巴西专利BR112019016914A2 processes for the preparation of benzodiazepine derivatives

专利PDF首页>>巴西专利

专利附录

专利说明

权利要求

类似技术

同族专利

引用文献

法律状态

优先权

专利摘要:
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 the compound (1-a).
公开号:BR112019016914A2
申请号:R112019016914
申请日:2018-02-16
公开日:2020-04-14
发明作者:C Shook Brian；Jong Kim In；Yu Jianming；Panarese Joseph；P Blaisdell Thomas；Sun Or Yat
申请人:Enanta Pharm Inc；
IPC主号:

专利说明:

PROCESSES FOR THE PREPARATION OF BENZODIAZEPINE DERIVATIVES
RELATED REQUESTS [001] This claim claims the benefit of US Provisional Application N62 / 459,955 filed on February 16, 2017 and US Provisional Application No. ² 62 / 459,953 filed on February 16, 2017. All teachings in the above application are incorporated in the present invention by reference.
TECHNICAL FIELD [002] 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 [003] The Human Respiratory Syncytial Virus (HRSV) is a single-stranded negative-stranded RNA paramyxovirus (KM. Empey, et a!., Rev. Anti-Infective Agents, 2010, 50 (May 1) , 1258-1267). RSV is the leading cause of acute lower respiratory tract infections (ALRI) and affects patients of all ages. Symptoms in adults are generally not severe and are typically analogous to a mild cold. However, in infants and young children, the virus can cause infections of the lower respiratory tract, including bronchiolitis or pneumonia, many of which require hospitalization. Almost all children were infected at 3 years of age. There are known high-risk groups where RSV infection is more likely to progress to ALRI. Premature infants and / or infants who suffer from lung or heart disease are at increased risk of developing ALRI. Additional high-risk groups include the elderly, adults with chronic heart and / or lung disease, stem cell transplant patients and immunosuppressed patients.
[004] Currently, there is no vaccine available to prevent infection by HRSV. Palivizumab is a monoclonal antibody that is used
Petition 870190100767, of 10/8/2019, p. 9/47
2/39 prophylactically to prevent HRSV infection in high-risk children, for example, premature infants and infants with heart and / or lung disease. The high cost of treatment with palivizumab limits its use for general purposes. Ribavirin has also been used to treat HRSV infections, but its effectiveness is limited. There is an important medical need for new and effective HRSV treatments that can be used in a general way by all types of population and ages.
[005] Several RSV fusion inhibitors have been disclosed in the following publications: W02010 / 103306, WO2012 / 068622, WO2013 / 096681, WO2014 / 060411, WO2013 / 186995, WO2013 / 186334, WO2013 / 186332, WO2012 / 080451, W02012 / 080450, W02012 / 080449, W02012 / 080447, W02012 / 080446 and J. Med. Chem. Chem. 2015, 58, 1630 - 1643. Examples of other protein N inhibitors for the treatment of HRSV have been disclosed in the following publications: W02004 / 026843, J. Med. Chem. Chem. 2006, 49, 2311 2319 and J. Med. Chem. 2007, 50, 1685-1692. Examples of protein L inhibitors for HRSV have been disclosed in the following publications: W02011 / 005842, W02005 / 042530, Antiviral Res. 2005, 65, 125 - 131 and Bioorg. Med. Chem. Lett. 2013, 23, 6789 - 6793. Examples of nucleoside / polymerase inhibitors have been disclosed in the following publications: WO2013 / 242525 and J. Med. Chem. Chem. 2015, 58, 1862 - 1878.
[006] There is a need for the development of effective treatments for HRSV. The present invention has identified compounds that are benzodiazepines substituted with amino-heteroaryl and inhibit HRSV. The invention includes methods for preparing the compounds, as well as methods of using these compounds to treat diseases.
SUMMARY OF THE INVENTION [007] The present invention provides methods for preparing compounds of the
Petition 870190100767, of 10/8/2019, p. 10/47
3/39 formula (I) or a pharmaceutically acceptable salt thereof:
wherein it is an optionally substituted aryl or optionally substituted heteroaryl, preferably "is optionally substituted pyridyl; each n is independently selected from 1 and 2; preferably each n is 1; m is 0, 1, 2, 3 or 4; preferably m is 0;
Ri is selected from the group consisting of:
1) optionally substituted C 1 -C 6 alkyl;
2) optionally substituted C3-C8 cycloalkyl; and
3) optionally substituted 3- to 12-membered heterocycle;
[008] Alternatively, two adjacent R1 groups are by the carbon atoms to which they are attached to form a fused ring; two germinal Ri groups are joined by the carbon atom to which they are attached to form a spiro ring; or two R1 groups on non-adjacent carbon atoms are joined to form a linking group, such as -CH2- or -CH2CH2-.
[009] Preferably, when m is not 0, each Ri is methyl.
[010] A preferred compound of formula (I) is compound (l-a):
[011] The invention also relates to methods for increasing the yield of the product and decreasing the process steps for intermediate and large-scale production of the compounds of the formula (I), such as compound (l-a). These
Petition 870190100767, of 10/8/2019, p. 11/47 compounds are useful as RSV inhibitors.
DETAILED DESCRIPTION OF THE INVENTION [012] In its main embodiment, the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
where, Ri, men are previously defined. In certain modalities,
[013] The process comprises the stages of
1) reacting a compound of formula (VII), the
(vii) in which R is selected from the group consisting of hydrogen, C1 -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocycle, 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),
Petition 870190100767, of 10/8/2019, p. 12/47
5/39
Η
PG ΝΗ ₂ (VII-X) where 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 the formula (VIII),
(VIII)
2) reacting the compound of formula (VIII) with a compound of formula (IX)
V-f n HN N O (4n (IX) where Ri, 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 Rs is selected from the group consisting of -O (CO) O-Rg, optionally substituted aryl, and optionally substituted heteroaryl; and Rg is selected from the group consisting of optionally substituted C1-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, 3 to 8 heterocycle members
Petition 870190100767, of 10/8/2019, p. 13/47
6/39 optionally substituted, optionally substituted aryl, and optionally substituted heteroaryl;
to form a compound of formula (V),
4) reacting the compound of formula (V) with a cyclization reagent to form the compound of formula (I).
[014] A preferred embodiment of a compound of formula (VIII) is a compound of formula (VIII-a), formula (VIII-b) or formula (VIII-c):
(Vlll-a) (Vlll-b) (VIII-c) where FU is selected from halogen, methyl, CF3 and CN. A more preferred embodiment of a compound of formula (VIII) is a compound of formula (VIII-d),
(Vlll-d) [015] A preferred embodiment of a compound of formula (X) is a compound of formula (X-a), formula (X-b) or formula (X-c):

Petition 870190100767, of 10/8/2019, p. 14/47
7/39 [016] A more preferred embodiment of a compound of formula (X) is a compound of formula (X-d):
(X-d) [017] In a preferred embodiment, the compound of formula (III) is the compound (II-a):
[018] A preferred embodiment of the compound of formula (V) is the compound
[019] The compound of formula (III) can be formed by reacting compound (IV),
with an activating agent of formula Y-C (O) Rs, where Y is an leaving group,
Petition 870190100767, of 10/8/2019, p. 15/47
8/39 such as halide or 1-imidazolyl.
[020] The compound (IV) can be prepared, for example, by resolving a racemic mixture of the compound (IV) and its enantiomer.
[021] In one embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a solid amorphous form. In this embodiment, the compound of formula I is preferably the compound (l-a) or a pharmaceutically acceptable salt thereof, and, more preferably, the compound of formula (I) is the compound (l-a) in conjugated base form.
[022] In another embodiment, the invention provides compositions comprising a solid amorphous form of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable hydrophilic polymer to increase activity.
[023] 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 Nvinylpyrrolidone homopolymer, N-vinylpyrrolidone copolymers, Nvinylpyrrolidone and vinyl acetate copolymers, N-vinylpyrrolidone and vinyl propionate copolymers, polyvinylpyrrolidone, methylcellulose, hydrocellulose, methylcellulose, hydroxycellulose, methylcellulose, methylcellulose, methylcellulose, methylcellulose, methylcellulose. hydroxylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, polyoxyethylene ethylene oxide, polyoxyethylene oxide, polyoxyethylene oxide, polyoxyethylene oxide, polyoxyethylene oxide, polyoxyethylene, oxide propylene oxide, methacrylic acid / ethyl acrylate copolymer,
Petition 870190100767, of 10/8/2019, p. 16/47
9/39 metracrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly (hydroxyalkyl acrylate), poly (hydroxyalkyl methacrylate), polyvinyl acetate copolymer and crotonic acid, partially hydrolyzed, carrageenan, galactomannan or xanthan gum.
[024] In yet another embodiment of this aspect of the invention, the hydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone. Preferably, the hydrophilic polymer is copovidone.
[025] 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, drying spraying, coprecipitation, lyophilization 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 that includes the active ingredient (s), the hydrophilic polymer (s) and, preferably, the surfactant (s) ), and then cool the melt until it solidifies. Fusion means a transition into a liquid or rubbery state, in which it is possible for one component to be incorporated, preferably homogeneously incorporated, into the other component or components. In many cases, the polymeric component (s) will melt and the other components including the active ingredient (s) will dissolve in the melt, thus forming a solution. The melting usually involves heating above the softening point of the polymer (s). Fusion preparation can take place in a variety of ways. The mixing of the components can occur before, during or after the formation of the melt. For example, components can be mixed first and then fused or
Petition 870190100767, of 10/8/2019, p. 17/47
10/39 simultaneously mixed and melted. The fusion can also be homogenized in order to efficiently disperse the active principle (s). In addition, it may be convenient to first melt the polymer (s) and then mix and homogenize the active principle (s). In one example, all materials except the surfactant (s) are mixed and fed into an extruder, while the surfactant (s) are externally melted and pumped during extrusion.
SYNTHETIC SCHEMES [026] The present invention will be better understood in connection with schemes 1-2, where ®, Ri, PG, X, m, n and Rs are as previously defined unless otherwise indicated.
[027] It will be readily apparent to one skilled in the art that the process of the present invention can be practiced by replacing the appropriate reagents and that the order of the steps themselves can be varied.
[028] A chemical pathway for hydrazide synthesis, the compound of formula (X) is summarized in Scheme 1.
Layout 1
selected from the group consisting of hydrogen, C1-Cs alkyl, C2-C8 alkenyl, Cz-Csalquinyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocycle, aryl, and heteroaryl. Preferably, the compound of formula (VII) is 3-halo-5- (trifluoromethyl) -2-pyridinecarboxylic acid or 3-halo-5 (trifluoromethyl) -picolinate and, more preferably, 3-chloro-5 (trifluoromethyl) - ethyl picolinate, which is commercially available. The
Petition 870190100767, of 10/8/2019, p. 18/47
Preferred compounds of formula (VII-X) include hydrazine monohydrate, Bochidrazine or Cbz-hydrazine.
[029] In one mode, R is C 1 -C 6 alkyl, preferably methyl or ethyl. In this embodiment, the reaction of the compound of formula (VII) and hydrazine monohydrate, typically occurs 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.
[030] In another mode, R is 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 Ι, Γ-carbonyldi -imidazole, phosphine bis (2-oxo-3-oxazolidinyl) chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3-hydroxy-1, 2,3-benzotriazin-4 (3H) -one, hydrochloride 1- (3-dimethiaminopropyl) -3ethylcarbodi-inide, 4-nitrophenol, pentafluorophenol, 2-hydroxypyridine, Nhydroxysuccinimide, N-hydroxyphthalamide, 2-mercaptobenzoxazole, trimethylacetyl chloride, isobutyl chloride, chlorohydrochloride, 2-hydroxychloride 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 skilled in the art.
[031] A compound of formula (VIII) can be transformed into 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
Petition 870190100767, of 10/8/2019, p. 19/47
12/39 stereoisomers, 3,5-dimethylmorphine and its stereoisomers, 2,6dimethylmorphine and its stereoisomers, 3-oxa-8-azabicyclo [3.2.1] octane, 2-oxa5-azabicyclo [2.2.1] heptane, 8-oxa -3-azabicycles [3.2.1] octane. The reaction typically occurs as pure 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.
[032] In one embodiment, where 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 generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis. ^Â 3 edition, John Wiley & Sons, New York (1999).
[033] Scheme 2 illustrates the synthesis of the compound of formula (I),
Layout 2
[034] The compound (XI) is commercially available or can be synthesized by methods known to those skilled in the art. 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),
Petition 870190100767, of 10/8/2019, p. 20/47
13/39 chromatography with supercritical fluid (SFC), capillary electrochromatography (CPB), gas chromatography (GC), high performance liquid chromatography (HPLC), and crystallization with chiral salts, followed by the separation of diasteromeric analogs to provide a chiral compound ( IV), S-isomer. In one embodiment, the compound (IV) is produced from the racemic compound (XI) using the method disclosed in US Provisional Application No. ² 62 / 585,192.
[035] In one embodiment, SFC is used to obtain the 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 a, methanol, ethanol, or 2-propanol; the temperature range is limited to 5 to 40-50 ° C, preferably the temperature is room temperature (about 25 ° C). CFS procedures and conditions will vary and depend on the nature of the racemic compounds and will be known to those skilled in the art.
[036] In one aspect, the chiral compound (IV) is obtained with more than 90% purity of enantiomeric excess (ee) after separation by SFC. In one aspect, the chiral compound (IV) is obtained with more than 95% purity of enantiomeric excess (ee) after separation by SFC. In one aspect, the chiral compound (IV) is obtained with more than 98% purity of enantiomeric excess (ee) after separation by SFC.
[037] In one embodiment, after chiral separation, in addition to the chiral compound (IV), another epimer, chiral compound (IV-A), isomer R, is also obtained:
(IV-A) [038] In one embodiment, the chiral compound (IV-A), is racemized under basic conditions to obtain the racemic compound (XI). Racemization occurs
Petition 870190100767, of 10/8/2019, p. 21/47
14/39 in a protic solvent such as, but not limited to, methanol, ethanol, uOH or isopropyl alcohol, in the presence of a base such as, but not limited to, NaOMe or UOK. The reaction temperature is typically about 10 ° C to about 70 ° C and the reaction time is typically about 3 to 24 hours.
(iV-A)
[039] In one embodiment, the chiral compound (IV) is transformed into a compound of formula (III) by reaction with an amine activating agent, such as, but not limited to, Ι, Γ-carbonyldiimidazole, chloroform nitrophenyl, 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 the compound (IV) and the amine activating agent is about 1 to 1. In one aspect, the molar ratio of the compound (IV) and the amine activating agent is about 1 to 2. In one aspect, the molar ratio of the chiral compound (IV) and the amine activating agent is about 1 to 3. Preferably, the molar ratio of the chiral compound (IV) and the amine activating agent is about 1 to 3.
[040] 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 1methyl-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) of about 1 M to 3 M,
Petition 870190100767, of 10/8/2019, p. 22/47
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.
[041] 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 [042] Listed below are definitions of various terms used to describe this invention. These definitions apply to terms as they are used throughout this specification and claims, unless otherwise limited in specific cases, individually or as part of a large group.
[043] The term aryl, as used in the present invention, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaftyl, indanyl, and indenyl . A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls may comprise fused rings, covalently bonded rings or a combination thereof.
[044] The term heteroaryl, as used in the present invention, refers to a mono- or polycyclic aromatic radical having one or more ring atoms selected from S, O and N; and the atoms in the remaining rings are
Petition 870190100767, of 10/8/2019, p. 23/47
16/39 carbon, where any N or S contained within the ring can 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, benzimidazoline, benzimidazoline, benzamine. A polycyclic heteroaryl may comprise fused rings, covalently bonded rings or a combination thereof.
[045] According to the invention, aromatic groups can be substituted or unsubstituted.
[046] The term bicyclic aryl or bicyclic heteroaryl refers to a ring system consisting of two rings, in which at least one ring is aromatic; and the two rings can be fused or covalently linked.
[047] The term alkyl, as used in the present invention, refers to saturated straight or branched chain hydrocarbon radicals. C1-C4 alkyl, C1-C6 alkyl, C-Cs alkyl, C1-C12 alkyl, C2-C4 alkyl or C3-C6 alkyl, 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 C 1 -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
[048] The term alkenyl, as used in the present invention, refers to straight or branched chain hydrocarbon radicals having at least one carbon-carbon double bond by removing 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 atoms of carbon respectively. Alkenyl groups include, but are not limited to, for example, ethylene, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
Petition 870190100767, of 10/8/2019, p. 24/47
17/39 [049] The term alkynyl, as used in the present invention, refers to straight or branched chain hydrocarbon radicals having at least one carbon-carbon double bond by removing a single hydrogen atom. C2-C8 Alquinyl, C2-C12 Alquinyl, C2-C4 Alquinyl, C3-C4 Alquinyl or C3-C6 Alquinyl, refer to Alquinyl 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, heptinyl, octinyl and the like.
[050] The term cycloalkyl, as used in the present invention, refers to a monocyclic or polycyclic saturated carbocyclic ring or a spiro, bridged or fused system of a bi- or tri-cyclic group, and the carbon atoms can be optionally oxo- substituted or optionally substituted with exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicycle [2.2.1] heptila, bicycle [3.1. 0] hexyl, spiro [2.5] octyl, 3methylene bicyclo [3.2.1] octyl, spiro [4.4] nonanil, and the like.
[051] The term cycloalkenyl, as used in the present invention, refers to a monocyclic or polycyclic carbocyclic ring or a spiro, bridged or fused bi- or tri-cyclic group having at least one carbon-carbon double bond and the carbon atoms can be optionally oxosubstituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. Examples of C3-C12 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] hept-2-enyl,
Petition 870190100767, of 10/8/2019, p. 25/47
18/39 bicycle [3.1.0] hex-2-enyl, spiro [2.5] oct-4-enila, spiro [4.4] non-l-enila, bicycle [4.2, l] non-3-en-9 -ila and the like.
[052] As used in the present invention, the term arylalkyl means a functional group, in which an alkylene chain is attached to an aryl group, for example, -CH ₂ CH ₂ -phenyl. The term substituted arylalkyl means a functional arylalkyl group, in which the aryl group is substituted. Similarly, the term heteroarylalkyl means a functional group, in which an alkylene chain is linked to a heteroaryl group. The term substituted heteroarylalkyl means a functional heteroarylalkyl group, in which the heteroaryl group is substituted.
[053] As used in the present invention, the term alkoxy used 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 through an atom oxygen, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher counterparts and isomers. Preferred alkoxys are (C1-C3) alkoxy.
[054] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described in the present invention can also be an aliphatic group or an alicyclic group.
[055] An aliphatic group is a non-aromatic portion 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, for example, bonds double and / or triple. Examples of aliphatic groups are functional groups, such as 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,
Petition 870190100767, of 10/8/2019, p. 26/47
19/39 groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group can be straight-chain, branched, cyclic or a combination thereof, and preferably contains about 24 carbon atoms thereon, more typically between about 1 and about 12 carbon atoms. In addition to the aliphatic hydrocarbon groups, as used in the present invention, the aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines and polyimines, for example. Aliphatic groups can be optionally substituted.
[056] The terms heterocyclic or heterocycloalkyl can be used interchangeably and refer to a non-aromatic ring or a spiro, bridged or fused, bi- or tri-cyclic group, 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 hetero atoms can optionally be oxidized, (iv) the nitrogen hetero atom can optionally be quatized, ( v) any of the above rings can be fused to an aromatic ring, and (vi) the atoms in the remaining rings are carbon atoms that can be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isotinazinin, 2 ] -heptila, 8
Petition 870190100767, of 10/8/2019, p. 27/47
20/39 azabicyclo [3.2.l] octyl, 5-azospiro [2.5] octyl, 1-oxa-7-azospiro [4.4] nonanyl, 7oxo-oxepan-4-yl and tetrahydrofuryl. Such heterocyclic groups can be further substituted. Heteroaryl or heterocyclic groups can be linked to C or linked to N (where possible).
[057] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic or similar moiety described in the present invention, can also be a divalent or multivalent group when used as a bond to connect two or more groups or substituents, which may be on the same atom (s) or on different atom (s). A person skilled in the art can easily determine the worth of any such group from the context in which it occurs.
[058] The term substituted refers to the substitution by independent substitution of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to -F, -Cl, -Br, -I, -OH, C1-C12 alkyl; C2C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, protected hydroxy, -NO2, -N3, CN, -NH2, protected amine, oxo, thioxy, -NH-C1-C12 alkyl, -NH-C2-C8 alkenyl, NH-C2-C8 alkynyl, -NH-C3-C12 cycloalkyl, -NH-aryl, -NH-heteroaryl, -NHheterocycloalkyl, -dialkylamine, -diarylamine, -di-heteroarylamine, -O-C1-C12 alkyl, -O- C2-C8 alkenyl, -O-C2-C8 alkynyl, -O-C3-C12 cycloalkyl, -O-aryl, -0 heteroaryl, -O-heterocycloalkyl, -C (O) -Ci-Ci2 alkyl, -C (O) -C2-Cs alkenyl, C (O) -C2-Csalquinyl, -C (O) -C3-Cy2cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) heterocycloalkyl, -CONH2 , -CONH-C1-C2alkyl, -CONH-C2-Csalkenyl, -CONHC2-C8 alkynyl, -CONH-C3-C12 cycloalkyl, -CONH-aryl, -CONH-heteroaryl, CONH-heterocycloalkyl, -OCO2-C1-C12 alkyl , -OCO2-C2-C8 alkenyl, -OCO2-C2Cs alkynyl, -OCO2-C3-C12 cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2heterocycloalkyl, -CO2-C1-C12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C12 cycloalkyl, -CO2-aryl a, CO2-heteroaryl, CO2-heterocycloalkyl,
Petition 870190100767, of 10/8/2019, p. 28/47
21/39
OCONhh, -OCONH-C1-C12 alkyl, -OCONH-C ₂ -C ₈ alkenyl, -OCONH-C ₂ -C ₈ alkynyl, -OCONH-C3-C12 cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, OCONH- heterocycloalkyl, -NHC (O) H, -NHC (O) -Ci-Ci ₂ alkyl, -NHC (O) -C ₂ -C ₈ alkenyl, -NHC (O) -C2-C ₈ alkynyl, -NHC (O ) -C3-C2 cycloalkyl, -NHC (O) -aryl, NHC (O) -heteroaryl, -NHC (O) -heterocycloalkyl, -NHCO2-C1-C12alkyl, -NHCO2C ₂ -C ₈ alkenyl, -NHCO2-C2- C ₈ alkynyl, -NHCO2-C3-C12 cycloalkyl, -NHCCh-aryl, -NHCCh-heteroaryl, -NHCCh-heterocycloalkyl, -NHC (O) NH ₂ , -NHC (O) NH-Ci-Ci ₂ alkyl, -NHC (O) NH-C ₂ -C ₈ alkenyl, -NHC (O) NH-C ₂ -C ₈ alkynyl, -NHC (O) NH-C ₃ C12 cycloalkyl, -NHC (O) NH-aryl, -NHC ( O) NH-heteroaryl, -NHC (O) NHheterocycloalkyl, NHC (S) NH ₂ , -NHC (S) NH-Ci-Ci ₂ alkyl, -NHC (S) NH-C ₂ -C ₈ alkenyl, -NHC ( S) NH-C ₂ -C ₈ alkynyl, -NHC (S) NH-C ₃ -Ci2 cycloalkyl, -NHC (S) NHaryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, - NHC (NH) NH2, NHC (NH) NH-C1 -C2 alkyl, - NHC (NH) NH-C ₂ -C ₈ alkenyl, -NHC (NH) NH-C ₂ -C ₈ alkynyl, -NHC (NH) NH-C ₃ -Ci2 cycloalkyl, -NHC (NH) NH-aryl, -NHC (NH) NHheteroaryl, -NHC (NH) NH-heterocycloalkyl, -NHC ( NH) -Ci-Ci2alkyl, -NHC (NH) C ₂ -C ₈ alkenyl, -NHC (NH) -C2-C ₈ alkynyl, -NHC (NH) -C3-Ci2 cycloalkyl, NHC (NH) -aryl, NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NHC1-C12 alkyl, -C (NH) NH-C ₂ -C ₈ alkenyl, -C (NH) NH-C ₂ -C ₈ alkynyl, -C (NH) NH-C ₃ C12 cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NHheterocycloalkyl, -S (O) -Ci-Ci2alkyl, -S (O) -C2-C ₈ alkenyl, -S (O) -C2-C ₈ alkynyl, -S (O) -C ₃ -Ci2 cycloalkyl, -S (O) -aryl, -S (O) - heteroaryl, -S (O) -heterocycloalkyl, SO2NH2, -SO2NH-C1-C12 alkyl, -SO2NH-C2-C ₈ alkenyl, -SO2NH-C2-C ₈ alkynyl, SO2NH-C3-C12 cycloalkyl, -SChNH-aryl, -SChNH-heteroaryl, -SO2NHheterocycloalkyl, -NHSO2-C1-C12 alkyl, -NHSO2-C2-C ₈ alkenyl, -NHSO2-C2-C ₈ alkynyl, -NHSO2-C3-C12 cycloalkyl, -NHSCh-aryl, -NHSCh-aryl, -NHSCh-aryl heteroaryl, -NHSO2heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -ar ilalkyl, -heteroaryl, heteroarylalkyl, -heterocycloalkyl, -C3-C12 cycloalkyl, polyalkoxyalkyl,
Petition 870190100767, of 10/8/2019, p. 29/47
22/39 polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12 alkyl, -S-C2-C8 alkenyl, -S-C2-C8 alkynyl, -S-C3-C12 cycloalkyl, -S-aryl , -S-heteroaryl, -Sheterocycloalkyl or methylthio-methyl. It is understood that aryl, heteroaryl, alkyl, cycloalkyl and the like can still be substituted.
[059] The term halo or halogen alone or as part of another substituent, as used in the present invention, refers to a fluorine, chlorine, bromine or iodine atom.
[060] The term optionally substituted, as used in the present invention, means that the referenced group can be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituent, that is, the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups individually and independently selected from groups described in the present invention.
[061] The term hydrogen includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom as long as the resulting compound is pharmaceutically acceptable.
[062] The term hydroxy activation group, as used in the present invention, refers to a labile chemical moiety that is known in the art for activating a hydroxyl group so that it exits during synthetic procedures, such as in a reaction replacement or disposal. Examples of the hydroxyl activating group include, but are not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
[063] The term activated hydroxyl, as used in the present invention, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, pnitrobenzoate and phosphonate groups, for example.
Petition 870190100767, of 10/8/2019, p. 30/47
23/39 [064] The term hydroxy protecting group, as used in the present invention, refers to a labile chemical moiety that is known in the art for protecting a hydroxyl group against unwanted reactions during synthetic procedures. After said synthetic procedure (s), the hydroxy protecting group as described in the present invention can be selectively removed. Hydroxy protecting groups as known in the art are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis. ^Â 3 edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, methoxyacetyl, methoxyacetyl, methoxyacetyl 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, trimethylsilyl, tri-isopropylsilyl and the like.
[065] The term protected hydroxy, as used in the present invention, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl and methoxymethyl groups, for example.
[066] The term hydroxy prodrug group, as used in the present invention, refers to a protecting group that is known in the art for changing the physicochemistry and, consequently, the biological properties of a precursor drug in a transient manner covering up or masking the hydroxy group. After said synthetic procedure (s), the hydroxy prodrug group as described used in the present invention must be able to revert back to the hydroxy group in vivo. Hydroxy prodrug groups as known in the art are generally described in Kenneth B. Sloan,
Petition 870190100767, of 10/8/2019, p. 31/47
24/39
Prodrugs, Topical and Ocular Drug Delivery. (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).
[067] The term amine protecting group, as used in the present invention, refers to a labile chemical moiety that is known in the art for protecting an amine group against unwanted reactions during synthetic procedures. After said synthetic procedure (s), the amine protecting group as described in the present invention can be selectively removed. Amine protecting groups as known in the art are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis. ^Â 3 edition, John Wiley & Sons, New York (1999). Examples of amine protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
[068] The term protected amine, as used in the present invention, refers to an amine group protected with an amine protecting group as defined above.
[069] The term leaving group means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include chlorine, bromine and iodine groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acycloxy groups, such as acetoxy, trifluoroacetoxy and the like.
[070] The term aprotic solvent, as used in the present invention, refers to a solvent that is relatively inert to proton activity, that is, it does not act as a proton donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example,
Petition 870190100767, of 10/8/2019, p. 32/47
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 ether -methoxymethyl. Such compounds are well known to those of skill in the art, and it will be obvious to those of skill in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on such factors as reagent solubility, reactivity of reactants and preferred temperature ranges, for example. Other discussions of aprotic solvents can 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 the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
[071] The term protic solvent, as used in the present invention, refers to a solvent that tends to supply protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like . Such solvents are well known to those of skill in the art, and it will be obvious to those of skill in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on such factors as reagent solubility, reactivity of reagents and preferred temperature ranges, for example. Other discussions of protogenic solvents can 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 the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
[072] The combinations of substituents and variables provided for by this
Petition 870190100767, of 10/8/2019, p. 33/47
26/39 inventions are only those that result in the formation of stable compounds. The term stable, as used in the present invention, refers to compounds that have sufficient stability to permit manufacture and that maintain the integrity of the compound for a period of time sufficient to be useful for the purposes detailed in the present invention (for example, therapeutic or prophylactic administration to an individual).
[073] The synthesized compounds can be separated from a reaction mixture and further purified by a method, such as column chromatography, high performance liquid chromatography or recrystallization. As can be appreciated by the skilled artisan, other methods of synthesizing the compounds of the formula in the present invention will be apparent to those skilled in the art. In addition, the various synthetic steps can be performed in an alternating sequence or order to provide the desired compounds. Synthetic chemical transformations and protection group (protection and deprotection) methodologies useful in synthesizing the compounds described in the present invention are known in the art and include, for example, those, as described in R. Larock, Comprehensive Organic Transformations. 2- Ed. WileyVCH (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis. 3 ^- 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 their subsequent editions.
[074] The term individual, as used in the present invention, refers to an animal. Preferably, the animal is a mammal. Most preferably, the mammal is a human being. An individual also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
[075] The compounds of this invention can be modified by attaching
Petition 870190100767, of 10/8/2019, p. 34/47
27/39 appropriate functionalities to enhance the selective biological properties. Such modifications are known in the art and may include those that increase biological penetration into a given biological system (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter the rate of excretion.
[076] The compounds described in the present invention contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) -, or as (D) - or (L) - for amino acids. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by resolving racemic mixtures. Resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques that are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers. Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described in the present invention contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include the geometric E and Z isomers or cis- and trans-isomers . Likewise, all tautomeric forms are also intended to be included. Tautomers can be cyclic or acyclic. The configuration of any carbon-carbon double bond that appears in the present invention is selected for convenience only and is not intended to designate a particular configuration to
Petition 870190100767, of 10/8/2019, p. 35/47
28/39 unless the text dictates clearly; thus, a carbon-carbon double bond or carbon-heteroatom double bond described in the present invention arbitrarily as trans can be cis, trans, or a mixture of the two in any proportion.
[077] Certain compounds of the present invention can also exist in different stable conformational forms that can be separable. Torsional asymmetry due to restricted rotation around a simple asymmetric connection, for example, due to the steric impediment or deformation of the ring, can allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.
[078] As used in the present invention, the term pharmaceutically acceptable salt, refers to those salts that are, within the scope of correct medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are proportionate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 11 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the base function in conjunction with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts are salts of an amine group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with acids organic, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
Petition 870190100767, of 10/8/2019, p. 36/47
29/39 or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfate, citrate, cyclopentanopropionate, digluconate, dodecyl sulfate, formane, ethan glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodhydrate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalate oxide, nitrate oxide, nitrate oxide, nitrate oxide , pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
[079] As used in the present invention, the term pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that break easily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formate, acetate,
Petition 870190100767, of 10/8/2019, p. 37/47
30/39 propionates, butyrates, acrylates and ethyl succinates.
[080] Suitable concentrations of reagents used in the synthetic processes of the invention are 0.01 M to 10 M, typically 0.1 M to 1 M. Suitable temperatures include -10 ° C to 250 ° C, typically -78 ° C to 150 ° C, more typically, -78 ° C to 100 ° C, even more typically, 0 ° C to 100 ° C. Reaction vessels are preferably made of any material that does not substantially interfere with the reaction. Examples include glass, plastic and metal. The reaction pressure can be advantageously operated at atmospheric pressure. Atmospheres include, for example, air, for reactions insensitive to oxygen and water, or nitrogen or argon, for reactions sensitive to oxygen or water.
[081] The term in situ, as used in the present invention, refers to the use of an intermediate in the solvent or solvents in which the intermediate was prepared without removing the solvent.
ABBREVIATIONS [082] Abbreviations that can be used in the schematic descriptions and the following examples are:
Ac to acetyl;
AcOH for acetic acid;
BoczO for di-tert-butyl-dicarbonate;
Boc for t-butoxycarbonyl;
Bz 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;
Cbz for carbobenzyloxy;
Petition 870190100767, of 10/8/2019, p. 38/47
31/39
ICD for Ι, Γ-carbonyldiimidazole;
CH2 Cl2 for dichloromethane;
CH3 for methyl;
CH3CN for acetonitrile;
CS2CO3 for cesium carbonate;
DIBAL-H for diisobutyl aluminum hydride;
DIPEA or (i-Pr) 2EtN for N, N-diisopropylethylamine;
DMAP for 4-dimethylaminopyridine;
DME for 1,2-dimethoxyethane;
DMF for N, N-dimethylformamide;
DMSO for dimethylsulfoxide;
EDC for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide;
EDC-HCI for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride;
EtOAc for ethyl acetate;
EtOH for ethanol;
Et2Ü for diethyl ether;
HATU for hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ', N'tetramethyluronium;
HCI for hydrogen chloride;
K2CO3 for potassium carbonate;
MeOH for methanol;
MTBE for tert-butyl methyl ether;
NaCI for sodium chloride;
NaH for sodium hydride;
NaHCCh for sodium bicarbonate or sodium hydrogen carbonate;
Na2CÜ3 for sodium carbonate;
NaOH for sodium hydroxide;
Petition 870190100767, of 10/8/2019, p. 39/47
32/39
NaOMe for sodium methoxide;
NazSCU for sodium sulfate;
NazSzOs for sodium thiosulfate;
NH4HCO3 for ammonium bicarbonate;
NH4CI for ammonium chloride;
NMP for N-Methyl-2-pyrrolidone o / n overnight;
OH for hydroxyl;
Pd for palladium;
PDC for pyridinium dichromate;
/ -PrOAc for isopropyl acetate;
Ph for phenyl;
PMB for p-methoxybenzyl;
rt for room temperature;
TBS for tert-butyl dimethylsilyl;
TEA or EtsN for triethylamine;
THF for tetrahydrofuran;
TPP or PPhs for triphenylphosphine;
Ts for tosyl or -SO2-C6H4CH3;
TsOH for p-tolylsulfonic acid;
TMS for trimethylsilyl;
TMSCI for trimethylsilyl chloride.
[083] All other abbreviations used in the present invention, which are not specifically outlined above, must be given the meaning that a person skilled in the art would associate.
EXAMPLES [084] The compounds and processes of the present invention will be better
Petition 870190100767, of 10/8/2019, p. 40/47
33/39 understood in relation to the following examples, which are intended as an illustration only and are not limiting the scope of the invention. Various changes and modifications to the disclosed modalities will be apparent to those skilled in the art and such changes and modifications including, without limitation, those that refer to the chemical structures, substituents, derivatives, formulations and / or methods of the invention can be made without departing from the spirit of the invention and the scope of the appended claims.
Example 1. Preparation of 3-morpholino-5- (trifluoromethyl) picolin-hydrazide Step 1. Synthesis of 3-Chloro-5- (trifluoromethyl) picolin-hydrazide
[085] In a 50 L 4-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere, 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 cooled to 24 L of ice water, stirred for 30 min. The solids were filtered. The resulting solution was extracted with 7 x 8.5 L of MTBE (7 x 8.8 L) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide 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) picolin-hydrazide
[086] In a 50 L 4-neck round-bottom flask purged and maintained with an inert nitrogen atmosphere, a
Petition 870190100767, of 10/8/2019, p. 41/47
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 in vacuo. The combined solid was washed with tetrahydrofuran (9 x 4.5 L). The solid was filtered. The filtrate was concentrated in vacuo. The residue was pasted with MTBE (10 L) and stirred for 2 h. The solid was collected by filtration. This reaction was repeated with another amount of 3 kg of SM under the same conditions and the same procedure. The two batch crude was combined, washed with MTBE (4 L) and vacuum dried to provide the title compound (6.1 kg) as a light yellow solid. LC-MS (ES, m / z): 291.0 [MS + H ⁺ ], ^X 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-2yl) -1, 3,4-oxadiazol-2-yl) amino-5-phenyl-1, 3-dihydro-2 / - / - benzo [e] [1,4] -diazepin-2ona (Compound (la))
Step 1: Chiral SFC separation of 3-amino-5-phenyl-1,3-dihydro-2Hbenzo [e] [1,4] -diazepin-2-one

fraction go phthalmic fraction j [087] 3-amino-5-phenyl-1,3-dihydro-2H-benzo [e] [1,4] -diazepin-2-one (13.0 kg) was separated by SFC [Instrument: Preparatory SFC Waters 200], Column: Chiral Pak AD, 250 x 50 mm ID, 10 pm. Mobile phase: A for CO2 and B for 2propanol (0.1% NH3H2O), Gradient: B 45%. Flow rate: 180 mL / min]. THE
Petition 870190100767, of 10/8/2019, p. 42/47
35/39 first fraction ((/ ) - 3-amino-5-phenyl-1,3-dihydro-2/7-benzo [e] [1,4] -diazepin-2ona, 5.0 kg, 38.5% yield) was collected as a light yellow solid. The second fraction ((S) -3-amino-5-phenyl-1,3-dihydro-2/7-benzo [e] [1,4] -diazepin-2one, was concentrated under reduced pressure, dried to high vacuum to provide the title compound (5.13 kg, 39.5% yield) as a light yellow solid. ^X H NMR: (DMSO-d ₆ 400 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.
[088] LC-MS (ESI, m / z): 252.0 [M + H] ⁺ .
Step 2: Racemization of (/ ) - 3-Amino-5-phenyl-1,3-dihydro-2/7-benzo [e] [1,4] -diazepin-2-one for 3-amino- 5-phenyl-1,3-dihydro-2H-benzo [e] [1,4] diazepin-2-one
[089] The first fraction ((/ ) - 3-amino-5-phenyl-1,3-dihydro-2/7-benzo [e] [1,4] diazepin-2-one) was racemized and used for SFC separation as follows: (7 ) - 3-amino-5-phenyl-1,3-dihydro-2/7-benzo [e] [1,4,] -diazepin-2-one ( 1.0 kg) in MeOH (10 L) was treated with NaOMe (171 g) and heated to 60 ° C for 16 h. After cooling to 25 ° C, the resulting mixture was cooled by adding ice water (10 L) to 25 ° C and concentrated under pressure to remove the majority of MeOH, providing a precipitate. The residue was crushed with an additional 5 L of water and filtered and vacuum dried to provide 3-amino-5-phenyl-1,3-dihydro-2 / 7benzo [e] [1,4] -diazepin-2- racemic powder (0.9 kg) as a light yellow solid. ¹ H NMR: (DMSO-d ₆ 400 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 (ESI, m / z): 252.2 [M + H] ⁺ .
Petition 870190100767, of 10/8/2019, p. 43/47
36/39 [090] The racemic amine obtained above was separated again using preparative SFC.
Step 3. Preparation of (S) -N- (2-oxo-5-phenyl-2,3-dihydro-1 / - / - benzo [e] [1,4] diazepin-3-yl) -lH -imidazole-l-carboxamide

[091] Ι, Γ-carbonyldiimidazole (1.65 kg, 3.0 eq.) Was added in a MeCN reactor (12.7 L) at 20 ± 5 ° C, stirred for 15 min and cooled to 0 ± 3 ° C. (S) -3amino-5-phenyl-1,3-dihydro-2 / - / - benzo [e] [1,4,] -diazepin-2-one (0.85 kg, 1.0 eq.) in batches keeping below 5 ° C during the addition. The reaction was stirred at 2 ± 3 ° C for 2 h and heated to 20 ± 5 ° C and stirred for 6 h. 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 heated to 20 ° C. The solid was filtered and washed with (1.7 L, 2 V) twice. The collected solid was dried in a vacuum oven at <25 ° C to provide the title compound (1.16 kg, 98.6% HPLC purity) as a white solid. LC-MS (ESI, m / z): 278.10, 346.13 [M + H] ⁺ .
Step 4: (S) -2- (3-morpholino-5- (trifluoromethyl) picolinoyl) - / V-2-oxo-5-phenyl-2,3dihydro-l / - / - benzo [e] [l , 4] -diazepin-3-yl) hydrazine-1-carboxamide
[092] 3-Morpholino-5- (trifluoromethyl) picolin-hydrazide (0.84 kg, 1.0 eq.) Was added in a 5 L flask with NMP (2 L) at 25 ± 5 ° C and stirred for 10 min.
[093] (S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] -diazepin-3-yl) -1H
Petition 870190100767, of 10/8/2019, p. 44/47
37/39 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 h. The reaction mixture was cooled to 15 ° C, poured into ice water (15 L, 3 ° C) in a 20 L flask, stirred for 30 min, filtered and washed with purified water (2 x 3 L). The collected cake was stirred with purified water (10 L) at 25 ± 5 ° C for 1 h, filtered and washed with purified water (2x3 L). The collected cake was dried in a vacuum oven at 27 ° C for 40 h to provide the crude (1.640 kg). The crude (1.64 kg) was dissolved in DCM (10 L), stirred for 30 min, loaded with activated carbon (0.15 kg) and stirred for 30 min, filtered through diatomite (1 w / w), washed with DCM (2 x 2.5 L). The filtrate was loaded with n-heptane (30 L) in a 50 L round-bottom flask at 25 ± 5 ° C and stirred for 1 h. The solid was filtered and the cake washed with n-heptane (2x2 L), dried in a vacuum oven at 27 ° C for 30 h to provide the title compound (1.43 kg, 95.3% HPLC purity) like a light yellow solid. LC-MS (ESI, m / z): 568.19 [M + H] ⁺ .
Step 5: (S) -3 - ((5- (3-morpholino-5- (trifluoromethyl) pyridin-2-yl) -1, 3,4oxadiazol-2-yl) amino-5-phenyl-1 , 3-dihydro-2/7-benzo [e] [1,4] -diazepin-2-one
[094] To a mixture of (S) -2- (3-morpholino-5- (trifluoromethyl) picolinoyl) - / V-2oxo-5-phenyl-2,3-dihydro-1/7-benzo [e ] [1,4, -diazepin-3-yl) hydrazine-1-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was loaded with 4Â-MS (1.4 kg ) and stirred at 20 ± 5 ° C for 2 h. Then, it was cooled to 0 ° C, loaded with triethylamine (0.62 kg, 2.5 eq.) And stirred for 10 min. P-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) In DCM solution (1.4 L) was added dropwise to the reaction mixture keeping below 5 ° C and stirred at 0 ± 5 ° C for 5 h. The reaction mixture was filtered and washed with DCM (2 x 4.2 L). The filtrate was treated with water (4.2 L) at
Petition 870190100767, of 10/8/2019, p. 45/47
38/39
0 ° C and stirred between 0 and 10 ° C for 5 min. After separation, the organic phase was washed with 5% aqueous NaHCOs (7 L), water (7 L) and brine (7 L) successively and separated. The DCM layer was concentrated in vacuo below 30 ° C to leave ~ 7 L of organic layer. MTBE (7 L) was added to the 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 h. The solid was filtered and washed with MTBE (3 x 2.1 L) and purified water (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12 h, loaded with n-heptane (14 L) and stirred at 20 ± 5 ° C for 5 h. The solid was filtered, washed with n-heptane (2 x 2.8 L) and vacuum dried at room temperature to provide the title compound (0.776 kg, 99.6% HPLC purity, 97.8% purity chiral by HPLC chiral) as a light yellow solid. LC-MS (ESI, m / z): 550.17 [M + H] ⁺ ;
^X H NMR: (DMSO-d6 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); ¹³ C (DMSOd6, 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 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-d ih id ro-2Hbenzo [e] [1,4] -diazepin-2-one [095] (S) -3 - ((5- (3-morpholino-5- (trifluoromethyl ) pyridin-2-yl) -1,3,4-oxadiazol2-yl) amino-5-phenyl-1,3-dihydro-2 / - / - benzo [e] [1,4] -diazepin-2 -one (60.0 g) was dissolved in acetic acid (170 mL), stirred for 10 min, filtered through a porous funnel in a 3 L flask and lyophilized, dried in a vacuum pump
Petition 870190100767, of 10/8/2019, p. 46/47
39/39 at room temperature for 3 days. It was ground in a mortar and vacuum dried with N2 flow for 3 days to provide an amorphous form of (5) -3 - ((5- (3morpholino-5- (trifluoromethyl) pyridin-2-yl) -l, 3 , 4-oxadiazol-2-yl) amino-5-phenyl-1,2,3-hydroxy-2/7-benzo [e] [1,4] -diazepin-2-one as a yellowish solid.
Example 4. Preparation of an amorphous Compound (la) complex ((5) -3 ((5- (3-morpholino-5- (trifluoromethyl) pyridin-2-yl) -1, 3,4-oxadiazole-2- il) amino-5-phenyl, 3-dihydro-2/7-benzo [e] [1,4,] -diazepin-2-one] with copovidone.
[096] A mixture of (5) -3 - ((5- (3-morpholino-5- (trifluoromethyl) pyridin-2-yl) 1,3,4-oxadiazol-2-yl) amino-5-phenyl- 1,3-dihydro-2/7-benzo [e] [1,4] -diazepin-2-one (6.4 g) and copovidone (poly (1-vinylpyrrolidone-co-vinyl acetate), 1 , 6 g) were dissolved in acetone (160 mL). The solution was concentrated in vacuo and dried under a 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 overnight to provide an amorphous form of (5) -3 - ((5- (3-morpholino-5 (trifluoromethyl) pyridin-2-yl) -1, 3,4-oxadiazole-2 complex -yl) amino-5-phenyl-1,3-dihydro-2 / 7benzo [e] [1,4] -diazepin-2-one / copovidone as a yellowish solid.
[097] Although this invention has been particularly shown and described with reference to its preferred modalities, it will be understood by those skilled in the art that various changes in form and details can be made without departing from the scope of the invention covered by the appended claims.

权利要求:
Claims (18)
[1]
1) optionally substituted C 1 -C 6 alkyl;
1. Process for preparing a compound of formula (I),

[2]
2. Process according to claim 1, characterized by the fact that

[3]
Process according to claim 1, characterized in that step (a) is carried out in a protic solvent at a temperature of about 10 ° C to about 70 ° C.
3/6 selected from the group consisting of optionally substituted C1-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, 3 to heterocycle 8 members optionally substituted, optionally substituted aryl, and optionally substituted heteroaryl;
to produce a compound of formula (V),

[4]
4 / Ç>
Process according to any one of claims 1 to 3, characterized by the fact that R it is hydrogen and step (a) is carried out in the presence of an amide coupling agent.
[5]
5/6 nitrophenyl.
Process according to claim 4, characterized in that the amide coupling agent is HATU or EDU.
Petition 870190100811, of 10/8/2019, p. 11/15
[6]
Process according to claim 4 or 5, characterized in that step (a) is carried out in a solvent selected from the group consisting of isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, NMP , 2-methyltetrahydrofuran, and acetonitrile.
[7]
Process according to any one of claims 1 to 3, characterized by the fact that R is C 1 -C 6 alkyl and step (a) is carried out in the presence of a protic solvent.
[8]
8. Process according to claim 7, characterized in that the protic solvent is methanol, ethanol or isopropyl alcohol.
[9]
Process according to claim 8, characterized in that step (a) is carried out at a temperature of about 10 ° C to about 70 ° C for about 3 to 12 hours.
[10]
Process according to any one of claims 1 to 9, characterized in that step (b) is carried out (i) pure or (ii) in an aprotic solvent at a temperature of about 10 ° C to about 100 ° C.
[11]
Process according to any one of claims 1 to 10, characterized in that it additionally comprises the step of reacting the compound (IV),

[12]
Process according to claim 11, characterized in that the compound of formula Y-C (O) Rsé Ι, Γ-carbonyldiimidazole or chloroformate
Petition 870190100811, of 10/8/2019, p. 12/15
[13]
Process according to claim 12, characterized in that the compound of formula IV is reacted with the amine activating agent is a solvent selected from the group consisting of acetonitrile, THF, DMSO and dichloromethane.
[14]
Process according to any one of claims 1 to 13, characterized in that step (c) is carried out in acetonitrile, THF, DMSO, DMF, sulfolane or 1-methyl-2-pyrrolidone.
[15]
Process according to claim 14, characterized in that step (c) is carried out for 6 to 48 hours at a temperature of about 10 ° C to 50 ° C.
[16]
Process according to any one of claims 1 to 15, characterized in that the cyclizing agent of step (d) is para-toluenesulfonyl chloride.
[17]
17. Process according to claim 16, characterized by the fact that step (d) 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 about 0 ° C to about 30 ° C, (iv) for about 3 to 15 hours; (v) with a concentration of the compound of formula (III) of about 1 M to 3 M and (vi) at a ratio of concentration of the compound of formula (III) and of concentration of the compound of formula (V) of about 1: 1.
[18]
18. Process according to any one of claims 1 to 17, characterized in that the compound of formula I is compound l-a:

类似技术:

公开号 | 公开日 | 专利标题

BR112019016914A2|2020-04-14|processes for the preparation of benzodiazepine derivatives

US10752598B2|2020-08-25|Aryldiazepine derivatives as RSV inhibitors

ES2718409T3|2019-07-01|Synthesis of polycyclic carbomoylpyridone compounds

US10647711B2|2020-05-12|Azepin-2-one derivatives as RSV inhibitors

US10398706B2|2019-09-03|Heteroaryldiazepine derivatives as RSV inhibitors

US9663527B2|2017-05-30|Factor XIa inhibitors

WO2017158381A1|2017-09-21|4,6 dihydropyrrolo [3,4-c] pyrazole-5 |-carbonitrile derivates for trating cancer

WO2019006291A1|2019-01-03|Heterocyclic compounds as rsv inhibitors

WO2019006295A1|2019-01-03|Heterocyclic compounds as rsv inhibitors

US10011585B2|2018-07-03|Factor XIa inhibitors

BRPI0614637A2|2011-04-12|macrocyclic hepatitis c virus inhibitors

IL274534D0|2020-06-30|Processes for the resolution of benzodiazepin-2-one and benzodiazepin-2-one derivatives

US10123995B2|2018-11-13|Factor XIa inhibitors

WO2015123093A1|2015-08-20|Factor xia inhibitors

EP3104702A1|2016-12-21|Factor xia inhibitors

CN112739698A|2021-04-30|Tetrahydropyrimidine derivatives as AHR modulators

ES2683716T3|2018-09-27|MIF inhibitors

JP5570434B2|2014-08-13|Imidazopyridazines as PAR1 inhibitors, their production and use as pharmaceuticals

BR112020022114A2|2021-01-26|tetrazole containing kinase-1 inhibitors regulating apoptosis signal and methods of using it

EP3383847A1|2018-10-10|FACTOR XIa INHIBITORS

CN105616408A|2016-06-01|Use of pyridino[3,4-b]indol derivative as IDO inhibitor

同族专利:

公开号 | 公开日

AU2018221820A1|2019-09-19|

MX2019009687A|2019-12-18|

US10358441B2|2019-07-23|

CN110809472A|2020-02-18|

IL268737D0|2019-10-31|

WO2018152413A1|2018-08-23|

CA3065368A1|2018-08-23|

KR20190130129A|2019-11-21|

US10906895B2|2021-02-02|

US20190308964A1|2019-10-10|

EP3582784A1|2019-12-25|

EP3582784A4|2020-09-16|

RU2019128300A|2021-03-17|

RU2019128300A3|2021-06-25|

JP2020507595A|2020-03-12|

US20180237425A1|2018-08-23|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

CH573928A5|1973-07-30|1976-03-31|Crc Ricerca Chim|

IT1087017B|1977-10-18|1985-05-31|Ravizza Spa|PROCESS FOR THE PREPARATION OF A 7-CHLORO-5- -BENZODIAZE PINONE|

FR2641280B1|1988-12-29|1994-01-21|Roussel Uclaf|NOVEL 2,4-DIOXO 2,3,4,5-TETRAHYDRO 1H-1,5-BENZODIAZEPINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS|

US5571809A|1989-04-20|1996-11-05|Boehringer Ingelheim Pharmaceuticals, Inc.|The treatment of HIV-1 infection using certain pyridodiazepines|

EP0538945A1|1991-10-24|1993-04-28|Glaxo Group Limited|Benzodiazepine derivatives, and their use as antagonists of gastrin and/or cholecystokinin|

GB9201180D0|1992-01-21|1992-03-11|Glaxo Group Ltd|Chemical compounds|

US5681833A|1992-03-24|1997-10-28|Merck, Sharp & Dohme Ltd.|Benzodiazepine derivatives|

GB9307833D0|1993-04-15|1993-06-02|Glaxo Inc|Modulators of cholecystokinin and gastrin|

KR960702444A|1993-05-13|1996-04-27|고야 마사시|3-AMINOAZEPINE COMPOUND AND PHARMACEUTICAL USE THEREOF|

PT1143946E|1999-04-30|2004-05-31|Univ Michigan|USE OF BENZODIAZEPINAS TO TREAT AUTOIMMUNITY DISEASES INDUCED BY APOPTOSIS|

AU2003267587B2|2002-09-20|2010-05-20|Arrow Therapeutics Limited|Benzodiazepine derivatives and pharmaceutical compositions containing them|

GB0312365D0|2003-05-30|2003-07-02|Univ Aston|Novel 3-substituted-1, 4-benzodiazepines|

CA2541618C|2003-10-30|2011-12-13|Boehringer Ingelheim Ltd.|Rsv polymerase inhibitors|

GB0406280D0|2004-03-19|2004-04-21|Arrow Therapeutics Ltd|Chemical compounds|

GB0406279D0|2004-03-19|2004-04-21|Arrow Therapeutics Ltd|Therapeutic compounds|

GB0406282D0|2004-03-19|2004-04-21|Arrow Therapeutics Ltd|Therapeutic compounds|

WO2005090319A1|2004-03-19|2005-09-29|Arrow Therapeutics Limited|Process for preparing benzodiazepines|

EP1807111A4|2004-10-08|2009-05-27|Abbott Biotech Ltd|Respiratory syncytial virus infection|

US20090274655A1|2006-11-17|2009-11-05|Richard Martin Grimes|2-carboxy thiophene derivatives as anti viral agents|

WO2010103306A1|2009-03-10|2010-09-16|Astrazeneca Uk Limited|Benzimidazole derivatives and their use as antivaral agents|

WO2011005842A1|2009-07-09|2011-01-13|Gilead Sciences, Inc.|Anti-rsv compounds|

EA023441B1|2009-11-05|2016-06-30|ГЛАКСОСМИТКЛАЙН ЭлЭлСи|Benzodiazepine bromodomain inhibitor|

WO2011151651A1|2010-06-03|2011-12-08|Arrow Therapeutics Limited|Benzodiazepine compounds useful for the treatment of hepatitis c|

US8796303B2|2010-11-26|2014-08-05|Biota Scientific Management Pty Ltd.|Imidazo[2,1-G][1,7]naphthyridines for treating respiratory syncytial virus infections|

CN103022058A|2011-09-21|2013-04-03|索尼公司|Multi-junction solar cell, compound semiconductor device, photovoltaic conversion component and compound semiconductor layer-by-layer structure|

EP2794611B1|2011-12-22|2017-10-11|Gilead Sciences, Inc.|Pyrazolo[1,5-a]pyrimidines as antiviral agents|

EP3276332A3|2012-06-14|2018-04-18|Sony Corporation|Information processing apparatus, information processing method, and information processing program|

JP2015519385A|2012-06-15|2015-07-09|ヤンセン・アールアンドデイ・アイルランド|Novel 4-substituted 1,3-dihydro-2H-benzimidazol-2-one derivatives substituted by benzimidazole as RS virus antiviral agents|

KR20150033645A|2012-06-15|2015-04-01|얀센 알 앤드 디 아일랜드|1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with benzimidazoles as respiratory syncytial virus antiviral agents|

US9187434B2|2012-09-21|2015-11-17|Bristol-Myers Squibb Company|Substituted 1,5-benzodiazepinones compounds|

UA114531C2|2012-10-16|2017-06-26|ЯНССЕН САЙЄНСІЗ АЙРЛЕНД ЮСі|Rsv antiviral compounds|

JO3603B1|2013-05-17|2020-07-05|Janssen Sciences Ireland Uc|Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b|

WO2015026792A1|2013-08-21|2015-02-26|Alios Biopharma, Inc.|Antiviral compounds|

JP2017523988A|2014-08-05|2017-08-24|アリオスバイオファーマインク．|Combination therapy to treat paramyxovirus|

US9732098B2|2014-10-10|2017-08-15|Pulmocide Limited|5,6-dihydro-4H-benzo[b]thieno-[2,3-d]azepine derivative|

WO2016097761A1|2014-12-18|2016-06-23|Pulmocide Limited|4,5-dihydro-6h-thieno[3,2-d]benzazepine derivatives and their use to treat respiratory syncytial virus infections|

GB201506448D0|2015-04-16|2015-06-03|Univ Durham|An antimicrobial compound|

CN108200760A|2015-07-22|2018-06-22|英安塔制药有限公司|Benzodiazepine derivatives as RSV inhibitor|

WO2017123884A1|2016-01-15|2017-07-20|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as rsv inhibitors|

WO2017136727A2|2016-02-05|2017-08-10|Denali Therapeutics Inc.|Compounds, compositions and methods|

WO2017175000A1|2016-04-08|2017-10-12|Pulmocide Limited|Compounds|

WO2018129287A1|2017-01-06|2018-07-12|Enanta Pharmaceuticals, Inc.|Heteroaryldiazepine derivatives as rsv inhibitors|

RU2019128300A3|2017-02-16|2021-06-25|

WO2018226801A1|2017-06-07|2018-12-13|Enanta Pharmaceuticals, Inc.|Aryldiazepine derivatives as rsv inhibitors|

WO2019006295A1|2017-06-30|2019-01-03|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as rsv inhibitors|

US10851115B2|2017-06-30|2020-12-01|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as RSV inhibitors|

KR20200087132A|2017-09-29|2020-07-20|이난타 파마슈티칼스, 인코포레이티드|Combination pharmaceutical preparations as RSV inhibitors|

WO2019094903A1|2017-11-13|2019-05-16|Enanta Pharmaceuticals, Inc.|Processes for the resolution of benzodiazepin-2-one and benzoazepin-2-one derivatives|

US10647711B2|2017-11-13|2020-05-12|Enanta Pharmaceuticals, Inc.|Azepin-2-one derivatives as RSV inhibitors|

US10975094B2|2018-04-11|2021-04-13|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as RSV inhibitors|CN108200760A|2015-07-22|2018-06-22|英安塔制药有限公司|Benzodiazepinederivatives as RSV inhibitor|

WO2017123884A1|2016-01-15|2017-07-20|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as rsv inhibitors|

WO2018129287A1|2017-01-06|2018-07-12|Enanta Pharmaceuticals, Inc.|Heteroaryldiazepine derivatives as rsv inhibitors|

RU2019128300A3|2017-02-16|2021-06-25|

WO2018226801A1|2017-06-07|2018-12-13|Enanta Pharmaceuticals, Inc.|Aryldiazepine derivatives as rsv inhibitors|

WO2019006295A1|2017-06-30|2019-01-03|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as rsv inhibitors|

US10851115B2|2017-06-30|2020-12-01|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as RSV inhibitors|

KR20200087132A|2017-09-29|2020-07-20|이난타 파마슈티칼스, 인코포레이티드|Combination pharmaceutical preparations as RSV inhibitors|

US10647711B2|2017-11-13|2020-05-12|Enanta Pharmaceuticals, Inc.|Azepin-2-one derivatives as RSV inhibitors|

WO2019094903A1|2017-11-13|2019-05-16|Enanta Pharmaceuticals, Inc.|Processes for the resolution of benzodiazepin-2-one and benzoazepin-2-one derivatives|

US10975094B2|2018-04-11|2021-04-13|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as RSV inhibitors|

CA3133300A1|2019-03-18|2020-09-24|Enanta Pharmaceuticals, Inc.|Benzodiazepine derivatives as rsv inhibitors|

US11179400B2|2019-04-09|2021-11-23|Enanta Pharmaceuticals, Inc.|Heterocyclic compounds as RSV inhibitors|

法律状态:
2021-05-04| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

申请号 | 申请日 | 专利标题

US201762459955P| true| 2017-02-16|2017-02-16|

US201762459953P| true| 2017-02-16|2017-02-16|

PCT/US2018/018511|WO2018152413A1|2017-02-16|2018-02-16|Processes for the preparation of benzodiazepine derivatives|

[返回顶部]