RU2794124C2 - Methods for obtaining benzodiazepine derivatives - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a process for the preparation of a compound of formula (Ia), wherein the said process comprises (a) reacting a compound of formula (VII), where R₇ is selected from the group consisting of hydrogen, C₁-C₈-alkyl, C₂-C₈- alkenyl, C₂-C₈-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, 3-8-membered heterocyclic fragment, aryl and heteroaryl; and X is chloro; with a compound of formula (VII-X), where PG is hydrogen; to form a compound of formula (VIII-d); (b) reacting a compound of formula (VIII) with morpholine to form a compound of formula (Xd); c) reaction of a compound of formula (IV) with 1.1'-carbonyldiimidazole or nitrophenylchloroformate to give a compound of formula (III) wherein R₅ is 1-imidazolyl or nitrophenyl-O-; d) isolation and purification of the compound of formula (III); (e) reacting a compound of formula (III) with a compound of formula (Xd), said reaction being carried out at a temperature of from about 10 to 50°C for 6 to 48 hours and at a concentration of the compound of formula (III) from about 1 M to 3 M and a molar ratio of compound of formula (III) and compound of formula (Xd) 1:1, to obtain a compound of formula (Va), and (f) reacting a compound of formula (Va) with a cyclization reagent to form a compound of formula (I-a).

EFFECT: method for obtaining biologically active molecules, respiratory syncytial virus (RSV) inhibitors.

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Description

RELATED APPLICATIONS

This application claims priority over U.S. Provisional Application No. 62/459955, filed February 16, 2017, and U.S. Provisional Application No. 62/459953, filed February 16, 2017. The inventive concept set forth in the above application is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

This invention relates to methods and intermediates suitable for the preparation of biologically active molecules, especially for the synthesis of respiratory syncytial virus (RSV) inhibitors.

BACKGROUND OF THE INVENTION

Human respiratory syncytial virus (HRV) is a paramyxovirus whose genome is a negative single-stranded RNA (KM. Empey, et al, Rev. Anti-Infective Agents, 2010, 50(1 May), 1258-1267). RSV is a major cause of acute lower respiratory tract infections (ALRIs) and affects patients of all ages. Symptoms in adults are usually not severe and are usually similar to a mild cold. However, in infants and preschool children, the virus can cause lower respiratory tract infections, including bronchiolitis and pneumonia, with many requiring hospitalization. Almost all children were infected before the age of 3 years. In known high-risk groups, RSV infection is more likely to progress to ALRTI. Premature infants and/or infants suffering from lung or heart disease are at the greatest risk of developing ALRTI. Additionally, high-risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant patients, and

immunocompromised patients.

There is currently no available vaccine to prevent RSV infection. Palivizumab is a monoclonal antibody that is used prophylactically to prevent RSV infection in high-risk infants, such as premature infants and infants with heart and/or lung disease. The high cost of palivizumab treatment limits its general use. Ribavirin is also used to treat RSV infections, but its effectiveness is limited. There is a great medical need for new and effective treatments for RSV, which, in general, can be used by populations of all types and ages.

Several RSV fusion inhibitors are disclosed in the following publications: WO2010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO2013/186332, WO2012/08WO0451 2012/080449, WO2012 /080447, WO2012/080446 and J. Med. Chem. 2015, 58, 1630-1643. Examples of other N protein inhibitors for the treatment of HDH are disclosed in the following publications: WO2004/026843, J. Med. Chem. 2006, 49, 2311-2319 and J Med. Chem. 2007, 50, 1685-1692. Examples of protein L inhibitors are disclosed in the following publications: WO2011/005842, WO2005/0422530, Antiviral Res . 2005, 65, 125-131 and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793. 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 HDS. The present invention defines compounds that are aminoheteroaryl substituted benzodiazepines and inhibit RSHF. The invention covers methods for preparing compounds, as well as methods for using these compounds to treat a disease.

SUMMARY OF THE INVENTION

The present invention provides methods for preparing compounds of formula (I), or a pharmaceutically acceptable salt thereof:

,

,

where A is an optionally substituted aryl or an optionally substituted heteroaryl; preferably A is an optionally substituted pyridyl; each n is chosen independently from 1 and 2; preferably, each n is 1; m is 0, 1, 2, 3, or 4; preferably m is 0;

R ₁ is selected from the group consisting of:

1) optionally substituted -C ₁ -C ₈ -alkyl;

2) optionally substituted -C ₃ -C ₈ -cycloalkyl; And

3) an optionally substituted 3-12 membered heterocyclic moiety.

Alternatively, two adjacent R groups₁ together with the carbon atoms to which they are attached, form a condensed ring; two geminal groups R₁ together with the carbon atom to which they are attached, they form a spiro ring; or two R groups₁ on non-adjacent carbons together form a bridging group, namely -CH₂- or -CH₂CH₂-.

Preferably, if m is not 0, each R ₁ is methyl.

A preferred compound of formula (I) is compound (I-a):

.

.

The invention further relates to methods for increasing product yield and reducing the number of process steps for medium- and large-scale production of compounds of formula (I), namely compound (I-a). These compounds are useful as RSV inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In a basic embodiment, the invention provides methods for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof:

,

,

where A, R ₁ , m and n are described above. In certain embodiments of the invention,

  выбирают из групп, перечисленных ниже:

choose from the groups listed below:

The method includes the steps

1) reactions of the compound of formula (VII)

,

,

where R ₇ is selected from the group consisting of hydrogen, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl , 3-8-membered heterocyclic fragment, aryl and heteroaryl; and X is a substitutable group, namely, but not limited to, halogen or -O-triflate;

with a compound of formula (VII-X),

,

,

where PG is hydrogen or an amine protecting group, namely, but not limited to, carbobenzyloxy (cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, or 9-fluorenylmethoxycarbonyl;

to form a compound of formula (VIII),

;

;

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

,

,

where R ₁ , m and n are described above;

to form a compound of formula (X):

;

;

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

,

,

where R ₅ is selected from the group consisting of -O(CO)O-R ₆ , optionally substituted aryl and optionally substituted heteroaryl; and R ₆ is selected from the group consisting of optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ -cycloalkenyl, optionally substituted 3-8 membered heterocyclic fragment, optionally substituted aryl and optionally substituted heteroaryl;

to form a compound of formula (V),

; и

; And

4) reacting a compound of formula (V) with a cyclization reagent to form a compound of formula (I).

A preferred embodiment of a compound of formula (VIII) is a compound of formula (VIII-a), formula (VIII-b), or formula (VIII-c):

,

,

where, R ₄ is selected from halogen, methyl, CF ₃ and CN. A more preferred embodiment of a compound of formula (VIII) is a compound of formula (Vlll -d),

.

.

A preferred embodiment of a compound of formula (X) is a compound of formula (X-a), formula (X-b), or formula (X-c):

.

.

A more preferred embodiment of a 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 a compound of formula (V) is compound (V-a):

The compound of formula (III) is formed by the reaction of the compound (IV),

,

,

with an activating reagent of the formula YC(O)R ₅ where Y is a substitutable group, namely halo or 1-imidazolyl.

Compound (IV) is obtained, for example, by separating a racemic mixture of compound (IV) and its enantiomer.

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

In another embodiment, the invention provides compositions containing a compound of formula (I), or a pharmaceutically acceptable salt thereof in a solid amorphous state, and a pharmaceutically acceptable hydrophilic polymer to increase activity.

In one embodiment of this aspect of the invention, the hydrophilic polymer is selected from N-vinyl lactam homopolymer, N-vinyl lactam copolymers, cellulose esters, cellulose ethers, polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharides, and polysaccharides. Non-limiting examples of suitable hydrophilic polymers include N-vinylpyrrolidone homopolymer, N-vinylpyrrolidone copolymers, N-vinylpyrrolidone-vinyl acetate copolymers, N-vinylpyrrolidone-vinyl propionate copolymers, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcellulose, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose acetate succinate, polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), poly(hydroxyalkyl acrylate), poly(hydroxyalkyl acrylate), copolymer 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 an N-vinylpyrrolidone homopolymer or copolymer. Preferably, the hydrophilic polymer is copovidone.

Compositions containing a compound of formula (I), or a pharmaceutically acceptable salt thereof in a solid amorphous state, and a pharmaceutically acceptable hydrophilic polymer are prepared by a variety of techniques, namely, without limitation, melt extrusion, spray drying, co-precipitation, freeze drying, or others. solvent evaporation techniques, with melt extrusion and spray drying being preferred. The melt extrusion process typically includes melt forming steps that include active ingredient(s), hydrophilic polymer(s), and preferably surfactant(s), and then cooling melt until it hardens. "Melting" means a transition to a liquid or highly elastic state, in which it becomes possible for one component to penetrate, preferably to penetrate homogeneously, into another component or components. In many cases, the polymer component(s) are melted and the other components, including the active ingredient(s), are dissolved in the melt, thus forming a solution. Melting typically involves heating above the softening temperature of the polymer(s). The melt is obtained in many ways. The mixing of the components occurs before, during or after the formation of the melt. For example, the components are first mixed, then melted, or simultaneously mixed and melted. The melt is homogenized in order to effectively distribute the active(s) ingredient(s). Additionally, it is convenient to first melt the polymer(s) and then add and homogenize the active(s) ingredient(s). In one example, all materials except the surfactant(s) are mixed and fed into the extruder, and the surfactant(s) are melted outside the extruder and pumped during extrusion.

SYNTHESIS SCHEMES

The present invention will be better understood in conjunction with Schemes 1-2, where A, R ₁ , PG, X, m, n and R ₅ are described above unless otherwise indicated.

An ordinary specialist in the art it is obvious that the method according to this invention can be carried out with the replacement of the corresponding reagents, and the order of the steps themselves is changed.

The sequence of chemical processes for the synthesis of hydrazide, compounds of formula (X) is shown in scheme (1).

Scheme 1

R ₇ is selected from the group consisting of hydrogen, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl, 3-8-membered heterocyclic fragment, aryl and heteroaryl. Preferably, the compound of formula (VII) is 3-halo-5-(trifluoromethyl)-2-pyridinecarboxylic acid or alkyl-3-halo-5-(trifluoromethyl)picolinate and more preferably ethyl-3-chloro-5-(trifluoromethyl )picolinate, which is commercially available. Preferred compounds of formula (VII-X) include hydrazine monohydrate, tert-butoxycarbonylhydrazine or carbobenzoxyhydrazine.

In one embodiment, R ₇ is C ₁ -C ₈ alkyl, preferably methyl or ethyl. In this embodiment, the reaction of a compound of formula (VII) and hydrazine monohydrate typically takes place in a protic solvent, such as, but not limited to, methanol, ethanol, or isopropyl alcohol, or a mixture of two or more of these. The reaction temperature is typically from about 10°C to about 70°C, and the reaction time is typically from about 3 to 12 hours.

In another embodiment, R ₇ is hydrogen and a compound of formula (VII) is converted to a compound of formula (VIII) by a coupling reaction with a compound of formula (VII-X) in the presence of an amide-forming agent, namely 1,1'-carbonyldiimidazole, bis (2-oxo-3-oxazolidinyl)phosphine chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one, 1-(3-dimethylaminopropyl) hydrochloride )-3-ethylcarbodiimide, 4-nitrophenol,

pentafluorophenol, 2-hydroxypyridine, N-hydroxysuccinimide, N-hydroxyphthalamide, 2-mercaptobenzoxazole, trimethylacetyl chloride, isobutyl chloroformate, chlordimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide, 5-nitro-2-hydroxypyridine, tert-butoxycarbonyl-L-valine anhydride or mixtures thereof. Examples of suitable solvents for these reactions include, but are not limited to, isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, N-methylpyrrolidone, 2-methyltetrahydrofuran, and acetonitrile. Specific reaction conditions vary depending on the nature of the coupling agent and are known to those of ordinary skill in the art.

Compounds of formula (VIII) are converted to a compound of formula (X) by amination with a compound of formula (IX). The compound of formula (IX) is, but is not limited to, morpholine, 2-methylmorpholine and its stereoisomers, 3-methylmorpholine and its stereoisomers, 3,5-dimethylmorpholine and its stereoisomers, 2,6-dimethylmorpholine 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 typically takes place 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 typically about 10°C to about 100°C, and the reaction time is typically 3 to 12 hours.

In one embodiment where PG is not hydrogen, the compound of formula (X) is deprotected by removal of PG. Suitable deprotection conditions depend on the type of PG and are known to those skilled in the art, for example, as generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis . 3rd edition, John Wiley & Sons, New York (1999).

Scheme 2 depicts the synthesis of a compound of formula (I),

Scheme 2

Compound (XI) is either commercially available or can be synthesized by methods known to those of ordinary skill in the art. Chiral separation of the racemic compound (XI) is carried out by methods such as, but not limited to, treatment with chiral acid and separation of the diastereomeric salt 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 obtain the S-isomer of the chiral compound (IV). In one embodiment, compound (IV) is prepared from racemic compound (XI) using the methods disclosed in Provisional Application US No. 62/585192.

In one embodiment of the invention, SFC is used to obtain a chiral compound (IV); the mobile phase is carbon dioxide (CO ₂ ) or a mixture of carbon dioxide and a polar organic co-solvent, namely, but not limited to, methanol, ethanol or 2-propanol; the temperature is limited to a range of 5 to 40-50°C, preferably the temperature is ambient temperature (about 25°C). SFC procedures and conditions vary depending on the nature of the racemic compounds and are known to those of ordinary skill in the art.

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

In one embodiment of the invention, after chiral separation, in addition to the chiral compound (IV), another epimer is also obtained - the R-isomer of the chiral compound (IV-A).

In one embodiment of the invention, the chiral compound (IV-A) is racemized under basic conditions to obtain the racemic compound (XI). Racemization occurs in a protic solvent, namely, but not limited to, methanol, ethanol, tert-butyl alcohol or isopropyl alcohol in the presence of a base, namely, but not limited to, NaOMe or t-BuOK. The reaction temperature is typically from about 10°C to about 70°C, and the reaction time is typically from about 3 to 24 hours.

In one embodiment of the invention, a chiral compound (IV) is converted to a compound of formula (III) using an amine activating agent, namely, but not limited to, 1,1'-carbonyldiimidazole, nitrophenyl chloroformate, triphosgene, or phosgene. This process is usually carried out in a protic or aprotic solvent, namely, but not limited to, acetonitrile, THF, DMSO or dichloromethane. A typical reaction temperature is from about 0° C. to about 30° C., and the reaction time is typically from about 6 to 15 hours. In one aspect, the molar ratio of compound (IV) to amine activating agent is about 1:1. In one aspect, the molar ratio of compound (IV) to amine activating agent is about 1:2. In one aspect, the molar ratio of compound (IV) to amine activating agent is about 1:3. Preferably, the molar ratio of the compound (IV) to the amine activating agent is about 1:3.

In one embodiment, PG is hydrogen; the reaction of a compound of formula (III) with a compound of formula (X) is carried out in a protic solvent, namely, but not limited to, acetonitrile, THF, DMSO, DMF, sulfolane, or 1-methyl-2-pyrrolidone. A typical reaction temperature is from about 10° C. to 50° C., and the reaction time is typically 6 to 48 hours. The reaction is generally carried out at a concentration of the compound of formula (III) from about 1 M to about 3 M, preferably the concentration of the compound of formula (III) is 1.5 M. The molar ratio of the compound of formula (III) to the compound of formula (X) is 1:1.

A compound of formula (V) is cyclized to a compound of formula (I) by reaction with a cyclization agent, namely, 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. This process is carried out in an aprotic solvent, namely, but not limited to, acetonitrile, THF, DMF, DMSO, N-methylpyrrolidone, acetone, dichloromethane, ethyl acetate, or isopropyl acetate. The reaction temperature is from about 0° C. to about 30° C., and the reaction time is typically 3 to 15 hours.

DEFINITIONS

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

As used herein, the term "aryl" refers to mono- or polycyclic carbocyclic ring systems containing at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that contains at least one aromatic ring. Polycyclic aryls contain conjugated rings, covalently linked rings, or combinations thereof.

As used herein, the term "heteroaryl" refers to a mono- or polycyclic aromatic radical having one or more ring-forming atom selected from S, O and N; and the remaining ring forming atoms are carbon, any N or S contained in the ring being optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryl contains conjugated rings, covalently linked rings, or combinations thereof.

In accordance with the invention, aromatic groups are substituted or unsubstituted.

The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one ring being aromatic; and two rings are conjugated or covalently linked.

Used in this document, the term "alkyl" refers to a saturated linear or branched hydrocarbon radical. "C ₁ -C ₄ -alkyl", "C ₁ -C ₆ -alkyl", "C ₁ -C ₈ -alkyl", "C ₁ -C ₁₂ -alkyl", "C ₂ -C ₄ -alkyl" or "C ₃ -C ₆ alkyl" refers to an alkyl group containing one to four, one to six, one to eight, one to twelve, 2 to 4, and 3 to 6 carbon atoms, respectively. Examples of C ₁ -C ₈ hydrocarbon radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

Used in this document, the term "alkenyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond as a result of the removal of one hydrogen atom. "C ₂ -C ₈ -alkenyl", "C ₂ -C ₁₂ -alkenyl", "C ₂ -C ₄ -alkenyl", "C ₃ -C ₄ -alkenyl" or "C ₃ -C ₆ -alkenyl" refer to alkenyl groups containing two to eight, two to twelve, two to four, three to four, or three to six carbon atoms, respectively. Alkenyl groups include, for example, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

Used in this document, the term "alkynyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond as a result of the removal of one hydrogen atom. "C ₂ -C ₈ alkynyl", "C ₂ -C ₁₂ alkynyl", "C ₂ -C ₄ alkynyl", "C ₃ -C ₄ alkynyl" or "C ₃ -C ₆ alkynyl" refer to to alkynyl groups containing two to eight, two to twelve, two to four, three to four, or three to six carbon atoms, respectively. Representative alkynyl groups include, for example, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tricyclic conjugated, bridged, or spiro system, and the carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C ₃ -C ₁₂ -cycloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₈ -cycloalkyl and C ₄ -C ₇ -cycloalkyl. Examples of C ₃ -C ₁₂ -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-methylenecyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl , 3-methylenebicyclo[3.2.1]octyl, spiro[4,4]nonanyl and the like.

As used herein, the term "cycloalkenyl" refers to a monocyclic or polycyclic carbocyclic ring or a bi- or tricyclic conjugated, bridged, or spiro system having at least one carbon-carbon double bond and the carbon atoms are optionally oxo-substituted or optionally substituted exocyclic olefinic double bond. Preferred cycloalenyl groups include C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₈ cycloalkenyl or C ₅ -C ₇ cycloalkenyl groups. Examples of C ₃ -C ₁₂ -cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl , spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.

Used in this document, the term "arylalkyl" means a functional group in which the alkenyl chain is attached to the aryl group, for example, to -CH ₂ CH ₂ -phenyl. The term "substituted arylalkyl" means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" means a functional group in which an alkenyl chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" means a heteroarylalkyl functional group in which the heteroaryl group is substituted.

As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise indicated, means an alkyl group having the specified number of carbon atoms attached to the rest of the molecule through an oxygen atom, namely, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologues or isomers. Preferred alkoxy are C ₁ -C ₃ -alkoxy.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein is also an aliphatic or alicyclic group.

An "aliphatic group" is a non-aromatic moiety of a molecule consisting of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen and other atoms, and optionally contains one or more units of unsaturation, such as double and/or triple bonds. Examples of aliphatic groups are functional groups, namely, alkyl, alkenyl, alkynyl, O, OH, NH, NH ₂ , C(O), S(O) ₂ , C(O)O, C(O)NH, OC (O) O, OC (O) NH, OC (O) NH ₂ , S (O) ₂ NH, S (O) ₂ NH ₂ , NHC (O) NH ₂ , NHC (O) C (O) NH, NHS(O) ₂ NH, NHS(O) ₂ NH ₂ , C(O)NHS(O) ₂ , C(O)NHS(O) ₂ NH or C(O)NHS(O) ₂ NH ₂ and the like , groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons from a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms in the aliphatic group are optionally oxo-substituted. The aliphatic group is linear, branched, cyclic, or a combination thereof, and preferably contains from 1 to about 24 carbon atoms, more preferably from about 1 to about 12 carbon atoms. In addition to the aliphatic hydrocarbon groups used herein, aliphatic groups intentionally include, for example, alkoxyalkyls, polyalkoxyalkyls, namely, for example, polyalkylene glycols, polyamines, and polyimines. Aliphatic groups are optionally substituted.

The terms "heterocyclic" or "heterocycloalkyl" are used interchangeably and refer to a non-aromatic ring or a bi- or tricyclic conjugated, bridged, or spiro system, wherein (1) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (2) each ring system is saturated or unsaturated, (3) the nitrogen and sulfur heteroatoms are optionally oxidized, (4) the nitrogen heteroatom is optionally quaternary, (5) any of the above rings is conjugated with an aromatic ring, and (6) the remaining ring forming atoms are carbon atoms that are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Exemplary heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinolyl, 2-azabicyclo[ 1]heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl and tetrahydrofuryl. Such heterocyclic groups are further substituted. Heteroaryl or heterocyclic groups are attached to C or N (if possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like disclosed herein is also a monovalent or multivalent group when used as a bridge to link two or more groups or substituents that occur on the same atom or on different atoms. One skilled in the art will readily determine the valency of any such group from the context in which it is used.

The term "substituted" refers to substitution through the independent replacement of one, two, three or more hydrogen atoms with substituents, which include, but are not limited to, -F, -CI, -Br, -I, -OH, C ₁ -C ₁₂ - alkyl; C ₂ -C ₁₂ -alkenyl, C ₂ -C ₁₂ -alkynyl, -C ₃ -C ₁₂ -cycloalkyl, protected hydroxy group, -NO ₂ , -N ₃ , -CN, -NH ₂ , protected amino group, oxo-, thioxo-, -NH-C ₁ -C ₁₂ -alkyl, -NH-C ₂ -C ₈ -alkenyl, -NH-C ₂ -C ₈ -alkynyl, -NH-C ₃ -C ₁₂ -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -0-C ₁ -C ₁₂ -alkyl, -0-C ₂ -C ₈ -alkenyl, -0-C ₂ -C ₈ -alkynyl, -OC ₃ -C ₁₂ -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C ₁ -C ₁₂ -alkyl, -C (O) -C2-C8-alkenyl, -C(O)-C ₂ -C ₈ -alkynyl, -C(O)-C ₃ -C ₁₂ -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl , -C(O)-heterocycloalkyl, -CONH ₂ , -CONH-C ₁ -C ₁₂ -alkyl, -CONH-C ₂ -C ₈ -alkenyl, -CONH-C ₂ -C ₈ -alkynyl, -CONH-C ₃ -C ₁₂ -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO ₂ -C ₁ -C ₁₂ -alkyl, -OCO ₂ -C ₂ -C ₈ -alkenyl, -OCO ₂ - C ₂ -C ₈ -alkynyl, -OCO ₂ -C ₃ -C ₁₂ -cycloalkyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocycloalkyl, -CO ₂ -C ₁ -C ₁₂ -alkyl, -CO ₂ -C ₂ -C ₈ -alkenyl, -CO ₂ -C ₂ -C ₈ -alkynyl, CO ₂ -C ₃ -C ₁₂ -cycloalkyl, -CO ₂ -aryl, CO ₂ -heteroaryl, CO ₂ -heterocycloalkyl , -OCONH ₂ , -OCONH-C ₁ -C ₁₂ -alkyl, -OCONH-C ₂ -C ₈ -alkenyl, -OCONH-C ₂ -C ₈ -alkynyl, -OCONH-C ₃ -C ₁₂ -cycloalkyl, - OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C ₁ -C ₁₂ -alkyl, -NHC(O) -C ₂ -C ₈ -alkenyl, - NHC (O) -C ₂ -C ₈ -alkynyl, -NHC (O) -C ₃ -C ₁₂ -cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -heterocycloalkyl , -NHCO ₂ -C ₁ -C ₁₂ -alkyl, -NHCO ₂ -C ₂ -C ₈ -alkenyl, -NHCO ₂ -C ₂ -C ₈ -alkynyl, -NHCO ₂ -C ₃ -C ₁₂ -cycloalkyl, - NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocycloalkyl, -NHC(O)NH ₂ , -NHC(O)NH-C ₁ -C1 ₂ -alkyl, -NHC(O)NH-C ₂ - C ₈ -alkenyl, -NHC(O)NH-C ₂ -C ₈ -alkynyl, -NHC(O)NH-C ₃ -C1 ₂ -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH -heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH ₂ , -NHC(S)NH-C ₁ -C ₁₂ -alkyl, -NHC(S)NH-C ₂ -C ₈ -alkenyl, - NHC(S)NH-C ₂ -C ₈ -alkynyl, -NHC(S)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC( S)NH-heterocycloalkyl, -NHC(NH)NH ₂ , -NHC(NH)NH-C ₁ -C ₁₂ -alkyl, -NHC(NH)NH-C ₂ -C ₈ -alkenyl, -NHC(NH)NH -C ₂ -C ₈ alkynyl, -NHC(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl , -NHC (NH) -C ₁ -C ₁₂ -alkyl, -NHC (NH) -C ₂ -C ₈ -alkenyl, -NHC (NH) -C ₂ -C ₈ -alkynyl, -NHC (NH) -C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C ₁ -C ₁₂ -alkyl, -C(NH )NH-C ₂ -C ₈ -alkenyl, -C (NH) NH-C ₂ -C ₈ -alkynyl, -C (NH) NH-C ₃ -C ₁₂ -cycloalkyl, -C (NH) NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C1 ₂ -alkyl, -S(O)-C ₂ -C ₈ -alkenyl, -S(O) -C ₂ -C ₈ -alkynyl, -S (O) -C ₃ -C1 ₂ -cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO ₂ NH ₂ , -SO ₂ NH-C1-C1 ₂ -alkyl, -SO ₂ NH-C ₂ -C ₈ -alkenyl, -SO ₂ NH-C ₂ -C ₈ -alkynyl, -SO ₂ NH-C ₃ -C1 ₂ -cycloalkyl, -SO ₂ NH-aryl, -SC NH-heteroaryl, -SO ₂ NH-heterocycloalkyl, -NHSO ₂ -C ₁ -C ₁₂ -alkyl, -NHSO ₂ -C ₂ -C ₈ -alkenyl, -NHSO ₂ -C ₂ -C ₈ -alkynyl, -NHSO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocycloalkyl, -CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C ₃ -C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -SC ₁ -C ₁₂ -alkyl, - SC ₂ -C ₈ -alkenyl, -SC ₂ -C ₈ -alkynyl, -SC ₃ -C ₁₂ -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthiomethyl. It is understood that aryls, heteroaryls, alkyls, cycloalkyls and the like are further substituted.

The term "halo" or "halogen", as used herein by itself or as part of another substituent, refers to a fluorine, chlorine, bromine or iodine atom.

Used in this document, the term "optionally substituted" means that the specified group is substituted or unsubstituted. In one embodiment of the invention, said group is optionally substituted with zero substituents, i.e., said group is unsubstituted. In another embodiment of the invention, the specified group is optionally substituted with one or more additional(s) group(s), separately and independently selected from the groups described in this document.

The term "hydrogen" includes hydrogen and deuterium. Additionally, the list of atoms includes other isotopes of that atom, provided that the resulting compound is pharmaceutically acceptable.

As used herein, the term "hydroxyl activating group" refers to an active chemical moiety of a molecule that is known in the art to activate a hydroxyl group, thus being removed during synthesis, namely a substitution or elimination reaction. Examples of the hydroxy activating group include, but are not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate, and the like.

As used herein, the term "activated hydroxyl group" refers to a hydroxyl group activated by a group that activates a hydroxyl group as defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate.

As used herein, the term "hydroxyl protecting group" refers to an active chemical moiety that is known in the art to protect the hydroxyl group from unwanted reactions during synthesis. After said synthetic procedure(s), the hydroxyl protecting group as described herein is selectively removed. Hydroxyl protecting groups known in the art are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis . 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, 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 hydroxyl group" refers to a hydroxyl group protected by a hydroxyl protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl.

As used herein, the term "inactive hydroxyl group" refers to an inactive molecular moiety known in the art to temporarily alter the physicochemical and hence biological properties of the parent drug by shielding or masking the hydroxyl group. Following said synthetic procedure(s), the inactive hydroxyl group, as described herein, should be capable of being converted back to a hydroxyl group in vivo. Inactive hydroxyl groups known in the art are generally described in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery . (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

As used herein, the term "amino protecting group" refers to an active chemical moiety that is known in the art to protect an amino group from unwanted reactions during synthesis. After the specified(s) method(s) of synthesis, the group protecting the amino group, as described in this document, is selectively removed. Amino protecting groups known in the art are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis . 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, for example, but not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

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

The term "substitutable group" means a functional group or atom that can be replaced by another functional group or atom during a substitution reaction, namely a nucleophilic substitution reaction. For example, typical substitutable groups include chlorine, bromine and iodine; sulfonic ester groups, namely mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, namely acetoxy, trifluoroacetoxy and the like.

As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to protic activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons, namely, for example, hexane and toluene, halogenated hydrocarbons, namely, for example, methylene chloride, ethylene chloride, chloroform and the like, heterocyclic compounds, namely, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers, namely diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be apparent to those skilled in the art that for certain compounds and reaction conditions, individual solvents or mixtures thereof are preferred depending on such factors as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred solvents. temperature ranges. Additional explanations regarding aprotic solvents can be found in textbooks on organic chemistry or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification . 4th ed., published by John A. Riddick et al, Vol. II, in Techniques of Chemistry Series . John Wiley & Sons, NY, 1986.

As used herein, the term "protic solvent" refers to a solvent that has the property of donating a proton, namely alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, t-butonal, and the like. Such compounds are well known to those skilled in the art, and it will be apparent to those skilled in the art that for certain compounds and reaction conditions, individual solvents or mixtures thereof are preferred depending on such factors as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred solvents. temperature ranges. Additional explanations regarding protic solvents can be found in textbooks on organic chemistry or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification . 4th ed., published by John A. Riddick et al, Vol. II, in Techniques of Chemistry Series . John Wiley & Sons, NY, 1986.

The combinations of substituents and variables contemplated by this invention are only those which lead to the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to produce and maintain compound integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compounds are separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. Those skilled in the art will appreciate that additional methods for synthesizing compounds of the formulas described herein are obvious to those of ordinary skill in the art. Additionally, to obtain the target compounds, the various steps of the synthesis are performed in an alternative sequence or order. Chemical transformations during synthesis and protecting group methodology (protection and deprotection) suitable for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations . ^2nd Ed. Wiley-VCH (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis . 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis . John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis . John Wiley and Sons (1995) and subsequent editions.

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

The compounds of this invention are modified by adding suitable functional groups to improve the selective biological properties. Such modifications are known in the art and include those that increase biopermeability in a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to facilitate injectability, alter metabolism, change the rate of excretion.

The compounds described herein contain one or more asymmetric centers and therefore form enantiomers, diastereomers, and other stereoisomeric forms, which for amino acids are defined in terms of absolute stereochemistry as (R)- or (S)-, or as (D) - or (L)-. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers are obtained from their respective optically active parent compounds using the procedures described above or by separation of racemic mixtures. Separation is carried out in the presence of a resolving agent by chromatography or recrystallization, or by any combination of these techniques that are known to those skilled in the art. Additional details regarding separation can be found in Jacques, et al, Enantiomers. racemates. and Resolutions (John Wiley & Sons, 1981). When compounds described herein contain an olefinic double bond, other units of unsaturation, or other centers of geometric asymmetry, and unless otherwise indicated, compounds are meant to include both E and Z geometric isomers or both cis and trans isomers. . Likewise, all tautomeric forms are also intended to be included. Tautomers are cyclic or acyclic. The geometry of any carbon-carbon double bond appearing herein is for convenience only and is not intended to indicate a particular geometry unless the text so indicates; therefore, a carbon-carbon double bond or a carbon-heteroatomic double bond, arbitrarily depicted herein as trans, is cis-. trans or a mixture of both in any proportion.

Certain compounds of this invention also exist in different stable conformational forms that can be separated. Rotational isomerism, due to limited rotation around an asymmetric single bond, for example due to steric hindrance or ring stress, promotes separation of different conformers. This invention includes each conformational isomer of these compounds or mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the scope of careful medical judgment, are suitable for use in contact with human and lower animal tissues without non-specific toxicity, irritation, allergic reaction, and the like, and are rational balance of benefits and risks. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. described in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts are prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reaction between the free base functionality and the appropriate organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts consisting of an amino group on an inorganic acid, namely hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or on organic acid, namely acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or obtained by other methods known in the art, namely ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate , gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Exemplary alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations associated with counterions, namely halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl 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, and include those that are readily degraded in the human body, leaving the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenoic, cycloalkanoic and dibasic alkenoic acids, in which each alkyl or alkenyl moiety preferably contains no more than 6 carbon atoms. Examples of certain esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates.

Suitable concentrations of reagents used in the synthesis methods of the invention are from 0.01 M to 10 M, typically from 0.1 M to 1 M. Suitable temperatures include from -10 °C to 250 °C, preferably from - 78°C to 150°C, preferably -78°C to 100°C, more preferably 0°C to 100°C. The reaction vessel is preferably made from any material that does not substantially interfere with the reaction. Examples include glass, plastic and metal. The reaction pressure is preferably atmospheric pressure. Atmospheres include, for example, air (for reactions insensitive to oxygen and water), or nitrogen or argon (for reactions sensitive to oxygen and water).

The term "in situ" as used herein refers to the use of an intermediate in a solvent or solvents in which the intermediate is prepared without removal of the solvent.

ABBREVIATIONS

Abbreviations that are used in the description for the following diagrams and examples:

Ac for acetyl;

AcOH for acetic acid;

Boc ₂ O for di-tert-butyl dicarbonate;

Boc for t-butoxycarbonyl;

Bz for benzoyl;

Bn for benzyl;

Brine for a solution of sodium chloride in water;

t-BuOH for tert-butanol;

t-BuOK for potassium tert-butoxide;

Bu ₄ NBr for tetrabutylammonium bromide;

Cbz for carbobenzyloxy;

CDI for 1,1-carbonyldiimidazole;

CH ₂ CI ₂ for dichloromethane;

CH ₃ for methyl;

CHsCN for acetonitrile;

CS ₂ CO ₃ for cesium carbonate;

DIBAL-H for diisobutylaluminum hydride;

DIPEA or (i-Pr) ₂ EtN for N,N-diisopropylethylamine;

DMAP for 4-dimethylaminopyridine;

DME for 1,2-dimethoxyethane;

DMF for N,N-dimethylformamide;

DMSO for dimethyl sulfoxide;

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

EDC-HCl for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide;

EtOAc for ethyl acetate;

EtOH for ethanol;

Et ₂ O for diethyl ether;

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

HC1 for hydrogen chloride;

K ₂ CO ₃ for potassium carbonate;

MeOH for methanol;

MTBE for methyl tert-butyl ether;

NaCl for sodium chloride;

NaH for sodium hydride;

NaHCO ₃ for sodium bicarbonate or sodium bicarbonate;

Na ₂ CO ₃ for sodium carbonate;

NaOH for sodium hydroxide;

NaOMe for sodium methoxide;

Na ₂ SO ₄ for sodium sulfate;

Na ₂ S ₂ O ₃ for sodium thiosulfate;

NH ₄ HCO ₃ for ammonium bicarbonate;

NH ₄ CI for ammonium chloride;

NMP for N-methyl-2-pyrrolidone;

i/n for during the night;

OH for hydroxyl;

Pd for palladium;

PDC for pyridine dichromate;

z-PrOAc for isopropyl acetate;

Ph for phenyl;

PMB for p-methoxybenzyl;

rt for room temperature;

TBS for tert-butyldimethylsilyl;

TEA or Et ₃ N for triethylamine;

THF for tetrahydrofuran;

TPP or PPh ₃ for triphenylphosphine;

Ts for tosyl or -SO ₂ -C ₆ H ₄ CH ₃ ;

TsOH for p-tolylsulfonic acid;

TMS for triimethylsilyl;

TMCC1 for trimethylsilyl chloride.

All other abbreviations used in this document, which are not specifically defined above, correspond to the meaning assigned to them by an ordinary person skilled in the art.

EXAMPLES

The compounds and methods of this invention will be better understood in connection with the following examples, which are intended to be illustrative only and do not limit the scope of the invention. Various changes and modifications to the disclosed embodiments of the invention will become apparent to those skilled in the art, and such changes and modifications, including, without limitation, relating to the chemical structure, substituents, derivatives, compositions and/or methods of the invention, can be made without deviating from the essence of the invention and the scope of the appended claims.

Example 1 Preparation of 3-morpholino-5-(trifluoromethyl)picolinohydrazide

Stage 1. Synthesis of 3-chloro-5-(trifluoromethyl)picolinohydrazide

Into a 50 L 4-necked round-bottom flask, cleaned and filled with an inert nitrogen atmosphere, add a solution of ethyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (4.0 kg, 15.81 mol, 1.00 eq. .) in ethanol (12 L) and treated with hydrazine monohydrate (1.98 kg, 2.00 eq.). The resulting solution was stirred for 2 h at 20°C in a water bath. The resulting solution was quenched to 24 L with freezing water and stirred for 30 minutes. Solids are filtered off. The resulting solution is extracted with 7 x 8.5 L MTBE (7 x 8.8 L), the organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.65 kg) as a yellow solid. LC-MS (electrospray ionization, m/z): 240.0 [M+H] ⁺ .

Step 2. Synthesis of 3-morpholino-5-(trifluoromethyl)picolinohydrazide

Into a 50 L 4-necked round-bottom flask, cleaned and filled with an inert nitrogen atmosphere, add a solution of 3-chloro-5-(trifluoromethyl)pyridine-2-carbohydrazide (3.5 kg, 14.61 mol, 1.00 eq.) in toluene (17.5 L), and morpholine (6.38 kg, 73.22 mol, 5.00 eq.). The resulting solution was stirred for 18 hours at 96°C in an oil bath. The reaction mixture is cooled to 25°C in a water bath. Solids are collected by filtration. The resulting mixture was concentrated in vacuo. The combined solids are washed with tetrahydrofuran (9 X 4.5 L). Solids are filtered off. The filtrate is concentrated in vacuo. The residue is taken up in suspension in MTBE (10 L) and stirred for 2 hours. The solids are collected by filtration. The reaction is repeated with a different amount of starting material (3 kg) under the same conditions and using the same procedure. The crude product of the two batches was combined, washed with MTBE (4 L) and dried in vacuo to give the title compound (6.1 kg) as a light yellow solid. LC-MS (electrospray ionization, m/z): 291.0 [MS+H ⁺ ]. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.63 (s, 1H), 8.49 (s, 1H), 7.71 (s, 1H), 4.54 (m, 2H) , 3.77-3.68 (m, 4H), 3.18-3.06 (m, 4H).

Example 2 Preparation of (S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1 ,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (Compound (I-a))

Step 1: Chiral SFC resolution of 3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one

3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one separated by SFC [Instrument: Waters 200 preparative SFC], column: Chiral Pak AD, 250 x 50 mm ID, 10 µm. Mobile phase: A for CO ₂ and B for 2-propanol (0.1% ΝΗ ₃ Η ₂ Ο), gradient: B 45%, flow rate: 180 ml/min]. The first part ((R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one, 5.0 kg, 38.5% yield) collected as a light yellow solid. The second part ((S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one) is concentrated under reduced pressure and dried under high vacuum to obtain of the title compound (5.13 kg, 39.5% yield) as a light yellow solid. ¹ H-NMR: (DSMO- d ₆₄₀₀ MHz): δ 10.68 (br, 1H), 7.60-7.56 (m, 1H), 7.48-7.40 (m, 5H), 7.27-7.24(m, 2H), 7.21-7.17(m, 1H), 4.24(s, 1H). HPLC purity: 100%; chiral purity: 99.94% ee.

LC-MS (electrospray ionization, m/z): 252.0 [M+H] ⁺ .

Step 2: Racemization of (R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one to 3-amino-5-phenyl-1, 3-dihydro-2H-benzo[e][1,4]-diazepin-2-one

The first part of (R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one was racemized and used for SFC separation as follows: ( R)-3-Amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (1.0 kg) in MeOH (10 L) was treated with NaOMe (171 d) and heated to 60°C for 16 h. After cooling to 25°C, the reaction mixture was quenched by adding freezing water (10 L) at 25°C and concentrated under pressure to remove most of the MeOH to give while the sediment. The residue is triturated with an additional 5 L of water, filtered and dried in vacuo to give racemic 3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (0. 9 kg) as a pale yellow solid. ¹ H-NMR: (DSMO- d ₆₄₀₀ MHz): δ 10.66 (br, 1H), 7.58-7.54 (m, 1H), 7.46-7.38 (m, 5H), 7.25-7.22(m, 2H), 7.19-7.15(m, 1H), 4.22(s, 1H). HPLC purity: 99.7%; LC-MS (electrospray ionization, m/z): 252.2 [M+H] ⁺ .

The racemic amine prepared above is re-separated by preparative SFC.

Step 3. Preparation of (S)-N-(2-oxo-5-phenyl-2,3-hydro-1H-benzo[e][1,4]-diazepin-3-yl)-1H-imidazol-1- carboxamide

1,1'-carbonyldiimidazole (1.65 kg, 3.0 equiv.) is introduced into a reactor filled with MeCN (12.7 L) at 20 ± 5 °C, stirred for 15 min and cooled to 0 ± 3 °C . (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (0.85 kg, 1.0 eq.) was added in batches. keeping it below 5°C. The reaction mixture is stirred at 2 ± 3 °C for 2 h, heated to 20 ± 5 °C and stirred for 6 h. Then, the reaction mixture is cooled to 0 ± 3 °C, at a temperature below 8 °C it is treated with purified water ( 365.5 g, 6.0 eq.) in MeCN solution (4.25 L) and heated to 20 °C. The solid is filtered twice and washed (1.7 L, 2 vol). The collected solid was dried in a vacuum oven at < 25 °C to give the title compound (1.16 kg, 98.6% pure by HPLC) as a white solid. LC-MS (electrospray ionization, m/z): 278.10, 346.13 [M+H] ⁺ .

Step 4. (S)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl-N-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [1.4]diazepine-3- yl) hydrazine-1-carboxamide

3-morpholino-5-(trifluoromethyl)picolinohydrazide (0.84 kg, 1.0 equiv.) at 25±5°C is introduced into a 5 L flask filled with NMP (2 L) and stirred for 10 min.

(S)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][l,4]-diazepin-3-yl)-1H-imidazole-1-carboxamide (1, 0 kg, 1.0 eq.) at 25 ± 5 °C are added in batches to the reaction mixture and heated to 45 °C for 10 h. The reaction mixture is cooled to 15 °C, poured into water cooled to freezing temperature (15 l , 3 °C), which is in a 20-liter flask, stirred for 30 minutes, filtered and washed with purified water (2 X 3 liters). The collected precipitate is stirred with purified water (10 L) at 25 ± 5 °C for 1 h, filtered and washed with purified water (2 X 3 L). The collected cake was dried in a vacuum oven at 27° C. for 40 h to obtain a crude product (1.640 kg). The crude product (1.64 kg) was dissolved in DCM (10 L), stirred for 30 minutes, covered with activated charcoal (0.15 kg) and stirred for 30 minutes, filtered through diatomaceous earth (1 w/w) and washed with DCM (2 X 2.5 L). The filtrate, together with n-heptane (30 L), is charged into a 50 L round-bottom flask at 25 ± 5 °C and stirred for 1 h. oven at 27°C for 30 h to give the title compound (1.43 kg, 95.3% pure by HPLC) as a light yellow solid. LC-MS (electrospray ionization, m/z): 568.19 [M+H] ⁺ .

Step 5: (S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1, 3-dihydro-2Н-benzo[e] [1.4]-diazepin-2-one

To a mixture of (S)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [l,4]diazepin- 3-yl)hydrazine-1-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) which is in the flask, load 4A-MS (1.4 kg) and stir at 20±5° C at 2 hours. Then, it is cooled to 0° C., triethylamine (0.62 kg, 2.5 eq.) is charged and stirred for 10 minutes. A solution of p-toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) is added dropwise to the reaction mixture, which is maintained at a temperature below 5 °C, and stirred at 0 ± 5 °C for 5 hours. The reaction mixture is filtered and washed with DCM (2 X 4.2 L). The filtrate is treated with water (4.2 L) at 0 °C and stirred at 0 to 10 °C for 5 minutes. After separation, the organic phase is washed successively with 5% NaHCO ₃ aqueous solution (7 L), water (7 L) and brine (7 L) and separated. The DCM layer is concentrated in vacuo below 30°C to leave ~7 L of the organic layer. Add MTBE (7 L) to the organic layer and concentrate in vacuo to leave ~7 L of the organic layer (This step is repeated once). Water (7 L) is poured into the organic layer and stirred at 20 ± 5 °C for 4 hours. The solid is filtered and washed with DCM (3 X 2.1 L) and purified water (2.8 L). The wet cake is stirred with ethyl acetate (7 L) for 12 h, poured into n-heptane (14 L) and stirred at 20 ± 5 °C for 5 h. The solid is filtered, washed with n-heptane (2 X 2.8 k) and dried in a vacuum oven at ambient temperature to give the title compound (0.776 kg, 99.6% pure by HPLC, chiral purity 97.8% by chiral HPLC) as a yellowish solid. LC-MS (electrospray ionization, m/z): 550.17 [M+H] ⁺ ;

¹H-NMR: (DMSO-d ₆ 400 MHz): δ 10.98 (br-s, 1H), 9.40 (d, J=8.0 Hz, 1H), 8.69 (br-d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.68 (dt, J=8.0 and 4.0 Hz, 1H), 7.56-7.51 (m, 3H), 7 .49-7.45 (m, 2H), 7.38-7.35 (m, 2H), 7.29 (br-t, J=8.0 Hz, 1H), 5.22 (d, J = 8.0 Hz, 1H), 3.75-3.72 (m, 4H), 3.09-3.07 (m, 4H);¹³C (DMSO-d ₆ 100 MHz): δ 167.3, 167.0, 162.8, 156.4, 147.2, 139.2, 138.7, 138.4, 138.3, 138.0, 132.30, 130 .7, 130.5, 129.5, 128.4, 126.2, 124.5, 123.4, 121.5, 71.8, 65.9, 51.0.

Example 3 Preparation of the amorphous form (S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl -1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one

(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro -2H-benzo[e][1,4]-diazepin-2-one (60.0 kg) was dissolved in acetic acid (170 ml), stirred for 10 min, filtered through a ceramic funnel into a 3 liter flask and lyophilized This is further dried with a vacuum pump at room temperature for 3 days It is ground in a mortar and dried under vacuum under N ₂ flow for 3 days to obtain amorphous form (S)-3-((5-(3-morpholino -5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepine -2-it is in the form of a yellowish solid.

Example 4 Preparation of a complex of an amorphous compound (I-a) (S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino -5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one with copovidone.

A mixture of (S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3- dihydro-2H-benzo[e][1,4]-diazepin-2-one (6.4 g) and copovidone (poly(1-vinylpyrrolidone-sovinyl acetate) (1.6 g) are dissolved in acetone (160 ml). The solution was concentrated in vacuo and further dried with a high vacuum pump for 2 days The resulting solid was ground in a mortar and pestle and further dried in a vacuum oven at 45° C. overnight to obtain the amorphous form of complex (S)-3-( (5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e] [1,4]-diazepin-2-one/copovidone as a yellowish solid.

While this invention has been specifically shown and described with reference to its preferred embodiments, those skilled in the art will appreciate that various changes may be made to its form and details without departing from the scope of the invention as encompassed by the appended claims.

Claims (36)

1. Process for the preparation of a compound of formula (Ia),

where said method includes the following steps: (a) reaction of a compound of formula (VII),

where R ₇ is selected from the group consisting of hydrogen, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl , 3-8-membered heterocyclic fragment, aryl and heteroaryl; and X is chloro; with a compound of formula (VII-X),

where, PG is hydrogen; to form a compound of formula (VIII-d):

b) reaction of a compound of formula (VIII) with morpholine to form a compound of formula (X-d):

c) reaction of a compound of formula (IV)

with 1,1'-carbonyldiimidazole or nitrophenyl chloroformate to give a compound of formula (III)

where R ₅ represents 1-imidazolyl or nitrophenyl-O-; d) isolation and purification of the compound of formula (III); e) reaction of a compound of formula (III) with a compound of formula (X-d), said reaction being carried out at a temperature of from about 10 to 50° C. for 6 to 48 hours and at a concentration of a compound of formula (III) from about 1 M to 3 M and the molar ratio of the compound of formula (III) and the compound of formula (X-d) 1:1, to obtain a compound of formula (V-a),

And (f) reacting a compound of formula (V-a) with a cyclization reagent to form a compound of formula (I-a). 2. The method according to p. 1, characterized in that step (a) is carried out in a protic solvent at a temperature of from about 10°C to about 70°C. 3. The method according to any one of paragraphs. 1, 2, characterized in that R ₇ is hydrogen and step (a) is carried out in the presence of an amide-forming agent. 4. The method of claim 3 wherein the amide forming agent is selected from the group consisting of 1,1'-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)phosphine chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3- hydroxy-1,2,3-benzotriazin-4(3H)-one, 1-(3-dimethylaminopropyl)-3-ethylcarbodiinide hydrochloride, 4-nitrophenol, pentafluorophenol, 2-hydroxypyridine, N-hydroxysuccinimide, N-hydroxyphthalamide, 2- mercaptobenzoxazole, trimethylacetyl chloride, isobutyl chloroformate, chlordimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide, 5-nitro-2-hydroxypyridine, and Boc-L-valine anhydride. 5. The method according to claim 1, characterized in that step (a) is carried out in a solvent selected from the group consisting of isopropyl acetate, ethyl acetate, dichloromethane, acetone, tetrahydrofuran (THF), 1-methyl-2-pyrrolidone, 2-methyltetrahydrofuran and acetonitrile. 6. The method according to any one of paragraphs. 1-3, characterized in that R ₇ represents C ₁ -C ₈ -alkyl and step (a) is carried out in the presence of a protic solvent. 7. The method according to claim 6, characterized in that the protic solvent is methanol, ethanol or isopropyl alcohol. 8. The method according to p. 6, characterized in that step (a) is carried out at a temperature of from about 10°C to about 70°C for 3 hours to 12 hours. 9. The method according to any one of paragraphs. 1-7, characterized in that step (b) is carried out (i) without a solvent or (ii) in an aprotic solvent at a temperature of from about 10°C to about 100°C. 10. The method according to any one of paragraphs. 1-9, characterized in that step (c) is carried out in a solvent selected from the group consisting of acetonitrile, THF, DMSO and dichloromethane. 11. The method according to any one of paragraphs. 1-10, characterized in that step (c) is carried out in acetonitrile, THF, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), sulfolane or 1-methyl-2-pyrrolidone. 12. The method according to p. 10, characterized in that in step (e) the concentration of the compound of formula (III) is 1.5 M. 13. The method according to any one of paragraphs. 1-11, characterized in that the cyclization agent in step (f) is p-toluenesulfonyl chloride. 14. The method according to p. 12, characterized in that stage (f) is carried out (i) in the presence of triethylamine or diisopropylethylamine; (ii) in a solvent selected from the group consisting of acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethyl acetate and isopropyl acetate; (iii) at a temperature of from about 0°C to about 30°C; and (iv) for 3 hours to 15 hours.