesulfonate, nitrobenzenesulfonate, and the like; and acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.

As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to protic activity, i.e., a solvent that does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene; example (b)Such as halogenated hydrocarbons, e.g., dichloromethane, dichloroethane, chloroform, etc.; heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidone; and ethers, such as diethyl ether, bismethoxymethyl ether. These compounds are well known to those skilled in the art and it will be apparent to those skilled in the art that depending on factors such as the solubility of the reagents, the reactivity of the reagents and the preferred temperature range, a single solvent or mixture thereof may be preferred for a particular compound and reaction conditions. Further discussion of aprotic solvents can be found in textbooks or professional monographs of organic chemistry, for example:Techniques of Chemistry Series,John Wiley&sons, NY,1986Organic Solvents Physical Properties and Methods of PurificationEdition 4, edited by John a. riddic et al, volume II.

As used herein, the term "protic solvent" refers to a solvent that tends to donate protons, such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like. Such solvents are well known to those skilled in the art and it will be apparent to those skilled in the art that depending on factors such as the solubility of the reagents, the reactivity of the reagents and the preferred temperature range, a single solvent or mixture thereof may be preferred for a particular compound and reaction conditions. Further discussion of proton donating solvents can be found in textbooks or professional monographs of organic chemistry, for example:Techniques of Chemistry Series,John Wiley&sons, NY,1986Organic Solvents Physical Properties and Methods of PurificationEdition 4, edited by John a. riddic et al, volume II.

Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to achieve preparation and maintain the integrity of the compound for a sufficient period of time for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compound can be separated from the reaction mixture by, for example, column chromatography, high pressure liquid chromatographyFurther purifying by spectrum or recrystallization. As will be appreciated by those skilled in the art, additional methods of synthesizing the compounds of the general formulae herein will be apparent to those of ordinary skill in the art. In addition, the various synthetic steps may be performed in alternating order or sequence to obtain the desired compound. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, in r.larock,Comprehensive Organic TransformationsWiley-VCH (1999), 2 nd edition; T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis3 rd edition, John Wiley and Sons (1999); l.fieser and m.fieser,Fieser and Fieser's Reagents for Organic Synthesisjohn Wiley and sons (1994); and compiled by l.paquette,Encyclopedia of Reagents for Organic Synthesisthose described in John Wiley and Sons (1995) and its subsequent versions.

As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subjects also refer to, for example, dogs, cats, horses, cattle, pigs, guinea pigs, fish, birds, and the like.

The compounds of the present invention may be modified by the addition of appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and may include those that increase bio-penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R) -or (S) -or, for amino acids, as (D) -or (L) -. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared by the above-described procedures from their corresponding optically active precursors, or by resolution of racemic mixtures. The disassembly can be carried outIn the presence of a partitioning agent, by chromatography or by repeated crystallization or by some combination of these techniques known to those skilled in the art. More details on the split can be found in Jacques et al,Enantiomers,Racemates,and Resolutions(John Wiley&sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturations, or other centers of geometric asymmetry, the compounds are intended to include both E and Z geometric isomers or both cis and trans isomers, unless otherwise specified. Likewise, all tautomeric forms are intended to be included. Tautomers can be cyclic or acyclic. The configuration of any carbon-carbon double bond present herein is chosen for convenience only and is not intended to designate a particular configuration unless the text so states; thus, a carbon-carbon double bond or a carbon-heteroatom double bond, optionally described herein as trans, may be cis, trans, or a mixture of both in any proportion.

Certain compounds of the invention may also exist in different stable conformational forms, which may be separable. Torsional asymmetry due to, for example, steric hindrance or ring tension, may allow separation of different conformers due to limited rotation about asymmetric single bonds. The present invention includes each conformational isomer of these compounds and mixtures thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences,66:1-19(1977) by S.M.Berge et al. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl groups having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo, including those that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, naphthenic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

Suitable concentrations of reactants for use in the synthesis process of the invention are in the range 0.01M to 10M, typically 0.1M to 1M. Suitable temperatures include-10 ℃ to 250 ℃, typically-78 ℃ to 150 ℃, more typically-78 ℃ to 100 ℃, still more typically 0 ℃ to 100 ℃. The reaction vessel is preferably made of any material that does not substantially interfere with the reaction. Examples include glass, plastic and metal. The reaction pressure can advantageously be operated at atmospheric pressure. For reactions that are not sensitive to oxygen or water, the atmosphere comprises, for example, air, and for reactions that are sensitive to oxygen and water, the atmosphere comprises, for example, nitrogen or argon.

As used herein, the term "in situ" refers to the use of an intermediate in the solvent or solvents in which it is prepared, without removal of the solvent.

Abbreviations

Abbreviations that may be used in the description of the schemes and examples below are:

ac is acetyl;

AcOH is acetic acid;

Boc₂o is di-tert-butyl dicarbonate;

boc is tert-butyloxycarbonyl;

bz is benzoyl;

bn is benzyl;

brine is sodium chloride aqueous solution;

t-BuOH is tert-butyl alcohol;

t-BuOK is potassium tert-butoxide;

Bu₄NBr is tetrabutylammonium bromide;

cbz is benzyloxycarbonyl;

CDI is 1, 1' -carbonyldiimidazole;

CH₂Cl₂is dichloromethane;

CH₃is methyl;

CH₃CN is acetonitrile;

Cs₂CO₃is cesium carbonate;

DIBAL-H is diisobutylaluminum hydride;

DIPEA or (I-Pr)₂EtN is N, N-diisopropylethylamine;

DMAP is 4-dimethylamino-pyridine;

DME is 1, 2-dimethoxyethane;

DMF is N, N-dimethylformamide;

DMSO is dimethyl sulfoxide;

EDC is N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide;

EDC & HCl is N- (3-dimethylamino-propyl) -N' -ethylcarbodiimide hydrochloride;

EtOAc is ethyl acetate;

EtOH is ethanol;

Et₂o is diethyl ether;

HATU is O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate;

HCl is hydrogen chloride;

K₂CO₃is potassium carbonate;

MeOH is methanol;

MTBE is methyl tert-butyl ether;

NaCl is sodium chloride;

NaH is sodium hydride;

NaHCO₃is sodium bicarbonate (sodium bicarbonate) or sodium hydrogenocarbonate (sodium hydrogenocarbonate);

Na₂CO₃is sodium carbonate;

NaOH is sodium hydroxide;

NaOMe is sodium methoxide;

Na₂SO₄is sodium sulfate;

Na₂S₂O₃is sodium thiosulfate;

NH₄HCO₃is ammonium bicarbonate;

NH₄cl is ammonium chloride;

NMP is N-methyl-2-pyrrolidone;

o/n is overnight;

OH is hydroxyl;

pd is palladium;

PDC is pyridinium dichromate;

i-PrOAc is isopropyl acetate;

ph is phenyl;

PMB is p-methoxybenzyl;

rt is room temperature;

TBS is tert-butyldimethylsilyl;

TEA or Et₃N is triethylamine;

THF is tetrahydrofuran;

TPP or PPh₃Is triphenylphosphine;

ts is tosyl or-SO₂-C₆H₄CH₃；

TsOH is p-toluenesulfonic acid;

TMS is trimethylsilyl;

TMSCl is trimethylchlorosilane.

All other abbreviations used herein that are not specifically described above shall have the meaning that would be appended by one of ordinary skill in the art.

Examples

The compounds and methods of the present invention will be better understood in conjunction with the following examples, which are intended to be illustrative only and not limiting as to the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention, may be made without departing from the spirit of the invention and scope of the appended claims.