Processes for the preparation of benzodiazepine derivatives

The present invention relates to processes and intermediates useful in the preparation of biologically active molecules, especially in the synthesis of Respiratory Syncytial Virus (RSV) inhibitors. The present invention also relates to processes and intermediates for the preparation of compounds of formula (I):In particular, the present invention also relates to processes and intermediates for the preparation of compound I-a:

TECHNICAL FIELD

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

BACKGROUND OF THE INVENTION

Human respiratory syncytial virus (HRSV) is a negative-sense, single stranded, RNA paramyxovirus (K M. Empey, et al.,Rev. Anti-Infective Agents,2010, 50 (1 May), 1258-1267). RSV is the leading cause of acute lower respiratory tract infections (ALRI) and affects patients of all ages. The symptoms in adults are usually not severe and are typically analogous to a mild cold. However, in infants and toddlers the virus can cause lower respiratory tract infections including bronchiolitis or pneumonia with many of them requiring hospitalization. Nearly all children have been infected by age 3. There are known high-risk groups that infection with RSV is more likely to progress into the ALRI. Premature infants and/or infants suffering from lung or cardiac disease are at the highest risk to develop ALRI. Additional high-risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant patients and the immunosuppressed.

Currently, there is no vaccine available to prevent HRSV infection. Palivizumab is a monoclonal antibody that is used prophylactically to prevent HRSV infection in high risk infants, e.g. premature infants, and infants with cardiac and/or lung disease. The high cost of palivizumab treatment limits its use for general purposes. Ribavirin has also been used to treat HRSV infections, but its effectiveness is limited. There is a major medical need for new and effective HRSV treatments that can be used generally by all population types and ages.

There is a need for the development of effective treatments for HRSV. The present invention has identified compounds that are aminoheteroaryl substituted benzodiazepines, and inhibit HRSV. The invention includes methods to prepare the compounds as well as methods of using these compounds to treat disease.

SUMMARY OF THE INVENTION

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

wherein {circle around (A)} is an optionally substituted aryl or optionally substituted heteroaryl, preferably {circle around (A)} 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;
R1is selected from the group consisting of:

Alternatively, two adjacent R1groups are taken together with the carbon atoms to which they are attached to form a fused ring; two geminal R1groups are taken together with the carbon atom to which they are attached to form a spiro ring; or two R1groups on nonadjacent carbon atoms are taken together to form a bridging group, such as —CH2— or —CH2CH2—.

Preferably, when m is not 0, each R1is methyl.

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

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

DETAILED DESCRIPTION OF THE INVENTION

In its principal embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein {circle around (A)}, R1, m and n are previously defined. In certain embodiments,

is selected from the groups set forth below:

The process comprises the steps of

1) reacting a compound of formula (VII),

wherein R7is selected from the group consisting of hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, 3- to 8-membered heterocyclic, aryl, and heteroaryl; and X is a leaving group, such as, but not limited to, halogen or —O-triflate; with a compound of formula (VII-X),

wherein PG is hydrogen or an amine protecting group, such as, but not limited to cbz, Boc, methoxycarbonyl, or 9-fluorenyl-methoxycarbonyl;
to produce a compound of formula (VIII),

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

wherein R1, m and n are as previously defined; to produce a compound of formula (X):

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

wherein R5is selected from the group consisting of —O(CO)O—R6, optionally substituted aryl, and optionally substituted heteroaryl; and R6is selected from the group consisting of 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 heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
to form a compound of formula (V),

and
4) reacting the compound of formula (V) with a cyclizing reagent to form the 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):

wherein R4is selected from halogen, methyl, CF3, and CN. A more preferred embodiment of a compound of formula (VIII) is a compound of formula (VIII-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 the compound of formula (V) is compound (V-a).

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

with an activating agent of the formula Y—C(O)R5, wherein Y is a leaving group, such as halide 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 invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an 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 invention provides compositions comprising an amorphous solid form of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable hydrophilic polymer to enhance activity.

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

The compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt in an amorphous solid form and a pharmaceutically acceptable hydrophilic polymer can be prepared by a variety of techniques such as, without limitation, melt-extrusion, spray-drying, coprecipitation, freeze drying, or other solvent evaporation techniques, with melt-extrusion and spray-drying being preferred. The melt-extrusion process typically comprises the steps of preparing a melt which includes the active ingredient(s), the hydrophilic polymer(s) and preferably a surfactant(s), and then cooling the melt until it solidifies. “Melting” means a transition into a liquid or rubbery state in which it is possible for one component to become embedded, preferably homogeneously embedded, in the other component or components. In many cases, the polymer component(s) will melt and the other components including the active ingredient(s) will dissolve in the melt thereby forming a solution. Melting usually involves heating above the softening point of the polymer(s). The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melted or be simultaneously mixed and melted. The melt can also be homogenized in order to disperse the active ingredient(s) efficiently. In addition, it may be convenient first to melt the polymer(s) and then to mix in and homogenize the active ingredient(s). In one example, all materials except surfactant(s) are blended and fed into an extruder, while the surfactant(s) is molten externally and pumped in during extrusion.

Synthetic Schemes

The present invention will be better understood in connection with schemes 1-2, wherein {circle around (A)}, R1, PG, X, m, n, and R5are as previously defined unless otherwise indicated.

It will be readily apparent to one of ordinary skill in the art that the process of the present invention can be practiced by substitution of the appropriate reactants and that the order of the steps themselves can be varied.

A chemical route to the synthesis of the hydrazide, the compound of formula (X) is summarized in scheme 1.

R7is selected from the group consisting of hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, 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 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, 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 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 thereof. The reaction temperature is typically about 10° C. to about 70° C. and the reaction time is typically about 3 to 12 hours.

In another embodiment, R7is hydrogen, and the compound of formula (VII) is converted to the 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 chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one, 1-(3-dimethyaminopropyl)-3-ethylcarbodiinide hydrochloride, 4-nitrophenol, pentafluorophenol, 2-hydroxypyridine, N-hydroxysuccinimide, N-hydroxyphthalamide, 2-mercaptobenzoxazole, trimethylacetyl chloride, isobutylchloroformate, chlorodimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide, 5-nitro-2-hydroxypyridine, Boc-L-valine anhydride, or mixtures thereof. Examples of suitable solvents for this reaction include, but are not limited to, isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, NMP, 2-methyltetrahydrofuran, and acetonitrile. Particular reaction conditions will vary depending on the nature of the coupling reagent and will be known to those of ordinary still in the art.

A compound of formula (VIII) can be transformed to a compound of formula (X) by amination with a compound of formula (IX), The compound of formula (IX) can be, but is not limited to, morpholine, 2-methylmorpholine and its stereoisomers, 3-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 typically takes place as neat 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, wherein PG is not hydrogen, the compound of formula (X) is deprotected by removing PG. Suitable deprotection conditions depend on the identity of PG and are known to those skilled in the art, for example, as described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis,3rd edition, John Wiley & Sons, New York (1999).

Scheme 2 illustrates the synthesis of the compound of formula (I),

The compound (XI) is either commercially available or can be synthesized by methods known to those of ordinary skill in the art. The chiral separation of the racemic compound (XI) can be performed using methods such as, but not limited to, treatment with a chiral acid and separation of the diastereoisomeric 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 chiral salts, then following separation of diasteromeric analogs to provide a chiral compound (IV), S-isomer. In one embodiment, compound (IV) is produced from racemic compound (XI) using the method disclosed in U.S. Provisional Application No. 62/585,192.

In one embodiment, SFC is used to obtain chiral compound (IV), the mobile phase is carbon dioxide (CO2) 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 from 5 to 40-50° C., preferably, the temperature is room temperature (about 25° C.). The procedures and conditions of SFC will vary and depend on the nature of racemic compounds and will be known to those ordinary skills in the art.

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

In one embodiment, after chiral separation, besides chiral compound (IV), another epimer, chiral compound (IV-A), R-isomer, is also obtained:

In one embodiment, the chiral compound (IV-A), is racemized under basic conditions to obtain racemic compound (XI). The racemization takes place in a protic solvent, such as, but not limited to, methanol, ethanol,tBuOH or isopropyl alcohol, in the presence of a base, such as, but not limited to NaOMe ortBuOK. The reaction temperature is typically about 10° C. to about 70° C. and the reaction time is typically about 3 to 24 hours.

In one embodiment, the chiral compound (IV) is transformed to a compound of formula (III) by reaction with an amine activation agent, such as, but not limited to, 1,1′-carbonyldiimidazole, nitrophenyl chloroformate, triphosgene or phosgene. This process is typically carried out in a protic or aprotic solvent such as, but not limited to, acetonitrile, THF, DMSO, or dichloromethane. The typical reaction temperature is about 0° C. to 30° C. and the reaction time is typically about 6 to 15 hours. In one aspect, the molar ratio of compound (IV) and amine activation agent is about 1 to 1. In one aspect, the molar ratio of compound (IV) and the amine activation agent is about 1 to 2. In one aspect, the molar ratio of the chiral compound (IV) and the amine activation agent is about 1 to 3. Preferably, the molar ratio of the chiral compound (IV) and the amine activation agent is about 1 to 3.

In one embodiment, PG is hydrogen, 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. The typical reaction temperature is about 10 to 50° C. and the reaction time is typically 6 to 48 hours. The reaction is typically conducted at a concentration of the compound of formula (III) about 1 M to 3 M, preferably the concentration of the compound of formula (III) is 1.5M. The molar ratio of the compound of formula (III) and the compound of formula (X) is 1:1.

The compound of formula (V) can be cyclized to a compound of formula (I) by reaction with a cyclizing agent, such as, but not limited to, p-toluenesulfonyl chloride, thionyl chloride, phosphorous 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, such as, but not limited to, acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethyl acetate or isopropyl acetate. The reaction temperature is about 0° C. to about 30° C., and the reaction time is typically 3 to 15 hours.

Definitions

The term “aryl,” as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising 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 comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.

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

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.

The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. “C1-C4alkyl,” “C1-C6alkyl,” “C1-C8alkyl,” “C1-C12alkyl,” “C2-C4alkyl,” or “C3-C6alkyl,” refer to alkyl groups containing from one to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of C1-C8alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C8alkenyl,” “C2-C12alkenyl,” “C2-C4alkenyl,” “C3-C4alkenyl,” or “C3-C6alkenyl,” refer to alkenyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C8alkynyl,” “C2-C12alkynyl,” “C2-C4alkynyl,” “C3-C4alkynyl,” or “C3-C6alkynyl,” refer to alkynyl groups containing from two to eight, two to twelve, two to four, three to four or three to six 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 monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12cycloalkyl, C3-C6cycloalkyl, C3-C8cycloalkyl and C4-C7cycloalkyl. Examples of C3-C12cycloalkyl include, but 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]nonanyl, and the like.

The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C3-C12cycloalkenyl, C3-C8cycloalkenyl or C5-C7cycloalkenyl groups. Examples of C3-C12cycloalkenyl include, but 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.

As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., —CH2CH2-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 wherein an alkylene 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” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are (C1-C3) alkoxy.

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

An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, 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)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.

The terms “heterocyclic” or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be 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 oxo-substituted or optionally substituted with 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, pyridazinonyl, 2-azabicyclo[2.2.1]-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 may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One of skill in the art can readily determine the valence of any such group from the context in which it occurs.

The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.

The term “hydroxy activating group,” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.

The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis,3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

The term “amino protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis,3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino group protected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example:Organic Solvents Physical Properties and Methods of Purification,4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The term “protic solvent,” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example:Organic Solvents Physical Properties and Methods of Purification,4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations,2ndEd. Wiley-VCH (1999); T. W. Greene and P. G. M. 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 thereof.

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

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

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

Suitable concentrations of reactants used in the synthesis processes of the invention are 0.01M to 10M, typically 0.1M to 1M. Suitable temperatures include −10° C. to 250° C., typically −78° C. to 150° C., more typically −78° C. to 100° C., still more typically 0° C. to 100° C. Reaction vessels are preferably made of any material which does not substantial interfere with the reaction. Examples include glass, plastic, and metal. The pressure of the reaction can advantageously be operated at atmospheric pressure. The atmospheres include, for example, air, for oxygen and water insensitive reactions, or nitrogen or argon, for oxygen or water sensitive reactions.

The term “in situ,” as used herein, refers to use of an intermediate in the solvent or solvents in which the intermediate was prepared without removal of the solvent.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme and the examples that follow are:Ac for acetyl;AcOH for acetic acid;Boc2O for di-tert-butyl-dicarbonate;Book for t-butoxycarbonyl;BSc for benzoyl;Bn for benzyl;Brine for sodium chloride solution in water;t-BuOH for tert-butanol;t-BuOK for potassium tert-butoxide;Bu4NBr for tetrabutylammonium bromide;Cob for carbobenzyloxy;CDI for 1,1′-carbonyldiimidazole;CH2C12for dichloromethane;CH3for methyl;CH3CN for acetonitrile;Cs2CO3for cesium carbonate;DIBAL-H for diisobutylaluminium hydride;DIPEA or (i-Pr)2EtN for N,N-diisopropylethylamine;DMAP for 4-dimethylamino-pyridine;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-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate;EtOH for ethanol;Et2O for diethyl ether;HATU for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;HCl for hydrogen chloride;K2CO3for potassium carbonate;MeOH for methanol;MTBE for methyl tert-butyl ether;NaCl for sodium chloride;NaH for sodium hydride;NaHCO3for sodium bicarbonate or sodium hydrogen carbonate;Na2CO3sodium carbonate;NaOH for sodium hydroxide;NaOMe for sodium methoxide;Na2SO4for sodium sulfate;Na2S2O3for sodium thiosulfate;NH4HCO3for ammonium bicarbonate;NH4Cl for ammonium chloride;NMP for N-Methyl-2-pyrrolidone o/n for overnight;OH for hydroxyl;Pd for palladium;PDC for pyridinium dichromate;i-PrOAc for isopropyl acetate;Ph for phenyl;PMB for p-methoxybenzyl;rt for room temperature;TBS for tert-butyl dimethylsilyl;TEA or Et3N for triethylamine;THF for tetrahydrofuran;TPP or PPh3for triphenylphosphine;Ts for tosyl or —SO2—C6H4CH3;TsOH for p-tolylsulfonic acid;TMS for trimethylsilyl;TMSCl for trimethylsilyl chloride.

All other abbreviations used herein, which are not specifically delineated above, shall be accorded the meaning which one of ordinary skill in the art would attach.

EXAMPLES

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

Step 1. Synthesis of 3-Chloro-5-(trifluoromethyl)picolinohydrazide

Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (4.0 kg, 15.81 mol, 1.00 equiv) in ethanol (12 L) and treated with hydrazine monohydrate (1.98 kg, 2.00 equiv). The resulting solution was stirred for 2 h at 20° C. in a water bath. The resulting solution was quenched to 24 L of ice water, stirred for 30 min. The solids were filtered out. The resulting solution was extracted with 7×8.5 L of MTBE (7×8.8 L) and the organic layers combined, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (3.65 kg) as a yellow solid. LC-MS(ESI, m/z): 240.0 [M+H]+.

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

Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-chloro-5-(trifluoromethyl)pyridine-2-carbohydrazide (3.5 kg, 14.61 mol, 1.00 equiv) in toluene (17.5 L), morpholine (6.38 kg, 73.22 mol, 5.00 equiv). The resulting solution was stirred for 18 h at 96° C. in an oil bath. The reaction mixture was cooled to 25° C. with a water bath. The solid was collected by filtration. The resulting mixture was concentrated under vacuum. The combined solid was washed with tetrahydrofuran (9×4.5 L). The solid was filtered out. The filtrate was concentrated under vacuum. The residue was slurried with MTBE (10 L) and stirred for 2 hrs. The solid collected by filtration. This reaction was repeated with another amount of 3 kg of SM under the same conditions and the same procedure. The crude of two batches was combined, washed with MTBE (4 L) and dried under vacuum to give the title compound (6.1 kg) as a light yellow solid. LC-MS (ES, m/z): 291.0 [MS+H+].1H-NMR (300 MHz, DMSO-d6): 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).

The racemic amine obtained above was separated again by using preparative SFC.

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

1,1′-carbonyldiimidazole (1.65 kg, 3.0 eq.) was added in 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.) in batches maintaining below 5° C. during addition. The reaction was stirred at 2±3° C. for 2 hrs. and warmed to 20±5° C. and stirred for 6 hrs. Then, the reaction was cooled to 0±3° C., treated with purified water (365.5 g, 6.0 eq.) in MeCN solution (4.25 L) below 8° C. within 1.5 h and warmed to 20° C. The solid was filtered and washed with (1.7 L, 2 V) twice. The collected solid was dried in vacuum oven at <25° C. to afford the title compound (1.16 kg, 98.6% purity by HPLC) as a white solid. LC-MS(ESI, m/z): 278.10, 346.13 [M+H]+.

(S)—N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-1H-imidazole-1-carboxamide (1.0 kg, 1.0 eq.) was added to the reaction in batches at 25±5° C. and heated at 45° C. for 10 hrs. The reaction mixture was cooled to 15° C., poured into ice-water (15 L, 3° C.) in 20 L flask, stirred for 30 min, filtered and washed with purified water (2×3 L). The collected cake was stirred with purified water (10 L) at 25±5° C. for 1 hr, filtered and washed with purified water (2×3 L). The collected cake was dried under vacuum oven at 27° C. for 40 h to give the crude (1.640 kg). The crude (1.64 kg) was dissolved in DCM (10 L), stirred for 30 min, charged with active carbon (0.15 kg) and stirred for 30 min, filtered through diatomite (1 wt/wt), washed with DCM (2×2.5 L). The filtrate was charged with n-heptane (30 L) in SOL round-bottomed flask at 25±5° C. and stirred for 1 hr. The solid was filtered and wash the cake with n-heptane (2×2 L), dried under vacuum oven at 27° C. for 30 hrs to give the title compound (1.43 kg, 95.3% purity by HPLC) as a light-yellow solid. LC-MS(ESI, m/z): 568.19 [M+H]+.

To a mixture of (S)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was charged with 4 Å-MS (1.4 kg) and stirred at 20±5° C. for 2 hrs. Then, it was cooled to 0° C., charged with triethylamine (0.62 Kg, 2.5 eq.) and stirred for 10 min. p-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) solution was dropwise added to the reaction mixture with maintaining below 5° C. and stirred at 0±5° C. for 5 hrs. The reaction mixture was filtered and washed with DCM (2×4.2 L). The filtrate was treated with water (4.2 L) at 0° C. and stirred between 0 and 10° C. for 5 min. After separation, the organic phase was washed with 5% aqueous NaHCO3solution (7 L), water (7 L) and brine (7 L) successively and separated. The DCM layer was concentrated in vacuo at below 30° C. to leave ˜7 L of organic layer. MTBE (7 L) was added to organic layer and concentrated in vacuo to leave ˜7 L of organic layer (This step was repeated once). The organic layer was charged with water (7 L) and stirred at 20±5° C. for 4 hrs. The solid was filtered and washed with MTBE (3×2.1 L) and purified water (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12 hrs, charged with n-heptane (14 L) and stirred at 20±5° C. for 5 hrs. The solid was filtered, washed with n-heptane (2×2.8 L) and dried under vacuum at ambient temperature to provide the title compound (0.776 kg, 99.6% purity by HPLC, 97.8% chiral purity by chiral HPLC) as a pale yellowish solid. LC-MS(ESI, m/z): 550.17 [M+H]+;

Preparation of an amorphous form 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

(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 g) was dissolved in acetic acid (170 mL), stirred for 10 min, filtered through a fritted funnel into 3 L-flask and lyophilized. It was dried further on vacuum pump at room temperature for 3 days. It was ground in a mortar and dried on vacuum with N2flow for 3 days to provide an amorphous form 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 as a yellowish solid.

Preparation of a complex of 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(l-vinylpyrrolidone-co-vinyl acetate), 1.6 g) were dissolved in acetone (160 mL). The solution was concentrated in vacuo and further dried under high vacuum pump for 2 days. The resulting solid was ground with a mortar and pestle and further dried in a vacuum oven at 45° C. for overnight to afford an amorphous form 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/copovidone complex as a yellowish solid.