HK40032676A - Fused polycyclic pyridone compounds as influenza virus replication inhibitors - Google Patents

Description

Fused polycyclic pyridone compounds as inhibitors of influenza virus replication

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application serial No. 62/827,754 filed on 1/4/2019, the entire contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention provides compounds that inhibit the replication of orthomyxoviruses and are therefore useful in the treatment of viral infections caused by orthomyxoviruses, such as influenza virus. The invention further provides pharmaceutical compositions comprising these compounds and methods of using these compounds to treat viral infections caused by orthomyxoviruses, such as influenza.

Background

Orthomyxoviruses have a negative-sense single-stranded RNA genome and replicate in the nucleus of infected cells because they lack the mechanism to produce cap structures to produce their own mRNA. Members of the orthomyxovirus family possess an RNA-dependent RNA polymerase that has endonuclease activity that cleaves a portion of the capped 5' end of cellular mRNA, which is then used as a primer to synthesize viral mRNA by transcribing the remaining viral RNA genome. This process is called cap-snatching. This is due to the requirement that the mRNA be 5 'capped for recognition by the cell's ribosomes for translation. The above viral endonucleases have been considered as promising targets for the development of antiviral drugs effective against orthomyxoviruses. ACS med. chem.letters,2014, vol.5, 61-64.

The orthomyxovirus family includes influenza a, influenza b, and influenza c viruses (all of which can infect humans), as well as several other viruses that do not normally infect humans. Influenza a and b are the strongest of these pathogens in humans, and usually account for the majority of severe influenza cases in a typical influenza season. It is estimated that influenza still causes as many as 40,000 deaths in the united states each year despite the widespread use of vaccines to reduce the incidence of influenza. Thus, there is a need for antiviral therapeutics that are effective in treating influenza, such as influenza a and b viruses.

Disclosure of Invention

Disclosed herein are compounds that inhibit replication of orthomyxoviruses, including at least one of influenza a, influenza b, and influenza c. Without being bound by theory, it is believed that these compounds achieve their antiviral effects by inhibiting the endonuclease function of viral RNA polymerase.

In a first aspect, there is provided a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, haloalkoxy, or alkyl substituted with one or two substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, and dialkylamino;

R²is hydrogen, halogen, alkyl, haloalkoxy, hydroxy or alkyl substituted with one, two or three substituents independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

R³is hydrogen, -C (O) R⁶、-C(O)-O-R⁷、-C(R⁸R⁹)-O-C(O)R¹⁰、-C(R¹¹R¹²)-O-C(O)-OR¹³、-P(＝O)(OR¹⁴)(OR¹⁵)、-(CR¹⁶R¹⁷)-O-P(＝O)(OR¹⁸)(OR¹⁹)、-C(O)-N(R²⁰R²¹) or-C (R)²²R²³)-O-C(O)N(R²⁴R²⁵) Wherein R is⁶、R⁷、R¹⁰、R¹³、R¹⁴、R¹⁵、R¹⁸、R¹⁹、R²⁰、R²¹、R²⁴And R²⁵Independently hydrogen, alkyl, phenyl, pyridyl, cycloalkyl and a 3-6 membered heterocycle, wherein alkyl, phenyl, pyridyl, cycloalkyl and a 3-6 membered heterocycleIndependently optionally substituted with one or two substituents independently selected from halogen, cyano, hydroxy, amino, alkyl, carboxy, alkoxycarbonyl, phenyl, alkoxy, haloalkyl, and haloalkoxy;

and R⁸、R⁹、R¹¹、R¹²、R¹⁶、R¹⁷、R²²And R²³Independently hydrogen or alkyl;

R⁴and R⁵Together with the atoms to which they are attached form a ring of formula (a), (b), (c) or (d):

wherein the ring of (a), (b), (c) or (d) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano; and

z is:

(i) a ring of formula (i):

wherein:

wherein X is CH₂、S、S(O)、S(O)₂Or O; and the ring of formula (i) is substituted with one, two, three or four substituents independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl and cyano; or

(ii) A ring of formula (ii):

wherein Ar is¹And Ar²Independently selected from phenyl and a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein Ar¹And Ar²Each independently optionally independently selected from halogen, alkyl, and,Haloalkyl, alkoxy, haloalkoxy, alkynyl and cyano, with one, two or three substituents.

In one embodiment of the first aspect, there is provided a compound of formula (I):

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or alkyl substituted with one or two substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

R²is hydrogen, halogen, alkyl, haloalkoxy or alkyl substituted with one, two or three substituents independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

and R³、R⁴、R⁵And Z is as defined above for the first aspect.

In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

In a third aspect, there is provided a method of treating a disease caused by a virus with cap-dependent endonuclease in a patient comprising administering to a patient in need thereof a compound of formula (I) (or any embodiment thereof described herein).

In a fourth aspect, there is provided a method of treating a disease caused by influenza a, influenza b and/or influenza c virus in a patient, comprising administering to a patient in need thereof a compound of formula (I) (or any embodiment thereof described herein). In a first sub-embodiment of the fourth aspect, the virus is influenza a. In a second sub-embodiment of the fourth aspect, the virus is influenza b. In a third sub-embodiment of the fourth aspect, the virus is influenza c. In a fourth sub-embodiment of the fourth aspect, the disease is caused by influenza a and influenza b. In a fifth sub-embodiment of the fourth aspect, the disease is caused by influenza a and influenza c. In a sixth sub-embodiment of the fourth aspect, the disease is caused by influenza b and influenza c.

In a fifth aspect, the present disclosure is directed to the use of a compound of formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof, as a medicament or for use in therapy.

In a sixth aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof (or any embodiment thereof described herein), in the manufacture of a medicament for the treatment of a disease caused by an influenza virus in a patient. In a first sub-embodiment of the sixth aspect, the virus is an influenza a, influenza b and/or influenza c virus. In a second sub-embodiment of the sixth aspect, the virus is influenza a. In a third sub-embodiment of the sixth aspect, the virus is influenza b. In a fourth sub-embodiment of the sixth aspect, the virus is influenza c. In a fifth sub-embodiment of the sixth aspect, the disease is caused by influenza a and influenza b. In a sixth sub-embodiment of the sixth aspect, the disease is caused by influenza a and influenza c. In a seventh sub-embodiment of the sixth aspect, the disease is caused by influenza b and influenza c.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

"alkyl" means a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. One skilled in the art will recognize that the term "alkyl" may include an "alkylene" group.

"alkylene" means a straight chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

"alkynyl" means a straight chain saturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, such as ethynyl, propynyl, and the like.

"amino" means-NH₂。

"aminocarbonyl" means-CONH₂。

"alkylamino" refers to the-NHR group, wherein R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, 2-propylamino, and the like.

"alkylaminocarbonyl" refers to the group-CONHR wherein R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, or 2-propylaminocarbonyl, and the like.

"alkoxy" means an-OR group wherein R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, OR 2-propoxy, n-, i-, OR t-butoxy, and the like.

"alkoxycarbonyl" refers to the group-C (O) R, wherein R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

"cycloalkyl" refers to a monocyclic saturated monovalent hydrocarbon radical having 3 to 10 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.

"carboxyl" means-COOH.

"cyano" means-CN.

"dimethylamino" refers to the group-NRR ', where R and R' are independently alkyl groups as defined above, e.g., dimethylamino, methylethylamino, and the like.

"Dialkylaminocarbonyl" refers to the group-CONRR ', where R and R' are alkyl groups as defined above, e.g., dimethylaminocarbonyl, diaminoaminocarbonyl, or (methyl) 2-propylaminocarbonyl, and the like.

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms (e.g., 1 to 5 halogen atoms, such as fluorine or chlorine), including alkyl groups substituted with a different halogen, e.g., -CH₂Cl、-CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CF(CH₃)₂And the like. When the alkyl group is substituted with only fluorine, it may be referred to as fluoroalkyl group in the present application.

"haloalkoxy" means a-OR group wherein R is haloalkyl as defined above, e.g., -OCF₃、-OCHF₂And the like. When R is haloalkyl wherein the alkyl is substituted only with fluorine, it is referred to herein as fluoroalkoxy.

"heterocycle" means a saturated or unsaturated monovalent monocyclic ring having 3 to 6 ring atoms, wherein one, two or three ring atoms are selected from the group consisting of N, O and S (O)_n(wherein n is an integer of 0 to 2), and the remaining ring atoms are carbon, unless otherwise specified. In addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally replaced by a-C (O) -group. More particularly, the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two double bonds, as long as the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino group, and is a subset of heterocyclyl groups.

"heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment one, two, or three) ring atoms is a heteroatom selected from N, O or S, the remaining ring atoms being carbon, unless otherwise specified. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. The terms "heteroaryl" and "aryl" are mutually exclusive, as defined herein. When a heteroaryl ring contains 5-or 6 ring atoms, it is also referred to herein as a 5-or 6-membered heteroaryl.

The term "oxo", as used herein, alone or in combination, refers to ═ O.

When desired, any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, any such defined tail element is an element that is connected to the parent moiety. For example, the complex group alkoxyalkyl means that the alkoxy group is linked to the parent molecule through an alkyl group.

The disclosure also includes protected derivatives of the compounds of the disclosure (I). For example, when the compounds of the present disclosure contain groups such as hydroxyl, carboxyl, or any group containing a nitrogen atom, these groups may be protected by suitable protecting groups. A comprehensive list of suitable protecting Groups can be found in t.w. greene, Protective Groups in Organic Synthesis, 5 th edition, John Wiley & Sons, inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure may be prepared by methods well known in the art.

The present disclosure also includes polymorphic forms of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof.

The present disclosure also includes prodrugs of compounds of formula (I) and/or pharmaceutically acceptable salts thereof. The term "prodrug" refers to a compound that has a higher activity in vivo. Certain compounds disclosed herein may also be present as prodrugs, as described in Hydrolysis in Drug and produgmetabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide active compounds. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or the parent drug. For example, they may be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug is a compound that is administered in the form of an ester ("prodrug"), but which is subsequently metabolically hydrolyzed to a carboxylic acid, the active entity. Additional examples include peptidyl derivatives of the compounds.

"pharmaceutically acceptable salts" of a compound refer to salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include:

acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, acid addition salts formed from ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or

Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a counterpart formed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, PA,1985, which is incorporated herein by reference in its entirety.

The compounds of formula (I) may have asymmetric centers. The compounds of formula (I) containing an asymmetric substituent atom may be isolated in optically active or racemic form. Individual stereoisomers of compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing mixtures of enantiomeric products, followed by separation (e.g., conversion to a mixture of diastereomers), then separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, mixtures of all chiral or diastereomeric forms and racemic forms are within the scope of the disclosure. It will also be understood by those of ordinary skill in the art that when a compound is represented as an (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity, and vice versa.

Certain compounds of formula (I) may exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, both as individual forms and as mixtures, are within the scope of the present disclosure. In addition, the term alkyl as used herein includes all possible isomeric forms of the alkyl group, although only a few examples are listed. In addition, when cyclic groups such as aryl, heteroaryl, heterocyclic groups are substituted, they include all positional isomers, although only some examples are listed. Furthermore, all hydrates of the compounds of formula (I) are within the scope of the present disclosure.

The compounds of formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope can be defined as amounts ranging from those found in nature to 100% of the atom in question, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of formula (I) (and any embodiments thereof, including particular compounds, disclosed herein) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. isotopically-labelled compounds (e.g. with³H and¹⁴c-labeled compounds) can be used in compound or substrate tissue distribution assays. Tritiated (i.e. tritiated)³H) And carbon-14 (i.e.¹⁴C) Isotopes can be used to make them easy to prepare and detectable. In addition, heavier isotopes such as deuterium (i.e., deuterium) are used²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of formula (I), including table 1 below, one or more hydrogen atoms are replaced with²H or³H instead, or one or more carbon atoms enriched¹³C or¹⁴Carbon substitution of C. Positron emitting isotopes such as¹⁵O、¹³N、¹¹C and¹⁵f can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the schemes herein or in the examples, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

"optional" or "optional" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "phenyl optionally substituted with alkyl" means that the alkyl may, but need not, be present, and that the description includes the case where phenyl is substituted with alkyl and the case where phenyl is not substituted with alkyl.

"pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in the preparation of a pharmaceutical composition, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier/excipient" includes one and more than one such excipient.

As used herein, the term "about" is intended to define the modified numerical value, which is expressed as a variable within a margin of error. The term "about" when there is no particular error range, such as the standard deviation of the mean values given in a data chart (chart) or data table (table), is understood to mean an inclusive range covering ± 10%, preferably ± 5%, of the recited values and ranges.

As used herein, the term "disease" is intended to be generally synonymous with and interchangeable with the terms "aberration", "syndrome" and "condition" (as in medical conditions), as they each reflect an abnormal condition that impairs normal function of the human or animal body or a part thereof, which typically manifests as distinct signs and symptoms and reduces the life time or quality of life of the human or animal.

The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a disease or disorder described in this disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, e.g., in a single capsule with a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In any event, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.

"treatment" or "treatment" of a disease includes:

(1) preventing a disease, i.e., not causing clinical symptoms of the disease in a mammal that may be exposed to the disease or susceptible to the disease but does not yet experience or exhibit symptoms of the disease;

(2) inhibiting a disease, i.e., arresting or reducing the development of a disease or its clinical symptoms; or

(3) Remission of a disease, i.e., causing regression of the disease or its clinical symptoms.

In one embodiment, treating refers to preventing a disease. In another embodiment, treatment refers to inhibition or alleviation of the disease.

"therapeutically effective amount" means an amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, which, when administered to a patient for treatment of a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

The terms "inhibit" and "reduce," or any change in these terms in relation to the endonuclease, include any measurable decrease or complete inhibition to achieve the desired result. For example, the activity may be reduced by about, up to about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, as compared to the normal activity of the endonuclease of the viral RNA polymerase.

Representative compounds of formula (I) are disclosed in table (I) below.

TABLE 1

Additional compounds of formula (I) that are contemplated are provided in table 2 below.

TABLE 2

The implementation scheme is as follows:

in the following embodiments 1A-17, the present disclosure includes:

1A, in embodiment 1A, a compound of formula (IA) or a pharmaceutically acceptable salt thereof is as described in the summary above.

1. In embodiment 1, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as described in the summary above.

2. In embodiment 2, the compound of any one of embodiments 1A and 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (II):

in a first sub-embodiment of embodiment 2, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the structure:

3. in embodiment 3, the compound of any one of embodiments 1A and 1, or a pharmaceutically acceptable salt thereof, has the formula (III):

in a first sub-embodiment of embodiment 3, the compound or pharmaceutically acceptable salt thereof, wherein the stereochemistry at C is (S). In a second sub-embodiment of embodiment 3, the compound or pharmaceutically acceptable salt thereof, wherein the stereochemistry at C is (R).

4. In embodiment 4, the compound of any one of embodiments 1A and 1, or a pharmaceutically acceptable salt thereof, has the structure of formula (IV):

5. in embodiment 5, the compound of any one of embodiments 1A and 1 to 4, and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein Z is a ring of formula (i). In a group of embodiment 5 in a first sub-embodiment the compound or pharmaceutically acceptable salt thereof, wherein X is S. In the radicals of embodiment 5, in the second subgroupIn this embodiment, the compound or pharmaceutically acceptable salt thereof, wherein X is s (o). In a third sub-embodiment of the group of embodiment 5, wherein X is S (O)₂. In a group of embodiment 5, in a first sub-embodiment, the compound or pharmaceutically acceptable salt thereof, wherein X is O.

In the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof, wherein Z is a ring of formula (i) substituted with 1,2 or 3 (preferably 1 or 2) halo. In the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of formula (i) substituted with 1,2 or 3 (preferably 1 or 2) fluoro.

In the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of the formula:

in the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of the formula:

in the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of the formula:

in the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of the formula:

in the group of embodiment 5, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of the formula:

6. in embodiment 6, the compound of any one of embodiments 1A and 1 to 4, and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein Z is a ring of formula (ii). In a group of embodiment 5 in a first sub-embodiment the compound or pharmaceutically acceptable salt thereof, wherein Ar is¹And Ar²Each is phenyl, wherein the phenyl is independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl, and cyano.

In the group of embodiment 6, the compound or pharmaceutically acceptable salt thereof, wherein Z is a ring of formula (ii) substituted with 1,2 or 3 (preferably 1 or 2) halo. In the group of embodiment 6, the compound or pharmaceutically acceptable salt thereof wherein Z is a ring of formula (ii) substituted with 1,2 or 3 (preferably 1 or 2) fluoro.

7. In embodiment 7, the compound of any one of embodiments 1A and 1 to 6 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R¹And R²Independently hydrogen, methyl, fluoro, hydroxy, trifluoromethyl or trifluoromethoxy. In a first sub-embodiment of embodiment 7, the compound or pharmaceutically acceptable salt thereof, wherein R is¹And R²Each is hydrogen.

8. In embodiment 8, the compound of any one of embodiments 1A and 1 to 7, and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R is³Is hydrogen.

9. In embodiment 9, the compound of any one of embodiments 1A and 1 to 7 and the sub-embodiments contained therein or a pharmaceutically acceptable salt thereofA salt of (I) wherein R is³is-C (O) R⁶Wherein R is⁶Is alkyl optionally substituted by methoxy, preferably R⁶Is methyl, ethyl, isopropyl, 2-methylpropyl, 2-methoxyethyl, 2-methoxy-2-methylethyl or 2-methoxy-2-methylpropyl.

10. In embodiment 10, the compound of any one of embodiments 1A and 1 to 7, and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R is³is-C (O) -O-R⁷Wherein R is⁷Is alkyl, preferably R⁷Is methyl, ethyl, isopropyl, 2-methylpropyl, 2-methoxyethyl, 2-methoxy-2-methylethyl or 2-methoxy-2-methylpropyl.

11. In embodiment 11, the compound of any one of embodiments 1A and 1 to 7 and sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R is³is-CH (R)⁹)-O-C(O)R¹⁰Wherein R is⁹Is hydrogen or alkyl and R¹⁰Is alkyl optionally substituted by methoxy, preferably R³is-CH₂-OC (O) -methyl, -CH₂-OC (O) - (2-methoxyethyl) or-CH₂-OC (O) -tert-butyl. In a sub-embodiment of embodiment 11, R³is-CH (R)⁹)-O-C(O)R¹⁰Wherein R is⁹Is hydrogen or alkyl and R¹⁰Is alkyl, preferably R³is-CH₂-OC (O) -methyl or-CH₂-OC (O) -tert-butyl.

12. In embodiment 12, the compound of any one of embodiments 1A and 1 to 7, and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R³is-CH (R)¹²)-O-C(O)-OR¹³Wherein R is¹²Is hydrogen or alkyl and R¹³Is alkyl optionally substituted by alkoxy, preferably R³is-CH₂-OC (O) O-methyl, -CH (CH)₃) -OC (O) O-methyl, -CH₂-OC (O) O-ethyl, -CH₂-OC (O) O-isopropyl or-CH₂-OC (O) O- (2-methoxyethyl).

13. In embodiment 13, embodiments1A, 1, 5-12 and the compound of any one of the sub-embodiments contained therein or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Together with the atoms to which they are attached form a ring of formula (a), wherein the ring of formula (a) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano.

14. In embodiment 16, the compound of any one of embodiments 1A, 1, 5 to 12 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Together with the atoms to which they are attached form a ring of formula (a), wherein the ring of formula (a) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano, preferably with one or two substituents independently selected from methyl, hydroxy, methoxy or fluoro.

15. In embodiment 14, the compound of any one of embodiments 1A, 1, 5 to 12 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Together with the atoms to which they are attached form a ring of formula (b), wherein the ring of formula (b) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano, preferably with one or two substituents independently selected from methyl, hydroxy, methoxy or fluoro.

16. In embodiment 16, the compound of any one of embodiments 1A, 1, 5 to 12 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Together with the atoms to which they are attached form a ring of formula (c), wherein the ring of formula (c) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano, preferably with one or two substituents independently selected from methyl, hydroxy, methoxy or fluoro.

17. In embodiment 16, the compound of any one of embodiments 1A, 1, 5 to 12 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Together with the atoms to which they are attached form a ring of formula (d), wherein the ring of formula (d) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano, preferably with one or two substituents independently selected from methyl, hydroxy, methoxy or fluoro.

It should be understood that the above-described embodiments include all combinations of the embodiments and sub-embodiments listed therein. For example, R as set forth in embodiment 12³The radicals and one or more preferred radicals therein may be combined independently with one or more of embodiments 1A and 1 to 7 and/or sub-embodiments contained therein.

General synthetic schemes

The compounds of the present disclosure can be prepared by the methods described in the reaction schemes shown below.

The starting materials and Reagents for preparing these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.) or Sigma (St. Louis, Mo.), or according to the following references such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-17 (John Wiley and Sons, 1991); rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplementary volumes (Elsevier Science Publishers, 1989); the procedures described in Organic Reactions, Vol.1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4 th edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) were prepared by methods known to those skilled in the art. These schemes are merely illustrative of some of the ways in which the compounds of the present disclosure may be synthesized, and various modifications may be made to these schemes, and will provide suggestions to those skilled in the art upon reading this disclosure. If desired, the starting materials, intermediates and end products of the reaction can be isolated and purified using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are carried out at atmospheric pressure, at a temperature in the range of from about-78 ℃ to about 150 ℃, such as from about 0 ℃ to about 125 ℃, further such as at about room (or ambient) temperature, for example, about 20 ℃.

Wherein R can be prepared as illustrated and described in scheme 1 below¹、R²、R³、R⁴And R⁵Compounds of formula (IA) and (I) as defined in the summary of the invention.

May be prepared by first deprotonating the NH groups with a base (e.g. n-butyllithium) and then treating with a suitable protecting group (e.g. an alkyl haloformate, e.g. allyl chloroformate) to give PG therein¹A compound of formula 1-b which is a protecting group, to a compound of formula (I) wherein R is⁴And R⁵Protection of the nitrogen atom in compounds of formula 1-a which together with the atoms to which they are attached form a ring of formula (a). Treatment of compound 1-b with a reducing agent, such as lithium diisobutylaluminum hydride, affords compounds of formula 1-c. Compound 1-c can be converted to L therein by treating it with an acid, such as p-toluenesulfonic acid or methanesulfonic acid in pure solvent¹A compound of formula 1-d which is alkyl.

In the presence of Lewis acids (e.g. SnCl)₄) With a compound of formula 1-e (wherein Bn is benzyl or other suitable protecting group, and R is¹And R²As defined in the summary of the invention) to give compounds of formula 1-f. Removal of the amino protecting group in 1-f, followed by cyclization of the resulting amine, affords compounds of formula 1-g.

At T₃Reacting 1-g of compound with a compound of formula L in the presence of P, methanesulfonic acid or P-toluenesulfonic acid²-Z compound (wherein L²Is a leaving group such as halogen, hydroxy or acetyl and Z is as in the summary of the inventionDefinition) to yield the compound of formula 1-h. Removal of the benzyl group from 1-h by methods well known in the art to give R wherein³A compound of formula (I) which is hydrogen. Wherein R may be substituted by methods well known in the art³Conversion of a compound of formula (I) which is hydrogen to a compound of formula (I) wherein R³A corresponding compound of formula (I) which is not hydrogen. A detailed synthesis of the compounds of formula 1-g is provided in synthetic example 1 below.

Alternatively, where R may be prepared as illustrated and described in scheme 2 below¹、R²、R³、R⁴And R⁵A compound of formula (I) as defined in the summary of the invention.

Scheme 2

Using a compound of formula 2-b (whereinIs composed of) Or with a compound of formula 2-c (wherein R is^aAnd R^bEach being alkyl) to give a compound of formula 2-d or 2-e, respectively. By using acids (e.g. water and organic solvents such as CH)₃CN, p-toluenesulfonic acid, methanesulfonic acid in a mixture of CN) and then cyclizing the resulting aldehyde by methods well known in the art, the compounds of formulae 2-d and 2-e are converted to compounds of 2-f and 2-g, respectively.

Then removing benzyl groups from compounds 2f and 2g to obtain compounds in which R³A compound of formula (I) which is hydrogen, which may then be converted into a compound of formula (I) wherein R is³A compound of formula (I) other than hydrogen.

Practicality of use

The compounds of formula (I), in free form or in salt form, inhibit replication of orthomyxoviruses and are therefore useful in therapy or as research chemicals, for example as tool compounds, such as for the study of replication of orthomyxoviruses, preferably influenza a, influenza b or influenza c, more preferably influenza a and b. Accordingly, the compound of formula (I) or a salt thereof is useful for the treatment of infections caused by orthomyxoviruses, preferably influenza a, influenza b or influenza c, more preferably influenza a and influenza b, especially in human subjects. In some embodiments, the subject to be treated is a human having or at risk of having an influenza virus infection. For example, a subject having a pre-existing condition that may be exacerbated by influenza infection, such as asthma or COPD, may be treated with the method or a compound of formula (I) or a salt thereof prior to exhibiting symptoms of influenza infection. In other embodiments, the subject treated by the method and the compound of formula (I) or salt thereof is a subject diagnosed as having symptoms consistent with influenza infection. In other embodiments, the subject may be a human that has been tested using known diagnostic methods, such as the Rapid Influenza Diagnostic Test (RIDT) or reverse transcriptase PCT (RT-PCR) methods, to detect the presence of influenza virus, and is found to be infected with influenza, regardless of the presence or absence of typical influenza symptoms.

In another embodiment, there is provided a method of treating a disease caused by an orthomyxovirus, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein, or any embodiment thereof. In some embodiments, the disease caused by an orthomyxovirus is selected from influenza a, influenza b and influenza c, preferably influenza a and influenza b.

Pharmaceutical composition

In general, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount by any acceptable mode of administration of an agent with similar utility. A therapeutically effective amount of a compound of the present disclosure may range from about 0.01 to about 500mg per kg body weight of the patient per day, which may be administered in single or multiple doses. Suitable dosage levels may be from about 0.1 to about 250mg/kg per day; about 0.5 to about 100mg/kg per day. Suitable dosage levels may be from about 0.01 to about 250mg/kg per day, from about 0.05 to about 100mg/kg per day, or from about 0.1 to about 50mg/kg per day. Within this range, the dose may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing from about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient. The actual amount of the compound of the present disclosure, i.e., the active ingredient, will depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and other factors.

The pharmaceutical compositions may be formulated for specific administration uses such as oral, parenteral, and rectal administration, and the like. In addition, the pharmaceutical compositions of the present invention may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional inert diluents, lubricants or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like.

Suitable compositions for oral administration include a compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may also contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated (e.g., enteric coated) by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. These compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating or coating methods and contain about 0.1-75% or about 1-50% of the active ingredient, respectively.

Compositions for transdermal use comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable carrier. Suitable carriers for transdermal delivery include absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. For example, a transdermal device is in the form of a bandage comprising a backing member, a reservoir containing a compound (optionally with a carrier), optionally a rate-controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and means to secure the device to the skin.

Compositions for topical application, e.g., to the skin and eye, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, e.g., by aerosol delivery and the like. Such topical delivery systems may involve inhalation or intranasal application suitable for the treatment of influenza and may, for example, contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. They may conveniently be delivered in the form of a dry powder from a dry powder inhaler (alone, or as a mixture, for example a dry blend with lactose, or a mixed particle of the ingredients, for example with a phospholipid), or an aerosol spray from a pressurised container, pump, nebuliser (spray), spray bottle (atomizer) or nebuliser (nebulizer), with or without the use of a suitable propellant.

Since water can promote the degradation of certain compounds, the present disclosure also provides anhydrous pharmaceutical compositions and dosage forms comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits (formulary kits). Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of decomposition of a compound of formula (I) as an active ingredient. Such agents are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, and the like.

The compound of formula (I) or a salt thereof may be administered simultaneously or sequentially with one or more therapeutic co-agents (therapeutic co-agents). The compound of formula (I) or a salt thereof and the co-agent may be administered separately, by the same or different routes of administration, or together in the same pharmaceutical composition. Suitable co-agents for use with the compounds of the present invention include antiviral agents active against influenza viruses, such as neuraminidase inhibitors, including oseltamivir, peramivir, zanamivir and ranimivir, ranimivir octanoate, and adamantanes, such as amantadine and rimantadine. Additional co-agents useful in these methods include M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, Favipiravir, influenza enzyme (fludase), ADS-8902, beraprost, beta-lactamase, beta-,Ribavirin, a compound of CAS registry number 1422050-75-6, VX-787, Flu MistQuadrivalent、Quadrivalent、And

in one embodiment, there is provided a product comprising a compound of formula (I) or a salt thereof and at least one other therapeutic co-agent for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is for the treatment of a viral infection caused by an orthomyxovirus, preferably influenza a, influenza b or influenza c, more preferably influenza a and influenza b. Products provided as a combined preparation include compositions comprising a compound of formula (I) and at least one other therapeutic co-agent together in the same pharmaceutical composition, or in separate forms, e.g. in the form of a kit, for treating a subject by a method described herein. Suitable co-agents include antiviral agents active against influenza viruses, such as neuraminidase inhibitors, including oseltamivir, peramivir, zanamivir, and ranimivir, and adamantanes, such as amantadine and rimantadine. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

In another embodiment, a kit is provided comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound of formula (I) or a salt thereof. Another pharmaceutical composition may comprise a suitable co-agent. In one embodiment, the kit comprises means for separately preserving the compositions, such as a container, a separate bottle, or a separate foil package. An example of such a kit is a blister pack, typically used for the packaging of tablets, capsules and the like. The kit may be used for administering different dosage forms, e.g. orally and parenterally, for administering separate compositions at different dosage intervals, or for titrating separate compositions against each other. To aid compliance, the kit typically contains administration instructions.

Thus, there is also provided the use of a compound of formula (I) or a salt thereof for the treatment of a viral infection caused by an orthomyxovirus, in particular influenza (which may be influenza a, influenza b or influenza c), wherein the medicament is prepared for administration with a therapeutic co-agent.

Examples

The preparation of the following intermediates (references) compounds of formula (I) is given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Example 1

(2R,4aR,14aS,14bS) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione [1] and (2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5, synthesis of 6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [2]

Step 1: n- (2, 4-Dimethoxybenzyl) -2- (furan-2-yl) ethan-1-amine

To a 2.0L four-necked round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added MeOH (730mL), 2- (furan-2-yl) ethan-1-amine (73.0g,656.8mmol,1.0 eq.), and 2, 4-dimethoxybenzaldehyde (109g,655.9mmol,1.0 eq.). The resulting solution was stirred at room temperature for 30 minutes. Adding NaBH in portions over 30 minutes at 0 ℃ with stirring₄(25g,660.9mmol,1.0 equiv.). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with water and then concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give 70g (crude) of the title compound as a dark yellow oil. MS (ES, m/z): [ M + 1]]⁺＝262.1。

Step 2: n- (2, 4-Dimethoxybenzyl) -N- (2- (furan-2-yl) ethyl) acrylamide

To a 1L four-necked round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added [ (2, 4-dimethoxyphenyl) methyl group][2- (Furan-2-yl) ethyl group]Amine (65.0g,248.7mmol,1.0 equiv.), DCM (650mL) and TEA (52.0g,513.9mmol,2.10 equiv.). Prop-2-enecarbonyl chloride (35.0g,386.7mmol,1.55 eq.) was added dropwise with stirring at 0 ℃. After stirring at 0 ℃ for 30 minutes, the reaction was quenched with water. The resulting mixture was extracted with DCM and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 40g (yield 50%) of the title compound as a yellow oil. MS (ES, m/z): [ M + 1]]⁺＝316.2。

And step 3: rac- (4aR,7R,8aS) -2- (2, 4-dimethoxybenzyl) -3,4,8,8 a-tetrahydro-2H-4 a, 7-epoxyisoquinoline (epoxyisoquinoline) -1(7H) -one

To a 2.0L round bottom flask purged and maintained under an inert nitrogen atmosphere was added N- [ (2, 4-dimethoxyphenyl) methyl group]-N- [2- (furan-2-yl) ethyl]Prop-2-enamide (40.0g,126.8 mmo)l) and toluene (1200 mL). The resulting solution was stirred at 110 ℃ for 10 hours and then concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether to give 32g (yield 80%) of the title compound as a pale yellow oil. MS (ES, m/z): [ M + 1]]⁺＝316.2。

And 4, step 4: racemic- (4aS,7S,8aS) -2- (2, 4-dimethoxybenzyl) hexahydro-2H-4 a, 7-oxisoquinolin-1 (5H) -one

To a 1L round bottom flask purged with and maintained under an inert nitrogen atmosphere was added rac- (4aR,7R,8aS) -2- (2, 4-dimethoxybenzyl) -3,4,8,8 a-tetrahydro-2H-4 a, 7-oxisoquinolin-1 (7H) -one (32.0g,101.5mmol,1.0 eq.), MeOH (600mL) and Pd/C (3g, 10% on charcoal). At room temperature, in H₂The resulting mixture was stirred under an atmosphere (2-3atm) for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give 30g (93%) of the title compound as a colorless oil. (ES, m/z): [ M + 1]]⁺＝318.2。

And 5: rac- (4aS,7S,8aS) -hexahydro-2H-4 a, 7-oxisoquinolin-1 (5H) -one

To a 50mL three-necked round bottom flask purged with and maintained under an inert nitrogen atmosphere was added rac- (4aS,7S,8aS) -2- (2, 4-dimethoxybenzyl) hexahydro-2H-4 a, 7-oxisoquinolin-1 (5H) -one (1.5g,4.75mmol,1.0 equiv.) and TFA (20 mL). The reaction mixture was stirred at 60 ℃ for 1 hour and then concentrated. The residue was diluted with water. The pH of the aqueous solution was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with DCM. The combined organic layers were concentrated in vacuo to give 1.3g (crude) of the title compound as a white solid. (ES, m/z): [ M + 1]]⁺＝168.2。

Step 6: rac-allyl (4aS,7S,8aS) -1-oxooctahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate

To a 50mL three-necked round bottom flask purged with and maintained under an inert nitrogen atmosphere was added rac- (4aS,7S,8aS) -hexahydro-2H-4 a, 7-oxiranquinolin-1 (5H) -one (1.30g,7.78mmol,1.0 eq.) and THF (15 mL). n-BuLi (3.11mL, 2.5M in hexanes, 7.78mmol,1.0 equiv.) was added dropwise with stirring at-78 deg.C, and the resulting solution was stirred for 1 hour at-78 deg.C. Prop-2-en-1-yl chloroformate (0.93g,7.72mmol,1.0 eq.) was added dropwise with stirring at-78 deg.C, and the resulting reaction mixture was stirred for 1 hour at-78 deg.C. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column on silica eluting with ethyl acetate/petroleum ether to give 0.75g (two steps 63%) of the title compound. (ES, m/z): [ M + 1]]⁺＝252.2。

And 7: rac-allyl (4aS,7S,8aS) -1-hydroxyoctahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate

At-78 ℃ under N₂To a stirred solution of rac-allyl (4aS,7S,8aS) -1-oxooctahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate (1000mg,3.98mmol,1.0 equiv.) in THF (10mL) under atmosphere was added LiAlH in portions₄(226.56mg,5.9mmol,1.5 equiv.). At-78 ℃ under N₂The resulting mixture was stirred for 1 hour under an atmosphere and then NaHCO at 0 deg.C₃(5.0mL) aqueous solution. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (800 mg). The crude product was used directly in the next step without further purification. MS (ES, m/z): [ M +41+23 ]]⁺＝317.1。

And 8: rac-allyl (4aS,7S,8aS) -1-methoxyoctahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate

At room temperature under N₂To a stirred solution of rac-allyl (4aS,7S,8aS) -1-hydroxyoctahydro-2H-4 a, 7-epoxy-isoquinoline-2-carboxylate (850mg,3.36mmol,1.0 equiv.) in MeOH (10mL) under atmosphere was added methanesulfonic acid (32.2mg,0.34mmol,0.1 equiv.). The resulting mixture was stirred at room temperature for 16 hours and then with NaHCO₃(510mL) aqueous solution quench. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1/1) to give the title compound as a pale yellow oil (210mg, 23.4%).

And step 9: rac-allyl (4aS,7S,8aR) -1- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) octahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate

At-20 ℃ under N₂To a stirred solution of rac-allyl (4aS,7S,8aS) -1-methoxyoctahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate (40mg,0.150mmol,1 equiv.) and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (43.14mg,0.150mmol,1 equiv.) in MeCN (1mL) under atmosphere was added dropwise SnCl₄(77.96mg,0.299mmol,2 equiv.). The reaction mixture was stirred at room temperature overnight and then with NaHCO at 0 deg.C₃Aqueous (5mL) was quenched and the resulting mixture was extracted with EtOAc. The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (40mg, 51%) which was used in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝524.3。

Step 10: (2R,4aR,14aS,14bS) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione and (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

At room temperature under N₂To a stirred solution of rac-allyl (4aS,7S,8aR) -1- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) octahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate and allyl (4aR,7R,8aS) -1- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) octahydro-2H-4 a, 7-epoxyisoquinoline-2-carboxylate (800mg,1.5mmol,1.0 equiv.) and morpholine (266.2mg,3.1mmol,2.0 equiv.) in THF (20mL) under an atmosphere was added Pd (PPh) portionwise.₃)₄(176.6mg,0.160mmol,0.1 equiv.). The resulting mixture was stirred at room temperature for 16 h, then Et₂Dilution with O (20 mL). The precipitated solid was collected by filtration and used for Et₂O wash to give 500mg of product as a yellow solid. MS (ES, m/z): [ M + 1]]⁺394.2. The solid was purified by chiral preparative-HPLC (CHIRALPAK IA-3) to give two enantiomers. (2R,4aR,14aS,14bS) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione trifluoroacetate salt: tR 1.47min, (240mg, 32.0%) and (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione trifluoroacetate salt: tR 3.3min, (220mg, 29.3%).

Step 11: (2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione

At room temperature under N₂To (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1, 6: -1, 6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione trifluoroacetate salt (220mg,0.45mmol,1.0 equiv.) and 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiepin-11-ol (119mg,0.45mmol,1.0 equiv.) in T₃To a stirred solution of P (2mL) and EtOAc (2mL) was added methanesulfonic acid (43mg,0.45mmol,1.0 equiv). At 70 ℃ under N₂The resulting mixture was stirred under an atmosphere for 24 hours. By H₂And O, quenching the reaction. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title product (390mg, crude). The crude product was used directly in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝640.3。

Step 12: (2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [1] and (2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [2]

(2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] is reacted at 70 ℃]Thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]A stirred mixture of isoquinoline-8, 10-dione (390mg,0.61mmol,110 equiv.) and LiCl (258mg,6.1mmol,10.0 equiv.) in DMF (4.0mL) was stirred for 3 hours. The reaction solution was purified by preparative-HPLC to give (2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] aS a white solid]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione [1]]And (2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e)]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino- [3,4-a]Isoquinoline-8, 10-dione [2]]. Compound [1]：MS(ES,m/z)：[M+1]⁺550.2. Compound [2]：MS(ES,m/z)：[M+1]⁺＝550.2。

Examples 3 and 4

(2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [3] and (2S,4aS,14aR,14bR) -14- ((R) -10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, synthesis of 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [4]

Step 1: (2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

At room temperature under N₂To (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1, 6: -1, 6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (80.0mg,0.20mmol,1.0 equiv.) and 10-fluoro-6, 11-dihydrodibenzo [ b, e]Thiepin-11-ol (49.3mg,0.20mmol,1.0 equiv.) in T₃To a stirred solution of P (1.0mL) and EtOAc (1.0mL) was added methanesulfonic acid (19.2mg,0.20mmol,1.0 equiv). At 70 ℃ under N₂The resulting mixture was stirred under an atmosphere for 16 hours and then treated with H₂And O quenching. Mixing the obtained mixtureExtracted with EtOAc. The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the crude title product (140mg, crude). It was used directly in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝622.3。

Step 2: (2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [3] and (2S,4aS,14aR,14bR) -14- ((R) -10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-Oxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [4]

(2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (10-fluoro-6, 11-dihydrodibenzo [ b, e ] at 90 ℃]Thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]A stirred mixture of isoquinoline-8, 10-dione (140mg, crude, 0.23mmol,1.0 equiv.) and LiCl (42.4mg,1.0mmol,5.0 equiv.) in DMA (1.0mL) was stirred for 3 hours. The crude product was purified by prep-HPLC to give the title product as a light yellow solid [3](10mg) and [4](15 mg). Compound [3]：MS(ES,m/z)：[M+1]⁺532.2. Compound [4]：MS(ES,m/z)：[M+1]⁺＝532.2。

Examples 5 and 6

(2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [5] and (2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14, synthesis of 14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [6]

Step 1: (2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

At room temperature under N₂To (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1, 6: -1, 6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (80mg,0.20mmol,1 equiv.) and 8, 9-difluoro-6, 11-dihydrodibenzo [ b, e]Thiepin-11-ol (52.9mg,0.20mmol,1.0 equiv.) in T₃To a stirred solution of P (1.0mL) and EtOAc (1.0mL) was added methanesulfonic acid (19.2mg,0.2mmol,1.0 equiv). At 70 ℃ under N₂The resulting mixture was stirred under an atmosphere for 16 hours and then treated with H₂And O quenching. The resulting mixture was extracted with EtOAc. The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (150mg, crude). It was used directly in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝640.3。

Step 2: (2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [5] and (2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [6]

At 90 deg.C, (2S,4 a)S,14aR,14bR) -9- (benzyloxy) -14- (8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]A mixture of isoquinoline-8, 10-dione (150mg, crude, 0.23mmol,1.0 equiv.) and LiCl (42.4mg,1.0mmol,5.0 equiv.) in DMA (1.0mL) was stirred for 3 hours. The reaction solution was purified by preparative-HPLC to give (2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] aS a pale yellow solid]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione [5]]And (2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e)]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione [6]]. Compound [5]：MS(ES,m/z)：[M+1]⁺550.2. Compound [6]]：MS(ES,m/z)：[M+1]⁺＝550.2。

Examples 7 and 8

(2S,4aS,14aR,14bR) -14- ((S) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [7] and (2S,4aS,14aR,14bR) -14- ((R) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14, synthesis of 14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [8]

Step 1: (2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

At room temperature under N₂To (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1, 6: -1, 6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (80mg,0.20mmol,1.0 equiv.) and 4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiepin-11-ol (52.9mg,0.20mmol,1.0 equiv.) in T₃To a stirred solution of P (1.0mL) and EA (1.0mL) was added methanesulfonic acid (19.2mg,0.20mmol,1 equiv). At 70 ℃ under N₂The resulting mixture was stirred under an atmosphere for 16 hours and then treated with H₂And O quenching. The resulting mixture was extracted with EtOAc. The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title product (140mg, crude). It was used directly in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝640.2。

Step 2: (2S,4aS,14aR,14bR) -14- ((S) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [7] and (2S,4aS,14aR,14bR) -14- ((R) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione [8]

(2S,4aS,14aR,14bR) -9- (benzyloxy) -14- (4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] is reacted at 90 ℃]Thiepin-11-yl) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]A stirred mixture of isoquinoline-8, 10-dione (140mg, crude, 0.22mmol,1.0 equiv.) and LiCl (42.4mg,1.0mmol,10.0 equiv.) in DMA (1.0mL) was stirred for 3 hours. The reaction solution was purified by preparative-HPLC to give (2S,4aS,14aR,14bR) -14- ((S) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e ] aS a pale yellow solid]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione [7]]And (2S,4aS,14aR,14bR) -14- ((R) -4, 10-difluoro-6, 11-dihydrodibenzo [ b, e)]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]-triazino [3,4-a]Isoquinoline-8, 10-dione [8]]. Compound [7]：MS(ES,m/z)：[M+1]⁺550.2. Compound [8]：MS(ES,m/z)：[M+1]⁺＝550.2。

Example 9

Synthesis of (2S,4aS,14aR,14bR) -14- (1, 9-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

At room temperature under N₂To 1, 9-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] in an atmosphere][7]Rotan-5-ol (50mg,0.20mmol,1.00 equiv.) and (2S,4aS,14aR,14bR) -9- (benzyloxy) -1,3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (80mg,0.20mmol,1.0 equiv.) in EtOAc (1.0mL) and T₃The stirred mixture in P was added methanesulfonic acid (20mg,0.20mmol,1.00 eq) in one portion. After stirring at 80 ℃ for 16 hours, the reaction mixture is cooled to room temperature and washed with H₂And O quenching. The mixture was then extracted with EtOAC. The combined organic layers were washed with water and brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was dissolved in DMA (1.0mL) and LiCl (54mg,1.29mmol,10.0 equiv.) was added. At 90 ℃ under N₂The resulting mixture was stirred under an atmosphere for 16 hours. After cooling at room temperature, the crude material was purified by prep-HPLC to give the title compound (13mg, 12%). MS (ES, m/z): [ M + H ]]⁺＝532.3。

Example 10

Synthesis of (2S,4aS,14aR,14bR) -14- (2, 8-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] -annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinoline-8, 10-dione

Analogously to what described in example 9, 2, 8-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] was used][7]Replacing 1, 9-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] with rotalen-5-ol][7]Rotanen-5-ol was used to synthesize compound 10. MS (ES, m/z): [ M + H ]]⁺＝532.3。

Example 11

Synthesis of (14aS) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -11-hydroxy-5 a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione

Step 1: 2- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] -isoindoline-1, 3-dione

To (5S) -5- (hydroxymethyl) pyrrolidin-2-one (10.00g,86.8mmol,1.0 equiv.), phthalimide (14.06g,95.5mmol,1.1 equiv.) and PPh under a nitrogen atmosphere at room temperature₃(25.06g,95.5mmol,1.1 equiv.) of THF (150mL) was stirred and DIAD (19.3g,95.5mmol,1.1 equiv.) was added dropwise. The resulting mixture was stirred for 3 hours. The precipitated solid was collected by filtration and washed with EtOAc to give the title compound as an off-white solid (13.4g, 63%). MS (ES, m/z): [ M + 1]]⁺＝245.1。

Step 2: 2- [ [ (2S) -5-oxo-1- (prop-2-en-1-yl) pyrrolidin-2-yl ] methyl ] isoindole-1, 3-dione

To 2- [ [ (2S) -5-oxopyrrolidin-2-yl group under nitrogen atmosphere at room temperature]Methyl radical]A stirred solution of isoindole-1, 3-dione (13.4g,54.8mmol,1.0 equiv.) in DMSO (300mL) was added NaH (2.63g,65.7mmol,1.2 equiv., 60% in mineral oil) in portions. The resulting mixture was stirred at room temperature for 0.5 hour. To the above mixture was added allyl bromide (13.27g,109.7mmol,2.0 equiv) dropwise at room temperature over 10 min. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with EtOAc and then quenched with aqueous HCl (1.0M) at 0 ℃. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give the title compound as a pale yellow oil (13.5g, 86.5%). MS (ES, m/z): [ M + 1]]⁺＝285.1。

And step 3: 2- [ (2S) -2- [ (1, 3-dioxo-3 a,7 a-dihydroisoindol-2-yl) methyl ] -5-oxopyrrolidin-1-yl ] acetaldehyde

To 2- [ [ (2S) -5-oxo-1- (prop-2-en-1-yl) pyrrolidin-2-yl ] at 0 deg.C]Methyl radical]-3a,7 a-dihydroisoindole-1, 3-dione (6.00g,20.1mmol,1.0 equiv.) in THF (120mL) and H₂Adding K in portions into O (30mL) stirring solution₂OSO₄.2H₂O (1.54g,4.2mmol,0.20 equiv.) and NaIO₄(22.4g,104.7mmol,5.0 equiv.). The resulting mixture was stirred at room temperature for 2 hours, and then filtered. The filter cake was washed with DCM and the filtrate was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a pale brown semi-solid (4.1g, 67%). MS (ES, m/z): [ M + 1]]⁺＝287.1。

And 4, step 4: synthesis of 2- [ [ (2S) -1- (2, 2-dimethoxyethyl) -5-oxopyrrolidin-2-yl ] methyl ] -isoindoline-1, 3-dione

2- [ (2S) -2- [ (1, 3-dioxo-3 a,7 a-dihydroisoindol-2-yl) methyl group was reacted at 70 ℃ under nitrogen atmosphere]-5-oxopyrrolidin-1-yl]A solution of acetaldehyde (4.1g,14.2mmol,1.0 equiv.) and TsOH (245mg,1.4mmol,0.1 equiv.) in MeOH (100mL) was stirred for 2 h. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DMF and then purified by reverse flash chromatography to give the title compound as a light brown oil (3.1g, 65%). MS (ES, m/z): [ M + Na ]]⁺＝355.2。

And 5: (5S) -5- (aminomethyl) -1- (2, 2-dimethoxyethyl) pyrrolidin-2-one

To 2- [ [ (2S) -1- (2, 2-dimethoxyethyl) -5-oxopyrrolidin-2-yl group at room temperature]Methyl radical]To a stirred solution of (3 a,7 a) -isoindoline-1, 3-dione (3.10g,9.3mmol,1.0 equiv.) in THF (60mL) was added hydrazine (1.49g,29.8mmol,3.2 equiv.). The resulting mixture was stirred at 65 ℃ for 4 hours. The mixture was cooled at room temperature and then filtered. The filter cake was washed with THF, the filtrate was concentrated under reduced pressure and dissolved in water. The resulting mixture was washed with EtOAc and the aqueous solution was freeze dried to give the title compound as a pale yellow oil (1.5g, 80%).¹HNMR(300MHz,CDCl3,ppm)4.55(dd,J＝5.7,5.0Hz,1H),3.80-3.62(m,2H),3.41(s,6H),3.16-3.03(m,1H),2.97-2.77(m,2H),2.56-2.27(m,2H),2.22-2.08(m,1H),1.94-1.81(m,1H)。

Step 6: 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino ] -4-oxopyridine-2-carboxylic acid

To 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino group at room temperature]-4-Oxopyridine-2-carboxylic acid ethyl ester (3.50g,9.0mmol, 1.0)Equivalent) of EtOH (40mL) and H₂A stirred solution of O (10mL) was added LiOH (0.86g,35.9mmol,4.0 equiv.). The resulting mixture was stirred at 60 ℃ for 16 hours and then concentrated under reduced pressure. The mixture was neutralized to pH6 with HOAc and the resulting mixture was purified by prep-HPLC to give the title compound as an off-white solid (1.8g, 55%). MS (ES, m/z): [ M + 1]]⁺＝361.2。

And 7: 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino ] -N- [ [ (2S) -1- (2, 2-dimethoxyethyl) -5-oxopyrrolidin-2-yl ] methyl ] -4-oxopyridine-2-carboxamide

To 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino group]To a stirred solution of-4-oxopyridine-2-carboxylic acid (700mg,1.9mmol,1.0 equiv.) and HATU (1.1g,2.9mmol,1.5 equiv.) in DMF (10mL) was added (5S) -5- (aminomethyl) -1- (2, 2-dimethoxyethyl) -pyrrolidin-2-one (785mg,3.9mmol,2.0 equiv.) and DIEA (627mg,4.8mmol,2.5 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was purified by reverse flash chromatography to give (550mg, 52%) the title compound as an off-white solid. MS (ES, m/z): [ M + 1]]⁺＝545.3。

And 8: (14aS) -11- (benzyloxy) -5a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] pyrrolo- [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione

To 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino group at 60 ℃ under nitrogen atmosphere]-N- [ [ (2S) -1- (2, 2-dimethoxyethyl) -5-oxopyrrolidin-2-yl]Methyl radical]-4-oxopyridine-2-carboxamide (550mg,1.0mmol,1.0 equiv.) in CH₃CN (9.0mL) and H₂To a stirred solution of O (1.5mL) was added methanesulfonic acid (291mg,3.0mmol,3.0 equiv) dropwise. The resulting mixture was stirred at 60 ℃ under nitrogen for 16 hours. Removing the organic solvent under reduced pressure, and recovering the obtained productThe mixture is mixed with Na₂CO₃The saturated aqueous solution was basified to pH 8 and then extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10:1) to give the title compound (200mg, 52%) as a light yellow solid. MS (ES, m/z): [ M + 1]]⁺＝381.1。

And step 9: (14aS) -11- (benzyloxy) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -5a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione

(14aS) -11- (benzyloxy) -5a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] at 80 ℃ under nitrogen atmosphere]Pyrrolo [1',2': 4,5]Pyrazino [2,1-c ] s][1,2,4]Triazine-3, 10,12(2H) -trione (100mg,0.26mmol,1.0 equiv.) and 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiepin-11-ol (77mg,0.2mmol,1.1 equiv.) in T₃The mixture in P (1.0mL) and EtOAc (0.5mL) was stirred for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (150mg, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification. MS (ES, m/z): [ M + 1]]⁺＝627.1。

Step 10: (14aS) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -11-hydroxy-5 a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione

To (14aS) -11- (benzyloxy) -6- (7, 8-difluoro-6, 11-dihydrodibenzo- [ b, e)]Thiepin-11-yl) -5a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f]Pyrrolo [1',2': 4,5]Pyrazino [2,1-c ] s][1,2,4]To a stirred solution of triazine-3, 10,12(2H) -trione (150mg, crude, 0.24mmol,1.0 equiv.) in DMA (2.0mL) was added LiCl (112mg,2.6mmol,10.0 equiv.). The resulting mixture was stirred at 80 ℃ for 2 hours, then purified by prep-HPLC to give the title compound as a white solid (100mg, two steps 71%). MS (ES, m/z): [ M + 1]]⁺＝537.1。

Separation of 100mg of the title compound by chiral-preparative-HPLC gave the four isomers 11a, 11b, 11c and 11 d.

First eluting isomer: tR 0.83min, (4.6mg, 4.6%), MS (ES, m/z): [ M + 1]]⁺537.2. Second eluting isomer: tR 1.06min, (8.5mg, 8.50%), MS (ES, m/z): [ M + 1]]⁺537.1, third eluting isomer: tR 1.28min, (36mg, 36.0%), MS (ES, m/z): [ M + 1]]⁺537.1, and the fourth eluting isomer: tR 1.69min, (33mg, 33.0%), MS (ES, m/z): [ M + 1]]⁺＝537.1。

Example 12

Synthesis of (14aR) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -11-hydroxy-5 a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione

The synthesis of compound 12 was performed analogously as described in example 11 above, but using (5R) -5- (hydroxymethyl) pyrrolidin-2-one instead of (5S) -5- (hydroxymethyl) -pyrrolidin-2-one in step 1. MS (ES, m/z): [ M + 1]]⁺＝537.1。

Example 13

Rac- (R) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1 ': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione and rac- (R) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', synthesis of 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione [ rac-13 a and rac-13 b ]

Step 1: 2- (2-Azidoethyl) isoindoline-1, 3-dione

To a 50-mL round bottom flask was added N- (2-bromoethyl) phthalimide (2.0g,7.87mmol,1.00 equiv.), acetone (20.0mL), H₂O (10.0mg) and sodium azide (1.54g,23.7mmol,3.0 equiv.). The reaction mixture was then stirred at 60 ℃ for 24 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/2) to give the title compound (1.5g, 88%). MS (ES, m/z): [ M + 1]]⁺＝245.1。

Step 2: 2- (2- (5- (diethoxymethyl) -1H-1,2, 3-triazol-1-yl) ethyl) isoindoline-1, 3-dione

To a 100-mL round bottom flask was added 2- (2-azidoethyl) isoindole-1, 3-dione (3.00g,13.8mmol,1.0 equiv.), 3-diethoxypropyne (3.56g,27.7mmol,2.0 equiv.), Cp RuCl (PPh)₃)₂(552mg,0.69mmol,0.05 eq.) and toluene (30 mL). The resulting solution was stirred at 100 ℃ for 6 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by a column of silica gel (ethyl acetate/petroleum ether 1/1) to give 3.15g (66%) of the title productA compound is provided. MS (ES, m/z): [ M + 1]]⁺＝345.1。

And step 3: 2- (5- (diethoxymethyl) -1H-1,2, 3-triazol-1-yl) ethan-1-amine

To a 50-mL round bottom flask was added 2- [2- [5- (diethoxymethyl) -1,2, 3-triazol-1-yl ] benzene]Ethyl radical]Isoindole-1, 3-dione (680mg,1.9mmol,1.0 equiv.), i-PrOH (10mL), and NH₂NH₂.H₂O (988mg,19.8mmol,10 equiv.). The reaction mixture was then stirred at 80 ℃ for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give 320mg (yield 75%) of the title compound. MS (ES, m/z): [ M + 1]]⁺＝215.1。

And 4, step 4: (3- (benzyloxy) -2- ((2- (5- (diethoxymethyl) -1H-1,2, 3-triazol-1-yl) ethyl) carbamoyl) -4-oxopyridin-1 (4H) -yl) carbamic acid tert-butyl ester

At room temperature, 2- [5- (diethoxymethyl) -1,2, 3-triazol-1-yl ] was added]Ethylamine (320mg,1.5mmol,1.0 eq), 3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino]A solution of-4-oxopyridine-2-carboxylic acid (538mg,1.5mmol,1.0 equiv.), HATU (681mg,1.8mmol,1.2 equiv.), and DIEA (386mg,3.0mmol,2.0 equiv.) in DMF (2.0mL,0.027mmol,0.02 equiv.) was stirred for 16 h. The resulting mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/ethanol 20/1) to give 450mg (54%) of the title compound. MS (ES, m/z): [ M + 1]]⁺＝557.3。

And 5: 9- (benzyloxy) -5,6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione

3- (benzyloxy) -1- [ (tert-butoxycarbonyl) amino group was reacted at 60 ℃ with methanol]-N- [2- [5- (diethoxymethyl) -1,2, 3-triazol-1-yl]Ethyl radical]-4-oxopyridine-2-carboxamide (775mg,1.4mmol,1.0 equiv.), H₂O (2.5) and MeSO₃CH for H (801mg,4.6mmol,3.3 equiv.)₃The CN (15mL) solution was stirred for 24 hours. After cooling to room temperature, the reaction mixture was basified to pH 8 by addition of TEA. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/ethanol, 10/1) to give 196mg (38%) of the title compound. MS (ES, m/z): [ M + 1]]⁺＝365.2。

Step 6: rac- (R) -9- (benzyloxy) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -5,6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione and rac- (R) -9- (benzyloxy) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -5,6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione

Adding 9- (benzyloxy) -5,6,14,14 a-tetrahydro- [1,2,3] to the reaction tube]-triazolo [5 ', 1': 3,4]Pyrazino [2,1-c ] s]Pyrido [2,1-f][1,2,4]Triazine-8, 10-dione (100mg,0.27mmol,1.0 equiv.), 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e]Thiepin-11-ol (72mg,0.27mmol,1.0 equiv.) and T₃EtOAc solution of P (2.50mL, T)₃P/EtOAc 2/1). The resulting solution was stirred at 100 ℃ for 2.5 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with EtOAc. Subjecting the organic layer to Na₂SO₄Dried and concentrated. The residue was purified by column on silica gel (dichloromethane/methanol 10/1) to give compounds rac-13A and rac-13B. MS (ES, m/z): [ M + 1]]⁺611.1. LCMS conditions: column: shim-pack XR-ODS, 50 x 3.0mm, 2. uM; mobile phase A: water/0.1%FA; mobile phase B: CH (CH)₃CN/0.05% FA. One of rac-13A and rac-13B was tR 1.36min, the other was tR 1.46 min.

And 7: rac- (R) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1 ': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione and rac- (R) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione [ rac-13 a and rac-13 b ]

9- (benzyloxy) -14- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] was reacted at 90 deg.C]Thiepin-11-yl) -5,6,14,14 a-tetrahydro- [1,2,3]Triazolo [5 ', 1': 3,4]Pyrazino [2,1-c ] s]Pyrido [2,1-f][1,2,4]A mixture of triazine-8, 10-dione (rac-13A or rac-13B, 25.00mg,0.041mmol,1.00 equiv.), LiCl (8.68mg,0.205mmol,5.00 equiv.) and DMA (1.00mL) was stirred for 1 hour. After cooling to room temperature, the reaction solution was purified by preparative-HPLC to give 3.3mg (15.4%) of compound rac-13 a or rac-13 b. MS (ES, m/z): [ M + 1]]⁺＝521.2。

9- (benzyloxy) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] was reacted at 90 deg.C]Thiepin-11-yl) -5,6,14,14 a-tetrahydro- [1,2,3]Triazolo [5 ', 1': 3,4]Pyrazino [2,1-c ] s]Pyrido [2,1-f][1,2,4]A mixture of triazine-8, 10-dione (rac-13A or rac-13B, 17.00mg,0.028mmol,1.00 equiv.), LiCl (5.90mg,0.139mmol,5.00 equiv.) and DMA (1.00mL) was stirred for 1 hour. The reaction was cooled and purified by prep-HPLC to give 2.3mg (15.9%) of compound rac-13 a or rac-13 b as an off-white solid. MS (ES, m/z): [ M + 1]]⁺＝521.2。

Example 14

((2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] -triazino [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate or (((2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, synthesis of 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] -triazino [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate

At room temperature under N₂To (2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo- [ b, e) under atmosphere]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6]-[1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione or (2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo- [ b, e)]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6]-[1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (10mg,0.018mmol,1.0 equiv.), K₂CO₃(5.0mg,0.036mmol,2.0 equiv.) and KI (6.0mg,0.036mmol,2.0 equiv.) chloromethyl methyl carbonate (4.5mg,0.036mmol,2.0 equiv.) are added portionwise to a stirred mixture of DMA (0.20 mL). The resulting mixture was stirred at 80 ℃ for 16 hours. The crude product was purified by prep-HPLC to give the title compound as a light yellow solid (2.0mg, 17%). MS (ES, m/z): [ M + 1]]⁺＝638.3。

Example 15

(2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] - [1,2,4] triazino [3,4-a ] isoquinolin-9-yl 3-methoxypropionate or (2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, synthesis of 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] - [1,2,4] triazino [3,4-a ] isoquinolin-9-yl 3-methoxypropionate

To (2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] at 0 ℃ under a nitrogen atmosphere]-thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6]-[1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione or (2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]-thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6]-[1,2,4]Triazino [3,4-a]A stirred mixture of isoquinoline-8, 10-dione (20mg,0.036mmol,1.0 equiv.) and DMAP (2.22mg,0.018mmol,0.5 equiv.) and TEA (18mg,0.18mmol,5.0 equiv.) in DCM (0.5mL) is added dropwise 3-methoxypropionyl chloride (13mg,0.11mmol,3.0 equiv.) and the resulting mixture stirred at room temperature for 16 h. The crude product was purified by prep-HPLC to give the title compound (5mg, 21% yield). MS (ES, m/z): [ M + 1]]⁺＝636.2。

Example 16

Synthesis of ((2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate

To (2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydrodibenzo- [ b, e) at room temperature]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (15mg,0.028mmol,1.0 equiv.), Ag₂CO₃A stirred mixture of (23mg,0.085mmol,3 equiv.) and KI (14mg,0.085mmol,3.0 equiv.) in DMA (0.1mL) was added chloromethyl methyl carbonate (10mg,0.085mmol,3.0 equiv.) in one portion and the resulting mixture stirred at 45 ℃ for 16 h. The reaction solution was purified by preparative-HPLC to give the title compound (1) as a white solid.8mg,10％)。MS(ES,m/z)：[M+1]⁺＝620.3。

Example 17

((2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] - [1,2,4] triazino [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate or (((2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -8, synthesis of 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] - [1,2,4] triazino [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate

To (2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e) at room temperature]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione or (2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e)]Thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6][1,2,4]Triazino [3,4-a]Isoquinoline-8, 10-dione (5.0mg,0.01mmol,1.0 equiv.), Ag₂CO₃A stirred mixture of (7.5mg,0.027mmol,3.0 equiv.) and KI (4.5mg,0.027mmol,3.0 equiv.) in DMA (0.1mL) was added chloromethyl methyl carbonate (3.4mg,0.027mmol,3.0 equiv.) in one portion and the resulting mixture was stirred at 45 ℃ for 16 h. The reaction solution was purified by preparative-HPLC to give the title compound (1.5mg) as a white solid. MS (ES, m/z): [ M + 1]]⁺＝638.2。

Biological assay

Biological example 1

The activity of the compounds against influenza virus was assessed by the following in vitro cytopathic effect (CPE) assay.

At 2X 10 per hole³Density of individual cells, MDCK cells were seeded in 384-well plates and then at 37 ℃ and 5% CO₂The culture was carried out overnight. Compounds of formula (I) were serially diluted and transferred to test plates via an Echo 555 liquid handler. Cells were infected with influenza A/PR/8/34(H1N1) at a concentration of 1X 90% tissue culture infectious dose (TCID90) per well. The final DMSO concentration was 0.5%. At 37 ℃ and 5% CO₂The cells were cultured for an additional 5 days. Cell viability was determined using CCK8 using a microplate spectrophotometer according to the manufacturer's instructions.

Antiviral activity (% inhibition) of the compound was calculated using the following formula.

Inhibition (%) ═ (compound raw data-average VC)/(average CC-average VC) × 100

The inhibitory efficacy of the compounds of formula (I) is provided in table 3 below. ND means no determination of EC₅₀。

TABLE 3

Biological example 2

Comparative PK data for Compound 3 and Baloxavir acid (Baloxavir acid)

Tables 4,5 and 6 provide compound 3 (after administration of its prodrug compound 16) and baroxavir acid (after administration of its prodrug compound 16) in mice, rats and dogsThereafter), wherein baroxavir acid is as shown below:

as follows:

the study was carried out as follows.

PK study protocol

Male Balb/c mice, male SD rats, male beagle dogs were used in the study. Animals were fasted for at least 12 hours prior to dosing and fed 2 hours after dosing. Water was provided ad libitum during the study. In each study, three animals were included, mice were dosed orally with 10mg/kg, rats with 5mg/kg, dogs with 2mg/kg of Compound 16 orEach suspended in 0.5% HPMC in water. Blood samples were taken at 0.25, 0.5, 1,2,4, 8 and 24 hours post PO administration. The collected blood samples were then centrifuged at 3500rpm for 10 minutes at 4 ℃ to obtain plasma. The plasma samples were transferred to polyethylene tubes and immediately stored at about-80 ℃ until analysis.

The concentrations of compound 3 and baroxavir (Baloxavir) in plasma samples were determined. The study used an unverified LC-MS/MS method.

Plasma concentration-time data for each animal was analyzed using Phoenix WinNonlin (version 7.0, Certara). Non-compartmental models were used for data analysis. PK parameters, Cmax, AUC, etc., were calculated for compound 3 and baroxavir acid in the present application.

Table 4: mouse PK comparison: 10mg/kg was administered orally.

Table 5: rat PK comparison: 5mg/kg of the composition was administered orally.

Table 6: dog PK comparison: 2mg/kg of the composition was administered orally.

The Cmax of compound 3 was at least 6-fold higher than baroxavir acid, and the AUC of compound 3 was at least 2-fold higher than baroxavir acid.

Formulation examples

The following are representative pharmaceutical dosage forms containing the disclosed compounds.

Tablet formulation

The following ingredients were intimately mixed and compressed into single scored tablets.

Capsule preparation

The following ingredients were intimately mixed and filled into hard shell gelatin capsules.

Injection preparation

A compound of the disclosure (e.g., compound 1) is in 2% HPMC, 1% tween 80 in deionized water, pH 2.2, with an appropriate amount of MSA to at least 20mg/mL

Inhalation composition

To prepare a pharmaceutical composition for inhalation delivery, 20mg of the compound disclosed herein is mixed with 50mg of anhydrous citric acid and 100mL of a 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit suitable for inhalation administration, such as a nebulizer.

Topical gel compositions

To prepare a pharmaceutical topical gel composition, 100mg of a compound disclosed herein is mixed with 1.75g of hydroxypropyl cellulose, 10mL of propylene glycol, 10mL of isopropyl myristate, and 100mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical application.

Ophthalmic solution composition

To prepare a pharmaceutical ophthalmic solution composition, 100mg of a compound disclosed herein is mixed with 0.9g NaCl in 100mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit suitable for ophthalmic administration, such as an eye drop container.

Intranasal spray solutions

To prepare a pharmaceutical intranasal spray solution, 10g of a compound disclosed herein was mixed with 30mL of 0.05M phosphate buffer (pH 4.4). The solution was placed in an intranasal dispenser designed to deliver 100 μ l of spray per application.

Although the claimed subject matter has been described in terms of various embodiments, those skilled in the art will appreciate that various modifications, substitutions, omissions, and/or changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the claimed subject matter be limited only by the scope of the appended claims (including equivalents thereof).

Claims (33)

1. A compound of formula (IA), or a pharmaceutically acceptable salt thereof:

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, haloalkoxy, or alkyl substituted with one or two groups independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, and dialkylamino;

R²is hydrogen, halogen, alkyl, haloalkoxy, hydroxy or alkyl substituted with one, two or three groups independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

R³is hydrogen, -C (O) R⁶、-C(O)-O-R⁷、-C(R⁸R⁹)-O-C(O)R¹⁰、-C(R¹¹R¹²)-O-C(O)-OR¹³、-P(＝O)(OR¹⁴)(OR¹⁵)、-(CR¹⁶R¹⁷)-O-P(＝O)(OR¹⁸)(OR¹⁹)、-C(O)-N(R²⁰R²¹) or-C (R)²²R²³)-O-C(O)N(R²⁴R²⁵) Wherein R is⁶、R⁷、R¹⁰、R¹³、R¹⁴、R¹⁵、R¹⁸、R¹⁹、R²⁰、R²¹、R²⁴And R²⁵Independently hydrogen, alkyl, phenyl, pyridyl, cycloalkyl and 3-6 membered heterocycle, wherein alkyl, phenyl, pyridyl, cycloalkyl and 3-6 membered heterocycle are independently optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, carboxy, alkoxycarbonyl, phenyl, alkoxy, haloalkyl and haloalkoxy;

and R⁸、R⁹、R¹¹、R¹²、R¹⁶、R¹⁷、R²²And R²³Independently hydrogen or alkyl;

R⁴and R⁵Together with the atoms to which they are attached form a ring of formula (a), (b), (c) or (d):

wherein the ring of formula (a), (b), (c) or (d) may be optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy and cyano; and

z is:

(i) a ring of formula (i):

wherein:

wherein X is CH₂、S、S(O)、S(O)₂Or O;and the ring of formula (i) is substituted with one, two, three or four substituents independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl and cyano; or

(ii) A ring of formula (ii):

wherein Ar is¹And Ar²Independently selected from phenyl and a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein Ar¹And Ar²Each independently optionally substituted with one, two or three substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl and cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or alkyl substituted with one or two substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; and

R²is hydrogen, halogen, alkyl, haloalkoxy or alkyl substituted with one, two or three substituents independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa):

4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula (III):

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or alkyl substituted with one or two substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; and

R²is hydrogen, halogen, alkyl, haloalkoxy or alkyl substituted with one or two substituents independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at C is (S).

6. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at C is (R).

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of formula (IV):

wherein:

R¹is hydrogen, halogen, alkyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or alkyl substituted with one or two substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; and

R²is hydrogen, halogen, alkyl, haloalkoxy or alkyl substituted with one, two or three substituents independently selected from halogen, CN, hydroxy, alkoxy, amino, alkylamino and dialkylamino.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Z is a ring of formula (i).

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X is S.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Z is a ring of the formula:

11. the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is a ring of the formula:

12. the compound according to any one of claims 2 to 11, or a pharmaceutically acceptable salt thereof, wherein R¹And R²Independently hydrogen, methyl, fluoro or trifluoromethyl.

13. The compound according to any one of claims 1 and 8 to 11, or a pharmaceutically acceptable salt thereof, wherein R¹And R²Independently hydrogen, methyl, fluoro, hydroxy, trifluoromethyl or trifluoromethoxy.

14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R¹And R²Each is hydrogen.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R³Is hydrogen.

16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R³is-C (O) R⁶Wherein R is⁶Is an alkyl group optionally substituted with an alkoxy group.

17. A compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R⁶Is methyl, ethyl, isopropyl, -2-methylpropyl, 2-methoxyethyl, 2-methoxy-2-methylethyl or 2-methoxy-2-methylpropyl.

18. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R³is-C (O) -O-R⁷Wherein R is⁷Is an alkyl group.

19. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R⁷Is methyl, ethyl, isopropyl, 2-methylpropyl, 2-methoxyethyl, 2-methoxy-2-methylethyl or 2-methoxy-2-methylpropyl.

20. The method of any one of claims 1 to 14Or a pharmaceutically acceptable salt thereof, wherein R³is-CH (R)⁹)-O-C(O)R¹⁰Wherein R is⁹Is hydrogen or alkyl and R¹⁰Is an alkyl group.

21. A compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R³is-CH₂-OC (O) -methyl or-CH₂-OC (O) -tert-butyl.

22. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R³is-CH (R)¹²)-O-C(O)-OR¹³Wherein R is¹²Is hydrogen or alkyl and R¹³Is an alkyl group optionally substituted with an alkoxy group.

23. A compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein R³is-CH₂-OC (O) O-methyl, -CH (CH)₃) -OC (O) O-methyl, -CH₂-OC (O) O-ethyl, -CH₂-OC (O) O-isopropyl or-CH₂-OC (O) O- (2-methoxyethyl).

24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

(2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -4, 10-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -4, 10-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- (1, 9-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- (2, 8-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(14aS) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -11-hydroxy-5 a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] -pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione;

(14aR) -6- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -11-hydroxy-5 a,6,14,14 a-tetrahydro-1H, 5H-pyrido [2,1-f ] -pyrrolo [1',2': 4,5] pyrazino [2,1-c ] [1,2,4] triazine-3, 10,12(2H) -trione;

rac- (R) -14- ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo- [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione;

rac- (R) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] -thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo- [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione;

((2S,4aS,14aR,14bR) -14- (7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) -oxy) methyl carbonate;

(2S,4aS,14aR,14bR) -14- (7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin-3, 4-a ] isoquinolin-9-yl-3-methoxypropionate;

((2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate;

((2S,4aS,14aR,14bR) -14- ((S) -10-8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate;

((2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate; and

rac- (R) -14- ((R) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-5, 6,14,14 a-tetrahydro- [1,2,3] triazolo- [5 ', 1': 3,4] pyrazino [2,1-c ] pyrido [2,1-f ] [1,2,4] triazine-8, 10-dione.

25. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, selected from:

(2S,4aS,14aR,14bR) -14- ((S) -7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((S) -4, 10-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- ((R) -4, 10-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- (1, 9-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

(2S,4aS,14aR,14bR) -14- (2, 8-difluoro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -9-hydroxy-1, 3,4,5,6,14,14a,14 b-octahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazino [3,4-a ] -isoquinoline-8, 10-dione;

((2S,4aS,14aR,14bR) -14- (7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) -oxy) methyl carbonate;

(2S,4aS,14aR,14bR) -14- (7, 8-difluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin-3, 4-a ] isoquinolin-9-yl-3-methoxypropionate;

((2S,4aS,14aR,14bR) -14- ((S) -10-fluoro-6, 11-dihydro-dibenzo [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido- [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate;

((2S,4aS,14aR,14bR) -14- ((S) -8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate; and

((2S,4aS,14aR,14bR) -14- ((R) -8, 9-difluoro-6, 11-dihydrodibenzo- [ b, e ] thiepin-11-yl) -8, 10-dioxo-1, 3,4,5,6,8,10,14,14a,14 b-decahydro-2H-2, 4 a-epoxypyrido [1',2':1,6] [1,2,4] triazin [3,4-a ] isoquinolin-9-yl) oxy) methyl carbonate.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. A method of treating a disease in a patient caused by a virus having a cap-dependent endonuclease, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 26.

28. A method of treating a disease caused by influenza a, influenza b and/or influenza c viruses in a patient comprising administering to a patient in need thereof a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 26.

29. The method of claim 28, wherein the virus is influenza a.

30. The method of claim 28, wherein the virus is influenza b.

31. The method of any one of claims 27 to 30, wherein the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 26 is administered with at least one additional therapeutic co-agent.

32. The method of claim 31, wherein the co-agent is an antiviral agent.

33. The method of claim 32, wherein the antiviral agent treats one or more influenza a and/or influenza b infections.