Influenza cap-dependent endonuclease inhibitors

Abstract

Disclosed herein are cap-dependent endonuclease (CEN) inhibitors, compositions comprising them, and methods of their use to treat influenza.

Description

[0001] TSRI 2263.1PC 18350.033W01

[0002] INFLUENZA CAP-DEPENDENT ENDONUCLEASE INHIBITORS

[0003] CROSS-REFERENCE TO RELATED APPLICATION

[0004] This application claims priority to U.S. provisional patent application no. 63 / 699,543, filed September 26, 2024, the entirety of which is incorporated herein by reference.

[0005] GOVERNMENT SUPPORT

[0006] This invention was made with government support under U 19AI171443 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0007] 1. BACKGROUND

[0008] Influenza is an acute respiratory infectious disease caused by infection with an influenza virus (IFV). Because influenza infect approximately 20% of the world’s population, its prevention and treatment are of worldwide importance.

[0009] Proliferation of an influenza virus requires cap-dependent endonuclease (CEN), an influenza virus-derived enzyme. CEN represents an attractive target for antiviral drugs because they are specific to viruses and no CEN enzymes are encoded in the human genome. Baloxavir marboxil (BXM) as baloxavir acid marboxil prodrug, is the only approved influenza CEN inhibitor for the treatment of acute uncomplicated influenza.

[0010] While it is approved for flu treatment in 2018, recent findings suggested that IFV could develop resistance against BXM with resistance rate of 7.9%-9.7% among baloxavir-treated immunocompetent adults and adolescents. There is also continuous emergence of drug-resistant influenza virus strains for neuraminidase (NA) inhibitors, the major anti -influenza drugs used in clinical practice. Thus, there is a need in the field for improved CEN inhibitors for the treatment of influenza.

[0011] 2. SUMMARY

[0012] This invention encompasses novel CEN inhibitors and pharmaceutical compositions comprising them. Particular inhibitors are of formulae I, II, or III, disclosed herein.

[0013] This invention also encompasses a method of treating or preventing an influenza infection, which comprises administering to a subject in need thereof a therapeutically effective amount of compound or composition disclosed herein. In some embodiments of the invention, the influenza infection is resistant to Baloxavir marboxil. In some, the influenza infection is resistant to neuraminidase (NA) inhibitors.

[0014] In particular methods, the compound is administered with another CEN inhibitor or an NA inhibitor. TSRI 2263.1PC 18350.033W01

[0015] 3. DESCRIPTION OF THE DRAWINGS

[0016] Certain aspects of the invention may be understood with reference to the accompanying figures.

[0017] FIG. 1. Structures of certain compounds of the invention.

[0018] FIG. 2. Pharmacokinetics of orally administered (100 mg / kg) Compound 12 (represented as circles) and Compound 3 (represented as squares).

[0019] FIG. 3. Release of Compound 12 and BXA from their corresponding prodrugs (i.e., Compound 5 and BXM) in mice (lOOmg / kg).

[0020] FIG. 4A. Depiction of a method used to test murine viral load.

[0021] FIG. 4B. In vivo efficacy experiment comparing the marboxil prodrug Compound 5 to Tamiflu and Baloxavir marboxil.

[0022] 4. DETAILED DESCRIPTION

[0023] This invention is directed to novel cap-dependent endonuclease (CEN) inhibitors, compositions comprising them, and methods of their use to treat viral infection.

[0024] 4.1. DEFINITIONS

[0025] Unless otherwise indicated, the term “about” means ± 10% of the indicated range.

[0026] When used herein, the term “alkenyl” is accorded its conventional meaning. Examples of alkenyl moieties include straight-chain and branched C2-20, C2-12 and C2-6 alkenyl such as vinyl, allyl, 1-butenyl, 2- butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2- butenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 1 -heptenyl, 2-heptenyl, 3 -heptenyl, 1 -octenyl, 2-octenyl, 3- octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1 -decenyl, 2-decenyl and 3 -decenyl.

[0027] The term “alkyl” is accorded its conventional meaning. Examples of alkyl moieties include straight-chain and branched C1-20 alkyl, C1-12 alkyl, C1-6 alkyl, C1-4 alkyl, and C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

[0028] The term “alkynyl” is accorded its conventional meaning. Examples of alkynyl moieties include straight-chain and branched C2-20, C2-12 and C2-6 alkynyl, such as ethynyl and 2-propynyl (propargyl).

[0029] The term “aryl” refers to a single all-carbon-backbone aromatic ring or a multiple condensed all- carbon-backbone ring system wherein at least one of the rings is aromatic. Examples include Ce-2o, Ce-i4, Ce-i2, and C2-10 rings and multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic. The rings of multiple condensed ring systems may be connected to each other via fused, spiro, or bridged bonds when valency allows. Examples of aryl moieties include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, phenanthrenyl, and 1, 2, 3, 4- tetrahy dronaphthyl .

[0030] Unless otherwise indicated, the term “combination”, when used to describe the administration of two or more drugs to a patient, means that the two or more drugs are administered in a way such that their effects TSRI 2263.1PC 18350.033W01 overlap or that one drug will affect the efficacy or safety of a second drug. The two or more drugs need not be administered at the same time or by the same route of administration.

[0031] The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon-backbone ring having 3 to 20 carbon atoms (e.g., C3-20, C3-15, C3-7, C4-6 and Ce cycloalkyl). Examples include multicyclic carbocyles such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane, and polycyclic carbocycles, such as tricyclic and tetracyclic carbocycles. The rings of multiple condensed ring systems may be connected to each other via fused, spiro, and bridged bonds when valency allows. For example, multicyclic carbocycles may be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane), via two adjacent carbon atoms to form a fused connection (e.g. , decahydronaphthalene, norsabinane, norcarane), or via two non-adjacent carbon atoms to form a bridged connection (e.g, norbomane, bicyclo [2.2.2] octane). Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, adamantane.

[0032] The term “cycloheteroalkyl” refers to a cyclic heteroalkyl moiety, defined below.

[0033] The term “halo” encompass fluoro, chloro, bromo, and iodo.

[0034] The term “heteroalkyl” refers to a saturated or partially unsaturated moiety having 3- to 20-atom backbone of carbon and at least one heteroatom (e.g., O, N, S). Examples of heteroalkyl moieties include 2-8-membered, 2-6-membered, and 2-4-membered heteroalkyl moieties. Particular examples include alkoxyl, acyl (e.g., formyl, acetyl, benzoyl), alkylamino (e.g., di-(Ci-3-alkyl)amino), arylamino, aryloxime, carbamates, carbamides, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfanyl, arylsulfanyl, alkylsulfmyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, and arylsulfonylamino .

[0035] The term “heteroaryl” encompasses a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur (e.g., single aromatic rings of from 1 to 6 carbon atoms and 1-4 heteroatoms ). The term also encompasses multiple condensed ring systems that have at least one such aromatic ring. Examles include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolyl, quinoxalyl, quinazolinyl, quinolinyl, thienyl, tetrazolyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0036] The term “heterocycle” refers to a cyclic (monocyclic or polycyclic) heterocarbyl moiety which may be aromatic, partially aromatic, or non-aromatic. Heterocycles include heteroaryls. Examples include 4-10-membered, 4-7-membered, 6-membered, and 5-membered heterocycles such as aziridinyl, azetidinyl, benzofl, 3]dioxolyl, benzoxazinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, cinnolinyl, chromanyl, 2, 3 -dihydro-benzof 1,4] dioxinyl, dihydrooxazolyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,4-dioxane, dioxolane, butyrolactam, furanyl, homopiperidinyl, hydantoinyl, isoindolinyl-l-one, 2-oxa-6-azaspiro[3.3]heptanyl, hydantoin, imidazolidin-2-one, imidazolidine, imidazolidinone, morpholinyl, oxetanyl, oxiranyl, phthalimidyl, piperazinyl, piperidinyl, pyrrolidinonyl, TSRI 2263.1PC 18350.033W01 piperidinyl, pyrrolidinyl, pyrazolidine, spi ro| cyclopropane- 1. 1 '-isoindolinyl | -3 '-one. tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, 1, 2,3,4 - tetrahydroquinolyl, tetrahydrothiopyranyl, thiomorpholinyl, and valerolactamyl.

[0037] The term “heterocycloalkyl” refers to a cyclic (monocyclic or polycyclic) heteroalkyl, and encompasses both saturated and partially unsaturated (e.g., heterocycloalkenyl) moeites.

[0038] The term “include” has the same meaning as “include, but are not limited to,” and the term “includes” has the same meaning as “includes, but is not limited to.” Similarly, the term “such as” has the same meaning as the term “such as, but not limited to.”

[0039] The term “lower alkyl” refers to alkyl having from 1 to 6 carbon atoms, e.g., Ci-4 alkyl. Examples include methyl, ethyl, propyl, isopropyl, and cyclobutyl.

[0040] The terms “manage,” “managing” and “management” mean preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and / or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder or changing the way that a patient responds to the disease or disorder.

[0041] The term “pharmaceutically acceptable salt” refers to a salt that is generally recognized as safe to administer to a subject. Examples of pharmaceutically acceptable salts include acetate, chloride, diphosphate, hydrochloride, maleate, phosphate, potassium, sodium, and sulfate.

[0042] The terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder. The terms encompass prophylaxis.

[0043] A “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A “prophylactically effective amount” of a compound means an amount, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0044] The terms “subject” and “patient” are used interchangeably. The terms “subject” and “subjects” refer to an animal, such as a non-primate mammal (e.g., cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., monkey, a chimpanzee, human). Preferred subjects are human (e.g, adult humans).

[0045] A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A “therapeutically effective amount” of a compound means an amount, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. TSRI 2263.1PC 18350.033W01

[0046] The terms “treat,” “treating” and “treatment” contemplate an action that occurs while a patient is suffering from a specified disease or disorder, which reduces the severity of the disease or disorder or retards or slows the progression of the disease or disorder.

[0047] Unless otherwise indicated, an adjective before a string of nouns should be construed to apply to each. For example, the phrase “optionally substituted pyridyl, pyrazyl, or furanyl” means the same as “optionally substituted pyridyl, optionally substituted pyrazyl, or optionally substituted furanyl”.

[0048] A dashed line “ — ” used to depict a bond in a chemical structure indicates that the bond may be delocalized (e.g. , as in a tautomer) or may or may not exist (e.g. , as in the case where a solid and a dashed line are used together to depict a bond that may exist as a single bond or a double bond).

[0049] A wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

[0050] Compounds disclosed herein may exist as tautomeric isomers. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.

[0051] Compounds disclosed herein may exist as zwitterions (e.g., at pharmacological pH). Unless otherwise indicated, it should be understood that a chemical drawing depicting the structure of such a compound encompasses all of its zwitterionic forms.

[0052] Some compounds may exist as stereoisomers. When a stereoisomer of compound is defined by its name (e.g. , with the use of R or .S') or is depicted in a drawn structure (e.g. , using a bold, bold-wedge, dashed, or dashed-wedge to depict the relevant chemical bond), the enantiomeric excess (ee) of that compound, unless otherwise indicated, is to be understood to be at least 60, 70, 80, 90, 95, or 99%. A compound or composition enriched with one stereoisomer of the compound has that one stereoisomer in an amount measurably greater than the compound’s other stereoisomer(s). For example, a compound enriched with an R enantiomer will have an enantiomeric excess of that enantiomer versus the S enantiomer.

[0053] Unless explicitly noted, chemical structures named or shown herein encompass derivatives wherein one or more of their constituent atoms is / are replaced or enriched (i.e., present in a quantity measurably greater than its natural abundance) with an isotope thereof. Thus, unless noted otherwise, a chemical structure that contains hydrogen atoms encompasses deuterated forms of the represented molecule or moiety. TSRI 2263.1PC 18350.033W01

[0054] 4.2. COMPOUNDS OF THE INVENTION

[0055] This invention is directed, in part, to compounds of formula I: and pharmaceutically acceptable salts thereof, wherein:

[0056] R1is OH or -CH2OC(=O)OCH3;

[0057] R2ais H or Ci-6 alkyl;

[0058] R2bis H or Ci-6 alkyl; and

[0059] R2Cis H or optionally substituted Ci-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; or

[0060] R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; and each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or two R2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl.

[0061] In particular embodiments of the invention, the compounds do not include: l-((S)-7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-3-(4-fluorobicyclo[l .1. l]pentan-2-yl)- 5-hydroxy-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-3-(3-cyclopropyl-3- hydroxycyclobutyl)-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-ll-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl) -5 - hydroxy-3-(l-oxaspiro[3.3]heptan-6-yl)-2,3-dihydro-lH-pyrido[2,l-f][l,2,4]triazine-4, 6-dione; (S)-((l- (7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3 -fluorobicyclo [1.1.1 ]pentan- 1 -yl)-4,6-dioxo- 2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; (S)-((3- (bicyclo [1.1.1 ]pentan- 1 -yl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl)-4,6-dioxo-2,3 ,4,6- tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; (S)-l-(7,8-difluoro-6,l 1- dihydrodibenzo [b,e]thiepin- 11 -yl) - 5 -hydroxy-3 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)-2,3 - dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-3 -(3 -fluorobicyclo [1.1. l]pentan-l-yl)-5-hydroxy-2,3-dihydro-lH-pyrido[2,l-f] [l,2,4]triazine-4,6- dione; (S)-3-(bicyclo[l .1. l]pentan-l-yl)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l 1 -yl)-5 - hydroxy-2, 3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-l-(7,8-difluoro-6,l 1- dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(2-oxaspiro[3.3]heptan-6-yl)-2,3-dihydro-lH-pyrido[2,l- f] [ 1 ,2, 4]triazine-4, 6-dione ; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3- (spiro[2.3]hexan-5-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-l-(7,8-difluoro-6,l 1- TSRI 2263.1PC 18350.033W01 dihydrodibenzo [b,e]thiepin- 11 -yl) - 5 -hydroxy-3 -( 1 -(oxetan-3 -yl)azetidin-3 -yl)-2, 3 -dihydro- 1H- pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; 1 -((S)-7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 - hydroxy-3-((S)-4-oxaspiro[2.5]octan-7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; or (S)- l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(spiro[3.3]heptan-2-yl)-2,3-dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione .

[0062] In some embodiments of the invention, R2ais H. In some embodiments, R2ais methyl.

[0063] In some embodiments, R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d.

[0064] In some embodiments, R2band R2ctogether form C3-7 cycloalkyl optionally substituted with one or more R2d. In some embodiments, R2band R2ctogether form cyclobutane optionally substituted with one or more R2d.

[0065] In some embodiments, R1is OH. In some embodiments, R1is -CH2OC(=O)OCH3.

[0066] This invention is also directed to compounds of formula II:

[0067] II and pharmaceutically acceptable salts thereof, wherein: each of Y1, Y2, Y3, Y4, Y5, Y6, and Y7is independently H, Cl, F, Me, or methoxy;

[0068] R1is OH or -CH2OC(=O)OCH3;

[0069] R2ais H or C1-6 alkyl;

[0070] R2bis H or C1-6 alkyl; and

[0071] R2Cis H or optionally substituted C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; or

[0072] R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; and each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or two R2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl.

[0073] In some embodiments, each of Y1-7are H. In some embodiments, at least two of Y1-7are not H. In some embodiments, two of Y1-7are F. In some embodiments, Y2and Y5are F. In some embodiments, Y1and Y6are F. In some embodiments, Y2and Y7are F. In some embodiments, Y3and Y4are F. In some embodiments, Y3and Y4are Cl. In some embodiments, Y3and Y4are Me. In some embodiments, wherein Y3and Y4are methoxy. In some embodiments, wherein Y2-5are F.

[0074] In some embodiments, wherein R2ais H. In some embodiments, R2ais methyl. TSRI 2263.1PC 18350.033W01

[0075] In some embodiments, R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d. In some embodiments, R2band R2ctogether form C3-7 cycloalkyl optionally substituted with one or more R2d. In some embodiments, R2band R2Ctogether form cyclobutane optionally substituted with one or more R2d.

[0076] In some embodiments, R1is OH. In some embodiments, R1is -CH2OC(=O)OCH3.

[0077] This invention is also directed to compounds of formula III: and pharmaceutically acceptable salts thereof, wherein: each of Y1and Y2is independently H or halo;

[0078] R1is OH or -CH2OC(=O)OCH3;

[0079] R2ais H or Ci-6 alkyl;

[0080] R2bis H or Ci-6 alkyl;

[0081] R2Cis H or optionally substituted Ci-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; or

[0082] R2band R2ctogether form optionally substituted C3-7 cycloalkyl or Ce-g heterocycloalkyl, which optional substitution is with one or more R2d; or

[0083] R2aand R2bare both H and R3and R2ctogether form Ce-g heterocycloalkyl; each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or two R2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl; and

[0084] R3is H.

[0085] In some embodiments, R1is OH.

[0086] In some embodiments, Y1and Y2are both F. In some embodiments, Y1and Y2are both H.

[0087] In some embodiments, R2ais H.

[0088] In some embodiments, R2band R2ctogether form optionally substituted C3-7 cycloalkyl or Ce-g heterocycloalkyl, which optional substitution is with one or more R2d. In some embodiments, R2band R2ctogether form cyclobutane optionally substituted with one or more R2d.

[0089] In some embodiments, R2aand R2bare both H and R3and R2ctogether form Ce-g heterocycloalkyl.

[0090] Particular compounds of the invention include:

[0091] (S)-3-cyclopropyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; TSRI 2263.1PC 18350.033W01

[0092] (S)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-3-(l-methylcyclobutyl)-

[0093] 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;

[0094] 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0095] (S)-((3 -cyclobutyl- l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-4, 6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;

[0096] 3-(cyclobutyhnethyl)-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0097] (S)-3 -(cyclobutylmethyl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0098] (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3 ,3 -difluorocyclobutyl)-5 -hydroxy-

[0099] 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;

[0100] 3 -cyclohexyl- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl)-5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0101] 3-cyclopropyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0102] (S)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0103] (S)-3 -cyclobutyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0104] (S)-3-cyclopentyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0105] 3-cyclopentyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0106] (S)-3 -cyclohexyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0107] 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3,3 -difluorocyclobutyl)-5 -hydroxy-

[0108] 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;

[0109] 1 -( 1 ,9-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0110] 3-(tert-butyl)-5-hydroxy-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0111] 3-cyclobutyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)-

[0112] 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;

[0113] 1 -(2, 8-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; TSRI 2263.1PC 18350.033W01

[0114] 5-hydroxy-3-(l-methylcyclobutyl)-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0115] 1 -(5H-dibenzo [a, d] [7] annulen-5 -y 1) -5 -hydroxy-3 -( 1 -methylcyclopropyl)-2, 3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0116] 5-hydroxy-3-isopropyl-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0117] 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3 -(oxetan-3 -yl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0118] 19,19-difluoro-8-hydroxy-2,3,4,5,12a,17,18,19-octahydro-l,20-dioxa-6,l la,12,17a-tetraaza-6,12- methanobenzo[5,6]cyclotrideca[l, 2, 3-gh]pleiadene-7, 9-dione;

[0119] 1 -(5H-dibenzo [a, d] [7] annulen-5 -y 1) -5 -hydroxy-3 -( 1 -methylcyclobutyl)-2, 3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0120] 3-cyclobutyl-5-hydroxy-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0121] 3 -cyclobutyl- 1 -(5H-dibenzo [a, d] [7]annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;

[0122] 3 -(bicyclo [1.1.1 ]pentan-2-yl)- 1 -(5H-dibenzo [a,d] [7]annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0123] (E)- 19,19-difluoro-8-hydroxy-2,5 , 12a, 17, 18, 19-hexahydro- 1 ,20-dioxa-6, 11 a, 12, 17a-tetraaza- 6,12-methanobenzo[5,6]cyclotrideca[l,2,3-gh]pleiadene-7,9-dione;

[0124] (S)-3 -cyclobutyl-5 -hydroxy- 1 -(2,2, 10, 11 -tetrafluoro- 1 ,2,7, 12-tetrahydro-3 -oxa- 12a-azapleiaden- 7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0125] (R)-3-cyclopropyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0126] (S)-3-cyclobutyl-8-(9, 10-difluoro-l-oxo-6, 11 -dihydro- 1H-2 -thia- 1 la-azadibenzo[cd,g]azulen-6- yl)-5-hydroxy-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0127] (R)-3-cyclobutyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0128] (R)-3 -cyclobutyl-5 -hydroxy- 1 -(2,2, 10, 11 -tetrafluoro- 1 ,2,7, 12-tetrahydro-3-oxa- 12a-azapleiaden- 7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0129] (R)-((3 -cyclobutyl- 1 -(7, 8-difluoro-6,l 1 -dihydrodibenzo [b,e]thiepin-l l-yl)-4,6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;

[0130] (R)-3 -(cyclobutylmethyl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0131] (R)-3-cyclopentyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0132] (R)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5 -hydroxy-3 -(1-methylcyclobutyl)- 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione; TSRI 2263.1PC 18350.033W01

[0133] 3 -cyclobutyl- 1 -( 10, 11 -dihydro-5H-dibenzo [a,d] [7] annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0134] 3 -cyclobutyl-5 -hydroxy- 1 -(2, 2, 10, 11 -tetrafluoro- 1,2, 7, 12-tetrahydro-3 -oxa- 12a-azapleiaden-7- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0135] (R)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-3-(3,3-difluorocyclobutyl)-5- hydroxy-2, 3 -dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0136] (R)-3-cyclohexyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0137] (S)-(( 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -( 1 -methylcyclobutyl)-4,6-dioxo- 2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclopropyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0138] 1 -(3 ,7-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(2,6-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0139] 1 -(5H-dibenzo [a, d] [7] annulen-5 -yl)-5 -hydroxy-3 -(4-methyltetrahydro-2H-pyran-4-yl)-2, 3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0140] 1 -( 1 ,9-dichloro-5H-dibenzo [a,d] [7]annulen-5 -yl) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(4-methyltetrahydro-2H-pyran-4- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-dimethoxy-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0141] 5-hydroxy-3-(l-methylcyclobutyl)-l-(l,2,8,9-tetrafluoro-10,l l-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;

[0142] 3 -cyclopropyl- 1 -(5H-dibenzo [a,d] [7]annulen-5 -yl)-5-hydroxy-2, 3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;

[0143] 3 -cyclopentyl- 1 -(5H-dibenzo [a,d] [7] annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;

[0144] 3-cyclopentyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; TSRI 2263.1PC 18350.033W01

[0145] 3-cyclopropyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0146] 3-cyclobutyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclopropyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;

[0147] (( 1 -( 1 ,9-difluoro-5H-dibenzo [a, d] [7] annulen-5 -y 1) -3 -( 1 -methylcyclobutyl)-4,6-dioxo-2,3 ,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate; methyl(((3-(l-methylcyclobutyl)-4,6-dioxo-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d] [7] annulen-5- yl)-2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl) carbonate; and pharmaceutically acceptable salts thereof.

[0148] Particular compounds are:

[0149] (S)-((3 -cyclobutyl- l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-4, 6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;

[0150] (S)-3 -cyclobutyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; and pharmaceutically acceptable salts thereof.

[0151] 4.3. METHODS OF USE

[0152] This invention encompasses methods of treating influenza infection, which comprise administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.

[0153] In some methods, the influenza infection is resistant to Baloxavir marboxil.

[0154] In some methods, the influenza infection is resistant to neuraminidase (NA) inhibitors (e.g., Tamiflu®).

[0155] In particular methods, a compound of the invention is administered in combination with a second CEN inhibitor. In some, a compound of the invention is administered in combination with an NA inhibitor.

[0156] 4.4. PHARMACEUTICAL FORMULATIONS

[0157] Compounds disclosed herein may be systemically administered in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable, edible carrier. They may be in the form of single unit dosage forms (e.g., enclosed in hard or soft shell gelatin capsules or compressed into tablets). For oral therapeutic administration, an active compound may be combined with one or more excipients in the form of ingestible tablets, buccal tablets, capsules, caplets, troches, elixirs, suspensions, syrups, and wafers. TSRI 2263.1PC 18350.033W01

[0158] Compounds may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of an active compound or its salts may be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0159] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0160] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0161] 4.5. EXAMPLES

[0162] The following examples include descriptions of the synthesis and characterization of some compounds of the invention.

[0163] 4.5.1. Abbreviations

[0164] Some abbreviations used herein include: acetyl (Ac), azo-his -isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc), di-tert- butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4- diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'- TSRI 2263.1PC 18350.033W01 dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di- / .so-propylazodicarboxylatc (DIAD), di- / .so-butylaliiminiimhydridc (DIBAL or DIBAL-H), 1,3 -Diisopropylcarbodiimide (DIC), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), l . l '-A.s-(diphcnylphosphino)cthanc (dppe), I . l '-A.s-(diphcnylphosphmo)fcrroccnc (dppf), 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-l -carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole-l-yl)-N, N,N’N’-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HO Ac), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), z.so-propanol (IP A), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), m-chloropcrbcnzoic acid (MCPBA), mass spectrum (ms), methyl / -butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso- propyl (z- Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t- BuMe2Si (TBDMS), triethylamine (TEA or EtsN), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1, l '- / ) / .s-2.2.6.6-tctra cthylhcptanc-2.6-dionc (TMHD), O- benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or McsSi (TMS), -toluene sulfonic acid monohydrate (TsOH or pTsOH), 4-Me-CeH4SO2- or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA).

[0165] 4.5.2. Synthesis and Characterization of Compounds 5, 12, and 38

[0166] To a solution of 3-(benzyloxy)-4-oxo-4H-pyran-2 -carboxylic acid (20.0 g, 81.2 mmol) in DMF (100 mb) was added ethyl iodide (22.8 g, 146 mmol) and diazabicycloundecene (18.4 mL,122 mmol). The reaction mixture was stirred for 16 hrs, poured into 10% aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification by SiO2 chromatography (EtOAc / Hexanes) provided the product (22.3 g, 76.4 mmol). 1H NMR (400 MHz, CDC13) 5 (ppm): 7.75 (d, J= 5.6 Hz, 1H), 7.48 (d, J= 7.0 Hz, 2H), 7.40 - 7.32 (m, 3H), 6.49 (d, J=5.6 Hz, 1H), 5.32 (s, 2H), 4.35 (q, J= 7.1 Hz, 2H), 1.32 (t, J= 7.1 Hz, 3H). TSRI 2263.1PC 18350.033W01

[0167] To a suspension of ethyl 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate (20.9 g, 76.4 mmol) in DMF (200 mL), was added Pyridinium p-toluenesulfonate (57.6, 229 mmol) and Boc hydrazine (15.1 g, 115 mmol). The reaction was stirred at 600C for 16 hrs. The reaction solution was cooled to rt, added to water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous ammonium chloride, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc / Hexanes) to afford ethyl 3 -(benzyloxy)- l-((tert-butoxycarbonyl)amino)-4-oxo- 1,4- dihydropyridine-2-carboxylate (17.8 g, 45.7 mmol). 1H NMR (400 MHz, CDC13) 5 (ppm): 7.44 (s, 1H), 7.42 (s, 1H), 7.37 - 7.31 (m, 3H), 7.28 (s, 1H), 6.40 (d, J = 7.8 Hz,lH), 5.27 (s, 2H), 4.28 (q, J= 7.1 Hz, 2H), 1.47 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H).

[0168] A suspension of ethyl 3-(benzyloxy)-l-((tert-butoxycarbonyl)amino)-4-oxo-l,4-dihydropyridine- 2 -carboxylate (2.5 g, 6.4 mmol) and LiOH (0.77 g, 32 mmol) in a 1: 1 ratio of THF / water (20 mL) was irradiated in a microwave reactor for 2.5 hr at 110 C. The reactions were combined, cooled to 0 C and acidified to a pH of 2 while stirring vigorously with IM HC1. The precipitated product was collected by filtration and dried under vacuum to give 3 -(benzyloxy)- l-((tert-butoxycarbonyl)amino)-4-oxo- 1,4- dihydropyridine-2-carboxylic acid (2.1 g, 5.8 mmol). 'HNMR (400 MHz, CD3OD) 5 (ppm): 7.78 (d, J=7.8 Hz, 1H), 7.48 (br d, J=6.5 Hz, 2H), 7.39 - 7.30 (m, 3H), 6.57 (br d, J=7.5 Hz, 1H), 5.17 (s, 2H),

[0169] 1.50 (br s, 9H).

[0170] A solution of 3 -(benzyloxy)- l-((tert-butoxycarbonyl)amino)-4-oxo-l,4-dihydropyridine-2- carboxylic acid (0.70 g, 1.94 mmol), HOBt (0.45 g, 2.91 mmol) and l-(3-Dimethylaminopropyl)-3- ethylcarbodiimideHydrochloride (0.75 g, 3.88 mmol) in DMF (8 mb) was stirred for 10 min at rt before TSRI 2263.1PC 18350.033W01 cyclobutylamine (0.41 g, 5.83 mmol) was added in one portion. The reaction was heated at 60 C for 1 hr, cooled to rt and diluted with 5 volumes of water. The aqueous mixture was extracted x3 with EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was used in the next reaction without further purification.

[0171] The crude material was dissolved in DCM (8 mL) and 4M HC1 in dioxane (3 mb) was added and the reaction was stirred for 2 hrs. Upon concentrating under reduced pressure, the crude material was purified by reverse phase C13 chromatography (10-70% MeCN in water) to give l-amino-3-(benzyloxy)- N-cyclobutyl -4-oxo- l,4-dihydropyridine-2-carboxamide (0.39 g, 1.24 mmol). MS: m / z=315 [M+H]+.

[0172] A suspension of l-amino-3-(benzyloxy)-N-cyclobutyl-4-oxo-l,4-dihydropyridine-2-carboxamide (500 mg, 1.60 mmol) and p -formaldehyde 53 mg, 1.76 mmol) in EtOH (7.5 m ) was irradiated in a microwave reactor at 140 C for 1 hr. The reaction was concentrated under reduced pressure to give 5- (benzyloxy)-3-cyclobutyl-2,3-dihydro-lH-pyrido[2, l-f][l, 2, 4]triazine-4, 6-dione (519 mg, 1.60 mmol). The material was used in the next step without further purification.

[0173] To a suspension of 5-(benzyloxy)-3-cyclobutyl-2,3-dihydro-lH-pyrido[2,l-f][l,2,4]triazine-4,6- dione (650 mg, 2.00 mmol) and 7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-ol (634 mg, 2.40 mmol) in EtOAc (10 mL) was added 50% Propylphosphonic anhydride in EtOAc (3.81 g) in one portion. The reaction was heated at 90 C for 1 hr. Upon cooling to rt, the solvent was removed under reduced pressure and the crude material was directly purified by reverse phase C13 chromatography (10-70% MeCN in water) to give 5-(benzyloxy)-3-cyclobutyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-2,3- dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione (650 mg, 1.14 mmol). MS: m / z=572 [M+H]+. TSRI 2263.1PC 18350.033W01

[0174] A suspension of (R)-5-(benzyloxy)-3-cyclobutyl-l-(7,8-difluoro-6,l 1-dihydrodibenzo- [b,e]thiepin-l l-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione (150 mg, 262 nmol) and LiCl (150 mg, 3.54 mmol) in DMF (1 mb), was heated at 90 C for 3 hr. Upon full conversion of the starting material (sm), the reaction was cooled to rt and acidified with strong stirring with IM aqueous HC1. The precipitated solid was collected by filtration and dried under vacuum to give (R)-3-cyclobutyl-l-(7,8- difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazine- 4, 6-dione (111 mg, 231 umol). MS: m / z=482 [M+H]+. ’H NMR (400 MHz, DMSO) 5 7.42 - 7.35 (m, 2H), 7.15 (m, 2H), 7.04 (d, J= 7.7 Hz, 1H), 6.96 - 6.84 (m, 2H), 5.61 (d, J= 7.7 Hz, 1H), 5.56 - 5.44 (m, 2H), 4.99 (d, J= 13.5 Hz, 1H), 4.83 (p, 1H), 4.61 (d, J= 13.6 Hz, 1H), 4.14 (d, J= 14.0 Hz, IH), 2.05 - 1.78 (m, 4H), 1.66 - 1.46 (m, 2H).

[0175] Compound 38 Compound 12

[0176] CHIRALPAK IH (250*4.6mm, 5um), 0.1% DEA IN IPA:ACN (50:50)

[0177] Compound 38: MS: m / z=482 [M+H]+. 'HNMR (400 MHz, DMSO) 5 7.42 - 7.35 (m, 2H), 7.15 (m, 2H), 7.04 (d, J= 7.7 Hz, IH), 6.96 - 6.84 (m, 2H), 5.61 (d, J= 7.7 Hz, IH), 5.56 - 5.44 (m, 2H), 4.99 (d, J= 13.5 Hz, IH), 4.83 (p, IH), 4.61 (d, J= 13.6 Hz, IH), 4.14 (d, J= 14.0 Hz, IH), 2.05 - 1.78 (m, 4H), 1.66 - 1.46 (m, 2H).

[0178] Compound 12: MS: m / z=482 [M+H]+. 'HNMR (400 MHz, DMSO) 5 7.42 - 7.35 (m, 2H), 7.15 (m, 2H), 7.04 (d, J= 7.7 Hz, IH), 6.96 - 6.84 (m, 2H), 5.61 (d, J= 7.7 Hz, IH), 5.56 - 5.44 (m, 2H), 4.99 (d, J= 13.5 Hz, IH), 4.83 (p, IH), 4.61 (d, J= 13.6 Hz, IH), 4.14 (d, J= 14.0 Hz, IH), 2.05 - 1.78 (m, 4H), 1.66 - 1.46 (m, 2H). TSRI 2263.1PC 18350.033W01

[0179] Compound 5

[0180] A suspension of (R)-3-cyclobutyl-l-(7.8-difliioro-6.1 l-dihydrodibcnzo|b.c|thicpin-l l-yl)-5- hydroxy-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione (30 mg, 62 nmol), methyl chloromethyl carbonate (36 uL, 0.37 mmol), K2CO3 (69 mg, 0.50 mmol) and sodium iodine (28 mg, 0.19 mmol) in DMF (0.5 mb) was heated at 90 C for 22 min. Upon cooling to rt, the reaction was diluted with stirring by dropwise addition of water. The resulting precipitate was collected by fdtration and dried under vacuum to give (R)-((3-cyclobutyl-l-(7,8-difluoro-6,ll-dihydrodibenzo[b,e]thiepin-l l-yl)-4,6-dioxo-2,3,4,6- tetrahydro- IH-pyrido [2, 1-f] [1, 2, 4]triazin-5-yl)oxy)methyl methyl carbonate 15 mg, 26 umol). MS: m / z=570 [M+H]+. ’H NMR (400 MHz, DMSO) 57.41 - 7.32 (m, 2H), 7.21 - 7.12 (m, 3H), 6.92 (d, J = 4.1 Hz, 2H), 5.85 (d, J= 7.8 Hz, 1H), 5.76 (d, J= 6.6 Hz, 1H), 5.56 (d, J= 6.6 Hz, 1H), 5.50 (d, J= 15.3

[0181] Hz, 1H), 5.30 (s, 1H), 4.97 (d, 1H), 4.76 (p, J= 8.8 Hz, 1H), 4.51 (d, J= 13.9 Hz, 1H), 4.14 (d, J= 14.1 Hz, 1H), 3.75 (s, 3H), 2.10 - 2.00 (m, 1H), 1.99 - 1.90 (m, 1H), 1.89 - 1.77 (m, 2H), 1.63 - 1.48 (m, 2H).

[0182] TSRI 2263.1PC 18350.033W01

[0183] 4.5.3. Synthesis and Characterization of Inter-A

[0184] This synthetic intermediate was prepared as described below.

[0185] Synthesis of Inter-A .

[0186] (1) (2)

[0187] (1.5eq)

[0188] EDC.HCI(1.5eq),Ho

[0189] LiOH(1.5eq), THF, BT(1eq),DMF,60° Water, 110°C, 1h C,12h step-3 step-4

[0190] NH, O

[0191] HCHO(1-5eq)

[0192] HCI in 1,4-dioxane, sodium acetate(3.0eq) PCM, 3h, rt ethanol, 90°C, 3h step-5 Step-6

[0193] Synthesis of compound (2). To a solution of compound (1) (60g, 0.2439mol) in acetone (60ml) was added K2CO3 (40.4g, 0.2926mol) and stirred for 15 minutes at rt then dimethyl sulfate (33.8 g, 0.2682mol) was added in reaction mass and stirred at 55 °C for 1 hour. The reaction mixture was concentrated under vacuum to obtained Inter-2 (62g, 97.76%), which was used for next step without further purification. LCMS M / Z =261.10 (M+l)+.

[0194] Synthesis of compound (3). To a solution of Inter-2 (62g, 0.2384mol) in N,N-dimethyl acetamide (620ml) was added pyridinium p-toluenesulfonate (179.5g, 0.7153mol) and stittirred reaction mixture at 60 °C and the solution of tert-butyl hydrazinecarboxylate (37.7g, 0.2861mol) in N,N-dimethyl acetamide was added to reaction mixture and stirred at 60 °C for 16h. Reaction mixture was quenched in water (2000ml) and product was extracted with ethyl acetate (3 X 500ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified TSRI 2263.1PC 18350.033W01 by column [aluminum oxide activated (neutral)] (50% ethyl acetate in hexane) to afford pure Inter-3 (50g, 56.06%). LCMS M / Z =375.39 (M+l)+.

[0195] Synthesis of compound (4). To a solution of Inter-3 (40g, 0.1069mol) in THF (400ml) was added solution of LiOH (6.73g, 0.1604mol) in water (5ml) at room temperature. Reaction mass was heated at 110 °C for 1 hour. After completion of reaction, reaction mixture was concentrated under vacuum. Obtained crude product was diluted with water (200ml) and acidified up to pH 2 with IN HC1 solution to get solid precipitate, which was filtered and washed with water and dried under vacuum to obtain Inter-4 (28g, 72.72% ) which was used for next step without further purification. LCMS M / Z = 361.20 (M+l)+.

[0196] Synthesis of compound (5). To a solution of Inter-4 (10g , 0.0277mol) in DMF (100ml) were added EDC.HC1 (7.95g, 0.04166mole), HoBT (3.75g, 0.0277 mole) and prop-2-en-l -amine (2.37g, 0.04166mol) at room temperature. The reaction mixture was stirred at 60 °C for 12h. Reaction mixture was quenched in water (400ml) and product was extracted with dichloromethane (2 X 400ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material, which was purified by column chromatography (pure product was eluted at 15% ethyl acetate in hexane) to obtain pure Inter-5 (6g, 69.90%). LCMS M / Z = 400.5 (M+l)+.

[0197] Synthesis of compound (6). To a solution of Inter-5 (6g, 0.0150) in DCM (60ml) was added 4M HC1 in dioxane (60ml, lOv) at 0 °C and stirred the reaction mixture at rt for Ih. Reaction was monitored by TLC. Reaction mixture was concentrated under vacuum to obtain crude material, which was triturated with n-pentane to obtain pure Inter-6 (5.2g, yield: quantitative). LCMS M / Z = 300.0 (M+H)+.

[0198] Synthesis of compound (7). To a solution of Inter-6 (5g, 0.01672mol) in ethanol (50ml, lOv) were added HCHO (0.75g, 0.02508mol) and sodium acetate (4. 11g, 0.05016mol) at rt and reaction mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated and quenched in water (300ml) then product was extracted with dichloro methane (2 X 150ml). Combine the organic layer and dried over Na2SC>4 followed by concentrated under vacuum to obtain crude material, which was purified by column chromatography (pure product was eluted at 5% methanol in dichloromethane) to obtain pure Comp. 3Int-A (4g, 76.91%). LCMS M / Z = 312.2 (M+H)+.

[0199] TSRI 2263.1PC 18350.033W01

[0200] 4.5.4. Synthesis and Characterization of Compound 33

[0201] Synthesis of Comp. 33 O (1eq)

[0202] Comp. 33

[0203] Synthesis of compound (3). To a solution ofNaH (10.35g, 0.4316mol) in DMF (600ml).

[0204] Reaction mass was cooled to 0 °C and stirred for 30 minutes. Inter-1 (60g, 0.4316mol) was added at 0 °C and stirred at 90 °C for 2h. Reaction mixture was quenched in water (500ml) and product was extracted with ethyl acetate (3 X 300ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (50% ethyl acetate in Hexane) to get pure Inter-3 (30g, 47.31%). LCMS M / Z =294.0 (M-l)'.

[0205] Synthesis of compound (4). To a solution of Inter-3 (30g, 0.1020mol) in N,N-dimethyl formamide (300ml) was added cesium carbonate (49.74g, 0. 1530mol) and stirred reaction mixture for 2 hour at 60 °C. Reaction mixture was quenched in water (600ml) and product was extracted with ethyl TSRI 2263.1PC 18350.033W01 acetate (3 X 300ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (20% Ethyl acetate in Hexane) to get pure Inter-3 (11g, 50.46%). LCMS M / Z =214.0 (M-H) . ’H NMR (400 MHz) : 11.89 (s, 1H), 7.24 (d, J=8Hz, 1H), 6.73-6.70 (m, 1H), 6.64-6.63 (d, J=2.8Hz, 1H), 3.74 (s, 3H).

[0206] Synthesis of compound (5). To a solution of Inter-4 (11g, 0.05116mol) in THF (110 ml), reaction mass was cooled to 0 °C and IM borane. THF (307ml, 0.3069mol, 6eq) was added dropwise at 0 °C. Reaction mass was stirred for 2h at 70 °C. Reaction mixture was quenched in ice cold water (400ml) and product was extracted with ethyl acetate (3 X 200ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (70% Ethyl acetate in Hexane) to get pure Inter-5 (8g, 77.78%). LCMS M / Z =202.2(M+l)+.

[0207] Synthesis of compound (7). To a solution ofNaH (1.5g, 0.05970mol) in DMF (80ml). Inter-5 (8g, 0.03980) was added at 0 °C and stirred for Ih at 0 °C. to this stirred solution Inter-6 (19.20g, 0.07960mol) in DMF (5ml) was added dropwise at 0 °C and stirred reaction mixture at rt for 4h. Reaction mixture was quenched in water (20ml) and product was extracted with ethyl acetate (3 X 25ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (10% Ethyl acetate in Hexane) to get pure Inter-7 (7g, 44.08%). LCMS M / Z =400.4 (M+l)+.

[0208] Synthesis of compound (8). To a solution of Inter-7 (7g, 0.01754mol) in THF (70ml) and MeOH (70ml) was added NaOH solution (3.5 g, 0.0877 mol in 20 ml of H2O) at 0 °C and stirred reaction mixture for 2h at 50 °C. After completion of reaction, reaction mixture was concentrated under vacuum. Obtained crude product was diluted with water (50ml) and acidified up to pH 2 with IN HC1 solution to get solid precipitate, which was filtered and washed with water and dried under vacuum to obtain pure Inter-8 (6g, Yield: quantitative) which was used for next step without further purification. LCMS M / Z = 336.27(M+1)+.

[0209] Synthesis of compound (9). To a solution of Inter-8 (4g, 0.01194mol) in DCM (40ml). Trifluoroacetic anhydride (10g, 0.04776mol) was added dropwice to the reaction mixture at 0 °C and stirred the reaction mixture for 15minutes at 0 °C. To this stirred solution Trifluoromethanesulfonic acid (3.6g, 0.02388mol) was added dropwise at 0 °C and srirred for 12h at rt. Reaction mixture was diluted with DCM (50ml) and quenched in aq. solution of NaHC’CF (500ml) and product was extracted with DCM (3 X 200ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (30% ethyl acetate in hexane) to get pure Inter-9 (2.7g, 71.33%). LCMS M / Z =318.23(M+1)+.

[0210] Synthesis of compound (10). To a solution of Inter-9 (2.7g, 0.0085 Imol) in DCM(27ml). IM BBr, in DCM (2.7 ml, 1 vol) was added dropwise to the reaction mixture at 0 °C. and stirred for Ih at 0 °C. Reaction mixture was quenched in water (100ml) and product was extracted with DCM (3 X 100ml). Combine the organic layer was dried over Na2SC>4 followed by concentrated under vacuum to obtained crude material which was purified by column (20% ethyl acetate in hexane) to get pure Inter- 10 (2g, 77.50%). LCMS M / Z =304.24(M+l)+. TSRI 2263.1PC 18350.033W01

[0211] Synthesis of compound (11). To a solution of Inter-10 (1.5 g, 0.004950 mol) in acetonitrile (15ml) were added allyl iodide (1.5 g, 0.01237mol) and K2CO3 (2 g, 0.01485 mol) at rt. Reaction mixture was stirred for 12h at 70 °C. Reaction mixture was concentrated under vacuum. Obtained crude product was diluted with water (30ml) and product was extracted with ethyl acetate (3 X 30ml). Combine the organic layer was dried over Na2SO4 followed by concentrated under vacuum to obtained crude material which was purified by column (10% Ethyl acetate in Hexane) to get pure Inter-11 (1.5g, 88.33%). LCMS M / Z =344.38 (M+l)+.

[0212] Synthesis of compound (12). To a solution of Inter-11 (1.5 g, 0.004373 mol) in DCM (15ml) and MeOH (15ml). NaBH4 (0.810 g, 0.02186 mol) was added at 0 °C and stirred for 12 hour at rt. Reaction mixture was concentrated under vacuum. Obtained crude product which was purified by column (20% Ethyl acetate in Hexane) to get pure Inter-12 (1g, 34.79%). LCMS M / Z =346.02 (M+l)+.

[0213] Synthesis of compound (13). To a solution of Inter-12 (1g, 0.002898mol) in 50% T3P in ethyl acetate (15ml, 15v) was added Compound 33_Inter-A (1g, w / w) at rt and reaction mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated, and Crude material was purified by reverse phase column purification by using C18 column (YMC, 20-45 mm, 100 A, 25g) (0.1% Formic acid in water: Acetonitrile) to get pure inter-13 (250mg, 13.05%). LCMS M / Z = 639.70 (M+H)+.

[0214] Synthesis of compound (14). Take Inter-13 (250mg, 0.000391mol) in ethylene dichloride (63ml) and degassed with argon gas for 20 min. Grubbs (II) catalyst (66 mg, 0.00007836mol) was added and again reaction mixture was degassed with argon for 5 minutes. Stirred reaction mixture in microwave for 25 minutes at 80 °C. The reaction mixture was concentrated and Crude material was purified by using C18 column (YMC, 20-45 mm, 100 A, 25g) (0.1% Formic acid in water: Acetonitrile) to get pure Inter- 14 (40mg, 16.74%). LCMS M / Z = 611.37 (M+H)+.

[0215] Synthesis of compound (33). To a solution of Inter-14 (40mg, 0.06557mmol) in DMF (1ml) was added Li Cl (40mg, w / w) at rt. Reaction mass was stirred at 100 °C for 2 hour. After completion of reaction, reaction mixture was concentrated under vacuum and purified by using C 18 column (YMC, 20- 45 mm, 100 A, 12g) (0.1% Formic acid in water: Acetonitrile) to obtain pure Compound 33 (4mg, 11.73%). LCMS M / Z = 521.56 (M+H)+.1H NMR(400MHz): 12.0 (bs, 1H), 7.38-7.32 (m, 2H), 7.10-7.05 (m, 2H), 6.94-6.92 (d, J=7.6Hz, 1H), 6.74-6.72 (d, J=7.6Hz, 1H), 6.66-6.63 (d, J=8.8Hz, 1H), 6.44-6.42 (m, 1H), 6.24-6.21 (m, 1H), 5.90-5.87 (m, 1H), 5.79 (s, 1H), 5.35-5.33 (d, J=8Hz, 1H), 5.08-5.04 (d, J=12.8Hz, 1H), 5.35-5.33 (d,J=16Hz, 1H), 5.08-5.04 (d,J=12.8Hz, 1H), 4.72-4.68 (m,lH), 4.57-4.49 (m, 2H), 4.21-4.17 (m, 1H), 4.14-4.09 (m, 1H), 4.00-3.95 (m, 1H), 3.67-3.62(m, 1H), 3.43-3.36 (m, 1H).

[0216] 4.5.5. Biological Assays

[0217] CC50 and IC50 determination against Influenza A in A549 cells

[0218] Influenza A Virus (A / WSN / 1933(H1N1)) was propagated and titered in MDCK cells (ATCC CCL-34). A549 cells were obtained from ATCC (CCL-185) and maintained in DMEM (Gibco 11965- 092) with 1% HEPES (Gibco 15630-080),!% Penicillin-Streptomycin (Coming 30-002), 10% FBS TSRI 2263.1PC 18350.033W01

[0219] (Gibco 16140-071), 1% MEM NEAA (Gibco 11140-050), 1% Pyruvate (Gibco 11360-070), in a 5% CO2humified incubator at 37 C.

[0220] Compounds were added to 384 well plates (Greiner 781092) using Labcyte Echo liquid dispenser. Compounds were spotted with a starting concentration of 10 uM, dilution factor =3, 10 points, with max DMSO concentration of 0. 1% (50 nL). All compounds and controls were tested in triplicate.

[0221] Confluent A549 cells were washed with PBS, detached with 0.25% trypsin-EDTA, resuspended in serum free DMEM (1% HEPES, P / S, MEM NEAA Pyruvate,) and diluted to a final concentration of 167,000 cells / mL. 30 uL of this cell suspension was seeded onto the 384 well plates. Plates were incubated at 37C 5% CO2. 2 hours after seeding, A549 cells were infected with 20 uL Influenza (A / WSN / 1933(H1N1)) in DMEM (1% HEPES, P / S, MEM NEAA Pyruvate, 0.3% BSA) at an MOI of 0.2. Infected cells were incubated at 5% CO2 37 C for 48 hours. After 48 hours, 50 uL of 10% PFA (Electron Microscopy 15714-5) was added to each well for 30 minutes. Cells were washed three times with 40 uL lx PBS. Cells were permeabilized with 40 uL of 0.5% triton-x (Fisher BP151-500) for 15 minutes. Cells were washed three times with 40 uL lx PBS. Cells were blocked with 40 uL 3% BSA. Cells were incubated with 20 uL 1: 1000 Influenza A NP antibody clone HT- 103 (Milipore MABF2164) for 2 hours. Cells were washed three times with 40 uL lx PBS. Cells were incubated with 20 uL 1: 1000 Alexa 488 anti-mouse (Invitrogen Al 1001) for 1 hour at room temperature protected from light. Cells were washed three times with 40 uL lx PBS. 40 uL of 1:4000 DAPI (Thermo 62248) was added to each well. Fluorescence was measured for each well using IXMC. With DAPI Xex = 377 nm and Xem = 447 nm, and FITC with Xex = 475 nm and Xem = 536 nm. Data was normalized to neutral control (DMSO). Neutral control (DMSO) / sample = relative cell number or relative infection. CC50 and IC50 and IC90 was determined and fit using GraphPad Prism inhibitor vs response IC50 function.

[0222] In vivo antiviral efficacy of Baloxavir analogs

[0223] Oral suspensions were prepared by suspending Baloxavir acid and Compound 12 in 0.5% (w / v) methylcellulose using sonicator. Oseltamivir phosphate dissolved in 0.5% (w / v) methylcellulose.

[0224] All the antiviral animal studies were performed in an animal biosafety level 2 (BSL2) facility at Scripps research institute. All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) or through an ethical review process.

[0225] Animal studies with the A / WSN / 1933(H1N1) were performed using 8-week-old female C57BL / 6J mice (Scripps Research Institute). Prophylactic efficacy studies in mice where the first dose of a treatment was given 24-hour prior infection with 200 PFU of A / WSN / 1933(H1N1) in 30 pL of PBS intranasally. All oral dosing was performed through oral route using as vehicle methylcellulose (05%; catalog number M0430; Sigma-Aldrich) at a volume of 0.2 ml / mouse. Mice were weighed daily throughout the study as a measure of pathology. On day 3 post infection, animals were humanely euthanized, and lung tissues were harvested. Lungs were homogenized in 700 pL PBS with silica glass TSRI 2263.1PC 18350.033W01 beads and frozen at -80°C for viral titration by plaque assay. Viral titers were determined by the standard plaque assay in MDCK cells.

[0226] 4.5.6. Compounds and Assay Results

[0227] A cell-based influenza nucleoprotein (NP) immunofluorescence assay (NP-IFA) was used to assess potency. Flu ECgo and IC50 values (pM) for particular compounds of the invention are provided below.

[0228] Table 1 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01 TSRI 2263.1PC 18350.033W01

[0229] It is apparent from these data that CEN inhibitors of the invention have good anti-influenza activities. For example, Compound 12 and its prodrug Compound 5 have favorable pharmacological and pharmacokinetic profdes. Compound 5 exhibits an in vivo efficacy comparable to BXM in a prophylactic mouse efficacy model (Scheme 1). TSRI 2263.1PC 18350.033W01

[0230] Scheme 1

[0231] Oral mouse PK studies of Compound 5 and Baloxavir (BXA) marboxil at 100 mg / kg observed no detectible levels of either prodrug in plasma (FIG. 3). Similar release kinetics of Compound 12 and Baloxavir acid were observed with comparable coverage over flu EC90 (EC90 = 3.3 ng / mL for BXA, 5.7 ng / mL for Compound 12). Due to higher plasma protein binding (PPB), Compound 12 has shorter coverage over PPB adjusted EC90 compared to Baloxavir acid (~ 2h vs 18 h). Reported minimum efficacious dose (MED) in mouse flu efficacy is around 0.5 mg / kg PO BID for Baloxavir marboxil, suggesting that the coverage over total ECso might be the efficacy driver, suggestive of the results found for the Compound 12 marboxil prodrug Compound 5 in mouse flu efficacy studies (FIGS. 4A-B). Compound 5 shows in vivo efficacy comparable to BXM in a prophylactic mouse efficacy model.

[0232] All publications (e.g, patents and patent applications) cited above are incorporated herein by reference in their entireties.

Claims

1. TSRI 2263.1PC 18350.033W01CLAIMSWhat is claimed is:

1. A compound, which compound is of formula I:I or a pharmaceutically acceptable salt thereof, wherein:R1is OH or -CH2OC(=O)OCH3;R2ais H or Ci-6 alkyl;R2bis H or Ci-6 alkyl; andR2Cis H or optionally substituted Ci-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; orR2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; and each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or two R2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl.

2. The compound of claim 1, with the proviso that the compound is not: l-((S)-7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-3-(4-fluorobicyclo[l .

1. l]pentan-2-yl)-5- hydroxy-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-3-(3-cyclopropyl-3- hydroxycyclobutyl)-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-ll-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl) -5 - hydroxy-3-(l-oxaspiro[3.3]heptan-6-yl)-2,3-dihydro-lH-pyrido[2,l-f][l,2,4]triazine-4, 6-dione; (S)-((l- (7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3 -fluorobicyclo [1.1.1 ]pentan- 1 -yl)-4,6-dioxo- 2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; (S)-((3- (bicyclo [1.1.1 ]pentan- 1 -yl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl)-4,6-dioxo-2,3 ,4,6- tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; (S)-l-(7,8-difluoro-6,l 1- dihydrodibenzo [b,e]thiepin- 11 -yl) - 5 -hydroxy-3 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)-2,3 - dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-3 -(3 -fluorobicyclo [1.

1. l]pentan-l-yl)-5-hydroxy-2,3-dihydro-lH-pyrido[2,l-f] [l,2,4]triazine-4,6- dione; (S)-3-(bicyclo[l .

1. l]pentan-l-yl)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l 1 -yl)-5 - hydroxy-2, 3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-l-(7,8-difluoro-6,l 1- dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(2-oxaspiro[3.3]heptan-6-yl)-2,3-dihydro-lH-pyrido[2,l-TSRI 2263.1PC 18350.033W01 f] [ 1 ,2, 4]triazine-4, 6-dione ; (S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3- (spiro[2.3]hexan-5-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; (S)-l-(7,8-difluoro-6,l 1- dihydrodibenzo [b,e]thiepin- 11 -yl) - 5 -hydroxy-3 -( 1 -(oxetan-3 -yl)azetidin-3 -yl)-2, 3 -dihydro- 1H- pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; 1 -((S)-7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 - hydroxy-3-((S)-4-oxaspiro[2.5]octan-7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; or (S)- l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(spiro[3.3]heptan-2-yl)-2,3-dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione .

3. The compound of claim 1 or 2, wherein R2ais H.

4. The compound of claim 1 or 2, wherein R2ais methyl.

5. The compound of claim 1 or 2, wherein R2band R2ctogether form optionally substitutedC3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d.

6. The compound of claim 1 or 2, wherein R2band R2ctogether form C3-7 cycloalkyl optionally substituted with one or more R2d.

7. The compound of claim 6, wherein R2band R2ctogether form cyclobutane optionally substituted with one or more R2d.

8. The compound of any of claims 1-7, wherein R1is OH.

9. The compound of any of claims 1-7, wherein R1is -CH2OC(=O)OCH3.

10. A compound, which compound is of formula II:II or a pharmaceutically acceptable salt thereof, wherein: each of Y1, Y2, Y3, Y4, Y5, Y6, and Y7is independently H, Cl, F, Me, or methoxy;R1is OH or -CH2OC(=O)OCH3;R2ais H or C1-6 alkyl;R2bis H or C1-6 alkyl; andR2Cis H or optionally substituted C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; orTSRI 2263.1PC 18350.033W01R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; and each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or two R2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl.

11. The compound of claim 10, wherein each of Y1-7are H.

12. The compound of claim 10, wherein at least two of Y1-7are not H.

13. The compound of claim 10, wherein two of Y1-7are F.

14. The compound of claim 10, wherein Y2and Y5are F.

15. The compound of claim 10, wherein Y1and Y6are F.

16. The compound of claim 10, wherein Y2and Y7are F.

17. The compound of claim 10, wherein Y3and Y4are F.

18. The compound of claim 10, wherein Y3and Y4are Cl.

19. The compound of claim 10, wherein Y3and Y4are Me.

20. The compound of claim 10, wherein Y3and Y4are methoxy.

21. The compound of claim 10, wherein Y2-5are F.

22. The compound of any of claims 10-21, wherein R2ais H.

23. The compound of any of claims 10-21, wherein R2ais methyl.

24. The compound of any of claims 10-21, wherein R2band R2ctogether form optionally substituted C3-7 cycloalkyl or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d.

25. The compound of claim 24, wherein R2band R2ctogether form C3-7 cycloalkyl optionally substituted with one or more R2d.

26. The compound of claim 25, wherein R2band R2ctogether form cyclobutane optionally substituted with one or more R2d.

27. The compound of any of claims 10-26, wherein R1is OH.

28. The compound of any of claims 10-26, wherein R1is -CH2OC(=O)OCH3.TSRI 2263.1PC 18350.033W0129. A compound, which compound is of formula III:or a pharmaceutically acceptable salt thereof, wherein: each of Y1and Y2is independently H or halo;R1is OH or -CH2OC(=O)OCH3;R2ais H or Ci-6 alkyl;R2bis H or Ci-6 alkyl;R2Cis H or optionally substituted Ci-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl, which optional substitution is with one or more R2d; orR2band R2ctogether form optionally substituted C3-7 cycloalkyl or Ce-s heterocycloalkyl, which optional substitution is with one or more R2d; orR2aand R2bare both H and R3and R2ctogether form Ce-s heterocycloalkyl; each R2dis independently halo, OH, C1-6 alkyl, C3-7 cycloalkyl, or C3-6 heterocycloalkyl; or twoR2dtogether form C3-7 cycloalkyl or C3-6 heterocycloalkyl; andR3is H.

30. The compound of claim 29, wherein R1is OH.

31. The compound of claim 29 or 30, wherein Y1and Y2are both F.

32. The compound of claim 29 or 30, wherein Y1and Y2are both H.

33. The compound of any of claims 29-32, wherein R2ais H.

34. The compound of any of claims 29-33, wherein R2band R2ctogether form optionally substituted C3-7 cycloalkyl or Ce-s heterocycloalkyl, which optional substitution is with one or more R2d.

35. The compound of claim 34, wherein R2band R2ctogether form cyclobutane optionally substituted with one or more R2d.

36. The compound of claim 29, wherein R2aand R2bare both H and R3and R2ctogether form Ce-g heterocycloalkyl.TSRI 2263.1PC 18350.033W0137. A compound, which compound is:(S)-3-cyclopropyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-((3 -cyclobutyl- l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-4, 6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;3-(cyclobutyhnethyl)-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-3 -(cyclobutylmethyl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3 ,3 -difluorocyclobutyl)-5 -hydroxy-2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;3 -cyclohexyl- 1 -(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -yl)-5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3-cyclopropyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(S)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-3 -cyclobutyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(S)-3-cyclopentyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;3-cyclopentyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-3 -cyclohexyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -(3,3 -difluorocyclobutyl)-5 -hydroxy-2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;1 -( 1 ,9-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;3-(tert-butyl)-5-hydroxy-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3-cyclobutyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;TSRI 2263.1PC 18350.033W01 l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)- 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;1 -(2, 8-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;5-hydroxy-3-(l-methylcyclobutyl)-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;1 -(5H-dibenzo [a, d] [7] annulen-5 -y 1) -5 -hydroxy-3 -( 1 -methylcyclopropyl)-2, 3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;5-hydroxy-3-isopropyl-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-3 -(oxetan-3 -yl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;19,19-difluoro-8-hydroxy-2,3,4,5,12a,17,18,19-octahydro-l,20-dioxa-6,l la,12,17a-tetraaza-6,12- methanobenzo[5,6]cyclotrideca[l, 2, 3-gh]pleiadene-7, 9-dione;1 -(5H-dibenzo [a, d] [7] annulen-5 -y 1) -5 -hydroxy-3 -( 1 -methylcyclobutyl)-2, 3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3-cyclobutyl-5-hydroxy-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3 -cyclobutyl- 1 -(5H-dibenzo [a, d] [7]annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;3 -(bicyclo [1.1.1 ]pentan-2-yl)- 1 -(5H-dibenzo [a,d] [7]annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(E)- 19,19-difluoro-8-hydroxy-2,5 , 12a, 17, 18, 19-hexahydro- 1 ,20-dioxa-6, 11 a, 12, 17a-tetraaza- 6,12-methanobenzo[5,6]cyclotrideca[l,2,3-gh]pleiadene-7,9-dione;(S)-3 -cyclobutyl-5 -hydroxy- 1 -(2,2, 10, 11 -tetrafluoro- 1 ,2,7, 12-tetrahydro-3 -oxa- 12a-azapleiaden- 7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(R)-3-cyclopropyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(S)-3-cyclobutyl-8-(9, 10-difluoro-l-oxo-6, 11 -dihydro- 1H-2 -thia- 1 la-azadibenzo[cd,g]azulen-6- yl)-5-hydroxy-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(R)-3-cyclobutyl-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(R)-3 -cyclobutyl-5 -hydroxy- 1 -(2,2, 10, 11 -tetrafluoro- 1 ,2,7, 12-tetrahydro-3-oxa- 12a-azapleiaden- 7-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(R)-((3 -cyclobutyl- 1 -(7, 8-difluoro-6,l 1 -dihydrodibenzo [b,e]thiepin-l l-yl)-4,6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;TSRI 2263.1PC 18350.033W01(R)-3 -(cyclobutylmethyl)- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 - dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(R)-3-cyclopentyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(R)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-5 -hydroxy-3 -(1-methylcyclobutyl)- 2,3 -dihydro- IH-pyrido [2, 1 -f] [ 1 ,2, 4]triazine-4, 6-dione;3 -cyclobutyl- 1 -( 10, 11 -dihydro-5H-dibenzo [a,d] [7] annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- 1H- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3 -cyclobutyl-5 -hydroxy- 1 -(2, 2, 10, 11 -tetrafluoro- 1,2, 7, 12-tetrahydro-3 -oxa- 12a-azapleiaden-7- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(R)-l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin-l l-yl)-3-(3,3-difluorocyclobutyl)-5- hydroxy-2, 3 -dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(R)-3-cyclohexyl-l-(7,8-difluoro-6,l l-dihydrodibenzo[b,e]thiepin-l l-yl)-5-hydroxy-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;(S)-(( 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -3 -( 1 -methylcyclobutyl)-4,6-dioxo- 2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl methyl carbonate; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclopropyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;1 -(3 ,7-difluoro-5H-dibenzo [a,d] [7]annulen-5 -y 1) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(2,6-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3-dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-yl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;1 -(5H-dibenzo [a, d] [7] annulen-5 -yl)-5 -hydroxy-3 -(4-methyltetrahydro-2H-pyran-4-yl)-2, 3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;1 -( 1 ,9-dichloro-5H-dibenzo [a,d] [7]annulen-5 -yl) - 5 -hydroxy-3 -( 1 -methylcyclobutyl)-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(4-methyltetrahydro-2H-pyran-4- yl)-2,3-dihydro- lH-pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-dimethoxy-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclobutyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;TSRI 2263.1PC 18350.033W015-hydroxy-3-(l-methylcyclobutyl)-l-(l,2,8,9-tetrafluoro-10,l l-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)-2,3-dihydro-lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione;3 -cyclopropyl- 1 -(5H-dibenzo [a,d] [7]annulen-5 -yl)-5-hydroxy-2,3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;3 -cyclopentyl- 1 -(5H-dibenzo [a,d] [7] annulen-5 -y 1) -5 -hydroxy-2,3 -dihydro- IH-pyrido [2,1- f] [ 1 ,2, 4]triazine-4, 6-dione ;3-cyclopentyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3-cyclopropyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;3-cyclobutyl-l-(l,9-difluoro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-lH- pyrido[2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione; l-(l,9-difluoro-5H-dibenzo[a,d] [7]annulen-5-yl)-5-hydroxy-3-(l-methylcyclopropyl)-2,3- dihydro- IH-pyrido [2, 1 -f] [ 1 , 2, 4]triazine-4, 6-dione;(( 1 -( 1 ,9-difluoro-5H-dibenzo [a, d] [7] annulen-5 -y 1) -3 -( 1 -methylcyclobutyl)-4,6-dioxo-2,3 ,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate; methyl(((3-(l-methylcyclobutyl)-4,6-dioxo-l-(l,2,8,9-tetrafluoro-5H-dibenzo[a,d] [7] annulen-5- yl)-2,3,4,6-tetrahydro-lH-pyrido[2,l-f][l,2,4]triazin-5-yl)oxy)methyl) carbonate; or a pharmaceutically acceptable salt thereof.

38. A compound, which compound is:(S)-((3 -cyclobutyl- l-(7,8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 1 l-yl)-4, 6-dioxo-2, 3,4,6- tetrahydro- IH-pyrido [2, 1 -f] [ 1 ,2,4]triazin-5 -yl)oxy)methyl methyl carbonate;(S)-3 -cyclobutyl- 1 -(7, 8-difluoro-6, 11 -dihydrodibenzo [b,e]thiepin- 11 -y 1) -5 -hydroxy-2,3 -dihydro- lH-pyrido[2,l-f][l, 2, 4]triazine-4, 6-dione; or a pharmaceutically acceptable salt thereof.

39. A composition comprising the compound of any one of claims 1-38 and a pharmaceutically acceptable carrier, diluent, or excipient.

40. The composition of claim 39, which further comprises an additional therapeutic compound.

41. The composition of claim 40, wherein the additional therapeutic compound is a second anti-influenza inhibitor.

42. The composition of claim 40, wherein the additional therapeutic compound is a second CEN inhibitor.

43. The composition of claim 42, wherein the second CEN inhibitor compound is Baloxavir marboxil (Xofluza®, BXM).TSRI 2263.1PC 18350.033W0144. The composition of claim 40, wherein the additional therapeutic compound is a neuraminidase (NA) inhibitor.

45. The composition of claim 44, wherein the neuraminidase inhibitor compound is oseltamivir or a salt thereof (e.g. , Tamiflu®).

46. A method of treating or preventing an influenza infection, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1-38.

47. The method of claim 46, wherein the compound is administered in combination with a second CEN inhibitor.

48. The method of claim 46, wherein the compound is administered in combination with an NA inhibitor.

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