1'-cyano nucleoside analogues and uses thereof

Abstract

Disclosed are compounds of Formula (I) for use in the treatment of viral infections and methods of using the compounds alone or in combination with additional pharmaceutical agents and pharmaceutical compositions of the compounds.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 043,349, filed June 24, 2020, and U.S. Provisional Patent Application No. 63 / 139,648, filed January 20, 2021, each of which is incorporated herein in its entirety for all purposes. BACKGROUND

[0003] There is a need for compositions and methods for treating viral infections, such as Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae infections. The present disclosure addresses the aforementioned and other needs. SUMMARY

[0004] Provided herein are compounds of Formula I:

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein

[0007] each R 1 and R 2 is independently H, -(CO)C1-C6 alkyl, or -(CO)OC1-C6 alkyl, wherein the -(C(O)C1-C6 alkyl or -(CO)OC1-C6 alkyl is optionally substituted with a NH2 group; or

[0008] R 1 and R 2 are combined to form -CO-, -CO-CO-, or -C(O)-C(R 1A )(R 1B )-C(O)-; wherein each R 1A and R 1B is independently H or C1-C6 alkyl;

[0009] R 3A is H or C 1- C6 alkyl; wherein the C 1- C6 alkyl is optionally substituted with -OH or phenyl;

[0010] R 3B is H or C1-C3 alkyl; and

[0011] R 4 is (i) C 1- C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C 10 cycloalkyl, (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, or (v) 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C1-C8alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one or two R 4A groups; wherein

[0012] each R 4A is independently C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C6alkyl, halo, C1-C6haloalkyl, and C1-C6alkoxy;

[0013] the base is wherein

[0014] R 6 is -N(H)R 6A ; and

[0015] each R 6A , R 7A , and R 7B is independently H or -CH2OP(O)(OH)2;

[0016] Ar is C6-C 10 aryl or 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S;

[0017] n is 0, 1, 2, or 3;

[0018] each R 5 is independently halo, cyano, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, -COOR 5A, -SO2R 5A , C3-C6cycloalkyl, C1-C6alkoxy, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, and S; wherein said C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, C1-C6alkoxy, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one or two R 5B groups; or

[0019] two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl;

[0020] R 5A is C 1- C6alkyl;

[0021] each R 5B is independently -OH, -OR 5C , -COOR 5C , and -NHCOOR 5D ; wherein R 5C is C 1- C6alkyl, and R 5D is C 1- C3alkyl;

[0022] each R 8 , R 9 , R 10 , R 11 , and R 12 is independently H or C1-C3alkyl;

[0023] m is 1, 2, 3, 4, or 5;

[0024] provided that when R 1 and R 2 are both H, then:

[0025] (i) n is 1, 2, or 3; or

[0026] (ii) R 4 is C1-C8alkyl substituted with one or two groups independently selected from C1-C3alkoxy, C1-C3haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having one to three heteroatoms independently selected from N, O, and S;

[0027] wherein said C3-C 10 cycloalkyl, C6-C 10The aryl or 4- to 6-membered heterocyclic group is optionally substituted by one or two independent substituents selected from the group consisting of C1-C6 alkyl, haloyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups; or

[0028] (iii)R 4 It is (a)-(CR) 8 R 9 CR 10 R 11 O) m R 12 (b) by one or two R 4A Monocyclic C3-C with substituent groups 10 cycloalkyl, (c) bicyclic C3-C 10 Cycloalkyl, (d) a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S, or (e) a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O and S;

[0029] The double-ring C3-C 10 Cycloalkyl, 4- to 6-membered heterocyclic or 5- to 6-membered heteroaryl groups are optionally surrounded by one or two R groups. 4A Group substitution; or

[0030] (iv) The base is

[0031] In some embodiments, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0032] In some embodiments, this disclosure provides methods for treating or preventing viral infections in a person in need, wherein the methods include administering to the person a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, this disclosure provides a method for preparing a medicament for treating or preventing viral infections in persons in need, characterized by using a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of viral infections in persons in need. Detailed Implementation

[0035] I. SUMMARY

[0036] The present invention relates to methods and compounds for treating or preventing viral infections, such as those from the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families (including but not limited to MERS, SARS, and SARS-CoV-2).

[0037] II. DEFINITIONS

[0038] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0039] As used herein, “compound of this disclosure” or “compound of formula I” means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, in contrast to separable intermediates, the phrase “compound of formula (number)” means a compound of that formula or a pharmaceutically acceptable salt thereof.

[0040] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20"alkyl" means an alkyl group having from 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1 -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0041] "alkoxy" means an alkyl group having the formula -O-, wherein the alkyl group is defined above attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propyloxy (-OCH2CH2CH3), i-propyloxy (-OCH(CH3)2), n-butyloxy (-OCH2CH2CH2CH3), i-butyloxy (-OC(CH3)2CH2CH3), s-butyloxy (-OCH(CH3)CH2CH3), t-butyloxy (-OC(CH3)3), n-pentyloxy (-OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butyloxy (-OC(CH3)2CH2CH3), 3-methyl-2-butyloxy (-OCH(CH3)CH(CH3)2), 3-methyl-1 -butyloxy (-OCH2CH2CH(CH3)2), 2-methyl-1 -butyloxy (-OCH2CH(CH3)CH2CH3), 1-hexyloxy (-OCH2CH2CH2CH2CH2CH3), 2-hexyloxy (-OCH(CH3)CH2CH2CH2CH3), 3-hexyloxy (-OCH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyloxy (-OC(CH3)2CH2CH2CH3), 3-methyl-2-pentyloxy (-OCH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyloxy (-OCH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyloxy (-OC(CH3)(CH2CH3)2), 2-methyl-3-pentyloxy (-OCH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyloxy (-OC(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyloxy (-OCH(CH3)C(CH3)3). 20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12Alkoxy groups are alkoxy groups with 1 to 8 carbon atoms (i.e., C1-C8 alkoxy groups), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy groups). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-OC(CH3)3 or -OtBu), etc.

[0042] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl moiety of the haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 Halogenated alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl groups), 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl groups). Examples of suitable alkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0043] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0044] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12C ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C1646-C ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0045] "Heterocyclo" or "heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl groups can be a single ring or multiple rings, where the multiple rings can be fused, bridged, or spiro. As used herein, heterocyclyl groups have 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4- to 12-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4- to 8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4- to 6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0046] The term "optionally substituted" with respect to a particular moiety of a compound of Formula I (e.g., an optionally substituted aryl group) means a moiety in which all substituents are hydrogen or in which one or more hydrogens of the moiety can be replaced by a listed substituent.

[0047] Unless otherwise indicated, carbon atoms of a compound of Formula I are intended to have a valence of four. If, in some chemical structures herein, a carbon atom is not connected to enough variables to result in a valence of four, it shall be presumed that the remaining carbon substituents necessary to provide a valence of four are hydrogens.

[0048] The term "treat" or "treatment" as used herein means to reverse, alleviate, or inhibit the progress of a disease or condition, or one or more symptoms thereof, to which the term applies, or to prevent the disease or condition, or one or more symptoms thereof. The term "treatment" as used herein refers to the act of treating as "treatment" is defined above.

[0049] The term "therapeutically effective amount" as used herein is the amount of a compound of Formula I present in a composition described herein that is required to provide a desired level of drug in secretions and tissues of the airways and lungs, or alternatively, to produce the intended physiological response or desired biological effect in the bloodstream of a subject to be treated when such a composition is administered by a selected route of administration. The precise amount will depend on numerous factors, e.g., the particular compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition and its intended use, and patient considerations such as the severity of the disease, patient compliance, etc., and can readily be determined by one of skill in the art based on the information provided herein.

[0050] The term "adjacent carbons" as used herein refers to consecutive carbon atoms that are directly connected to each other. For example, in In particular, C1and C2are adjacent carbons, C2and C3are adjacent carbons, C3and C4are adjacent carbons, and C4and C5are adjacent carbons. Similarly, in In particular, C1and C2are adjacent carbons, C2and C3are adjacent carbons, C3and C4are adjacent carbons, and C4and C5are adjacent carbons, C5and C6are adjacent carbons, and C6and C1are adjacent carbons.

[0051] The compound structure using the "P * " notation refers to the isolated (R)- or (S) isomer, where the specific stereochemistry at that position is not specified.

[0052] III. COMPOUNDS

[0053] Provided herein are compounds of Formula I:

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein

[0056] each R 1 and R 2 is independently H, -(CO)C1-C6alkyl, or -(CO)OC1-C6alkyl, wherein the -(C(O)C1-C6alkyl or -(CO)OC1-C6alkyl is optionally substituted with a NH2group; or

[0057] R 1 and R 2 are combined to form -CO-, -CO-CO-, or -C(O)-C(R 1A )(R 1B )-C(O)-; wherein each R 1A and R 1B is independently H or C1-C6alkyl;

[0058] R 3A is H or C 1- C6alkyl; wherein the C 1- C6alkyl is optionally substituted with -OH or phenyl;

[0059] R 3B is H or C1-C3alkyl; and

[0060] R 4 is (i) C 1- C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C10 C3-C8cycloalkyl, (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, or (v) 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein said Ci-C8alkyl, C3-C8cycloalkyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one or two R 10 C3-C8cycloalkyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one or two R 4A wherein

[0061] each R 4A is independently Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein said C3-C 10 Cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein said C3-C

[0062] the base is wherein

[0063] R 6 is -N(H)R 6A ; and

[0064] each R 6A , R 7A , and R 7B is independently H or -CH2OP(O)(OH)2;

[0065] Ar is C6-C 10 aryl, or 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S;

[0066] n is 0, 1, 2, or 3;

[0067] each R 5 is independently halo, cyano, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, C3-C6cycloalkoxy, -COOR 5A , -SO2R 5A, C3-C6cycloalkyl, C3-C6cycloalkoxy, C1-C6alkoxy, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one or two R 5B groups; or

[0068] two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group;

[0069] R 5A is C 1- C6alkyl;

[0070] each R 5B is independently -OH, -OR 5C , -COOR 5C , and -NHCOOR 5D ; wherein R 5C is C 1- C6alkyl, and R 5D is C 1- C3alkyl optionally substituted with a phenyl group;

[0071] each R 8 , R 9 , R 10 , R 11 , and R 12 is independently H or C1-C3alkyl;

[0072] m is 1, 2, 3, 4, or 5;

[0073] provided that when R 1 and R 2 are both H, then:

[0074] (i) n is 1, 2, or 3; or

[0075] (ii) R 4 is C1-C8alkyl substituted with one or two groups independently selected from C1-C3alkoxy, C1-C3haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S;

[0076] wherein the C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl is optionally substituted with one or two groups independently selected from C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C6-C10aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S;The aryl or 4- to 6-membered heterocyclic group is optionally substituted by one or two independent substituents selected from the group consisting of C1-C6 alkyl, haloyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups; or

[0077] (iii)R 4 It is (a)-(CR) 8 R 9 CR 10 R 11 O) m R 12 (b) by one or two R 4A Monocyclic C3-C with substituent groups 10 cycloalkyl, (c) bicyclic C3-C 10 Cycloalkyl, (d) a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S, or (e) a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O and S;

[0078] The double-ring C3-C 10 Cycloalkyl, 4- to 6-membered heterocyclic or 5- to 6-membered heteroaryl groups are optionally surrounded by one or two R groups. 4A Group substitution; or

[0079] (iv) The base is In some embodiments, the compound of formula I is the same as the compound of formula Ia:

[0080]

[0081] In some embodiments, the compound of formula I is a compound of formula Ib:

[0082]

[0083] In some embodiments of the compounds of formulas I, Ia, and Ib, the base is In some implementations, the base is In some implementations, the base is In some implementations, the base is

[0084] In some embodiments, the compound of formula I has formula II:

[0085]

[0086] In some embodiments, the compounds of formula I, Ia, or II have formula IIa:

[0087]

[0088] In some embodiments, the compound of Formula I, Ib, or II is of Formula IIb:

[0089]

[0090] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3A is C1-C6 alkyl optionally substituted with -OH or phenyl. In some embodiments, R 3A is C1-C6 alkyl optionally substituted with -OH. In some embodiments, R 3A is C1-C6 alkyl optionally substituted with phenyl.

[0091] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3A is C1-C3 alkyl optionally substituted with -OH or phenyl. In some embodiments, R 3A is C1-C3 alkyl optionally substituted with -OH. In some embodiments, R 3A is C1-C3 alkyl optionally substituted with phenyl.

[0092] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3A is H or C1-C6 alkyl. In some embodiments, R 3A is H or C1-C3 alkyl. In some embodiments, R 3A is H. In some embodiments, R 3A is C1-C6 alkyl. In some embodiments, R 3A is C1-C3 alkyl. In some embodiments, R 3A is methyl.

[0093] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3B is H. In some embodiments, R 3B is C1-C3 alkyl. In some embodiments, R 3B is methyl.

[0094] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3A and R 3B are both H. In some embodiments, R 3A is C1-C6 alkyl and R 3B is H. In some embodiments, R 3A is C1-C3 alkyl and R 3B is H. In some embodiments, R3A is methyl, and R 3B is H. In some embodiments, R 3A and R 3B are each C1-C3 alkyl. In some embodiments, R 3A and R 3B are each methyl.

[0095] In some embodiments of the compound of Formula I, la, lb, II, Ila, or lib, R 3A is C1-C6 alkyl optionally substituted with -OH or phenyl, and R 3B is H. In some embodiments, R 3A is C1-C3 alkyl optionally substituted with -OH or phenyl, and R 3B is H. In some embodiments, R 3A is methyl optionally substituted with -OH or phenyl, and R 3B is H.

[0096] In some embodiments, the compound of Formula I, la, lb, II, Ila, or lib is a compound of Formula III:

[0097]

[0098] In some embodiments, the compound of Formula I, la, II, or Ila is a compound of Formula IIIa:

[0099]

[0100] In some embodiments, the compound of Formula I, lb, II, or lib is of Formula IIIb:

[0101]

[0102] In some embodiments, the compound of Formula I, la, II, Ila, III, or IIIa is of Formula IIIc:

[0103]

[0104] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, IIIa, IIIb, and IIIc, or a pharmaceutically acceptable salt thereof, one of R 1 and R 2 is H and the other is -(CO)C1-C6 alkyl or -(CO)OC1-C6 alkyl. In some embodiments, R 1 is H, and R 2-(CO)C1-C6alkyl or -(CO)OC1-C6alkyl. In some embodiments, R 1 is H, and R 2 -(CO)C1-C3alkyl or -(CO)OC1-C3alkyl. In some embodiments, R 1 -(CO)C1-C6alkyl or -(CO)OC1-C6alkyl, and R 2 is H. In some embodiments, R 1 -(CO)C1-C3alkyl or -(CO)OC1-C3alkyl, and R 2 is H.

[0105] In some embodiments of the compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 1 and R 2 is H and the other is -(CO)C1-C6alkyl. In some embodiments, R 1 is H and R 2 -(CO)C1-C6alkyl. In some embodiments, R 1 is H and R 2 -(CO)C1-C3alkyl. In some embodiments, R 1 is H and R 2 -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is H and R 2 -(CO)methyl. In some embodiments, R 1 is H and R 2 -(CO)ethyl. In some embodiments, R 1 is H and R 2 -(CO)n-propyl. In some embodiments, R 1 is H and R 2 -(CO)i-propyl.

[0106] In some embodiments of the compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 1 -(CO)C1-C6alkyl, and R 2 is H. In some embodiments, R 1 -(CO)C1-C3alkyl, and R 2 is H. In some embodiments, R 1is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl and R 2 is H. In some embodiments, R 1 is -(CO)methyl, and R 2 is H. In some embodiments, R 1 is -(CO)ethyl, and R 2 is H. In some embodiments, R 1 is n-(CO)propyl, and R 2 is H. In some embodiments, R 1 is -(CO)i-propyl, and R 2 is H.

[0107] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 1 is -COCH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH(CH3)2, or -COCH(NH2)CH(CH3)2.

[0108] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 2 is -COCH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH(CH3)2, or -COCH(NH2)CH(CH3)2.

[0109] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently selected from the group consisting of -COCH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH(CH3)2, or -COCH(NH2)CH(CH3)2.

[0110] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, or a pharmaceutically acceptable salt thereof, R 1 is -(CO)Ci-C6alkyl, and R 2 is -(CO)Ci-C6alkyl. In some embodiments, R 1 is -(CO)Ci-C3alkyl, and R 2is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl.

[0111] In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, and R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, and R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, and R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, and R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl. In some embodiments, R

[0112] In some embodiments, R 1 and R 2 are each -(CO)methyl. In some embodiments, R 1 and R 2 are each -(CO)ethyl. In some embodiments, R 1 and R 2 are each -(CO)n-propyl. In some embodiments, R1 and R 2 are each -(CO)isopropyl.

[0113] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc, R 1 and R 2 combine to form -C(O)-, -C(O)-C(R 1A )(R 1B )-C(O)-, or -C(O)-C(O)-, wherein each R 1A and R 1B are independently H or Ci-C6alkyl. In some embodiments, R 1 and R 2 combine to form -C(O)- or -C(O)-C(R 1A )(R 1B )-C(O)-, wherein each R 1A and R 1B are independently H or Ci-C6alkyl. In some embodiments, R 1 and R 2 combine to form -C(O)-C(R 1A )(R 1B )-C(O)-, wherein each R 1A and R 1B are independently H or Ci-C6alkyl. In some embodiments, R 1 and R 2 combine to form -C(O)-C(R 1A )(R 1B )-C(O)-, wherein each R 1A and R 1B are independently H, methyl, or ethyl. In some embodiments, R 1 and R 2 combine to form -C(O)-C(R 1A )(R 1B )-C(O)-, wherein R 1A is H, and R 1B is H, methyl, or ethyl. In some embodiments, R 1 and R 2 combine to form -C(O)-C(R 1A )(R 1B )-C(O)-, wherein R 1A is H, and R 1B is methyl or ethyl.

[0114] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, and IIIc, R 1 and R 2 The combination forms -C(O)-C(O)-.

[0115] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, and IIIc, R 1 and R 2 The combination forms -C(O)-.

[0116] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc, R 1 and R 2 Both are H; and

[0117] (i) n is 1, 2, or 3; or

[0118] (ii)R 4 It is a C1-C8 alkyl group substituted with one or two groups independently selected from the following: C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or 4- to 6-membered heterocyclic groups having 1 to 3 heteroatoms independently selected from N, O, and S;

[0119] The C3-C 10 cycloalkyl, C6-C 10 The aryl or 4- to 6-membered heterocyclic group is optionally substituted by one or two independent substituents selected from the group consisting of C1-C6 alkyl, haloyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups; or

[0120] (iii)R 4 It is (a)-(CR) 8 R 9 CR 10 R 11 O) m R 12 (b) by one or two R 4A Monocyclic C3-C with substituent groups 10 cycloalkyl, (c) bicyclic C3-C 10 Cycloalkyl, (d) a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S, or (e) a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O and S;

[0121] The double-ring C3-C 10cycloalkyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one or two R 4A group; or

[0122] (iv) the base is

[0123] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc, R 1 and R 2 are each H, and R 4 is (a) -CR 8 R 9 CR 10 R 11 O) m R 12 , (b) monocyclic C3-C 4A cycloalkyl substituted with one or two R 10 groups, (c) bicyclic C3-C 10 cycloalkyl, (d) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, or (e) 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the bicyclic C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one or two R 4A groups.

[0124] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc, R 1 and R 2 are each H, and R 4 is monocyclic C3-C 4A cycloalkyl substituted with one or two R 10 groups. In some embodiments, R 1 and R 2 are each H, and R 4 is bicyclic C3-C 4A cycloalkyl optionally substituted with one or two R 10 groups. In some embodiments, R 1 and R 2 are each H, and R 4 is 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, and optionally substituted with one or two R 4A groups. In some embodiments, R 1 and R 2 are each H, and R 4It has 1 to 3 heteroatoms independently selected from N, O and S and optionally bounded by one or two R atoms. 4A Five to six-membered heteroaryl groups substituted with functional groups.

[0125] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc, R 1 and R 2 Both are H, and R 4 It is a C1-C8 alkyl group substituted with one or two groups independently selected from the following: C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C3-C 10 cycloalkyl, C6-C 10 The aryl or 4- to 6-membered heterocyclic group is optionally substituted by one or two substituents independently selected from the group consisting of C1-C6 alkyl, haloyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups. In some embodiments, R 1 and R 2 Both are H, and R 4 It is a C1-C8 alkyl group substituted with one or two groups independently selected from the following: C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or 4- to 6-membered heterocyclic groups having 1 to 3 heteroatoms independently selected from N, O and S.

[0126] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc, R 1 and R 2 Both are H. In some implementations, R 1 and R 2 All are H, and n is 1, 2, or 3. In some implementations, R 1 and R 2 Both are H, and R 4 Yes - (CR) 8 R 9 CR 10 R 11 O) m R 12 In some implementations, R 1 and R 2 All are H, and the bases are

[0127] In some embodiments, for the compounds of Formulae I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C 10 cycloalkyl, (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, or (v) 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C1-C8alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally substituted with one or two R 4A In some embodiments, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C 10 cycloalkyl, or (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C1-C8alkyl, C3-C 10 cycloalkyl, or 4- to 6-membered heterocyclyl are optionally substituted with one or two R 4A In some embodiments, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , or (iii) C3-C 10 cycloalkyl; wherein the C1-C8alkyl or C3-C 10 cycloalkyl are optionally substituted with one or two R 4A

[0128] In some embodiments, for the compounds of Formulae I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 ​or (iii) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C1-C8alkyl or 4- to 6-membered heterocyclyl is optionally substituted with one or two R 4A In some embodiments, R 4 is (i) C3-C 10 cycloalkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , or (iii) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C3-C 10 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted with one or two R 4A In some embodiments, R 4 is C1-C8alkyl optionally substituted with one or two R 4A In some embodiments, R 4 is C3-C 4A cycloalkyl optionally substituted with one or two R 10 In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted with one or two R 4A In some embodiments, R 4 is 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted with one or two R 4A In some embodiments, R

[0129] In some embodiments, for the compounds of Formulae I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C 10 cycloalkyl, or (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12, or (iii) C3-C 10 Cycloalkyl. In some embodiments, R 4 It is (i) C1-C8 alkyl, (ii)-(CR 8 R 9 CR 10 R 11 O) m R 12 (iii) or (iv) a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 It is (i)C3-C 10 (ii) A cycloalkyl group or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 It is a C1-C8 alkyl group. In some embodiments, R 4 It is C3-C 10 Cycloalkyl. In some embodiments, R 4 It is a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O and S.

[0130] In some implementation schemes, R 4 It is arbitrarily assigned to an R 4A Substituted C1-C8 alkyl groups. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Replacement C 1-6 Alkyl group. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted C1-C4 alkyl groups. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted methyl, ethyl, propyl, or butyl. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted methyl groups. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted ethyl group. In some embodiments, R 4 It is arbitrarily assigned to an R 4A The substituted propyl group. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Replaced butyl.

[0131] In some implementation schemes, R 4 It is a C1-C8 alkyl group. In some embodiments, R 4 It is C1-6 Alkyl group. In some embodiments, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is methyl, ethyl, propyl, or butyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is propyl. In some implementations, R 4 It is butyl.

[0132] In some implementation schemes, R 4 It is arbitrarily assigned to an R 4A Replacement C3-C 10 Cycloalkyl groups. For example, R 4 It is arbitrarily assigned to an R 4A Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some examples, R 4 It is arbitrarily assigned to an R 4A Substituted cyclobutyl, cyclohexyl, or cyclooctyl. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted cyclopropyl group. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted cyclobutyl. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Substituted cyclopentyl. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Replaced cyclohexyl. In some implementations, R 4 It is arbitrarily assigned to an R 4A Substituted cycloheptanyl. In some embodiments, R 4 It is arbitrarily assigned to an R 4A Replaced cyclooctyl.

[0133] In some implementation schemes, R 4 It is C3-C 10 Cycloalkyl groups. For example, R 4 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some embodiments, R 4 It is cyclobutyl, cyclohexyl, or cyclooctyl. In some embodiments, R 4 It is cyclopropyl. In some implementations, R 4 It is cyclobutyl. In some implementations, R 4 It is cyclopentyl. In some implementations, R 4 It is cyclohexyl. In some implementations, R4 is cycloheptyl. In some embodiments, R 4 is cyclooctyl.

[0134] In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is substituted with one R 4A In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is optionally substituted with one R 4A In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 heteroatom selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is optionally substituted with one R 4A In some embodiments, R 4 is 4- to 6-membered heterocyclyl having one O atom, wherein the 4- to 6-membered heterocyclyl is optionally substituted with one R 4A In some embodiments, R 4 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with one R 4A In some embodiments, R 4 is oxetanyl or tetrahydropyranyl, each optionally substituted with one R 4A In some embodiments, R 4 is oxetanyl optionally substituted with one R 4A In some embodiments, R 4 is tetrahydropyranyl optionally substituted with one R 4A

[0135] In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 is 4- to 6-membered heterocyclyl having 1 heteroatom selected from N, O, and S. In some embodiments, R 4 is 4- to 6-membered heterocyclyl having one O atom. In some embodiments, R 4 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, R 4 is oxetanyl or tetrahydropyranyl. In some embodiments, R 4 is oxetanyl. In some embodiments, R 4 is tetrahydropyranyl.​

[0136] In some implementation schemes, R 4 It is a C1-C8 alkyl, C3-C 10 Cycloalkyl or a 4-6 membered heterocyclic group containing a heteroatom selected from N, O, and S, wherein the C1-C8 alkyl, C3-C 10 cycloalkyl or 4-6 membered heterocyclic group optionally surrounded by an R 4A Replacement. In some implementations, R 4 It is a C1-C8 alkyl, C3-C 10 Cycloalkyl or 4-6 membered heterocyclic groups containing one O atom, wherein the C1-C8 alkyl, C3-C... 10 cycloalkyl or 4-6 membered heterocyclic group optionally surrounded by an R 4A Replacement. For example, R 4 It is C 1-6 Alkyl, C3-C8 cycloalkyl, or a 4-6 membered heterocyclic group containing a heteroatom selected from N, O, and S, wherein the C 1-6 Alkyl, C3-C8 cycloalkyl, or 4-6 membered heterocyclic group optionally separated by an R 4A Replacement. In some implementations, R 4 It is C 1-4 Alkyl, C3-C8 cycloalkyl, or a 4-6 membered heterocyclic group containing a heteroatom selected from N, O, and S, wherein the C 1-4 Alkyl, C3-C8 cycloalkyl, or 4-6 membered heterocyclic group optionally separated by an R 4A Replacement. In some implementations, R 4 It is methyl, ethyl, propyl, butyl, cyclobutyl, cyclohexyl, cyclooctyl, oxetyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally marked with an R 4A replace.

[0137] In some implementation schemes, R 4 It is a C1-C8 alkyl, C3-C 10 Cycloalkyl groups or 4-6 membered heterocyclic groups containing a heteroatom selected from N, O, and S. For example, R 4 It is a C1-C6 alkyl, C3-C8 cycloalkyl, or a 4-6 membered heterocyclic group containing a heteroatom selected from N, O, and S. In some embodiments, R 4 It is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclobutyl, cyclohexyl, cyclooctyl, oxecyclobutyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0138] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, and IIIc, R 4 Yes - (CR) 8 R9 CR 10 R 11 O) m R 12 wherein m is 1, 2, 3, 4, or 5; each R 8 , R 9 , R 10 , and R 11 is independently H or methyl; and R 12 is C1-C3 alkyl. In some embodiments, m is 1, 2, 3, 4, or 5; each R 8 , R 9 , R 10 , and R 11 is H; and R 12 is C1-C3 alkyl.

[0139] In some embodiments of the compound of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, or IIIc, R 4 is methyl, ethyl, n-propyl, i-propyl, cyclobutyl, cyclohexyl, cyclooctyl,

[0140] In some embodiments of the compound of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc, R 4 is methyl, ethyl, oxetanyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, cyclooctyl, C1 alkyl substituted with tetrahydropyranyl,

[0141] In some embodiments of the compound of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc, R 1 is -(CO)C1-C3 alkyl, R 2 is -(CO)C1-C3 alkyl, and R 4 is C1-C8 alkyl, -(CR 8 R 9 CR 10 R 11 O) m R 12 , C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl containing one heteroatom selected from the group consisting of N, O, and S, wherein the C1-C8 alkyl, C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one R4A substituted. For example, R 1 is -(CO)C1-C3 alkyl, R 2 is -(CO)C1-C3 alkyl, and R 4 is C1-C6 alkyl, -(CR 8 R 9 CR 10 R 11 O) m R 12 , C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl containing one O atom, wherein the C1-C6 alkyl, C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one R 4A In some embodiments, R 1 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, R 2 is -(CO)methyl, -(CO)ethyl, -(CO)n-propyl, or -(CO)i-propyl, and R 4 is methyl, ethyl, propyl, butyl, cyclobutyl, cyclohexyl, cyclooctyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with one R 4A substituted.

[0142] In some embodiments of the compounds of Formulae I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, R 4A is C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. In some embodiments, R 4A is C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4A is C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10aryl or 4- to 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R 4A is C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 4- to 6-membered heterocyclyl having one heteroatom selected from N, O, and S. In some embodiments, R 4A is C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, or 4- to 6-membered heterocyclyl having one heteroatom selected from N, O, and S. For example, R 4A is methyl, ethyl, propyl, halomethyl, methoxy, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, R 4A is methyl, ethyl, propyl, methoxy, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, R 4A is methyl, ethyl, methoxy, cyclobutyl, cyclohexyl, oxetanyl, or tetrahydropyranyl. In some embodiments, R 4A is methoxy, cyclobutyl, cyclohexyl, oxetanyl, or tetrahydropyranyl.

[0143] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, n is 0, 1, 2, or 3. For example, n is 0, 1, or 2, or n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0144] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, each R 5 is independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, -COOR 5A , -SO2R 5A , 4- to 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one or two R5B groups are optionally substituted with one or two R 5 groups are optionally substituted with one or two R

[0145] In some embodiments of the compounds of Formulae I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, each R 5 is independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C6 alkoxy, -COOR 5A or -SO2R 5A ; wherein said C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, and C1-C6 alkoxy are optionally substituted with one or two R 5B groups.

[0146] In some embodiments of the compounds of Formulae I, la, lb, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, R 5 is independently halo, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or -SO2R 5A ; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy are optionally substituted with one or two R 5B groups. In some embodiments, each R 5 group is independently -COOR 5 and -NHCOOR 5A ; wherein said C1-C6 alkyl is optionally substituted with one or two R 5B groups. In some embodiments, each R 5A is independently C 1- C6 alkyl and each R 5B is independently -COOR 5C and -NHCOOR 5D ; wherein R 5C is C 1- C6 alkyl and R 5D is C 1- C3 alkyl.

[0147] In some embodiments, two R 5 groups on adjacent carbon atoms are joined to form a C5-C6 cycloalkyl group. In some embodiments, each R 5independently halo, cyano, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, or -SO2R 5 independently C1-C6alkyl or C3-C6cycloalkyl. In some embodiments, n is 1 or 2, and each R 5 independently methyl, t-butyl, or cyclopropyl.

[0148] In some embodiments, n is 1, 2, or 3, and each R 5 independently C1-C6alkyl or C3-C6cycloalkyl. In some embodiments, n is 1 or 2, and each R 5 independently C1-C6alkyl or C3-C6cycloalkyl. In some embodiments, n is 1, 2, or 3, and each R 5 independently methyl, t-butyl, or cyclopropyl.

[0149] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, and IIIc described herein, R 5 is C1-C4alkyl. In some embodiments, R 5 is methyl, ethyl, propyl, or butyl. In some embodiments, R 5 is methyl or t-butyl.

[0150] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, or IIIc, is a 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S.

[0151] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, or IIIc, is C6-C 10 aryl; n is 0, 1, 2, or 3; and each R 5 independently halo, cyano, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, or -SO2R 5A ; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

[0152] In some embodiments of the compounds of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, or IIIc, is C6-C 10 aryl; n is 0, 1, or 2; and each R 5independently halo, cyano, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, or -SO2R 5A ; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is C6-C 10 aryl, n is 0, 1, 2, or 3, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is C6-C 10 aryl, n is 0, 1, or 2, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is phenyl or naphthyl; n is 0, 1, 2, or 3, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is phenyl or naphthyl; n is 0, 1, or 2, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is phenyl, n is 0, 1, 2, or 3, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is phenyl, n is 0, 1, or 2, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is naphthyl, n is 0, 1, 2, or 3, and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl group. In some embodiments, is naphthyl; n is 0, 1, or 2; and each R 5It is independently a C1-C6 alkyl or C3-C6 cycloalkyl; or two R on adjacent carbon atoms. 5 Groups are linked to form C5-C6 cycloalkyl groups.

[0153] In some implementation schemes, It is phenyl or naphthyl; n is 0, 1, 2 or 3; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is phenyl or naphthyl; n is 0, 1, or 2; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is phenyl; n is 0, 1, 2 or 3; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is phenyl; n is 0, 1, or 2; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is naphthyl; n is 0, 1, 2 or 3; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is naphthyl; n is 0, 1, or 2; and each R 5 It is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. In some embodiments, It is phenyl and n is 0. In some embodiments, Ar is naphthyl and n is 0.

[0154] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc, It is optional to be one or two R 5 C6-C substituent 10 Aryl; wherein each R 5 It is independently a halogenated group, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, or -SO2R group. 5A ; or two R atoms on adjacent carbon atoms 5 Groups are linked to form C5-C6 cycloalkyl groups. In some embodiments, It is optional to be one or two R 5 C6-C substituent 10 Aryl; wherein each R 5 It is independently a C1-C6 alkyl or C3-C6 cycloalkyl; or two R on adjacent carbon atoms. 5 Groups are linked to form C5-C6 cycloalkyl groups. In some embodiments, is optionally substituted with one or two R 5 group; wherein each R 10 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl. In some embodiments, is phenyl or naphthyl; wherein the phenyl or naphthyl is optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6 cycloalkyl. In some embodiments, is phenyl or naphthyl; wherein the phenyl or naphthyl is optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl. In some embodiments, is phenyl optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6 cycloalkyl. In some embodiments, is phenyl optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl. In some embodiments, is phenyl.

[0155] In some embodiments of the compound of Formula I, Ia, Ib, II, Ila, lib, III, Ilia, Illb, or IIIc, is naphthyl optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6 cycloalkyl. In some embodiments, is naphthyl optionally substituted with one or two R 5 group; wherein each R 5 is independently C1-C6 alkyl or C3-C6 cycloalkyl. In some embodiments, is 1-naphthyl or 2-naphthyl.

[0156] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc, is selected from the group consisting of:

[0157] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc,

[0158] R 1 is -(CO)Ci-C3alkyl;

[0159] R 2 is -(CO)Ci-C3alkyl;

[0160] R 4 is Ci-C8alkyl, -(CR 8 R 9 CR 10 R 11 O) m R 12 , C3-C 10 cycloalkyl or 4-6 membered heterocyclyl containing one heteroatom selected from the group consisting of N, O, and S, wherein said Ci-C8alkyl, C3-C 10 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or two R 4A substituents;

[0161] each R 8 , R 9 , R 10 , R 11 and R 12 is independently H or Ci-C3alkyl;

[0162] R 4A is Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, C3-C 10 cycloalkyl or 4 to 6 membered heterocyclyl having one heteroatom selected from the group consisting of N, O, and S;

[0163] is naphthyl or phenyl;

[0164] n is 0, 1, or 2; and

[0165] R 5 is Ci-C6alkyl or C3-C6cycloalkyl.

[0166] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc:

[0167] R 1 is -(CO)C1-C3alkyl;

[0168] R 2 is -(CO)C1-C3alkyl;

[0169] R 4 is C1-C8alkyl, -(CR 8 R 9 CR 10 R 11 O) m R 12 , C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl containing one O atom, wherein said C1-C8alkyl, C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or two R 4A ;

[0170] each R 8 , R 9 , R 10 , R 11 , and R 12 is independently H or C1-C3alkyl;

[0171] R 4A is methyl, ethyl, propyl, halomethoxy, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl;

[0172] is naphthyl or phenyl;

[0173] n is 0, 1, or 2; and

[0174] R 5 is C1-C6alkyl or C3-C6cycloalkyl.

[0175] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc:

[0176] R 1 is -(CO)C1-C3alkyl;

[0177] R 2 is -(CO)C1-C3alkyl;

[0178] R 4 is C1-C8alkyl, C3-C10 Cycloalkyl or 4-6 membered heterocyclic groups containing one O atom, wherein the C1-C8 alkyl, C3-C... 10 Cycloalkyl or 4-6 membered heterocyclic groups are optionally surrounded by one or two R groups. 4A replace;

[0179] R 4A It is methyl, methoxy, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, oxetyl, tetrahydrofuranyl, or tetrahydropyranyl;

[0180] It is naphthyl or phenyl;

[0181] n is 0 or 1; and

[0182] R 5 It is a C1-C6 alkyl or a C3-C6 cycloalkyl.

[0183] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb or IIIc:

[0184] R 1 It is a -(CO)C1-C3 alkyl group;

[0185] R 2 It is a -(CO)C1-C3 alkyl group;

[0186] R 4 It is a C1-C8 alkyl group, -(CR 8 R 9 CR 10 R 11 O) m R 12 C3-C 10 Cycloalkyl or 4-6 membered heterocyclic groups containing one O atom, wherein the C1-C8 alkyl, C3-C... 10 Cycloalkyl or 4-6 membered heterocyclic groups are optionally surrounded by one or two R groups. 4A replace;

[0187] Each R 8 R 9 R 10 R 11 and R 12 It is either H or methyl independently;

[0188] R 4A It is methyl, methoxy, ethyl, cyclobutyl, cyclohexyl, oxetyl, or tetrahydropyranyl;

[0189] It is naphthyl or phenyl;

[0190] n is 0, 1, or 2; and

[0191] R 5 is C1-C6 alkyl or cyclopropyl.

[0192] In some embodiments of the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc:

[0193] R 1 is -(CO)C1-C3 alkyl;

[0194] R 2 is -(CO)C1-C3 alkyl;

[0195] R 4 is C1-C8 alkyl, -(CR 8 R 9 CR 10 R 11 O) m R 12 , C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl containing one O atom, wherein the C1-C8 alkyl, C3-C 10 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or two R 4A ;

[0196] each R 8 , R 9 , R 10 , R 11 , and R 12 is independently H or methyl;

[0197] R 4A is cyclobutyl, cyclohexyl, methoxy, oxetanyl, or tetrahydropyranyl;

[0198] n is 0, 1, or 2; and

[0199] R 5 is C1-C6 alkyl or cyclopropyl.

[0200] In some embodiments, the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc is selected from the group consisting of:

[0201]

[0202]

[0203]

[0204]

[0205] In some embodiments, the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, IIIb, or IIIc is selected from the group consisting of:

[0206]

[0207]

[0208]

[0209]

[0210] In some embodiments, the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, IIIb, or IIIc is selected from the group consisting of:

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc is selected from the group consisting of:

[0232]

[0233]

[0234] Any reference to a compound of the present application described herein is also a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of a compound of the present application include salts derived from appropriate bases such as alkali or alkaline earth (for example, Na + , Li + , K + , Ca +2 , and Mg +2 ), ammonium and NR4 + (wherein R is defined herein). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include: (a) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoic acid, biphthalic acid, salicylic acid, stearic acid, o-phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts derived from elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of a hydroxyl group include the anion of the compound in combination with a suitable cation such as Na + and NR4 + .

[0235] The compounds disclosed herein (e.g., compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc) and pharmaceutically acceptable salts thereof can exist in different polymorphic or pseudopolymorphic forms. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can arise from differences in crystal packing (packing polymorphism) or from packing differences between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. Pseudopolymorphic forms of the present application can exist due to differences in crystal packing (packing pseudopolymorphism) or due to packing differences between different conformers of the same molecule (conformational pseudopolymorphism). The present application includes all polymorphic and pseudopolymorphic forms of the compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc and pharmaceutically acceptable salts thereof.

[0236] The compounds disclosed herein (e.g., compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc) and pharmaceutically acceptable salts thereof can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which atomic positions are not long-range ordered. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to produce amorphous forms of the present application. The present application includes all amorphous forms of the compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc and pharmaceutically acceptable salts thereof.

[0237] For therapeutic use, salts of the active ingredient of the compounds of the present application will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of acids or bases that are non-pharmaceutically acceptable can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether derived from a pharmaceutically acceptable acid or base, are within the scope of the present application.

[0238] Finally, it should be understood that the compositions herein include the compounds of the present application in non-ionized as well as zwitterionic form, in combination with stoichiometric amounts of water of hydration.

[0239] It should be noted that the present application encompasses all enantiomers, diastereomers and racemic mixtures of the compounds within the scope of Formula I and pharmaceutically acceptable salts thereof. All mixtures of such enantiomers and diastereomers, in all proportions, are also within the scope of the present application.

[0240] Compounds of the application exemplified by Formula I can have chiral centers, e.g., chiral carbon or phosphorus atoms. Accordingly, the compounds of the application include all racemic, optically pure or enriched stereoisomeric forms. In addition, the compounds of the application include optically isomers that are enriched or resolved at any or all of the asymmetric, chiral atoms. In other words, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomeric mixtures, as well as isolated or synthetic individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are within the scope of the application. Racemic mixtures are separated into their individual, substantially optically pure isomers by appropriate techniques, such as separation of diastereomeric salts formed with an optically active base, e.g., an acid or a base, followed by conversion back to the optically active compounds. In most cases the desired optical isomer is synthesized by stereospecific reactions using enantiomerically pure starting materials.

[0241] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E and Wilen, S, Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. "McGraw-Hill Dictionary of Chemical Terms” "Stereochemistry of Organic Compounds” (1984) McGraw-Hill Book Company, New York; and Eliel, E and Wilen, S, IV. PHARMACEUTICAL FORMULATIONS (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with S, (-), or 1 indicating that the compound is levorotatory and R, (+), or d that it is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer when it is not a mirror image of the other (i.e., when it is a pure enantiomer). A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can occur in chemical reactions or processes without stereocontrol. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species lacking optical activity.

[0242] In certain instances, the compounds of the application can also exist as tautomers. Although only one tautomer can be depicted, all such forms are intended to be included within the scope of the application. For example, for purine, pyrimidine, imidazole, guanidine, amidine and tetrazole systems, keto-enol tautomers can exist, and all possible tautomeric forms are within the scope of the application.

[0243] Any formula or structure given herein, including the compounds of Formula I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated. Such isotopically labeled compounds are useful in metabolic studies, receptor binding assays, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radioactive treatment of patients.

[0244] The present disclosure also includes compounds of Formula I, wherein from 1 to n hydrogens attached to a carbon atom are replaced by deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, therefore, can be useful in prolonging the half-life of any compound of Formula I when administered to a mammal, especially a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods known in the art, given the present disclosure, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0245] Deuterium labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic 18F-labeled compounds can be used in PET or SPECT studies. Isotopically-labeled compounds of the disclosure and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent in a

[0246] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the disclosure, any atom not specifically designated as a particular isotope means that any stable isotope of that atom is contemplated. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen," that position is understood to have its natural abundance isotopic composition of hydrogen. Thus, in the compounds of the disclosure, any atom specifically designated as deuterium (D) means that deuterium is specified.

[0247] Whenever a compound described herein is substituted with more than one of the same designated group (e.g., "R" or "R"), then unless stated otherwise it is understood that the groups can be the same or different, i.e., each group is independently selected.

[0248] wavy line, indicates the position covalently linked to an adjacent substructure, group, moiety, or atom.

[0249] V. KITS

[0250] The compounds disclosed herein (e.g., compounds of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc) can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration, generally will be isotonic. All formulations can optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulations can be about 3 to about 11, but is generally about 7 to 10. In some embodiments, the pH of the formulation is about 2 to about 5, but is generally about 3 to 4.

[0251] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it is preferable to present them as a pharmaceutical formulation. Both the veterinary and human formulations of the present application comprise at least one active ingredient as defined above, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients, in particular those additional therapeutic ingredients discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient thereof.

[0252] These formulations include those suitable for the aforementioned routes of administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods known in the art of pharmacy. Techniques and formulations generally are found in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the preparations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0253] Formulations of the present application suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

[0254] Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0255] For infections of the eye or other external tissues, such as the mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount, for example, from 0.075% to 20% w / w (active ingredient in the range of 0.1% to 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% to 15% w / w, and most preferably from 0.5% to 10% w / w, of the active ingredient. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base.

[0256] If desired, the aqueous phase of the cream base can include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulations can desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogs.

[0257] The oil phase of the emulsions of the present application can be constructed in known fashion from known ingredients. While this phase can include only an emulsifier (or emulsifiers), it desirably includes a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both an oil and a fat. The emulsifiers, with or without stabilizers, together with the waxes, constitute so-called emulsifying waxes, and the waxes, together with the oils and fats, constitute so-called emulsifying ointment bases, which form the oily dispersed phase of the cream formulations.

[0258] Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present application include 60、 80, cetyl stearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate, and sodium lauryl sulfate. Additional emulsifiers and emulsion stabilizers suitable for use in the formulations of the present application include 80.

[0259] The choice of oil or fat for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product, with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain mono- or di-alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol di-ester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic acid-2-ethylhexyl ester or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oil.

[0260] Pharmaceutical formulations according to the present application comprise a compound according to the present application together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use the tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended to be administered orally are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient are also acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium 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. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0261] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0262] The aqueous suspensions of the present application contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, such as a naturally occurring phosphatide (e.g., soybean lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene

[0263] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oral suspensions can contain suspending agents, as described above, and priming agents, such as acacia, tragacanth or soy lecithin.

[0264] Dispersible powders and granules of the present application suitable for preparation of an aqueous suspension by the addition thereto of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0265] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening or flavoring agents. Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring or coloring agents.

[0266] The pharmaceutical compositions of the present application can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above as appropriate. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared as a lyophilized powder. Among the acceptable solvents and vehicles that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable solvents and vehicles are water, Ringer's solution, isotonic sodium chloride solution and high osmolarity sodium chloride solution.

[0267] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to a human can contain approximately 1 mg to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material to make a dosage unit form that is suitably adapted to be ingested, for example, between about 5% and about 95% by weight of the total composition. The pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of the solution, in order that infusion of an appropriate amount (for example, between 3 mL and 100 mL) with an apparatus capable of delivering that amount at a rate of about 30 mL / hr can be effectively performed.

[0268] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0269] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0270] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0271] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have, for example, a particle size that is in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, or the like, which are administered by rapid inhalation delivery through the nasal passage or by inhalation into the buccal cavity to reach the alveolar sacs. Suitable formulations include aqueous or oil-based solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration are prepared according to conventional methods and can deliver other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as a dry powder. In some embodiments, the compounds used herein are formulated and administered as an aerosolized formulation. In some embodiments, the compounds used herein are formulated for delivery by face mask. In some embodiments, the compounds used herein are formulated for delivery by a face mask inhaler.

[0272] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0273] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.

[0274] The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose quantity of the active ingredient as defined above.

[0275] It will be appreciated that, in addition to the ingredients particularly mentioned above, the formulations of the application can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavouring agents.

[0276] The present application further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier.

[0277] Veterinary carriers are materials which can be used to administer a composition and can be solid, liquid or gaseous materials which are otherwise inert and nontoxic to animals and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

[0278] The compounds of the present application are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present application as active ingredients, wherein the release of the active ingredients is controlled and regulated to allow less frequent dosaging or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0279] VI. ADMINISTRATION

[0280] Also provided are kits comprising a compound disclosed herein (e.g., a compound of Formula I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc), a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. In some embodiments, the kits described herein can comprise a label and / or instructions for using the compound to treat a disease or disorder in a subject (e.g., a human) in need thereof. In some embodiments, the disease or disorder is a viral infection.

[0281] In some embodiments, the kits can also comprise one or more additional therapeutic agents and / or instructions for using the additional therapeutic agent(s) in combination with the compound of Formula I to treat a disease or disorder in a subject (e.g., a human) in need thereof.

[0282] In some embodiments, the kits provided herein comprise individual dosage units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units can include pills, tablets, capsules, pre-filled syringes or cartridges for an injection device, IV bags, inhalers, nebulizers, etc., each of which includes a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kits can contain a single dosage unit, and in other embodiments there are multiple dosage units, e.g., the number of dosage units required for a specified regimen or cycle.

[0283] Also provided are articles of manufacture comprising: a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampoule, pre-filled syringe, blister pack, can, flask, bottle, box, intravenous bag, inhaler, or nebulizer.

[0284] VII. METHODS OF USE

[0285] The compound(s) of the application are administered by any route appropriate to the condition to be treated, according to the appropriate route of administration. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. It will be appreciated that the preferred route can vary with, for example, the condition of the recipient.

[0286] In the methods of the application for treating viral infections, the compounds of the application can be administered to a person who can be exposed to a virus or who already has a viral infection at any time. In some embodiments, the compounds of the application can be administered prophylactically to a person who is in contact with or at risk of being in contact with a person who has a viral infection, for example, a health care provider. In some embodiments, administration of the compounds of the application can be to a person who tests positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compounds of the application can be administered to a person at the onset of symptoms of a viral infection.

[0287] In some embodiments, the methods disclosed herein comprise event- driven administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject.

[0288] As used herein, the term “event-driven” or “event-driven administration” means that a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered (1) prior to an event that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection), for example, 2 hours, 1 day, 2 days, 5 days, or 7 days or more days prior to the event; and / or (2) during an event (or more than one repeated event) that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection); and / or (3) after an event (or after the final event in a series of repeated events) that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection). In some embodiments, event-driven administration occurs prior to exposure of the subject to a virus. In some embodiments, event-driven administration occurs after exposure of the subject to a virus. In some embodiments, event-driven administration occurs both prior to and after exposure of the subject to a virus.

[0289] In certain embodiments, the methods disclosed herein involve administration prior to and / or after an event that will expose an individual to a virus or otherwise increase the risk of the individual acquiring a viral infection, for example, as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein comprise post-exposure prophylaxis (PEP).

[0290] In some embodiments, the compound of Formula I, or pharmaceutically acceptable salt thereof, is administered prior to exposure of the subject to the virus.

[0291] In some embodiments, the compound of Formula I, or pharmaceutically acceptable salt thereof, is administered prior to and after exposure of the subject to the virus.

[0292] In some embodiments, the compound of Formula I, or pharmaceutically acceptable salt thereof, is administered after exposure of the subject to the virus.

[0293] An example of an event-driven dosing regimen includes administration of the compound of Formula I, or pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to the virus, followed by administration of the compound of Formula I, or pharmaceutically acceptable salt thereof, every 24 hours during exposure, followed by further administration of the compound of Formula I, or pharmaceutically acceptable salt thereof, after the last exposure, and a last administration of the compound of Formula I, or pharmaceutically acceptable salt thereof, 24 hours later.

[0294] Another example of an event-driven dosing regimen includes administration of the compound of Formula I, or pharmaceutically acceptable salt thereof, within 24 hours prior to virus exposure, then daily during exposure, then a last administration about 24 hours after the last exposure (which can be an increased dose, such as a double dose).

[0295] The effective dosage of active ingredients depends on the nature of the condition being treated, the toxicity, whether the compound is used preventatively or to combat an active viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies. The dosage can be expected to be from about 0.0001 to about 100 mg / kg body weight per day; typically, from about 0.01 to about 10 mg / kg body weight per day; more typically, from about 0.01 to about 5 mg / kg body weight per day; most typically, from about 0.05 to about 0.5 mg / kg body weight per day. For example, a daily candidate dosage for an adult human of about 70 kg would range from 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and can be given in single or divided doses.

[0296] Any suitable period of time for administering the compounds of the present application is contemplated. For example, administration can be for 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also be for 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer periods of administration are also contemplated.

[0297] In some embodiments, a compound disclosed herein is administered once daily. In some embodiments, a compound disclosed herein is administered once every other day. In some embodiments, a compound disclosed herein is administered once a week. In some embodiments, a compound disclosed herein is administered twice a week.

[0298] In some embodiments, one or more compounds disclosed herein are administered once a day. The once daily dose can be administered for as long as needed, for example, for up to 5 days, for up to 7 days, for up to 10 days, for up to 15 days, for up to 20 days, for up to 25 days, for up to one month, or longer. In some embodiments, the once daily dose is administered for up to 20 days, for up to 15 days, for up to 14 days, for up to 13 days, for up to 12 days, for up to 10 days, for up to 8 days, for up to 6 days, for up to 4 days, for up to 3 days, for up to 2 days, or for 1 day.

[0299] In some embodiments, one or more compounds disclosed herein are administered once a day for about 6 days to 12 days, for example, for about 8 days to 10 days. In some embodiments, the one or more compounds are administered once a day for about 9 days. In some embodiments, the one or more compounds are administered once a day for about 10 days. In some embodiments, about 50 mg to 150 mg of one or more compounds disclosed herein are administered once a day for about 5 to 12 days, for example, for about 10 days. In some embodiments, about 100 mg of one or more compounds disclosed herein are administered once a day for about 5-12 days, for example, for about 10 days.

[0300] VIII. COMBINATION THERAPIES

[0301] The present disclosure also provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0302] In some embodiments, the present disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0303] In some embodiments, the present disclosure provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0304] In some embodiments, the present disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0305] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a compound disclosed herein, whereby viral polymerase is inhibited.

[0306] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a compound disclosed herein and at least one additional active therapeutic agent, whereby viral polymerase is inhibited.

[0307] Also provided herein are uses of a compound disclosed herein for treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of a compound disclosed herein for treating a viral infection in a subject in need thereof.

[0308] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the disclosure provides methods for treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, a Nipah virus, a Hendra virus, a measles virus, a mumps virus, and a parainfluenza virus.

[0309] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the disclosure provides methods of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, a respiratory syncytial virus and a human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0310] In some embodiments, the disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0311] In some embodiments, the disclosure provides methods for treating an RSV infection in a human in need thereof, the method comprising administering to the human a compound provided herein. In some embodiments, the human has a chronic respiratory syncytial virus infection. In some embodiments, the human has an acute RSV infection.

[0312] In some embodiments, methods of inhibiting RSV replication are provided, wherein the method comprises administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0313] In some embodiments, the present disclosure provides a method for reducing viral load associated with RSV infection, wherein the method comprises administering to a human infected with RSV a compound disclosed herein.

[0314] In some embodiments, the viral infection is a picornaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound of the present disclosure. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic myalgia (an acute, febrile, infectious illness that occurs in epidemics), hand-foot-and-mouth syndrome, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the picornaviridae virus infection is a human rhinovirus infection.

[0315] In some embodiments, the present disclosure provides a compound for use in treating a picornaviridae virus infection in a human in need thereof. In some embodiments, the picornaviridae virus infection is a human rhinovirus infection.

[0316] In some embodiments, the viral infection is a flaviviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is a dengue fever virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a Zika virus infection. In some embodiments, the flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection.

[0317] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a flaviviridae virus infection in a human in need thereof. In some embodiments, the flaviviridae virus infection is a dengue fever virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a Zika virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection.

[0318] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, provided herein are methods of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (variant Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0319] In some embodiments, the present disclosure provides compounds for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0320] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a compound provided herein. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection.

[0321] In some embodiments, the present disclosure provides compounds for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0322] In some embodiments, the viral infection is an arenavirus infection. Accordingly, in some embodiments, the disclosure provides methods of treating an arenavirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0323] In some embodiments, the disclosure provides compounds for use in treating an arenavirus infection in a human in need thereof. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0324] In some embodiments, the viral infection is an orthomyxovirus infection, e.g., an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0325] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus along with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected individual simultaneously with, or prior to, or subsequent to, administration of the compounds of the disclosure.

[0326] 1. Combination therapies for the treatment of the family of pneumoviridae

[0327] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein are methods of treating a viral infection in a subject in need thereof, wherein the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents.

[0328] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0329] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0330] In some embodiments, the additional therapeutic agent is a nucleoside analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, beta-D-N4-hydroxycytidine, or combinations thereof.

[0331] In some embodiments, the additional therapeutic agent is a pyrophosphate analogue. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0332] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0333] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0334] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, ribavirin, danoprevir, fidaprevir, velpatasvir, sovaprevir, deldeprefir, and narlaprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, and combinations thereof.

[0335] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0336] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fosdevirine, leronlimab, ibalizumab, fosdevirine, leronlimab, palivizumab, Respiratory Syncytial Virus Immune Globulin [RSV-IGIV], Varicella-Zoster Immune Globulin [VariZIG], Varicella-Zoster Immune Globulin [VZIG]), and combinations thereof.

[0337] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0338] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, lifamavirin, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof.

[0339] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protease inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide type of NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside type of NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0340] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, ribavirin, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirumab, laninamivir octanoate, zanamivir, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0341] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, peginterferon alfacon 1, peginterferon alfa 1b, peginterferon alfa 2a (PegIFN alpha-2a), and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2a (PegIFN alpha-2a), and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, peginterferon alfa 2a (PegIFN alpha-2a), PegIFN alpha-2b, and ribavirin. In some embodiments, the additional therapeutic agent is peginterferon alfa-2a, peginterferon alfa-2b, or a combination thereof.

[0342] In some embodiments, the additional therapeutic agent is an immune stimulator. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: formivirsen, pudafitlox, imiquimod, resiquimod, and a combination thereof.

[0343] In some embodiments, the additional therapeutic agent is selected from the group consisting of: becespofavir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and a combination thereof.

[0344] In some embodiments, the additional therapeutic agent is an agent for treating RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or predfivir. For example, in some embodiments, the antiviral agent is ALS-8112 or predfivir.

[0345] In some embodiments, the additional therapeutic agent is an agent for treating picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of: hydantoin, guanidine hydrochloride, L-methionine sulfoximine, Py-11, and a combination thereof. In some embodiments, the additional therapeutic agent is a picornaviral polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0346] In some embodiments, the additional therapeutic agent is an agent for treating malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0347] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, chloroguanide, tafenoquine, pyronaridine, artesunate, dihydroartemisinin, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, ethylpyrimidine, MMV-390048, ferroquine, artemisinin methanesulfonate, ganaplacide, DSM-265, cepidame, artemotil, and combinations thereof.

[0348] In some embodiments, the additional therapeutic agent is an agent for treating a coronavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, bavituximab, nafamostat, LB-2, AM-1, anti-viral pore protein, and combinations thereof.

[0349] In some embodiments, the additional therapeutic agent is an agent for treating an Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, ZMab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3- (dimethylamino)propyl]-3,9-dimethylquinoline[8,7-h]quinolin-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenoviral vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0350] In some embodiments, the additional therapeutic agent is an agent for treating HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, veldolsevir, voxilaprevir, and combinations thereof.

[0351] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0352] In some embodiments, the additional therapeutic agent is an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine or a combination thereof. Examples of additional anti-HBV agents include, but are not limited to, a-hydroxytopiketone, amdoxovir, andrographolide, b-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicroside (gentiopicroside), HH-003, heprapide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotide, mivitript, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, carotene, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014--01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as the compounds disclosed in US20150210682 (Roche), US2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir emtricitabine Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir Entecavir maleate, telbivudine Felosivir, Pradefovir, Clavudine, Ribavirin, Lamivudine Azidoxime, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. In some implementations, the additional treatment agent is an HBV capsid inhibitor.

[0353] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent used to treat HIV. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0354] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0355] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0356] In some embodiments, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Bictegravir, Emtricitabine, and Tenofovir alafenamide); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Tenofovir disoproxil fumarate and Emtricitabine; TDF + FTC); (Tenofovir alafenamide and Emtricitabine); (Tenofovir alafenamide, Emtricitabine, and Rilpivirine); (Tenofovir alafenamide, Emtricitabine, Cobistat, and Etravirine); (Darunavir, Tenofovir alafenamide hemifumarate, Emtricitabine, and Cobistat); SYMFI TM (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); CIMDU TM (Lamivudine and Tenofovir disoproxil fumarate); Tenofovir and Lamivudine; Tenofovir alafenamide and Emtricitabine; Tenofovir alafenamide hemifumarate and Emtricitabine; Tenofovir alafenamide hemifumarate, Emtricitabine, and Rilpivirine; Tenofovir alafenamide hemifumarate, Emtricitabine, Cobistat, and Etravirine; (Zidovudine and Lamivudine; AZT + 3TC); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Abacavir sulfate and Lamivudine; ABC + 3TC); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Lopinavir and Ritonavir); (Dolutegravir, Abacavir, and Lamivudine); (abcam, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil fumarate; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, efavirenz + emtricitabine + tenofovir disoproxil fumarate, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine.

[0357] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some embodiments, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0358] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, elvitegravir, curcumin, a derivative of curcumin, chlorogenic acid, a derivative of chlorogenic acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurogygones tricarboxylic acid, a derivative of aurogygones tricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0359] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Additional examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adatatribe (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0360] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0361] In some embodiments, the additional therapeutic agent is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (ddl), abacavir, abacavir sulfate, alovudine, alitaskin, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, eduvirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rofavirine-ethavirine amide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0362] In some embodiments, the additional therapeutic agent is an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, eduvirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, efavirenz rilp (VM-1500), and combinations thereof.

[0363] In some embodiments, the additional therapeutic agent is selected from (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (etravirine, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); (Tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (Dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( Lopinavir and ritonavir); (Zidovudine and lamivudine; AZT + 3TC); ( Abacavir sulfate and lamivudine; ABC + 3TC); (Abaca vir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; pritelivir; fosamprenavir; fosamprenavir calcium efavirenz; efcavirenz; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0364] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, ibutilide, betahistine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, dexzopiclone, and zopiclone.

[0365] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton’s tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4- phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvatirine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor A9 (A9).

[0366] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0367] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0368] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, an anti-RSV human monoclonal antibody REGN2222, palivizumab, respiratory syncytial virus immune globulin, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, (i) an influenza A monovalent vaccine (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) an influenza A and B trivalent vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) an influenza A and B quadrivalent vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., Adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9 and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., M-M-R II and ProQuad).In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a smallpox virus (variola) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0369] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an anti-2019-nCov antibody selected from the group consisting of: a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting SARS-CoV-2 spike protein, an antibody that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is a PD-1 antibody.

[0370] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0371] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0372] In some embodiments, the additional therapeutic agent is selected from the group consisting of: lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, delaviradine, and combivir, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0373] In some embodiments, the additional therapeutic agent is selected from the group consisting of 6'-fluorinated mannoquin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogs, pyrithioxate derivatives, pannatin and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]decane-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, ala- porevir, imatinib mesylate, dasatinib, semetinib, trametinib, rapamycin, serabtinib, chloφromazine, triflurpromazine, fluphenazine, thioridazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof.

[0374] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a 2019-nCoV viral antibody.

[0375] The compositions of the present application are also used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably, the other active therapeutic agent has activity against coronavirus infection, e.g., activity against 2019-nCoV viral infection. The compounds and compositions of the present application are also intended for use in the general care of patients with 2019-nCoV viral infection, including parenteral fluids (including dextrose saline and Ringer’s lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory drugs (e.g., interferons), other small molecule or biologic antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in the patient population, such as anti-malarial agents (including artemether and artemisinin-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine.

[0376] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; hydroxychloroquine (Plaquenil); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethylenimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, Novilun, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent refers to fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0377] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example, tocilizumab, sarilumab, or a combination thereof.

[0378] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0379] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, baricinib, or a combination thereof.

[0380] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example, pirfenidone.

[0381] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia. For example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0382] In some embodiments, the compounds disclosed herein are used in combination with standard of care for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment will depend on several factors, including the type and severity of the pneumonia, the age and overall health of the individual. Options include: (i) antibiotics, (ii) cough medicine, and (iii) fever / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0383] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from convalescing COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0384] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, visamminode (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod. RO-7020531.

[0385] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurizan, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, serazide, clevidipine, atorvastatin, cinoxolone, clofazimine, fosaprepitant, and combinations thereof.

[0386] In some embodiments, the additional therapeutic agent is coleimycin, suramin, triazirine, dipyridamole, bevacizumab, mepolizumab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0387] In some embodiments, the additional therapeutic agent is an antiviral porin therapeutic. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Additional examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0388] Any of the compounds of the present application can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0389] Co-administration of a compound of the present application with one or more other active therapeutic agents generally refers to administration of a compound of the present application and one or more other active therapeutic agents simultaneously, or sequentially, such that a therapeutically effective amount of both the compound of the present application and the one or more other active therapeutic agents are present in the patient's body.

[0390] Co-administration includes administration of a unit dose of a compound of the present application prior to or following administration of a unit dose of one or more other active therapeutic agents, for example, within seconds, minutes, or hours of administration of the one or more other active therapeutic agents. For example, a unit dose of a compound of the present application can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the present application. In some cases, it can be desirable to administer a unit dose of a compound of the present application first, followed by administration of a unit dose of one or more other active therapeutic agents several hours (e.g., 1-12 hours) later. In other cases, it can be desirable to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of a compound of the present application several hours (e.g., 1-12 hours) later.

[0391] Combination therapy can provide "synergy" and "potentiation" such that the effect of the active ingredients when used together is greater than the sum of the effects of the compounds when given alone. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be attained when the compounds are administered or delivered e.g. hours, days or weeks apart but often enough to constitute one treatment cycle, and the treatment cycles are repeated e.g. 2, 3, 4, 5 or 6 times or until disease progression has stalled or ceased. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together in closely controlled proportions. A synergistic antiviral effect means that the antiviral effect is greater than the predicted purely additive effect of the compounds in the combination.

[0392] 2. Combination therapies for the treatment of the family of picornaviridae

[0393] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, preferably the other active therapeutic agent has activity against Pneumoviridae virus infections, in particular respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents with activity against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include inhibitors of respiratory syncytial virus protein F, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and pritelivir; RNA polymerase inhibitors, such as lumicitabine and ALS-8112; anti-RSV G protein antibodies, such as anti-G protein mAbs; viral replication inhibitors, such as nitazoxanide.

[0394] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0395] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181; RNA polymerase inhibitors such as ALS-8112; and antibodies for treating metapneumovirus infection such as EV-046113.

[0396] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccine.

[0397] 3. Combination therapies for respiratory infections

[0398] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infection, preferably the other active therapeutic agent has activity against Picornaviridae virus infection, in particular enterovirus infection. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0399] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing Picornaviridae virus infection, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adenoviral vector-based vaccine.

[0400] Glucocorticoids

[0401] Many infections of Pneumoviridae and Picornaviridae viruses are respiratory tract infections. Thus, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional therapeutic agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for treating viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids.

[0402] Anti-inflammatory agents

[0403] Glucocorticoids, first introduced as a therapy for asthma in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most effective and consistently effective therapy for this disease, but their mechanism of action is not fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10thEdition, 2001). A solution to the systemic side effects is to deliver the steroid drug directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to reduce the serious side effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol etabonate, loteprednol etabonate ophthalmic solution, hydrocortisone, prednisolone, flurandrenolide, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone acetonide, fluocinolone acetonide acetate, flunisolide, fluocinbutte-21 -butylate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or a pharmaceutically acceptable salt thereof.

[0404] Beta2-adrenergic receptor agonist bronchodilators

[0405] Other anti-inflammatory agents that act through anti-inflammatory cascades can also be used as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. The use of "anti-inflammatory signal transduction modulators" (referred to herein as AISTMs) such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., block NFκB through IKK inhibition), or kinase inhibitors (e.g., block P38 MAP, JNK, PI3K, EGFR, or Syk) is a logical approach to cut off inflammation because these small molecules target a limited number of common intracellular pathways (these signal transduction pathways are the key points for anti-inflammatory therapeutic intervention) (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-l-isobutyl-lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-difluoromethoxy-8-[(methylsulfonyl)amino]-l-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-l-oxo-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0406] Anticholinergic agents

[0407] Combinations comprising inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol, salbutamol or salmeterol in combination with the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0408] Combinations of inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol or salmeterol in combination with ICS are also used to treat bronchoconstriction and inflammation (respectively and ). Combinations comprising these ICS and beta2-adrenergic receptor agonist combinations in combination with the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0409] Other examples of beta2-adrenergic receptor agonists are bevonol, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0410] Mucolytic agents

[0411] Anticholinergic agents have potential use for the treatment or prevention of bronchoconstriction in the lungs and thus can be used in combination with the compounds provided herein as an additional therapeutic agent for the treatment of viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype) that have proven therapeutic efficacy in humans for the control of cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}- pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino- acetyloxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonio-bicyclo[3.2.1]octane (isopropylamine-N,N-diethylglycine); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solfenazin); 2-hydroxymethyl-4-methane-sulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin); 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide); 7-[3-(2-diethylamino-acetyloxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycine); 7-[2-(2-diethylamino-acetyloxy)-2,2-di-thiophen-2-yl-acetyloxy]-9,9-dimethyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N- dimethylglycine); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)- pyrrolidinium; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]-4,4-bis-(4-fluorophenyl)-imidazolidin-2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetyloxy)-2,2-dithiophen-2-yl-acetyloxy]-1-(3-phenoxy-propyl)-1-azonio- bicyclo[2.2.2]octane (atropine-N,N-diethylglycine); or (2-diethylamino-acetyloxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; rafenamin, glycopyrronium, umclidinium, tiotropium, aclidinium, benzquinonium.

[0412] 4. Combination therapies for the treatment of flaviviridae viral infections

[0413] The compounds provided herein can also be combined with mucolytic agents to treat infections and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat infections and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0414] Aerosolized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung disease (Kuzik, Pediatrics 2007, 266). Accordingly, the compounds provided herein can also be combined with aerosolized hypertonic saline, particularly when the viral infection is complicated by bronchiolitis. The combination of the compounds provided herein with hypertonic saline can also include any of the additional agents discussed above. In one embodiment, aerosolized about 3% hypertonic saline is used.

[0415] 5. Combination therapies for the treatment of filoviridae viral infections

[0416] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae viral infections, preferably the other active therapeutic agent has activity against Flaviviridae viral infections.

[0417] For the treatment of dengue viral infections, non-limiting examples of other active therapeutic agents are host cytokine modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor la modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0418] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2delta30-7169, and DENV-1 PIV.

[0419] IX. PREPARATION OF COMPOUNDS

[0420] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae virus infections, preferably the other active therapeutic agents have activity against Filoviridae virus infections, in particular Marburg virus, Ebola virus, and Quelea virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolo[8,7-h]quinolin-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as Galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators such as GMV-006; Cadherin-5 / Factor la modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0421] Non-limiting active therapeutic agents with activity against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick Cl protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0422] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing Ebola, including but not limited to VRC-EBOADC076-00-VP, an adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0423] The compounds provided herein can also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process by forming base-paired duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0424] The compounds provided herein are also intended for use with the general care provided to patients infected with an Orthomyxoviridae virus, including parenteral fluids (including dextrose saline and Ringer’s lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common ailments in the patient population, such as anti-malarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines.

[0425] General Synthetic Procedure

[0426] In some embodiments, the present disclosure provides methods and intermediates useful for making the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0427] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase as well as ion resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0428] During any of the processes for preparation of the compounds provided herein, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 4th edition, Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known from the art.

[0429] Exemplary chemical entities of the methods useful in embodiments will now be described by reference to illustrative synthetic schemes of the general preparations herein and the specific examples below. The skilled person will recognize that, in order to obtain the various compounds herein, the starting materials can be appropriately chosen such that the reaction scheme, with or without protection as appropriate, will carry the ultimately desired substituents to yield the desired product. Alternatively, it can be necessary or desirable to employ suitable groups in place of the ultimate desired substituents, which suitable groups can be carried through the reaction scheme and replaced with the desired substituents as appropriate. Furthermore, the skilled person will recognize that the transformations shown in the schemes below can be performed in any order that is compatible with the functionality of the particular side groups.

[0430] The methods of the present disclosure generally provide a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that particular stereocenter, even though the compound can be substantially enantiomerically or diastereomerically pure.

[0431] Representative syntheses of compounds of the present disclosure are described in the following schemes and in the specific examples below.

[0432] Reaction Scheme I

[0433] General reaction schemes I, II, and III are provided as additional embodiments of the present disclosure and illustrate general methods for preparing certain compounds of the present disclosure and can be used to prepare additional compounds of the present disclosure. Each variable of formulae (i)-(xiv) (e.g., R 1 , R 2 , R 3AR 3B R 4 R 5 ) as defined herein.

[0434] The compounds of the present disclosure can be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent to the skilled artisan in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, routine and well-known synthetic methods can be used. Synthesis of typical compounds described herein can be achieved as described in the following examples. Reagents can be purchased from the market, if available, for example from Sigma Aldrich or other chemical suppliers. Generally, the compounds described herein are typically stable and isolable at room temperature and pressure. Compounds prepared herein can be purified using methods known to one of ordinary skill in the art, including those described herein. The skilled artisan will appreciate that when an acid, for example TFA, is present in the purification solvent, then the final product can be isolated as a salt, for example a TFA salt.

[0435] Typical embodiments of the compounds disclosed herein can be synthesized using the general reaction schemes described below. It will be apparent to the skilled artisan, in light of the description herein, that the general schemes can be altered by substituting the starting materials with other materials having analogous structures to produce a corresponding different product. The description of the synthesis that follows provides many examples of how the starting materials can be varied to provide the corresponding product. In light of the desired product defining the substituent groups, the necessary starting materials can often be determined by inspection. The starting materials are often obtained from commercial sources or synthesized using published methods. For synthesizing the compounds of the embodiments disclosed in the present disclosure, an inspection of the structure of the compound to be synthesized will provide the identification of each of the substituent groups. In light of the examples herein, the identification of the starting materials will often be apparent from the identification of the final product by a simple inspection process.

[0436] The term "solvent," "inert organic solvent," or "inert solvent" means a solvent that is inert under the reaction conditions described in connection therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.

[0437] Reaction Scheme II :

[0438] Exemplary compounds of Formula I, Formula la, and Formula lb can be prepared using methods analogous to Reaction Scheme I shown below.

[0439]

[0440] In the presence of a base (e.g., N,N-diisopropylethylamine), in a suitable solvent (e.g., dichloromethane), at a suitable temperature (e.g., -78 °C to room temperature), phenol (iii) and phosphorus oxychloride (V) are mixed. Once the reaction is complete, the natural or unnatural amino acid ester (ii) is added with a suitable base at a suitable temperature (e.g., -78 °C). After the reaction, pentafluorophenol and a suitable base are added to generate the phosphoramidate reagent. Alternatively, the natural or unnatural amino acid ester (ii) is reacted with phenyl dichlorophosphate in the presence of a suitable base (e.g., triethylamine) at a suitable temperature (e.g., -78 °C to room temperature). Once the reaction is complete, pentafluorophenol and a suitable base are added to form the phosphoramidate reagent. The phosphoramidate reagent can be purified using any suitable method, e.g., chromatography (e.g., HPLC).

[0441] Nucleoside (i) is converted to (iv) by adding the phosphoramidate reagent as described above to (i) in a suitable solvent (e.g., acetonitrile), followed by the addition of magnesium chloride and a base (e.g., N,N-diisopropylamine). The reaction is carried out at any suitable temperature (e.g., 0 °C to room temperature). Intermediate (iv) is then treated with an acid (e.g., HC1) to give the phosphoramidate nucleoside (v). Separation of isomers at the phosphorus can be carried out using HPLC, chiral HPLC methods, or other suitable methods.

[0442] Intermediate (v) is treated with an acid anhydride (e.g., isobutyric anhydride, acetic anhydride, or propionic anhydride, etc.) in the presence of a suitable base (e.g., 4-dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) to form compound (viii). Compounds (viiia) and (viiib) can then be separated using a suitable method, e.g., chiral chromatography other chromatography such as HPLC.

[0443] Reaction Scheme III :

[0444] Exemplary compounds of Formula III, Formula Ilia, and Formula Illb can be prepared using methods analogous to Reaction Scheme II shown below.

[0445]

[0446] Reaction Scheme II follows the same general methods as described for Reaction Scheme 1, except that the amino acid ester is a D or L alanine amino acid ester or a mixture of D or L alanine amino acid esters.

[0447] X. EXAMPLES :

[0448] Exemplary compounds of Formula IIIc can be prepared using methods analogous to Reaction Scheme III shown below.

[0449]

[0450] This protocol follows the same general procedure as described for Reaction Scheme I except that the amino acid ester is L-alanine amino acid ester.

[0451] Intermediate

[0452] Exemplary chemical entities of the present disclosure are provided in the following specific examples. Those skilled in the art will recognize that, in order to obtain the various compounds herein, starting materials can be appropriately selected such that the final desired substituents will be in place, as appropriate, in a reaction scheme to yield the desired product, either with or without protection of a given functionality. Alternatively, it can be necessary or desirable to employ suitable protecting groups for a given functionality in order to synthesize the final desired compound. The protecting groups can be removed at a convenient subsequent point in accordance with established practices. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular side groups.

[0453] The examples provided herein describe the synthesis of the compounds disclosed herein as well as intermediates used to prepare these compounds. It will be appreciated that individual steps described herein can be combined. It will also be appreciated that individual batches of compounds can be combined prior to proceeding to the next synthetic step.

[0454] In the following example description, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other embodiments can be utilized and logical and other changes can be made without departing from the scope of the disclosure. The following description is, therefore, not to be taken in a limiting sense.

[0455] Intermediate A1: (2S)-2-[[(4-tert-Butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid :

[0456] 2-ethylbutyl ester Intermediate B1. (2S)-2-[[(4-tert-Butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid methyl ester

[0457]

[0458] To a solution of phosphorus oxychloride (V) (5.00 g, 32.6 mmol) in dichloromethane (80 mL) was added 4-tert-butylphenol (4.90 g, 32.6 mmol) at -78 °C under an atmosphere of argon. N,N-diisopropylethylamine (5.68 mL, 32.6 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to 0 °C. After 15 minutes, the reaction was cooled to -78 °C. (2S)-2-aminopropanoic acid 2-ethyl butyl ester hydrochloride (6.84 g, 32.6 mmol) was added. N,N-diisopropylethylamine (11.4 mL, 65.2 mmol) was added over 5 minutes. After 30 minutes, 2,3,4,5,6-pentafluorophenol (6.0 g, 32.6 mmol) was added. N,N-diisopropylethylamine (5.68 mL, 32.6 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was acidified with acetic acid (5 mL). The reaction was washed with water (50 mL). The organics were dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give Intermediate Al. LCMS: MS m / z = 551.8 [M+1], t R = 1.39 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, DMSO-d6) d (1:1 mixture of diastereomers) 7.44 - 7.39 (m, 2H), 7.22 - 7.11 (m, 2H), 6.96 - 6.81 (m, 1H), 4.09 - 3.91 (m, 3H), 1.54 - 1.40 (m, 1H), 1.36 - 1.22 (m, 16H), 0.90 - 0.77 (m, 6H). 31 P NMR (162 MHz, DMSO-d6) d 0.82 - 0.49 (m). 19 F NMR (376 MHz, DMSO-d6) d -153.93 - -154.64 (m, 2F), -160.57 - -161.18 (m, 1F), -163.37 - -163.90 (m, 2F).

[0459] Intermediate C1. (2S)-2-[[(4-tert-Butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid ethyl ester Intermediate D1. (2S)-2-[[(2,6-Dimethylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid 2-ethylbutyl ester

[0460]

[0461] Intermediate B1 was prepared in a similar manner to Intermediate Al, except that (2S)-2-aminopropanoic acid methyl ester hydrochloride was used instead of (2S)-2-aminopropanoic acid 2-ethylbutyl ester hydrochloride. LCMS: MS m / z = 481.8 and 481.8 [M+1], t R = 1.23 and 1.29 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u Cl 8 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, DMSO-d6) d (1:1 mixture of diastereomers) 7.45 - 7.40 (m, 2H), 7.23 - 7.11 (m, 2H), 6.96 - 6.84 (m, 1H), 4.08 - 3.94 (m, 1H), 3.61 - 3.58 (m, 3H) 1.34 - 1.23 (m, 12H). 31 P NMR (162 MHz, DMSO-d6) d 5.67 - 3.80 (m). 19 F NMR (376 MHz, DMSO-d6) d -154.04 - -154.40 (m, 2F), -160.57 - -160.99 (m, 1F), -163.41 - -163.87 (m, 2F).

[0462] Intermediate E1. L-alanine spiro[3.3]heptan-2-yl ester hydrochloride Intermediate E2. (2S)-2-[[(4-tert-Butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid spiro[3.3]heptan-2-yl ester

[0463]

[0464] Intermediate C1 was prepared in a similar manner to Intermediate Al, except that (2S)-2-aminopropanoic acid ethyl ester hydrochloride was used instead of (2S)-2-aminopropanoic acid 2-ethylbutyl ester hydrochloride. LCMS: MS m / z = 495.8 and 495.8 [M+1], t R= 1.23 and 1.20 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, DMSO-d6) d (1 : 1 mixture of diastereomers) 7.47 - 7.38 (m, 2H), 7.21 - 7.11 (m, 2H), 6.93 - 6.81 (m, 1H), 4.10 - 4.02 (m, 2H), 4.00 - 3.90 (m, 1H), 1.32 - 1.24 (m, 12H), 1.19 - 1.11 (m, 3H). 31 P NMR (162 MHz, DMSO-d6) d 0.98 - 0.49 (m). 19 F NMR (376 MHz, DMSO-d6) d -153.96 - -154.41 (m, 2F), -160.63 - -160.98 (m, 1F), -163.35 - -163.82 (m, 2F).

[0465] Intermediate G1. (tert-Butoxycarbonyl)-L-alanine 2-(2-ethoxyethoxy)ethyl ester Intermediate G2. ((Perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine 2-(2-ethoxyethoxy)ethyl ester

[0466]

[0467] Intermediate D1 was prepared in a similar manner to Intermediate Al, except 2,6-dimethylphenol was used instead of 4-tert-butylphenol (43% yield). LCMS: MS m / z = 523.8 [M+1], t R = 1.29 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, DMSO-d6) δ (1 : 1 mixture of diastereomers) 6.97 - 6.89 (m, 2H), 6.86 - 6.76 (m, 1H), 4.15 - 4.07 (m, 1H), 4.05 - 3.91 (m, 2H), 1.55 - 1.44 (m, 1H), 1.38 - 1.20 (m, 7H), 0.91 - 0.80 (m, 6H). 31 P NMR (162 MHz, DMSO-d6) δ -4.16 - -4.87 (m). 19 F NMR (376 MHz, DMSO-d6) δ -163.11 - -163.56 (m, 2F), -166.91 - -167.32 (m, 2F), -175.35 - -176.22 (m 1F).

[0468] Intermediate H1. (tert-Butoxycarbonyl)-L-alanine 2-methoxy-2-methylpropyl ester

[0469]

[0470] To a stirred solution of (tert-butoxycarbonyl)-L-alanine (2.5 g, 13.2 mmol) and spiro[3.3]heptan-2-ol (1.48 g, 13.2 mmol) in dry dichloromethane (35 mL) at 0 °C under an argon atmosphere was added N-methylmorpholine (2.9 mL, 26.4 mmol), 4-(dimethylamino)pyridine (0.016 g, 0.13 mmol) and tripropyl phosphine acid cyclizing anhydride (T3P, 10.3 g, 16.1 mmol, 50% in ethyl acetate). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with water (50 mL), washed twice with 10% citric acid solution (2 x 40 mL), washed twice with saturated aqueous sodium bicarbonate solution (2 x 40 mL) and once with brine (50 mL), dried over sodium sulfate, filtered through a 3 cm silica gel plug which was washed with additional dichloromethane. The combined organics were concentrated under reduced pressure, co-distilled with dichloromethane and dried under high vacuum overnight to give the title compound. The residue was used without further purification.

[0471] The residue was then dissolved in 10 mL of a 4M HCI solution in 1,4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, co-distilled with toluene to give the product which was dried under high vacuum for 1 hour. The residue was used without further purification. LCMS: MS m / z = 184.1 [M+1]

[0472] Intermediate H2. ((Perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine 2-methoxy-2-methylpropyl ester Example

[0473]

[0474] To a solution of phosphorus oxychloride (V) (0.33 g, 2.16 mmol) in dichloromethane (8 mL) was added 4-tert-butylphenol (0.325 g, 2.16 mmol) at -78 °C under an argon atmosphere. N,N- Diisopropylethylamine (0.38 mL, 2.16 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to 0 °C. After 15 minutes, the reaction was cooled to -78 °C. (2S)-2-Aminopropanoic acid spiro[3.3]heptan-2-yl ester hydrochloride (0.475 g, 2.16 mmol) was added. N,N- Diisopropylethylamine (0.75 mL, 4.32 mmol) was added over 5 minutes. After 30 minutes, 2,3,4,5,6-pentafluorophenol (0.40 g, 2.16 mmol) was added. N,N- Diisopropylethylamine (0.38 mL, 2.16 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was acidified with acetic acid (3 mL). The reaction was washed with water (50 mL). The organics were dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid spiro[3.3]heptan-2-yl ester. LCMS: MS m / z = 562.5 [M+1]; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid.

[0475] Example 1: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((((S)-(((S)-1-(2- ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0476]

[0477] To a stirred solution of (tert-butoxycarbonyl)-L-alanine (12.41 g, 66 mmol) and 2-(2-ethoxyethoxy)ethan-1-ol (8.00 g, 60 mmol) in anhydrous dichloromethane (100 mL) at 0 °C under an argon atmosphere was added N-methylmorpholine (19.67 mL, 179 mmol), 4-(dimethylamino)pyridine (0.15 g, 1.2 mmol) and tripropyl phosphine acid cyclizing anhydride (T3P, 42.6 mL, 72 mmol, 50% in ethyl acetate). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with water (50 mL), washed twice with 10% citric acid solution (2 x 40 mL), washed twice with saturated aqueous sodium bicarbonate solution (2 x 40 mL) and once with brine (50 mL), dried over sodium sulfate, filtered through a 3 cm silica gel plug which was washed with additional dichloromethane. The combined organics were concentrated under reduced pressure, co-distilled with dichloromethane and dried under high vacuum overnight to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 7.4 Hz, 1H), 4.23 - 4.14 (m, 1H), 4.14 - 4.06 (m, 1H), 4.05 - 3.94 (m, 1H), 3.64 - 3.56 (m, 2H), 3.55 - 3.49 (m, 2H), 3.49 - 3.39 (m, 4H), 1.38 (s, 9H), 1.23 (d, J = 7.4 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H).

[0478] Example 2: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((((S)-(((S)-1-(2- ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0479]

[0480] Intermediate G1 (18.3 g, 59.93 mmol) was dissolved in 50 mL of 4M HCI in 1,4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, co-distilled with toluene, to give a solidified solid which was dried under high vacuum for 1 hour. The solid was suspended in dichloromethane (100 mL) and at -78°C phenyldichlorophosphine (9.81 mL, 65.92 mmol) and triethylamine (18.28 mL, 131.84 mmol) were added sequentially and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C and then pentafluorophenol (11.03 g, 59.93 mmol) and triethylamine (10.80 mL, 78.05 mmol) were added sequentially and the resulting mixture was allowed to warm to room temperature. After 3 hours the reaction mixture was cooled to 0°C and the solid was filtered off, the filtrate was washed with saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and brine (50 mL). The organics were dried over sodium sulfate and filtered through a 3 cm silica gel bed which was washed with a 1:1 mixture of ethyl acetate and dichloromethane (100 mL). The combined organics were concentrated under reduced pressure to give the crude product. The solid was dissolved in a minimal amount of boiling diisopropyl ether and the mixture was stirred vigorously at room temperature overnight. The product was filtered off, washed with cold diisopropyl ether (2 x 20 mL) and hexanes (3 x 40 mL) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.36 (m, 2H), 7.30 - 7.20 (m, 3H), 6.92 (dd, J = 14.2, 9.9 Hz, 1H), 4.21 - 4.08 (m, 2H), 4.07 - 3.92 (m, 1H), 3.62 - 3.56 (m, 2H), 3.53 - 3.47 (m, 2H), 3.45 - 3.36 (m, 4H), 1.29 (d, J = 7.1 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -154.24 (d, J = 21.5 Hz, 2F), -160.86 (t, J = 23.1 Hz, IF), -163.68 (t, J = 21.7 Hz, 2F). 31 P NMR (162 MHz, DMSO-d6) δ 0.40. LCMS: MS m / z = 528.06 [M+l], t R= 1.64 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Chromatography column: Kinetex 2.6 pm XB-C18 100 A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min - 0.2 min 2% acetonitrile, 0.2 min - 1.5 min 2 - 100% acetonitrile, 1.5 min - 2.2 min 100% acetonitrile, 2.2 min - 2.4 min 100% - 2% acetonitrile, 2.4 min - 2.5 min 2% acetonitrile, 2 pi / min.

[0481] ​

[0482]

[0483] To a stirred solution of (tert-butoxycarbonyl)-L-alanine (4.00 g, 21 mmol) and 2-methoxy-2-methylpropan-1-ol (2.00 g, 19 mmol) in dry dichloromethane (50 mL) was added N-methylmorpholine (6.33 mL, 58 mmol), 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) and tripropyl phosphine acid cyclizing anhydride (T3P, 13.72 mL, 23 mmol, 50% in ethyl acetate) at 0 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with water (30 mL), washed twice with 10% citric acid solution (2 x 20 mL), washed twice with saturated aqueous sodium bicarbonate solution (2 x 20 mL) and once with brine (20 mL), dried over sodium sulfate, filtered through a 3 cm silica gel plug which was washed with a 3:1 mixture of dichloromethane and ethyl acetate. The combined organics were concentrated under reduced pressure, co-distilled with dichloromethane and dried under high vacuum overnight to give the title compound. 1 H NMR (400 MHz, DMSO-d6) d 7.30 (d, J = 7.4 Hz, 1H), 4.10 - 3.77 (m, 3H), 3.11 (s, 3H), 1.37 (s, 9H), 1.24 (d, J = 7.4 Hz, 3H), 1.10 (s, 6H).

[0484] ​

[0485]

[0486] Intermediate H1 (5.1 g, 18.52 mmol) was dissolved in 15 mL of 4M HCI in 1,4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, co-distilled with toluene, to give a solidified solid which was dried under high vacuum for 1 hour. The solid was suspended in dichloromethane (100 mL) and at -78°C, phenyl phosphorodichloridate (3.03 mL, 20.37 mmol) and triethylamine (5.65 mL, 40.75 mmol) were added sequentially and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, then pentafluorophenol (3.41 g, 18.52 mmol) and triethylamine (3.59 mL, 25.93 mmol) were added sequentially, then the resulting mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was cooled to 0°C and the solid was filtered off, the filtrate was washed with saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and brine (50 mL). The organics were dried over sodium sulfate and filtered through a 3 cm silica gel plug which was washed with a 1:3 mixture of ethyl acetate and dichloromethane (100 mL). The combined organics were concentrated under reduced pressure to give the crude product (a mixture of isomers on phosphorus based on NMR). The solid was dissolved in boiling diisopropyl ether (50 mL) and the mixture was stirred vigorously at room temperature overnight. The solid product was filtered off and washed with cold diisopropyl ether (2 x 10 mL) and hexanes (3 x 20 mL) to give the title compound (a single isomer on phosphorus based on NMR). 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.36 (m, 2H), 7.29 - 7.16 (m, 3H), 6.92 (dd, J = 14.2, 9.9 Hz, 1H), 4.12 - 3.86 (m, 3H), 3.09 (s, 3H), 1.31 (d, J = 7.1 Hz, 3H), 1.09 (s, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -154.22 (d, J = 21.4 Hz, 2F), -160.89 (td, J = 23.4, 3.2 Hz, 1F), -163.69 (td, J = 23.4, 4.0 Hz, 2F). 31 P NMR (162 MHz, DMSO-d6) δ 0.43. LCMS: MS m / z = 497.9 [M+l], t R= 1.65 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Chromatography column: Kinetex 2.6 μ XB-C18 100A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min - 0.2 min 2% acetonitrile, 0.2 min - 1.5 min 2 - 100% acetonitrile, 1.5 min - 2.2 min 100% acetonitrile, 2.2 min - 2.4 min 100% - 2% acetonitrile, 2.4 min - 2.5 min 2% acetonitrile, 2 μl / min.

[0487] Intermediate M1. ((S)-(((2R,3S,4R,5R)-5-(3-((((benzyloxy)(hydroxy)phosphoryl)oxy)methyl)-4- imino-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester

[0488]

[0489] To a solution of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (prepared according to WO2016069825, 300 mg, 0.498 mmol) and sodium iodide (224 mg, 1.49 mmol) in HMPA (5.50 mL) was added dibenzyl chloromethyl phosphate (0.244 g, 0.747 mmol) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with ethyl acetate, washed with sodium bicarbonate, water then brine. The organics were dried over sodium sulfate, filtered and concentrated. The product was purified by HPLC chromatography (using a gradient of 0-100% acetonitrile / water) to give Intermediate M1. LCMS: MS m / z = 803.2 [M+1], t R= 0.85 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Chromatography column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.48 - 7.15 (m, 11H), 7.01 (d, J = 4.7 Hz, 1H), 6.65 - 6.60 (m, 1H), 6.15 - 6.06 (m, 1H), 5.72 - 5.64 (m, 2H), 5.52 (s, 1H), 4.79 (d, J = 7.0 Hz, 2H), 4.54 - 4.48 (m, 1H), 4.32 - 4.22 (m, 2H), 4.16 - 4.07 (m, 1H), 4.03 - 3.78 (m, 5H), 1.48 - 1.39 (m, 1H), 1.32 - 1.20 (m, 7H), 0.85 - 0.77 (m, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 4.17 - 3.77 (m), 0.33 - 0.08 (m).

[0490] Intermediate L1. ((2-Isopropyl-5-methylphenoxy)(perfluorophenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester

[0491]

[0492] To a solution of phosphorus oxychloride (5.30 g, 34.6 mmol) in anhydrous dichloromethane (75 mL) at -78 °C under an argon atmosphere was added 2-isopropyl-5- methylphenol (5.19 g, 34.6 mmol). N,N-diisopropylethylamine (6.02 mL, 34.6 mmol) was added slowly over 5 minutes. After 15 minutes, the reaction was allowed to warm to 0 °C. After 15 minutes, the reaction was cooled to -78 °C. (2S)-2-aminopropanoic acid 2-ethyl butyl ester hydrochloride (7.25 g, 34.6 mmol) was added. N,N-diisopropylethylamine (12.04 mL, 69.2 mmol) was added slowly over 5 minutes. After 30 minutes, 2,3,4,5,6-pentafluorophenol (6.36 g, 34.6 mmol) was added. N,N-diisopropylethylamine (6.02 mL, 34.6 mmol) was added slowly over 5 minutes. After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was acidified with acetic acid (5 mL). The reaction was washed with water (50 mL). The organics were dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give intermediate LI. LCMS: MS m / z = 551.7 [M+1], t = 1.34 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile, 2 uL / min. R = 1.34 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, DMSO-d6) δ 7.27-7.13 (m, 2H), 7.03-6.99 (m, 1H), 6.98-6.88 (m, 1H), 4.13-3.80 (m, 3H), 3.23-2.98 (m, 1H), 2.25 (s, 3H), 1.51-1.37 (m, 1H), 1.37-1.19 (m, 7H), 1.18-1.05 (m, 6H), 0.85-0.74 (m, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -153.87 - -154.49 (m, 2F), -160.25 - -161.26 (m, 1F), -163.46 - -164.19 (m, 2F). 31P NMR (162 MHz, DMSO-d6) δ (1 : 1 mixture of diastereomers) 0.40-0.15 (m, 1P), 0.09 - 0.35 (m, 1P).

[0493] ​ :

[0494] ​ ​ ​

[0495]

[0496] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine 2-ethyl butyl ester (prepared according to WO2016 / 069826 or WO2016069825, 500 mg, 0.83 mmol) and 4-(dimethylamino)pyridine (15.2 mg, 0.124 mmol) in tetrahydrofuran (8 mL) was added isobutyric anhydride (275 μί, 1.66 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes (0% - 100%) to afford the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.24 (m, 2H), 7.21 - 7.12 (m, 3H), 6.88 - 6.81 (m, 2H), 6.20 (d, J = 5.9 Hz, 1H), 5.57 (dd, J = 5.8, 3.7 Hz, 1H), 4.64 - 4.59 (m, 1H), 4.47 - 4.34 (m, 2H), 4.07 (dd, J = 10.9, 5.8 Hz, 1H), 3.98 (dd, J = 10.9, 5.7 Hz, 1H), 3.95 - 3.86 (m, 1H), 2.75 - 2.58 (m, 2H), 1.55 - 1.45 (m, 1H), 1.41 - 1.22 (m, 13H), 1.20 (d, J = 7.0 Hz, 6H), 0.89 (t, J = 7.5 Hz, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.51. MS m / z = 743.20 [M+1].

[0497] ​ 5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl diacetate

[0498]

[0499] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine 2-ethyl butyl ester (prepared according to WO2016 / 069826, WO2016 / 069825 or WO2016069825, 500 mg, 0.83 mmol) and 4-(dimethylamino)pyridine (15.2 mg, 0.124 mmol) in tetrahydrofuran (8 mL) was added acetic anhydride (157 μί, 1.66 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes (0% - 100%) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.33 - 7.24 (m, 2H), 7.20 - 7.11 (m, 3H), 6.89 - 6.81 (m, 2H), 6.21 (d, J = 5.9 Hz, 1H), 5.55 (dd, J = 5.9, 4.3 Hz, 1H), 4.65 - 4.59 (m, 1H), 4.46 - 4.33 (m, 2H), 4.06 (dd, J = 11.0, 5.8 Hz, 1H), 3.97 (dd, J = 10.9, 5.6 Hz, 1H), 3.94 - 3.86 (m, 1H), 2.17 (s, 3H), 2.14 (s, 3H), 1.54 - 1.43 (m, 1H), 1.41 - 1.28 (m, 7H), 0.89 (t, J = 7.5 Hz, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.53. MS m / z = 687.20 [M+1].

[0500] Example 3: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl) tetrahydrofuran-3,4-diyl dipropionate

[0501]

[0502] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine 2-ethyl butyl ester (prepared according to WO2016 / 069826, WO2016 / 069825 or WO2016069825, 500 mg, 0.83 mmol) and 4-(dimethylamino)pyridine (15.2 mg, 0.124 mmol) in tetrahydrofuran (8 mL) was added propionic anhydride (214 μL, 1.66 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes (0% - 100%) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.25 (m, 2H), 7.20 - 7.12 (m, 3H), 6.88 - 6.82 (m, 2H), 6.22 (d, J = 5.9 Hz, 1H), 5.58 (dd, J = 5.9, 4.1 Hz, 1H), 4.65 - 4.59 (m, 1H), 4.47 - 4.33 (m, 2H), 4.06 (dd, J = 10.9, 5.8 Hz, 1H), 3.97 (dd, J = 10.9, 5.7 Hz, 1H), 3.95 - 3.85 (m, 1H), 2.52 - 2.37 (m, 4H), 1.55 - 1.44 (m, 1H), 1.41 - 1.28 (m, 8H), 1.20 (t, J = 7.6 Hz, 3H), 1.16 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.4 Hz, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.53. MS m / z = 715.20 [M+1].

[0503] Example 4: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl bis(2-methylpropanoate)

[0504]

[0505] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine methyl ester (prepared according to WO2017049060, 100 mg, 0.18 mmol) and 4-(dimethylamino)pyridine (3.4 mg, 0.028 mmol) in tetrahydrofuran (2 mL) was added isobutyric anhydride (62 μL, 0.376 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.31 - 7.25 (m, 2H), 7.21 - 7.13 (m, 3H), 6.86 (d, J = 4.7 Hz, 1H), 6.83 (d, J = 4.7 Hz, 1H), 6.21 (d, J = 5.9 Hz, 1H), 5.60 - 5.57 (m, 1H), 4.66 - 4.60 (m, 1H), 4.45 - 4.34 (m, 2H), 3.93 - 3.83 (m, 1H), 3.66 (s, 3H), 2.77 - 2.57 (m, 2H), 1.30 - 1.16 (m, 15H). 31 P NMR (162 MHz, Methanol-d4) δ 3.54. MS m / z = 673.20 [M+1].

[0506] Example 5: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl dipropionate

[0507]

[0508] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine methyl ester (prepared according to WO2017049060, 100 mg, 0.188 mmol) and 4-(dimethylamino)pyridine (3.4 mg, 0.028 mmol) in tetrahydrofuran (8 mL) was added propionic anhydride (48 μL, 0.376 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.36 - 7.25 (m, 3H), 7.22 - 7.12 (m, 3H), 6.88 - 6.83 (m, 2H), 6.22 (d, J = 5.8 Hz, 1H), 5.62 - 5.56 (m, 1H), 4.68 - 4.61 (m, 1H), 4.49 - 4.33 (m, 2H), 3.93 - 3.82 (m, 1H), 3.66 (s, 3H), 2.54 - 2.35 (m, 4H), 1.29 (dd, J = 7.1, 1.0 Hz, 3H), 1.24 - 1.12 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.53. MS m / z = 645.10 [M+1].

[0509] Example 6: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl diacetate

[0510]

[0511] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanin methyl ester (prepared according to WO2017049060, 100 mg, 0.188 mmol) and 4-(dimethylamino)pyridine (3.4 mg, 0.028 mmol) in tetrahydrofuran (8 mL) was added acetic anhydride (35 μL, 0.376 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.36 - 7.25 (m, 2H), 7.21 - 7.13 (m, 3H), 6.88 - 6.84 (m, 2H), 6.21 (d, J = 5.9 Hz, 1H), 5.56 (dd, J = 5.9, 4.2 Hz, 1H), 4.68 - 4.60 (m, 1H), 4.48 - 4.33 (m, 2H), 3.93 - 3.82 (m, 1H), 3.66 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H), 1.28 (d, J = 7.1 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 3.54. MS m / z = 617.20 [M+1].

[0512] Example 7: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl bis(2-methylpropanoate)

[0513]

[0514] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine isopropyl ester (prepared according to WO2017049060, 100 mg, 0.18 mmol) and 4-(dimethylamino)pyridine (3.3 mg, 0.027 mmol) in tetrahydrofuran (2 mL) was added isobutyric anhydride (59.2 μL, 0.36 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.33 - 7.25 (m, 2H), 7.21 - 7.11 (m, 3H), 6.86 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 6.22 (d, J = 5.9 Hz, 1H), 5.58 (dd, J = 5.8, 3.7 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.68 - 4.59 (m, 1H), 4.50 - 4.32 (m, 2H), 3.91 - 3.77 (m, 1H), 2.78 - 2.55 (m, 2H), 1.35 - 1.14 (m, 21H). 31 P NMR (162 MHz, Methanol-d4) δ 3.64. MS m / z = 700.80 [M+1].

[0515] Example 8: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl dipropionate

[0516]

[0517] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine isopropyl ester (prepared according to WO2017049060, 100 mg, 0.18 mmol) and 4-(dimethylamino)pyridine (3.3 mg, 0.027 mmol) in tetrahydrofuran (2 mL) was added propionic anhydride (46 μL, 0.36 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.33 - 7.25 (m, 2H), 7.21 - 7.13 (m, 3H), 6.88 - 6.82 (m, 2H), 6.23 (d, J = 5.9 Hz, 1H), 5.62 - 5.55 (m, 1H), 5.00 - 4.90 (m, 1H), 4.66 - 4.59 (m, 1H), 4.48 - 4.33 (m, 2H), 3.90 - 3.77 (m, 1H), 2.53 - 2.37 (m, 4H), 1.28 (dd, J = 7.1, 1.1 Hz, 3H), 1.23 - 1.13 (m, 12H). 31 P NMR (162 MHz, Methanol-d4) δ 3.60. MS m / z = 672.80 [M+1].

[0518] Example 9: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 5-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl diacetate

[0519]

[0520] To a mixture of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanine isopropyl ester (prepared according to WO2017049060, 100 mg, 0.18 mmol) and 4-(dimethylamino)pyridine (3.3 mg, 0.027 mmol) in tetrahydrofuran (2 mL) was added acetic anhydride (36 μL, 0.36 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.24 (m, 2H), 7.21 - 7.12 (m, 3H), 6.89 - 6.81 (m, 2H), 6.22 (d, J = 5.9 Hz, 1H), 5.56 (dd, J = 5.9, 4.2 Hz, 1H), 5.01 - 4.90 (m, 1H), 4.66 - 4.60 (m, 1H), 4.48 - 4.31 (m, 2H), 3.88 - 3.78 (m, 1H), 2.17 (s, 3H), 2.14 (s, 3H), 1.28 (dd, J = 7.1, 1.1 Hz, 3H), 1.21 (dd, J = 6.3, 1.4 Hz, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.64. MS m / z = 644.80 [M+1].

[0521] Example 10: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- Base-5-((((((S)-1-ethoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diol bis(2-methylpropanoate)

[0522]

[0523] To a mixture of ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester (prepared according to WO2017049060, 200 mg, 0.37 mmol) and 4- (dimethylamino)pyridine (6.7 mg, 0.055 mmol) in tetrahydrofuran (2 mL) was added isobutyric anhydride (121 μL, 0.73 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.37 - 7.25 (m, 2H), 7.23 - 7.12 (m, 3H), 6.94 - 6.81 (m, 2H), 6.30 (d, J = 5.9 Hz, 0.5H), 6.21 (d, J = 5.9 Hz, 0.5H), 5.62 - 5.55 (m, 1H), 4.69 - 4.59 (m, 1H), 4.54 - 4.33 (m, 2H), 4.19 - 4.03 (m, 2H), 3.92 - 3.70 (m, 1H), 2.77 - 2.55 (m, 2H), 1.36 - 1.10 (m, 18H). 31 P NMR (162 MHz, Methanol-d4) δ 3.60. MS m / z = 686.80 [M+l].

[0524] Example 11: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano Base-5-((((((S)-1-ethoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diol dipropionate

[0525]

[0526] To a mixture of ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester (prepared according to WO2017049060, 200 mg, 0.37 mmol) and 4- (dimethylamino)pyridine (6.7 mg, 0.055 mmol) in tetrahydrofuran (2 mL) was added propionic anhydride (94 μL, 0.73 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 - 7.84 (m, 1H), 7.37 - 7.25 (m, 2H), 7.22 - 7.12 (m, 3H), 6.94 - 6.82 (m, 2H), 6.32 (d, J = 5.9 Hz, 0H), 6.23 (d, J = 5.8 Hz, 1H), 5.64 - 5.54 (m, 1H), 4.68 - 4.61 (m, 1H), 4.54 - 4.31 (m, 2H), 4.20 - 4.02 (m, 2H), 3.94 - 3.70 (m, 1H), 2.55 - 2.37 (m, 4H), 1.33 - 1.10 (m, 12H). 31 P NMR (162 MHz, Methanol-d4) δ 3.60. MS m / z = 658.80 [M+1].

[0527] Example 12: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano Base-5-((((((S)-1-ethoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diol diacetate

[0528]

[0529] To a mixture of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester (prepared according to WO2017049060, 200 mg, 0.37 mmol) and 4- (dimethylamino)pyridine (6.7 mg, 0.055 mmol) in tetrahydrofuran (2 mL) was added acetic anhydride (69 μL, 0.73 mmol) at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 0.5H), 7.86 (s, 0.5H), 7.36 - 7.25 (m, 2H), 7.22 - 7.13 (m, 3H), 6.93 - 6.90 (m, 1H), 6.88 - 6.84 (m, 1H), 6.30 (d, J = 5.9 Hz, 0.5H), 6.21 (d, J = 5.9 Hz, 0.5H), 5.62 - 5.52 (m, 1H), 4.69 - 4.59 (m, 1H), 4.53 - 4.29 (m, 2H), 4.18 - 4.01 (m, 2H), 3.91 - 3.70 (m, 1H), 2.19 - 2.12 (m, 6H), 1.31 - 1.15 (m, 6H). 31 PNMR (162 MHz, Methanol-d4) δ 3.60. MS m / z = 630.80 [M+1].

[0530] Example 13: (2S)-2-[[[(2R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoic acid 2-ethylbutyl Example 14: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-

[0531]

[0532] To a suspension of (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propionic acid 2-ethylbutyl ester (Intermediate Al, 0.366 g, 0.664 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ylium-4-carbonate (prepared according to WO2017049060, 0.200 g, 0.604 mmol) and magnesium chloride (0.058 g, 0.604 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.263 mL, 1.51 mmol) at 0 °C under an argon atmosphere. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics washed with water, dried over sodium sulfate, filtered and concentrated to give Intermediate A2 (LCMS: MS m / z = 698.8 and 698.8 [M+1], t R = 1.13 and 1.16 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Chromatography column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min).

[0533] Intermediate A2 was taken up in tetrahydrofuran (2 mL) and concentrated hydrochloric acid (1 1.7 M, 0.400 mL, 4.66 mmol) was added. After 2 h, the reaction was diluted with ethyl acetate and neutralised with saturated aqueous sodium bicarbonate solution. The layers were separated and the organics washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product was purified by HPLC chromatography (0 - 100% acetonitrile in water) to give the title compound (13). LCMS: MS m / z = 658.9 and 658.9 [M+1], t R= 1.00 and 1.01 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvents: Acetonitrile with 0.1% Acetic acid, Water with 0.1% Acetic acid; Gradient: 0 - 1.00 min 10% - 100% Acetonitrile, 1.00 - 1.35 min 100% Acetonitrile, 1.35 - 1.36 min 100 - 10% Acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) δ (3:2 mixture of diastereomers) 7.89 (s, 0.6H), 7.87 (s, 0.4H), 7.36 - 7.28 (m, 2H), 7.14 - 7.09 (m, 1H), 7.09 - 7.04 (m, 1H), 6.98 - 6.91 (m, 2H), 4.82 - 4.79 (m, 1H), 4.48 - 4.26 (m, 3H), 4.20 - 4.16 (m, 1H), 4.10 - 3.83 (m, 3H), 1.55 - 1.44 (m, 1H), 1.40 - 1.25 (m, 16H), 0.95 - 0.85 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.99 - 3.73 (m). HPLC: t R = 3.10 min; HPLC system: Agilent 1100 series; Column: Gemini 5u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0534] The individual isomers of compound 13 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0535] Peak 1 Example 13a: LCMS: MS m / z = 659.3 [M+1], 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.26 (m, 2H), 7.09 - 7.02 (m, 2H), 6.93 (d, J = 1.2 Hz, 2H), 4.80 (d, J = 5.5 Hz, 1H), 4.48 - 4.36 (m, 2H), 4.32 (ddd, J = 11.0, 5.7, 3.8 Hz, 1H), 4.17 (t, J = 5.5 Hz, 1H), 4.08 - 3.95 (m, 2H), 3.88 (dq, J = 9.2, 7.1 Hz, 1H), 1.50 (dt, J = 12.4, 6.2 Hz, 1H), 1.35 (pd, J = 7.4, 1.2 Hz, 4H), 1.30 - 1.25 (m, 12H), 0.89 (t, J = 7.5 Hz, 6H); 31 P NMR (162 MHz, Methanol-d4) δ 3.85.

[0536] Peak 2 Example 13b: LCMS: MS m / z = 659.3 [M+1], 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.36 - 7.29 (m, 2H), 7.14 - 7.08 (m, 2H), 6.98 - 6.88 (m, 2H), 4.81 (d, J = 5.4 Hz, 1H), 4.47 - 4.33 (m, 2H), 4.33 - 4.24 (m, 1H), 4.18 (t, J = 5.6 Hz, 1H), 4.04 (dd, J = 10.9, 5.8 Hz, 1H), 3.93 (ddd, J = 19.5, 10.3, 6.4 Hz, 2H), 1.48 (dt, J = 12.4, 6.1 Hz, 1H), 1.41 - 1.20 (m, 16H), 0.87 (t, J = 7.5 Hz, 6H); 31 P NMR (162 MHz, Methanol-d4) δ 3.81.

[0537] ((((4-(tert-butyl)phenoxy)(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2-cyano tetrahydrofuran-3,4-diol bis(2-methylpropanoate) Example 15: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alanine methyl ester

[0538]

[0539] To a solution of (2S)-2-[[[(2R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino] propanoic acid 2-ethyl butyl ester (Example 13, 50 mg, 0.0759 mmol) and 2-methylpropionyl 2- methylpropanoate (26.4 mg, 0.167 mmol) in tetrahydrofuran (1 mL) was added 4- (dimethylamino)pyridine (1.4 mg, 0.011 mmol). After 1 h, the reaction was purified by HPLC chromatography (25-100% acetonitrile in water) to give the title compound 14. LCMS: MS m / z = 798.8 and 798.8 [M+1], t R = 1.23 and 1.29 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) δ (1:1 mixture of diastereomers) 7.89 - 7.87 (m, 1H), 7.41 - 7.24 (m, 2H), 7.13 - 7.05 (m, 2H), 6.96 - 6.82 (m, 2H), 6.28 (d, J = 5.9 Hz, 0.5H), 6.15 (d, J = 5.9 Hz, 0.5H), 5.66 - 5.51 (m, 1H), 4.68 - 4.57 (m, 1H), 4.49 - 4.33 (m, 2H), 4.12 - 3.79 (m, 3H), 2.79 - 2.56 (m, 2H), 1.60 - 1.46 (m, 1H), 1.43 - 1.11 (m, 28H), 0.93 - 0.84 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.85 - 3.55 (m). HPLC: t R = 3.71 min; HPLC system: Agilent 1100 series; Column: Gemini 5 u C18 110A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0540] Example 16: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2-cyano tetrahydrofuran-3,4-diol bis(2-methylpropanoate)

[0541]

[0542] Intermediate B2 was prepared in a similar manner to Intermediate A2, except Intermediate Bl was used in place of Intermediate Al. LCMS: MS m / z = 628.9 and 628.9 [M+l], t R = 0.80 and 0.82 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min.

[0543] Compound 15 was prepared in a similar manner to Compound 13, except Intermediate B2 was used in place of Intermediate A2. LCMS: MS m / z = 588.8 and 588.8 [M+l], t R = 0.80 and 0.82 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) d (1 : 1 mixture of diastereomers) 7.89 (s, 0.5H), 7.87 (s, 0.5H), 7.34 - 7.29 (m, 2H), 7.13 - 7.08 (m, 1H), 7.07 - 7.02 (m, 1H), 6.98 - 6.90 (m, 2H), 4.83 - 4.80 (m, 1H), 4.46 - 4.37 (m, 2H), 4.36 - 4.27 (m, 1H), 4.23 - 4.16 (m, 1H), 3.95 - 3.79 (m, 1H), 3.68 - 3.63 (m, 3H), 1.38 - 1.23 (m, 12H). 31P NMR (162 MHz, Methanol-d4) d 3.84. HPLC: t R = 2.62 and 2.65 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0544] Example 17: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alanine ethyl ester Example 18: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-

[0545]

[0546] Compound 16 was prepared in a similar manner to compound 14, except that compound 15 was used instead of compound 13. LCMS: MS m / z = 728.8 [M+1], t R = 1.09 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 μL / min. 1 H NMR (400 MHz, Methanol-d4) d (1 : 1 mixture of diastereomers) 7.88 (s, 0.5H), 7.87 (s, 0.5H), 7.37 - 7.32 (m, 1H), 7.31 - 7.26 (m, 1H), 7.17 - 7.01 (m, 2H), 6.98 - 6.84 (m, 2H), 6.29 (d, J = 5.9 Hz, 0.5H), 6.16 (d, J = 5.9 Hz, 0.5H), 5.62 - 5.54 (m, 1H), 4.71 - 4.61 (m, 1H), 4.51 - 4.32 (m, 2H), 3.93 - 3.83 (m, 0.5H), 3.82 - 3.72 (m, 0.5H), 3.69 - 3.62 (m, 3H), 2.82 - 2.57 (m, 2H), 1.39 - 1.15 (m, 24H). 31 P NMR (162 MHz, Methanol-d4) d 3.84 - 3.56 (m). HPLC: t R= 3.29 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0547] ((((4-(tert-butyl)phenoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2-cyano ​

[0548]

[0549] Intermediate C2 was prepared in a similar manner to Intermediate A2, except Intermediate Cl was used in place of Intermediate Al. LCMS: MS m / z = 642.8 and 642.8 [M+l], t R = 0.98 and 1.00 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min.

[0550] Compound 17 was prepared in a similar manner to Compound 13, except Intermediate C2 was used in place of Intermediate A2. LCMS: MS m / z = 602.8 and 602.8 [M+l], t R = 0.98 and 1.00 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, Methanol-d4) δ (1 : 1 mixture of diastereomers) 7.89 (s, 0.5H), 7.87 (s, 0.5H), 7.36-7.28 (m, 2H), 7.13-7.08 (m, 1H), 7.08-7.04 (m, 1H), 6.98-6.90 (m, 2H), 4.84-4.79 (m, 1H), 4.48-4.36 (m, 2H), 4.35-4.25 (m, 1H), 4.21-4.17 (m, 1H), 4.15-4.05 (m, 2H), 3.92-3.78 (m, 1H), 1.36-1.14 (m, 15H). 31 P NMR (162 MHz, Methanol-d4) δ 4.04-3.76 (m). HPLC: t R = 2.78 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0551] ​ ​ Tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0552]

[0553] Compound 18 was prepared in a similar manner to compound 14, except that compound 17 was used instead of compound 13. LCMS: MS m / z = 742.8 and 742.8 [M+1], t R = 1.12 and 1.13 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 μL / min. 1H NMR (400 MHz, Methanol-d4) δ (1 : 1 mixture of diastereomers) 7.89-7.87 (m, 1 H), 7.37-7.32 (m, 1 H), 7.31-7.27 (m, 1 H), 7.12-7.05 (m, 2 H), 6.94-6.85 (m, 2 H), 6.28 (d, J = 5.9 Hz, 0.5 H), 6.17 (d, J = 5.9 Hz, 0.5 H), 5.60-5.54 (m, 1 H), 4.68-4.60 (m, 1 H), 4.48-4.34 (m, 2 H), 4.18-4.05 (m, 2 H), 3.93-3.83 (m, 0.5 H), 3.81-3.71 (m, 0.5 H), 2.74-2.57 (m, 2 H), 1.34-1.16 (m, 27 H). 31 P NMR (162 MHz, Methanol-d4) δ 3.84-3.59 (m). HPLC: t R = 3.37 min; HPLC system: Agilent 1100 series; Column: Gemini 5 μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0554] The individual isomers of compound 18 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0555] Peak 1 : Example 18a: LCMS: MS m / z = 743.3 [M+1], 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1 H), 7.37-7.31 (m, 2 H), 7.14-7.06 (m, 2 H), 6.96-6.85 (m, 2 H), 6.28 (d, J = 5.9 Hz, 1 H), 5.56 (dd, J = 5.9, 3.9 Hz, 1 H), 4.64 (dt, J = 5.8, 2.8 Hz, 1 H), 4.42 (qdd, J = 11.6, 5.6, 3.5 Hz, 2 H), 4.10 (qd, J = 7.2, 2.5 Hz, 2 H), 3.77 (dq, J = 9.2, 7.1 Hz, 1 H), 3.62 (q, J = 7.0 Hz, 1 H), 2.66 (dp, J = 20.9, 7.0 Hz, 2 H), 1.31 (s, 9 H), 1.29-1.22 (m, 8 H), 1.19 (dt, J = 6.9, 2.0 Hz, 13 H); 31PNMR (162 MHz, Methanol-d4) δ 3.69.

[0556] Peak 2: Example 18b: LCMS: MS m / z = 743.3 [M+1], 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.32 - 7.26 (m, 2H), 7.12 - 7.04 (m, 2H), 6.93 - 6.84 (m, 2H), 6.17 (d, J = 5.9 Hz, 1H), 5.57 (dd, J = 5.9, 3.8 Hz, 1H), 4.62 (qd, J = 3.8, 1.8 Hz, 1H), 4.48 - 4.32 (m, 2H), 4.12 (qd, J = 7.1, 3.1 Hz, 2H), 3.88 (dq, J = 9.8, 7.1 Hz, 1H), 3.62 (q, J = 7.0 Hz, 1H), 3.37 (s, 1H), 2.66 (dp, J = 23.6, 7.0 Hz, 2H), 1.33 - 1.27 (m, 14H), 1.26 (s, 3H), 1.25 - 1.22 (m, 4H), 1.22 - 1.17 (m, 8H); 31 PNMR (162 MHz, Methanol-d4) δ 3.81 - 3.56 (m).

[0557] Example 19: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(2,6-dimethylphenoxy)phosphoryl)- L-alanine 2-ethyl butyl ester Example 20: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((2,6-dimethylphenoxy)(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) Example 21: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((((S)-1-cyclobutoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3,4-diyl bis(2-methylpropanoate)

[0558]

[0559] Intermediate D2 was prepared in a similar manner to Intermediate A2, except Intermediate D1 was used instead of Intermediate Al. LCMS: MS m / z = 670.8 and 670.8 [M+1], t R = 1.08 and 1.11 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min.

[0560] Compound 19 was prepared in a similar manner to Compound 13, except Intermediate D2 was used instead of Intermediate A2. LCMS: MS m / z = 630.8 and 630.8 [M+1], t R= 0.92 and 0.94 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% Acetic acid, Water with 0.1% Acetic acid; Gradient: 0 - 1.00 min 10% - 100% Acetonitrile, 1.00 - 1.35 min 100% Acetonitrile, 1.35 - 1.36 min 100 - 10% Acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) δ (5:2 mixture of diastereomers) 7.89 (s, 0.7H), 7.88 (s, 0.3H), 7.01 - 6.88 (m, 5H), 4.70 (d, J = 5.6 Hz, 0.3H), 4.67 (d, J = 5.4 Hz, 0.7H), 4.40 - 4.19 (m, 3H), 4.15 - 4.11 (m, 1H), 4.09 - 3.89 (m, 3H), 2.33 - 2.27 (m, 6H), 1.53 - 1.45 (m, 1H), 1.41 - 1.26 (m, 7H), 0.91 - 0.84 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ (5:2 mixture of diastereomers) 4.29 - 4.08 (m, 0.3P), 3.92 - 3.64 (m, 0.7P). HPLC: t R = 2.91 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0561] Example 22: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-(2-ethoxyethoxy) ethyl ester Example 23: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((((S)-1-(2-(2-ethoxyethoxy)ethoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) Example 24: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-methoxy-2- methylpropan-1-yl ester

[0562]

[0563] Compound 20 was prepared in a similar manner to compound 14, except that compound 19 was used instead of compound 13. LCMS: MS m / z = 770.8 and 770.8 [M+1], t R= 1.19 and 1.21 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% Acetic acid, Water with 0.1% Acetic acid; Gradient: 0 - 1.00 min 10% - 100% Acetonitrile, 1.00 - 1.35 min 100% Acetonitrile, 1.35 - 1.36 min 100 - 10% Acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) δ (1:1 mixture of diastereomers) 7.88 (s, 1H), 7.03 - 6.92 (m, 3H), 6.89 - 6.87 (m, 1H), 6.83 - 6.79 (m, 1H), 6.12 (s, 0.5H), 6.11 (s, 0.5H), 5.53 - 5.49 (m, 1H), 4.56 - 4.51 (m, 1H), 4.37 - 4.33 (m, 2H), 4.10 - 4.04 (m, 1H), 4.01 - 3.91 (m, 2H), 2.73 - 2.57 (m, 2H), 2.36 - 2.22 (m, 6H), 1.56 - 1.45 (m, 1H), 1.41 - 1.31 (m, 7H), 1.29 - 1.22 (m, 6H), 1.20 - 1.16 (m, 6H), 0.92 - 0.87 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ 3.80 - 3.55 (m). HPLC: t R = 3.57 min; HPLC system: Agilent 1100 series; Column: Gemini 5u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0564] Example 25: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((((S)-1-(2-methoxy-2-methylpropan-1-yl)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) Example 26. ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(2-isopropyl-5-methylphenoxy)phosphoryl)-L- alanine 2-ethyl butyl ester ​

[0565]

[0566] Compound 21 was prepared in a similar manner to compound 14, except that (((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninyl cyclobutyl ester (prepared according to US 201514926062) was used instead of compound 13. LCMS: MS m / z = 712.8 and 712.8 [M+1], t R = 1.05 and 1.06 min; HPLC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% Acetic acid, Water with 0.1% Acetic acid; Gradient: 0 - 1.00 min 10% - 100% Acetonitrile, 1.00 - 1.35 min 100% Acetonitrile, 1.35 - 1.36 min 100 - 10% Acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) d (1:1 mixture of diastereomers) 7.89 - 7.85 (m, 1H), 7.36 - 7.26 (m, 2H), 7.22 - 7.15 (m, 3H), 6.93 - 6.89 (m, 1H), 6.88 - 6.81 (m, 1H), 6.30 (d, J = 5.9 Hz, 0.5H), 6.22 (d, J = 5.9 Hz, 0.5H), 5.61 - 5.54 (m, 1H), 4.92 - 4.89 (m, 1H), 4.67 - 4.59 (m, 1H), 4.50 - 4.32 (m, 2H), 3.92 - 3.73 (m, 1H), 2.76 - 2.58 (m, 2H), 2.37 - 2.25 (m, 2H), 2.11 - 1.98 (m, 2H), 1.85 - 1.72 (m, 1H), 1.71 - 1.60 (m, 1H), 1.34 - 1.15 (m, 15H). 31 P NMR (162 MHz, Methanol-d4) d 3.60. HPLC: t R = 3.17 min; HPLC system: Agilent 1100 series; Column: Gemini 5 u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0567] The individual isomers of compound 21 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0568] Peak 1 : Example 21a LCMS: MS m / z = 713.3 [M+1], 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.25 (m, 2H), 7.22 - 7.12 (m, 3H), 6.89 - 6.81 (m, 2H), 6.22 (d, J = 5.9 Hz, 1H), 5.58 (dd, J = 5.9, 3.8 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.61 (qd, J = 3.9, 1.7 Hz, 1H), 4.40 (qdd, J = 11.5, 6.2, 3.9 Hz, 2H), 3.85 (dq, J = 9.8, 7.1 Hz, 1H), 2.66 (dp, J = 24.1, 7.0 Hz, 2H), 2.37 - 2.23 (m, 1H), 2.12 - 1.95 (m, 1H), 1.85 - 1.72 (m, 1H), 1.71 - 1.58 (m, 1H), 1.34 - 1.22 (m, 9H), 1.19 (d, J = 7.0 Hz, 6H), 1.11 (d, J = 6.9 Hz, 1H). 31 P NMR (162 MHz, Methanol-d4) δ 3.55.

[0569] Peak 2: Example 21b: LCMS: MS m / z = 713.3 [M+1], 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.32 - 7.25 (m, 2H), 7.22 - 7.12 (m, 3H), 6.89 - 6.81 (m, 2H), 6.22 (d, J = 5.9 Hz, 1H), 5.58 (dd, J = 5.9, 3.8 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.61 (qd, J = 3.9, 1.7 Hz, 1H), 4.40 (qdd, J = 11.5, 6.2, 3.9 Hz, 2H), 3.85 (dq, J = 9.8, 7.1 Hz, 1H), 2.66 (dp, J = 24.1, 7.0 Hz, 2H), 2.37 - 2.23 (m, 1H), 2.12 - 1.95 (m, 1H), 1.85 - 1.72 (m, 1H), 1.71 - 1.58 (m, 1H), 1.34 - 1.22 (m, 9H), 1.19 (d, J = 7.0 Hz, 6H), 1.11 (d, J = 6.9 Hz, 1H).31 P NMR (162 MHz, Methanol-d4) δ 3.61.

[0570] ​ ​ ​

[0571]

[0572] Tetrahydrofuran (14 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-carbonitrile (prepared according to WO2016069825, 2.00 g, 6.04 mmol), Intermediate G2 (4.14 g, 7.85 mmol) and magnesium chloride (862 mg, 9.05 mmol) at room temperature. The mixture was heated to 40 °C for 10 min and N,N-diisopropylethylamine (2.63 mL, 15.1 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate (100 mL) and the resulting mixture was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile (100 mL) and concentrated hydrochloric acid aqueous solution (5.03 mL) was added dropwise at 0 °C. After 4 h at 0 °C, the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) at 0 °C and the resulting mixture was washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient of 0-10% methanol / dichloromethane to give the title compound. LCMS: MS m / z = 634.8 [M+1], t R = 0.71 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.83 (m, 3H), 7.40 - 7.29 (m, 2H), 7.22 - 7.09 (m, 3H), 6.88 (d, J = 4.5 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.35 (d, J = 6.1 Hz, 1H), 6.17 - 5.98 (m, 1H), 5.39 (d, J = 5.7 Hz, 1H), 4.70 - 4.54 (m, 1H), 4.29 - 4.19 (m, 2H), 4.18 - 4.02 (m, 3H), 4.00 - 3.91 (m, 1H), 3.88 - 3.73 (m, 1H), 3.60 - 3.51 (m, 2H), 3.50 - 3.44 (m, 2H), 3.45 - 3.36 (m, 4H), 1.20 (d, J = 7.1 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H). 31 P NMR (162 MHz, DMSO-d6) δ 3.81. HPLC: t R = 2.36 min; HPLC system: Agilent 1100 series; Column: Gemini 5 u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0573] ​ ​ ​

[0574]

[0575] Compound 23 was prepared in a similar manner to compound 14, except that compound 22 was used instead of compound 13. LCMS: MS m / z = 774.8 [M+1], t R = 1.00 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.33 - 7.26 (m, 2H), 7.21 - 7.13 (m, 3H), 6.86 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 6.20 (d, J = 5.8 Hz, 1H), 5.59 (dd, J = 5.8, 3.6 Hz, 1H), 4.67 - 4.61 (m, 1H), 4.47 - 4.36 (m, 2H), 4.27 - 4.16 (m, 2H), 3.95 - 3.84 (m, 1H), 3.69 - 3.65 (m, 2H), 3.62 - 3.59 (m, 2H), 3.58 - 3.48 (m, 4H), 2.76 - 2.57 (m, 2H), 1.34 - 1.24 (m, 9H), 1.21 - 1.15 (m, 9H). 31 P NMR (162 MHz, Methanol-d4) δ 3.62 - 3.33 (m). HPLC: t R = 3.02 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0576] ​ ​ ​

[0577]

[0578] Tetrahydrofuran (11 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-carbonitrile (prepared according to WO2016069825, 1500 mg, 4.53 mmol), Intermediate H2 (2480 mg, 4.98 mmol) and magnesium chloride (647 mg, 6.79 mmol) at room temperature. The mixture was heated to 40 °C for 10 min and N,N- diisopropylethylamine (1.97 mL, 11.3 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate (100 mL) and the resulting mixture was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile (75 mL) and concentrated hydrochloric acid aqueous solution (3.77 mL) was added dropwise at 0 °C. After 4 h at 0 °C, the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) at 0 °C and the resulting mixture was washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient of 0-10% methanol / dichloromethane to give the title compound. LCMS: MS m / z = 604.8 [M+1], t R = 0.72 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, DMSO-d6) δ 8.17 - 7.81 (m, 3H), 7.41 - 7.27 (m, 2H), 7.27 - 7.06 (m, 3H), 6.89 (d, J = 4.5 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 6.21 - 5.97 (m, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.71 - 4.51 (m, 1H), 4.35 - 4.18 (m, 2H), 4.14 - 4.03 (m, 1H), 4.01 - 3.89 (m, 2H), 3.90 - 3.74 (m, 2H), 3.06 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H), 1.06 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 3.83. HPLC: t R = 2.36 min; HPLC system: Agilent 1100 series; Column: Gemini 5 u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0579] ​ ​ ​

[0580]

[0581] Compound 25 was prepared in a similar manner to compound 14, except that compound 24 was used instead of compound 13. LCMS: MS m / z = 744.8 [M+l], t R = 1.01 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.31-7.26 (m, 2H), 7.21-7.13 (m, 3H), 6.86 (d, J = 4.7 Hz, 1H), 6.82 (d, J = 4.7 Hz, 1H), 6.19 (d, J = 5.9 Hz, 1H), 5.57 (dd, J = 5.9, 3.7 Hz, 1H), 4.70-4.58 (m, 1H), 4.52-4.34 (m, 2H), 4.07 (d, J = 11.5 Hz, 1H), 4.00-3.90 (m, 2H), 3.21 (s, 3H), 2.75-2.57 (m, 2H), 1.36-1.31 (m, 3H), 1.29-1.23 (m, 6H), 1.21-1.16 (m, 12H). 31 P NMR (162 MHz, Methanol-d4) δ 3.63-3.28 (m). HPLC: t R = 3.04 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0582] ​ ​ ​

[0583]

[0584] Tetrahydrofuran (11 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-carbonitrile (prepared according to WO2016069825, 1000 mg, 3.02 mmol), Intermediate LI (2160 mg, 3.92 mmol) and magnesium chloride (431 mg, 4.53 mmol) at room temperature. The mixture was heated to 40 °C for 10 min and N,N-diisopropylethylamine (1.3 mL, 7.55 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate (30 mL) and the resulting mixture was washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude Intermediate L2. LCMS: MS m / z = 698.8 and 698.8 [M+1], tR= 1.48 min.R = 1.15 and 1.17 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min.

[0585] The crude residue was dissolved in acetonitrile (50 mL) and concentrated hydrochloric acid in water (2.52 mL) was added dropwise at 0 °C. After 4 hours at 0 °C, the reaction mixture was diluted with ethyl acetate (100 mL) and water (30 mL) at 0 °C and the resulting mixture was washed with saturated aqueous sodium bicarbonate (30 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient of 0-10% methanol / dichloromethane to give the title compound 26. Individual isomers of 26 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0586] Peak 1 (26a) (faster eluting isomer) data: LCMS: MS m / z = 658.9 [M+1], t R = 1.15 and 1.17 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, DMSO-d6) δ 8.07 - 7.83 (m, 3H), 7.14 (d, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 4.5 Hz, 1H), 6.80 (d, J = 4.5 Hz, 1H), 6.34 (d, J = 6.2 Hz, 1H), 6.13 - 6.01 (m, 1H), 5.41 (d, J = 5.7 Hz, 1H), 4.67 - 4.53 (m, 1H), 4.29 - 4.21 (m, 2H), 4.16 - 4.04 (m, 1H), 4.02 - 3.85 (m, 3H), 3.82 - 3.64 (m, 1H), 3.23 - 3.10 (m, 1H), 2.15 (s, 3H), 1.51 - 1.36 (m, 1H), 1.31 - 1.22 (m, 4H), 1.19 (d, J = 7.0 Hz, 3H), 1.13 - 1.06 (m, 6H), 0.85 - 0.74 (m, 6H). 31 PNMR (162 MHz, DMSO-d6) δ 3.69. HPLC: t R = 3.03 min; HPLC system: Agilent 1100 series; Column: Gemini 5m C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0587] Peak 2 (26b) (slower eluting isomer) Data: LCMS: MS m / z = 658.9 [M+1], t R = 1.01 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 pL / min. 1H NMR (400 MHz, DMSO-d6) δ 8.01 - 7.81 (m, 3H), 7.16 (d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 4.5 Hz, 1H), 6.79 (d, J = 4.5 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 6.17 - 5.87 (m, 1H), 5.38 (d, J = 5.8 Hz, 1H), 4.71 - 4.54 (m, 1H), 4.29 - 4.16 (m, 2H), 4.12 - 4.01 (m, 1H), 4.00 - 3.72 (m, 4H), 3.27 - 3.11 (m, 1H), 2.19 (s, 3H), 1.54 - 1.31 (m, 1H), 1.32 - 1.18 (m, 7H), 1.12 (d, J = 6.9 Hz, 6H), 0.79 (t, J = 7.4 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 3.74. HPLC: t R = 3.04 min; HPLC system: Agilent 1100 series; Column: Gemini 5u C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0588] Example 27: (2R,3R,4R,5R)-2-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- cyano-5-((((((S)-1-(2-ethylbutyloxy)-1-oxopropan-2-yl)amino)(2-isopropyl-5- methylphenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) Example 28. ((S)-(((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-imino-3-((phosphonooxy)methyl)- 3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)- L-alanine 2-ethylbutyl ester Example 29. (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoic acid spiro[3.3]heptan-2-yl ester

[0589]

[0590] Compound 27 was prepared in a similar manner to compound 14, except that compound 26 was used instead of compound 13. LCMS: MS m / z = 798.8 and 798.8 [M+1], t R = 1.24 and 1.26 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1H NMR (400 MHz, Methanol-d4) δ (1 : 1 mixture of diastereomers) 7.86 (s, 0.5H), 7.85 (s, 0.5H), 7.19-7.10 (m, 2H), 6.97-6.92 (m, 1H), 6.91-6.87 (m, 1H), 6.86-6.80 (m, 1H), 6.29 (d, J = 6.0 Hz, 0.5H), 6.20 (d, J = 5.9 Hz, 0.5H), 5.65-5.59 (m, 0.5H), 5.59-5.52 (m, 0.5H), 4.70-4.64 (m, 0.5H), 4.64-4.59 (m, 0.5H), 4.51-4.35 (m, 2H), 4.10-3.79 (m, 3H), 3.30-3.22 (m, 1H), 2.73-2.58 (m, 2H), 2.26-2.18 (m, 3H), 1.55-1.45 (m, 1H), 1.39-1.29 (m, 5H), 1.29-1.12 (m, 20H), 0.93-0.85 (m, 6H). 31 P NMR (162 MHz, Methanol-d4) δ (1 : 1 mixture of diastereomers) 3.69-3.47 (m, 0.5P), 3.44-3.27 (m, 0.5P). HPLC: t R = 3.71 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0591] Example 30. (2S)-2-[[(4-tert-butylphenoxy)-[[(2R,3R,4R,5R)-3,4-diacetyloxy-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-tetrahydrofuran-2-yl]methoxy]phosphoryl]amino] propanoic acid spiro[3.3]heptan-2-yl ester Intermediate T1. ((4-(tert-Butyl)phenoxy)(perfluorophenoxy)phosphoryl)-L-alanine cyclobutyl ester Example 31: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alanine cyclobutyl ester

[0592]

[0593] A solution of intermediate M1 (0.130 g, 0.162 mmol) in ethanol was evacuated and filled with argon 3 times under reduced pressure. Palladium (10.0% palladium on carbon, 17.2 mg, 0.0162 mmol) was added. The reaction vessel was evacuated and filled with hydrogen 5 times under reduced pressure. The reaction was allowed to stir under a hydrogen atmosphere. After 4 hours, the reaction was evacuated and filled with argon 2 times. The reaction was filtered through a pad of celite and concentrated. The product was purified by HPLC chromatography using a gradient of 0-100% acetonitrile / water to give compound 28. LCMS: MS m / z = 713.1 [M+1], t R= 0.78 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 pL / min. 1 H NMR (400 MHz, DMSO-d6) d 10.37 (s, 1H), 8.54 (s, 1H), 7.44 (d, J = 4.7 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.22 - 7.15 (m, 3H), 6.99 (d, J = 4.7 Hz, 1H), 6.61 - 6.56 (m, 1H), 6.17 - 6.02 (m, 1H), 5.69 - 5.59 (m, 2H), 5.54 - 5.45 (m, 1H), 4.55 - 4.46 (m, 1H), 4.31 - 4.21 (m, 2H), 4.14 - 4.04 (m, 1H), 4.02 - 3.79 (m, 4H), 1.51 - 1.38 (m, 1H), 1.34 - 1.20 (m, 7H), 0.87 - 0.78 (m, 6H). 31 P NMR (162 MHz, DMSO-d6) d 4.18 - 3.79 (m), 0.59 - 0.35 (m). HPLC: t R = 2.78 min; HPLC system: Agilent 1100 series; column: Gemini 5pC18 110A, 50 x 4.6 mm; solvents: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min - 5.0 min 2% - 98% ACN, 5.0 min - 6.0 min 98% ACN, at a rate of 2 mL / min.

[0594] Example 32: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert- butyl)phenoxy)(((S)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2- cyano tetrahydrofuran-3,4-diyl dipropionate Example 33: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert- butyl)phenoxy)(((S)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2- cyano tetrahydrofuran-3,4-diyl diacetate Intermediate T6: L-alanine (S)-tetrahydrofuran-3-yl ester hydrochloride

[0595]

[0596] To a suspension of (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid spiro[3.3]heptan-2-yl ester (Intermediate E2, 0.110 g, 0.020 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile (prepared according to WO2017049060, 0.065 g, 0.20 mmol) and magnesium chloride (0.019 g, 0.0.20 mmol) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (0.07 mL, 0.39 mmol) at 0 °C under an argon atmosphere. After 10 min, the reaction was heated to 50 °C. After 30 min, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics washed with water, dried over sodium sulfate, filtered and concentrated to give (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoic acid spiro[3.3]heptan-2-yl ester (LCMS: MS m / z = 709.7 and 709.7 [M+1], t R = 1.13 and 1.16 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6uC18 100A, 50 mm x 2.1 mm; Solvents: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min).

[0597] Spir[3.3]heptan-2-yl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol- 6-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoate was dissolved in tetrahydrofuran (2 mL) and concentrated hydrochloric acid (11.7 M, 0.400 mL, 4.66 mmol) was added. After 2 hours, the reaction was diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The layers were separated, and the organics were washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The product was purified by HPLC chromatography (0-100% acetonitrile in water) to give the title compound. LCMS: MS m / z = 669.7 [M+1], t R = 1.01 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 - 1.00 min 10% - 100% acetonitrile, 1.00 - 1.35 min 100% acetonitrile, 1.35 - 1.36 min 100 - 10% acetonitrile, 2 uL / min. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.09 (dd, J = 8.8, 1.3 Hz, 2H), 6.96 - 6.86 (m, 2H), 4.81 - 4.74 (m, 2H), 4.43 - 4.32 (m, 2H), 4.27 (ddd, J = 10.3, 5.8, 4.1 Hz), 4.15 (t, J = 5.6 Hz, 1H), 3.81 (dq, J = 9.7, 7.1 Hz, 1H), 2.42 - 2.31 (m, 2H), 2.03 - 1.97 (m, 2H), 1.92 (qd, J = 7.9, 7.1, 3.4 Hz, 4H); 31 P NMR (162 MHz, Methanol-d4) δ 3.83 (s).

[0598] Intermediate T7: ((4-(tert-Butyl)phenoxy)(perfluorophenoxy)phosphoryl)-L-alanine (S)- tetrahydrofuran-3-yl ester ​ ​

[0599]

[0600] 4-(dimethylamino)pyridine (1.4 mg, 0.011 mmol) was added to a solution of (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propionate spiro[3.3]hept-2-yl ester (29, 25 mg, 0.04 mmol) and acetic anhydride (0.12 mL, 0.12 mmol) in tetrahydrofuran (1 mL). After 30 minutes, the reactants were purified by HPLC (25-100% aqueous acetonitrile) to give the title compound. LCMS: MS m / z = 753.8 [M+1], t R = 1.11 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm × 2.1 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile, 2 μL / min. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.84 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.10–7.04 (m, 2H), 6.90 (d, J = 1.0 Hz, 2H), 6.26 (d, J = 6.0 Hz, 1H), 5.53 (dd, J = 6.0, 4.2 Hz, 1H), 4.75 (p, J = 7.3 Hz, 2H), 4.63 (s, 1H), 4.4 4-4.34(m,2H),3.74(t,J=8.1Hz,1H),2.37(dd,J=11.7,7.6Hz,2H),2.14(d,J=12.2Hz,6H),1. 96(dd,J=15.9,9.1Hz,5H),1.83(q,J=8.1Hz,2H),1.33(s,2H),1.29(s,9H),1.17-1.14(m,1H). 31 P NMR (162 MHz, methanol-d4) δ 3.70 (s).

[0601] ​

[0602]

[0603] Intermediate T1 was prepared in a similar manner to Intermediate E2 (2.52 g, 42%) except that L-alanine cyclobutyl ester hydrochloride (1.76 g, 9.78 mmol) was used instead of (2S)-2-aminopropanoic acid spiro[3.3]heptan-2-yl ester hydrochloride. LCMS: MS m / z = 522.1 [M+1], t R = 1.25 min; 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (dd, J = 8.7, 1.7 Hz, 2H), 7.16 (ddd, J = 14.9, 8.7, 1.1 Hz, 2H), 6.86 (td, J = 13.9, 9.9 Hz, 1H), 4.87 (q, J = 7.8 Hz, 1H), 3.94 (ddd, J = 10.4, 6.8, 3.6 Hz, 1H), 2.23 (dtq, J = 10.2, 8.0, 2.3 Hz, 2H), 1.98 - 1.87 (m, 2H), 1.75 - 1.53 (m, 2H), 1.34 - 1.23 (m, 12H). 19 F NMR (376 MHz, DMSO-d6) δ -154.23 (dd, J = 26.2, 21.0 Hz, 2F), -160.49 - -161.47 (m, 1F), -163.73 (td, J = 24.0, 19.7 Hz, 2F). 13 P NMR (162 MHz, DMSO-d6) δ 0.70 (dd, J = 27.6, 13.5 Hz).

[0604] ​ ​

[0605]

[0606] Intermediate T2 was prepared in a similar manner to Intermediate A2 except that Intermediate T1 (389 mg, 0.746 mmol) was used instead of Intermediate A1. T2 was isolated after column chromatography eluting with ethyl acetate / hexanes (0-100%). LCMS: MS m / z = 669.2 and 669.2 [M+1], t R = 1.02 and 1.05 min.

[0607] Compound 31 was prepared in a similar manner to compound 13, except intermediate T2 (346 mg, 0.517 mmol) was used instead of intermediate A2. The diastereomeric 1 : 1 mixture was separated by column chromatography using 10% methanol in dichloromethane as eluting solvent mixture. 50 mg of compound 31 was further purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient). LCMS: MS m / z = 629.2 and 629.2 [M+1], t R = 0.89 and 0.90 min; 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 3.0 Hz, 3H), 7.38 - 7.26 (m, 2H), 7.12 - 6.99 (m, 2H), 6.92 (d, J = 4.5 Hz, 1H), 6.85 (dd, J = 5.9, 4.5 Hz, 1H), 6.35 (dd, J = 9.1, 6.1 Hz, 1H), 6.04 - 5.93 (m, 1H), 5.42 (dd, J = 5.7, 3.8 Hz, 1H), 4.89 - 4.75 (m, 1H), 4.65 (td, J = 5.5, 2.9 Hz, 1H), 4.31 - 4.18 (m, 2H), 4.18 - 4.02 (m, 1H), 3.96 (d, J = 5.5 Hz, 1H), 3.82 - 3.62 (m, 1H), 2.27 - 2.11 (m, 2H), 1.92 (dtt, J = 9.9, 4.8, 2.4 Hz, 2H), 1.56 (s, 2H), 1.25 (d, J = 5.7 Hz, 9H), 1.21 - 1.08 (m, 3H). 31 P NMR (162 MHz, DMSO-d6) δ 4.16 - 3.73 (m).

[0608] The individual isomers of compound 31 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0609] Peak 1 (31a) (faster eluting isomer) data: LCMS: MS m / z = 629.2 [M+1], t R = 0.89 min; 1HNMR (400 MHz, DMSO-d6) δ 7.93 (s, 3H), 7.35 - 7.22 (m, 2H), 7.09 - 6.99 (m, 2H), 6.92 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 4.5 Hz, 1H), 6.33 (d, J = 6.2 Hz, 1H), 6.00 (dd, J = 13.1, 10.0 Hz, 1H), 5.41 (d, J = 5.6 Hz, 1H), 4.87 - 4.74 (m, 1H), 4.65 (dd, J = 6.2, 5.0 Hz, 1H), 4.27 (d, J = 7.6 Hz, 2H), 4.16 - 4.06 (m, 1H), 3.99 - 3.90 (m, 1H), 3.76 - 3.61 (m, 1H), 2.26 - 2.13 (m, 2H), 1.92 (ddq, J = 11.9, 7.3, 2.5, 2.0 Hz, 2H), 1.74 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H), 1.25 (s, 10H), 1.18 - 1.06 (m, 3H). 31 P NMR (162 MHz, DMSO-d6) δ 3.84.

[0610] Peak 2 (31b) (slower eluting isomer) data: LCMS: MS m / z = 629.2 [M+1], t R = 0.90 min; 1 HNMR (400 MHz, DMSO-d6) δ 8.05 - 7.83 (m, 3H), 7.38 - 7.26 (m, 2H), 7.14 - 7.03 (m, 2H), 6.92 (d, J = 4.5 Hz, 1H), 6.86 (d, J = 4.6 Hz, 1H), 6.35 (d, J = 6.2 Hz, 1H), 6.00 (dd, J = 13.1, 10.0 Hz, 1H), 5.41 (d, J = 5.7 Hz, 1H), 4.83 (t, J = 7.5 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.24 (tt, J = 5.7, 2.9 Hz, 2H), 4.14 - 4.02 (m, 1H), 3.96 (q, J = 5.7 Hz, 1H), 3.81 - 3.67 (m, 1H), 2.20 (ddt, J = 10.0, 7.5, 2.5 Hz, 2H), 1.91 (dddd, J = 9.7, 7.1, 4.8, 2.2 Hz, 2H), 1.75 - 1.47 (m, 2H), 1.26 (s, 9H), 1.19 (d, J = 7.1 Hz, 3H). 31 P NMR (162 MHz, DMSO-d6) δ 4.00.

[0611] ​​ ​

[0612]

[0613] Compound 32 was prepared in a similar manner to Example 5, except that 31 (42.5 mg, 0.068 mmol) was used instead of ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alanin methyl ester.

[0614] The individual isomers of compound 32 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0615] Peak 1 (32a) (faster eluting isomer) data: LCMS: MS m / z = 741.2 [M+1], t R = 1.09 min; 1 HNMR (400 MHz, DMSO-d6) δ 7.93 (s, 3H), 7.38 - 7.24 (m, 2H), 7.10 - 6.99 (m, 2H), 6.95 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.05 (d, J = 5.9 Hz, 1H), 5.97 (dd, J = 13.3, 10.1 Hz, 1H), 5.45 (dd, J = 5.9, 4.1 Hz, 1H), 4.86 - 4.76 (m, 1H), 4.64 (d, J = 3.5 Hz, 1H), 4.27 (t, J = 4.9 Hz, 2H), 2.47 - 2.31 (m, 4H), 2.29 - 2.13 (m, 2H), 1.99 - 1.83 (m, 2H), 1.69 (d, J = 10.1 Hz, 1H), 1.61 - 1.49 (m, 1H), 1.25 (s, 7H), 1.15 - 1.02 (m, 7H). 31 P NMR (162 MHz, DMSO-d6) δ 3.65.

[0616] Peak 1 (32a) (faster eluting isomer) data: LCMS: MS m / z = 741.2 [M+1], t R = 1.09 min; 1HNMR (400 MHz, DMSO-d6) δ 8.08 - 7.87 (m, 3H), 7.34 - 7.21 (m, 2H), 7.11 - 6.98 (m, 2H), 6.94 (d, J = 4.5 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.09 - 5.96 (m, 2H), 5.46 (dd, J = 6.0, 4.1 Hz, 1H), 4.90 - 4.78 (m, 1H), 4.60 (d, J = 4.3 Hz, 1H), 4.31 - 4.15 (m, 2H), 3.81 - 3.65 (m, 1H), 2.46 - 2.33 (m, 4H), 2.27 - 2.15 (m, 2H), 1.92 (q, J = 9.6 Hz, 2H), 1.70 (d, J = 10.3 Hz, 1H), 1.62 - 1.50 (m, 1H), 1.25 (s, 7H), 1.18 (d, J = 7.1 Hz, 2H), 1.07 (dt, J = 17.1, 7.5 Hz, 5H). 31 P NMR (162 MHz, DMSO-d6) δ 3.90.

[0617] ​ ​ ​

[0618]

[0619] Compound 33 was prepared in a similar manner to Example 30, except that 31 (42.5 mg, 0.068 mmol) was used instead of 29.

[0620] The individual isomers of compound 33 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0621] Peak 1 (33a) (faster eluting isomer) data: LCMS: MS m / z = 713.2 [M+l], t R = 1.02 min; 1HNMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 31.4 Hz, 2H), 7.94 (s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.05 - 5.95 (m, 2H), 5.41 (dd, J = 5.9, 4.2 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.64 (d, J = 4.0 Hz, 1H), 4.26 (t, J = 4.9 Hz, 2H), 3.64 (d, J = 7.1 Hz, 1H), 2.19 (dt, J = 12.3, 4.2 Hz, 2H), 2.12 (s, 6H), 1.99 - 1.83 (m, 2H), 1.69 (d, J = 10.0 Hz, 1H), 1.55 (dd, J = 10.4, 8.1 Hz, 1H), 1.25 (s, 9H), 1.09 (d, J = 7.0 Hz, 3H). 31 PNMR (162 MHz, DMSO-d6) δ 3.64.

[0622] Peak 1 (33b) (slower eluting isomer) data: LCMS: MS m / z = 713.2 [M+1], t R = 1.03 min; 1 HNMR (400 MHz, DMSO-d6) δ 8.13 - 7.89 (m, 3H), 7.33 - 7.21 (m, 2H), 7.03 (dt, J = 9.6, 2.0 Hz, 2H), 6.94 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.12 - 5.94 (m, 2H), 5.42 (dd, J = 6.0, 4.3 Hz, 1H), 4.88 - 4.76 (m, 1H), 4.60 (d, J = 4.2 Hz, 1H), 4.23 (ddd, J = 18.8, 6.4, 4.4 Hz, 2H), 3.72 (d, J = 7.1 Hz, 1H), 2.21 (td, J = 7.8, 2.8 Hz, 2H), 2.12 (d, J = 3.7 Hz, 6H), 1.99 - 1.86 (m, 2H), 1.75 - 1.63 (m, 1H), 1.56 (dd, J = 10.4, 8.1 Hz, 1H), 1.25 (s, 9H), 1.17 (d, J = 7.1 Hz, 3H). 31 PNMR (162 MHz, DMSO-d6) δ 3.90.

[0623] ​

[0624]

[0625] Intermediate T6 was prepared in a similar manner to Intermediate El, except that (3S)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol) was used instead of spiro[3.3]heptan-2-ol. 1 H NMR (400 MHz, Methanol-d4) δ 5.55 - 5.37 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 4.00 - 3.79 (m, 4H), 2.37 - 2.22 (m, 1H), 2.17 - 2.00 (m, 1H), 1.56 (d, J=7.3 Hz, 3H).

[0626] ​ ​

[0627]

[0628] Intermediate T7 was prepared in a similar manner to Intermediate E2, except that T6 (467 mg, 3.26 mmol) was used instead of (2S)-2-aminopropanoic acid spiro[3.3]heptan-2-yl ester hydrochloride. LCMS: MS m / z = 538.1 [M+l], t R = 1.15 min.

[0629] Example 34: ((((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxy tetrahydrofuran-2-yl)methoxy)(4-(tert-butyl)phenoxy) phosphoryl)-L-alanine (S)-tetrahydrofuran-3-yl ester Example 35: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-1-(((S)-tetrahydrofuran-3-yl)oxy)propan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate Example 36: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-1-(((S)-tetrahydrofuran-3-yl)oxy)propan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2- methylpropanoate)

[0630]

[0631] Intermediate T8 was prepared in a similar manner to Intermediate A2, except that Intermediate T7 (520 mg, 0.968 mmol) was used instead of Intermediate Al. LCMS: MS m / z = 685.2 and 685.2 [M+l], t R = 0.939 and 0.963 min.

[0632] Compound 34 was prepared in a similar manner to Compound 13, except that Intermediate T8 (516 mg, 0.754 mmol) was used instead of Intermediate A2. The diastereomeric 1:1 mixture was separated by column chromatography using 10% methanol in dichloromethane as the eluting solvent mixture. Mixture of isomers: LCMS: MS m / z = 645.2 [M+l], t R = 0.803 min and 0.814 min; 1H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 5.7 Hz, 1H), 7.32 (dd, J = 10.5, 7.8 Hz, 2H), 7.16 - 7.03 (m, 2H), 6.99 - 6.90 (m, 2H), 5.25 (td, J = 6.6, 4.6 Hz, 1H), 4.81 (dd, J = 9.2, 5.4 Hz, 1H), 4.48 - 4.26 (m, 3H), 4.19 (td, J = 5.6, 3.5 Hz, 1H), 3.91 - 3.70 (m, 5H), 2.14 (ddd, J = 14.0, 9.1, 7.0 Hz, 1H), 1.96 (dd, J = 13.3, 6.4 Hz, 1H), 1.35 - 1.22 (m, 12H); 31 P NMR (162 MHz, Methanol-d4) δ 3.83.

[0633] Example 37: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-1-(((S)-tetrahydrofuran-3-yl)oxy)propan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate Example 38: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-1-(((S)-tetrahydrofuran-3-yl)oxy)propan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2- methylpropanoate) Intermediate T9: ((4-cyanophenoxy)(perfluorophenoxy)phosphoryl)-L-alanine 2- ethylbutyl ester

[0634]

[0635] Compound 35 was prepared in a similar manner as Example 30, except that 34 (43.6 mg, 0.064 mmol) was used instead of 29. The desired analog was isolated using preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient). Mixture of stereoisomers: LCMS: MS m / z = 729.2 and 729.2 [M+l], t R = 0.924 min and 0.934 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 4.9 Hz, 1H), 7.39 - 7.23 (m, 2H), 7.12 - 7.04 (m, 2H), 6.96 - 6.86 (m, 2H), 6.23 (dd, J = 36.9, 6.0 Hz, 1H), 5.55 (ddd, J = 5.9, 4.2, 1.4 Hz, 1H), 5.30 - 5.19 (m, 1H), 4.70 - 4.59 (m, 1H), 4.41 (ttd, J = 11.6, 5.7, 3.2 Hz, 2H), 3.95 - 3.68 (m, 5H), 2.23 - 2.09 (m, 7H), 2.03 - 1.91 (m, 1H), 1.38 - 1.23 (m, 12H); 31 P NMR (162 MHz, Methanol-d4) δ 3.69.

[0636] Example 39: ((((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxy tetrahydrofuran-2-yl)methoxy)(4-cyanophenoxy)phosphoryl)- L-alanine 2-ethylbutyl ester Example 40: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((4-cyanophenoxy)(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)Example 40: (2R,3R,4R,5R)-2-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((((4-cyanophenoxy)(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0637]

[0638] Compound 36 was prepared in a similar manner as Example 14, except that 34 (51.5 mg, 0.080 mmol) was used instead of A3. Mixture of stereoisomers: LCMS: MS m / z = 785.2 [M+l], tR= 1.07 min; R = 0.925 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 0.9 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.14 - 7.04 (m, 2H), 6.94 - 6.84 (m, 2H), 6.22 (dd, J = 47.4, 5.9 Hz, 1H), 5.56 (dt, J = 6.0, 3.6 Hz, 1H), 5.31 - 5.21 (m, 1H), 4.67 - 4.58 (m, 1H), 4.49 - 4.36 (m, 2H), 3.93 - 3.71 (m, 5H), 2.75 - 2.56 (m, 2H), 2.15 (ddd, J = 13.9, 6.4, 1.4 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.36 - 1.13 (m, 24H); 31 P NMR (162 MHz, Methanol-d4) δ 3.67.

[0639] ​ ​ ​

[0640]

[0641] Compound 37 was prepared in a similar manner as Example 30, except that the single isomer of compound 34 (52.5 mg, 0.081 mmol) was used instead of 29.

[0642] Single isomer: LCMS: MS m / z = 729.2 [M+l], tR= 0.925 min; R = 0.925 min; 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.97 - 6.87 (m, 2H), 6.27 (d, J = 6.0 Hz, 1H), 5.56 (dd, J = 5.9, 4.2 Hz, 1H), 5.28 - 5.19 (m, 1H), 4.70 - 4.62 (m, 1H), 4.42 (ddd, J = 15.0, 5.6, 3.6 Hz, 2H), 3.90 - 3.70 (m, 5H), 2.16 (d, J = 11.6 Hz, 7H), 2.01 - 1.92 (m, 1H), 1.31 (s, 9H), 1.18 (d, J = 7.1 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.67.

[0643] ​ ​ ​

[0644]

[0645] Compound 38 was prepared in a similar manner as Example 14, except that a single isomer of 34 (52.5 mg, 0.081 mmol) was used instead of A3. Single isomer: LCMS: MS m / z = 785.2 [M+l], t R = 1.07 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.37 - 7.32 (m, 2H), 7.13 - 7.08 (m, 2H), 6.95 - 6.87 (m, 2H), 6.27 (d, J = 5.9 Hz, 1H), 5.56 (dd, J = 6.0, 3.7 Hz, 1H), 5.24 (ddd, J = 6.2, 4.0, 1.8 Hz, 1H), 4.65 (dd, J = 3.7, 2.4 Hz, 1H), 4.50 - 4.36 (m, 2H), 3.91 - 3.72 (m, 6H), 2.66 (dp, J = 22.3, 7.0 Hz, 2H), 2.20 - 2.11 (m, 1H), 1.97 (dd, J = 13.0, 6.5 Hz, 1H), 1.34 - 1.16 (m, 28H); 31 P NMR (162 MHz, Methanol-d4) δ 3.66.

[0646] ​

[0647]

[0648] Intermediate T9 (682 mg, 34%) was prepared in a similar manner to intermediate A1, except that 4-hydroxybenzyl nitrile (388 mg, 3.26 mmol) was used instead of 4-(tert-butyl)phenol. LCMS: MS m / z = 521.1 [M+1], t R =1.16min.

[0649] ​ ​

[0650]

[0651] Intermediate T10 was prepared in a similar manner to intermediate A2, except that intermediate T9 (340 mg, 0.653 mmol) was used instead of intermediate A1. LCMS: MS m / z = 668.2 [M+1],t R =0.994min.

[0652] Compound 39 was prepared in a similar manner to compound 13, except that intermediate T10 (140 mg, 0.210 mmol) was used instead of intermediate A2. A 1:1 mixture of diastereomers was separated by preparative HPLC (Gemini 5 μm NX-C18 110A LC column 100 × 30 mm, 95% to 0% water / acetonitrile gradient). Mixture of isomers: LCMS:MS m / z = 628.2 [M+1], t R =0.856min; 1 H NMR (400MHz, methanol-d4) δ7.86 (d, J = 6.3 Hz, 1H), 7.68 (dd, J = 10.3, 8.7 Hz, 2H), 7. 35(ddd,J=19.8,8.9,1.1Hz,2H),6.98-6.84(m,2H),4.84(t,J=5.8Hz,1H),4 .51-4.31(m,3H),4.22(d,J=5.4Hz,1H),4.07-3.88(m,3H),1.48(d,J=6.1Hz ,1H),1.33(dddd,J=13.4,8.6,5.4,1.5Hz,8H),0.88(td,J=7.4,3.6Hz,6H); 31 P NMR (162MHz, methanol-d4) δ 3.34.

[0653] ​ ​ ​

[0654]

[0655] Compound 40 was prepared in a similar manner as Example 14, except using 39 (38 mg, 0.061 mmol) instead of A3. Mixture of stereoisomers: LCMS: MS m / z = 768.4 and 768.4 [M+1], tR= 1.10 min and 1.11 min; R = 1.10 min and 1.11 min; 1 HNMR (400 MHz, Methanol-d4) δ 7.86 (d, J = 3.3 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.33 (td, J = 9.0, 1.1 Hz, 2H), 6.95 - 6.79 (m, 2H), 6.22 (dd, J = 35.5, 5.9 Hz, 1H), 5.56 (ddd, J = 6.8, 6.0, 3.7 Hz, 1H), 4.64 (ddd, J = 12.8, 3.8, 2.0 Hz, 1H), 4.46 (ddd, J = 18.7, 6.1, 3.8 Hz, 2H), 4.12 - 3.84 (m, 3H), 2.75 - 2.57 (m, 2H), 1.49 (dt, J = 12.4, 6.2 Hz, 1H), 1.41 - 1.13 (m, 19H), 0.89 (td, J = 7.5, 4.4 Hz, 6H); 31 P NMR (162 MHz, Methanol-d4) δ 3.22.

[0656] Intermediate T11: ((4-(Bicyclo[1.1.1]pentan-1-yl)phenoxy)(perfluorophenoxy)phosphoryl)-L-alanine ethyl ester ethyl ester

[0657]

[0658] Intermediate T11 was prepared in a similar manner as Intermediate CI, except using 4-(bicyclo[l. l. l ]pentan-l -yl)phenol (522 mg, 3.26 mmol) instead of 4-(tert-butyl)phenol. LCMS: MS m / z = 506.1 [M+l], tR= 1.19 min. R = 1.19 min.

[0659] Example 41: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(4-(bicyclo[1.1.1]pentan-1-yl)phenoxy)phosphoryl)-L- alanine ethyl ester Example 42: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(bicyclo[1.1.1]pentan-1-yl)phenoxy)(((S)-1-ethoxy-1-oxopropan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate Example 43: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(bicyclo[1.1.1]pentan-1-yl)phenoxy)(((S)-1-ethoxy-1-oxopropan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0660]

[0661] Intermediate T12 was prepared in a similar manner as Intermediate A2, except using Intermediate T11 (377 mg, 0.746 mmol) instead of Intermediate Al. LCMS: MS m / z = 653.2 [M+l],

[0662] Compound 41 was prepared in a similar manner to compound 13, except intermediate T12 (318 mg, 0.487 mmol) was used instead of intermediate A2. The diastereomeric 1 : 1 mixture was separated by column chromatography using 10% methanol in dichloromethane as eluting solvent mixture. 50 mg of compound 41 was further purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient). Mixture of stereoisomers: LCMS: MS m / z = 613.2 and 613.2 [M+1], t = 0.99 min and 1.02 min. R = 0.99 min and 1.02 min. 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 5.6 Hz, 1H), 7.15 - 7.02 (m, 4H), 6.99 - 6.88 (m, 2H), 4.81 (t, J = 5.8 Hz, 1H), 4.46 - 4.36 (m, 2H), 4.31 (ddd, J = 10.8, 5.9, 3.8 Hz, 1H), 4.20 (td, J = 5.5, 1.8 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.90 - 3.77 (m, 1H), 2.53 (d, J = 1.5 Hz, 1H), 2.07 (d, J = 3.1 Hz, 6H), 1.35 - 1.14 (m, 6H); 31 PNMR (162 MHz, Methanol-d4) δ 3.78.

[0663] Example 43: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(bicyclo[1.1.1]pentan-1-yl)phenoxy)(((S)-1-ethoxy-1-oxopropan-2- yl)amino)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2-methylpropanoate) Intermediate T16: ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine spiro[3.3]heptan-2-yl ester Example 44: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine spiro[3.3]heptan-2-yl ester

[0664]

[0665] Compound 42 was prepared in a similar manner to example 30, except 41 (48 mg, 0.078 mmol) was used instead of 29.

[0666] The individual isomers of compound 42 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0667] Peak 1 (42a) (faster eluting isomer): LCMS: MS m / z = 697.2 [M+1], t = 0.97 min; R = 0.97 min; 1H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.18 - 7.02 (m, 4H), 6.96 - 6.87 (m, 2H), 6.27 (d, J = 6.0 Hz, 1H), 5.56 (dd, J = 6.0, 4.3 Hz, 1H), 4.65 (dd, J = 4.0, 2.3 Hz, 1H), 4.50 - 4.34 (m, 2H), 4.09 (qd, J = 7.2, 3.2 Hz, 2H), 3.76 (dd, J = 9.2, 7.1 Hz, 1H), 2.54 (s, 1H), 2.31 - 1.84 (m, 12H), 1.28 - 1.06 (m, 6H); 31 P NMR (162 MHz, Methanol-d4) δ 3.64.

[0668] Peak 2 (42b) (slower eluting isomer): LCMS: MS m / z = 697.2 [M+1], t R = 0.99 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (d, J = 3.9 Hz, 1H), 7.14 - 7.02 (m, 4H), 6.93 - 6.86 (m, 2H), 6.17 (d, J = 6.0 Hz, 1H), 5.55 (dd, J = 6.0, 4.3 Hz, 1H), 4.62 (dd, J = 3.8, 1.9 Hz, 1H), 4.39 (ddd, J = 12.2, 6.1, 3.7 Hz, 2H), 4.11 (qd, J = 7.2, 3.6 Hz, 2H), 3.86 (dd, J = 9.8, 7.1 Hz, 1H), 2.53 (s, 1H), 2.16 (d, J = 12.7 Hz, 6H), 2.07 (d, J = 5.7 Hz, 6H), 1.32 - 1.15 (m, 6H); 31 P NMR (162 MHz, Methanol-d4) δ 3.66.

[0669] Example 45: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- (((( ((S)-1-oxo-1-(spiro[3.3]heptan-2-yloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl diacetate Example 45: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- (((( ((S)-1-oxo-1-(spiro[3.3]heptan-2-yloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl diacetate Intermediate P1: L-alanine 1-propyl ester hydrochloride

[0670]

[0671] Compound 43 was prepared in a similar manner as Example 14, except that 41 (48 mg, 0.078 mmol) was used instead of A3. Mixture of stereoisomers: LCMS: MS m / z = 753.2 and 753.2 [M+1], t R = 1.11 min and 1.13 min; 1HNMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.19 - 7.00 (m, 4H), 6.95 - 6.81 (m, 2H), 6.21 (dd, J = 46.8, 5.9 Hz, 1H), 5.57 (ddd, J = 5.8, 3.9, 1.4 Hz, 1H), 4.69 - 4.56 (m, 1H), 4.49 - 4.33 (m, 2H), 4.11 (dqd, J = 9.4, 7.1, 2.6 Hz, 2H), 3.82 (ddd, J = 40.8, 9.5, 7.1 Hz, 1H), 2.74 - 2.59 (m, 2H), 2.53 (d, J = 3.0 Hz, 1H), 2.07 (d, J = 6.4 Hz, 6H), 1.38 - 1.12 (m, 18H); 31 P NMR (162 MHz, Methanol-d4) δ 3.62.

[0672] Intermediate P2: (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino] propanoic acid 1-propyl ester

[0673]

[0674] Intermediate T16 was prepared in a similar manner to Intermediate H2, except that Intermediate T15 (590 mg, 2.69 mmol) was used instead of L-alanine 2-methoxy-2-methylpropyl ester hydrochloride and N-ethyl-N-isopropyl-propan-2-amine (1.4 mL, 8.06 mmol, 3 eq) was used as the base instead of triethylamine. LCMS: MS m / z = 506.0 [M+1], t = 1.19 min. R = 1.19 min.

[0675] Example 47: (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy](phenoxy)phosphoryl]amino] propanoic acid 1-propyl ester ​

[0676]

[0677] Intermediate T17 was prepared in a similar manner to Intermediate A2, except that Intermediate T16 (408 mg, 0.808 mmol) was used instead of Intermediate Al. LCMS: MS m / z = 653.2 and 6.53.2 [M+1], t = 0.997 min and 1.01 min. R = 1.19 min.

[0678] Compound 44 was prepared in a similar manner to Compound 13, except that Intermediate T17 (431 mg, 0.662 mmol) was used instead of Intermediate A2. The diastereomeric 1 : 1 mixture was separated by column chromatography using 10% methanol in dichloromethane as the eluting solvent mixture. Mixture of stereoisomers: LCMS: MS m / z = 613.2 and 613.2 [M+1], t = 0.997 min and 1.01 min. R= 0.859 min and 0.870 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 7.0 Hz, 1H), 7.32 (dt, J = 8.7, 7.0 Hz, 2H), 7.24 - 7.13 (m, 3H), 6.98 - 6.84 (m, 2H), 4.83 - 4.75 (m, 2H), 4.41 (ddd, J = 11.5, 5.4, 2.3 Hz, 2H), 4.35 - 4.27 (m, 1H), 4.20 (dt, J = 14.0, 5.5 Hz, 1H), 3.90 - 3.77 (m, 1H), 2.45 - 2.34 (m, 2H), 2.07 - 1.90 (m, 6H), 1.89 - 1.79 (m, 2H), 1.25 (ddd, J = 17.4, 7.1, 1.1 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.67.

[0679] Compound 44 was further purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to isolate the individual isomers.

[0680] Peak 1 (44a) (faster eluting isomer): LCMS: MS m / z = 613.2 [M+l], t R = 0.86 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.20 - 7.12 (m, 3H), 6.98 - 6.88 (m, 2H), 4.83 - 4.75 (m, 2H), 4.46 - 4.37 (m, 2H), 4.32 (ddd, J = 10.7, 5.7, 3.7 Hz, 1H), 4.22 (t, J = 5.4 Hz, 1H), 3.88 - 3.75 (m, 1H), 2.40 (ddt, J = 9.4, 7.2, 2.6 Hz, 2H), 2.09 - 1.78 (m, 9H), 1.23 (dd, J = 7.1, 1.2 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.70.

[0681] Peak 2 (44b) (slower eluting isomer): LCMS: MS m / z = 613.2 [M+l], t R = 0.87 min; 1H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.38 - 7.29 (m, 2H), 7.21 (dd, J = 7.6, 1.1 Hz, 3H), 6.96 - 6.86 (m, 2H), 4.84 - 4.75 (m, 2H), 4.45 - 4.35 (m, 2H), 4.34 - 4.25 (m, 1H), 4.19 (s, 1H), 3.84 (dq, J = 9.8, 7.1 Hz, 1H), 2.42 - 2.32 (m, 2H), 2.04 - 1.81 (m, 8H), 1.28 (dd, J = 7.1, 1.1 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.65.

[0682] ​ ​ ​

[0683]

[0684] Compound 45 was prepared in a similar manner as Example 30, except that compound 44 (50 mg, 0.082 mmol) was used instead of 29. Mixture of stereoisomers: LCMS: MS m / z = 697.2 and 697.2 [M+l], t R = 0.975 min and 0.990 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (d, J = 4.4 Hz, 1H), 7.31 (ddd, J = 15.5, 8.8, 7.3 Hz, 2H), 7.17 (q, J = 7.5 Hz, 3H), 6.96 - 6.81 (m, 2H), 6.26 (dd, J = 33.3, 5.9 Hz, 1H), 5.56 (ddd, J = 7.9, 5.9, 4.2 Hz, 1H), 4.85 - 4.75 (m, 1H), 4.64 (ddt, J = 9.6, 3.9, 1.9 Hz, 1H), 4.48 - 4.32 (m, 2H), 3.81 (ddd, J = 26.1, 9.5, 7.1 Hz, 1H), 2.43 - 2.35 (m, 2H), 2.16 (dd, J = 12.8, 2.0 Hz, 6H), 2.08 - 1.77 (m, 7H), 1.33 - 1.24 (m, 2H); 31 P NMR (162 MHz, Methanol-d4) δ 3.54 (d, J = 11.9 Hz).

[0685] Compound 45 was further purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100x30mm, 95% to 0% water / acetonitrile gradient) to isolate the individual isomers.

[0686] Peak 1 (45a) (faster eluting isomer): LCMS: MS m / z = 697.2 [M+1], t R = 0.98 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.37 - 7.29 (m, 2H), 7.19 (dq, J = 8.1, 1.1 Hz, 3H), 6.98 - 6.89 (m, 2H), 6.30 (d, J = 6.0 Hz, 1H), 5.57 (dd, J = 6.0, 4.2 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.65 (dq, J = 3.8, 1.7 Hz, 1H), 4.49 - 4.34 (m, 2H), 3.77 (dd, J = 9.2, 7.1 Hz, 1H), 2.45 - 2.31 (m, 2H), 2.15 (d, J = 12.5 Hz, 6H), 2.05 - 1.77 (m, 8H), 1.18 (dd, J = 7.1, 1.2 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.63.

[0687] Peak 2 (45b) (slower eluting isomer): LCMS: MS m / z = 697.2 [M+1], t R = 1.00 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.29 (dd, J = 8.7, 7.1 Hz, 2H), 7.17 (dt, J = 8.0, 1.1 Hz, 3H), 6.87 (s, 2H), 6.21 (d, J = 5.9 Hz, 1H), 5.55 (dd, J = 5.9, 4.3 Hz, 1H), 4.84 - 4.76 (m, 1H), 4.62 (dd, J = 3.9, 1.7 Hz, 1H), 4.42 - 4.27 (m, 2H), 3.84 (dd, J = 9.8, 7.1 Hz, 1H), 2.45 - 2.33 (m, 2H), 2.16 (d, J = 13.2 Hz, 6H), 2.07 - 1.77 (m, 8H), 1.28 (dd, J = 7.1, 1.1 Hz, 3H); 31 P NMR (162 MHz, Methanol-d4) δ 3.54.

[0688] ​ ​ ​

[0689]

[0690] Compound 46 was prepared in a similar manner as Example 14, except that 44 (54 mg, 0.078 mmol) was used instead of A3. Mixture of stereoisomers: LCMS: MS m / z = 753.4 and 753.4 [M+1], t R = 1.12 min and 1.13 min; 1 HNMR (400 MHz, Methanol-d4) δ 7.87 (d, J = 1.4 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.24 - 7.13 (m, 3H), 6.97 - 6.81 (m, 2H), 6.25 (dd, J = 36.6, 5.9 Hz, 1H), 5.58 (td, J = 5.6, 3.7 Hz, 1H), 4.80 (dt, J = 18.8, 7.4 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.49 - 4.34 (m, 2H), 3.81 (ddd, J = 23.0, 9.5, 7.1 Hz, 1H), 2.73 - 2.59 (m, 2H), 2.44 - 2.34 (m, 2H), 2.07 - 1.77 (m, 8H), 1.32 - 1.16 (m, 15H); 31 P NMR (162 MHz, Methanol-d4) δ 3.53.

[0691] Compound 46 was further purified by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient) to isolate individual isomers.

[0692] Peak 1 (46a) (faster eluting isomer): LCMS: MS m / z = 753.2 [M+1], t R = 1.14 min; 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.39 - 7.27 (m, 2H), 7.26 - 7.05 (m, 3H), 6.91 (s, 2H), 6.30 (d, J = 5.9 Hz, 1H), 5.58 (dd, J = 5.9, 3.8 Hz, 1H), 4.78 (p, J = 7.4 Hz, 1H), 4.65 (dd, J = 3.8, 2.0 Hz, 1H), 4.49 - 4.35 (m, 2H), 4.12 (dd, J = 24.1, 5.3 Hz, 1H), 3.87 - 3.74 (m, 1H), 3.65 - 3.45 (m, 1H), 2.66 (dp, J = 23.0, 7.0 Hz, 2H), 2.45 - 2.34 (m, 2H), 2.10 - 1.56 (m, 8H), 1.35 - 1.18 (m, 15H); 31 P NMR (162 MHz, Methanol-d4) δ 3.63.

[0693] Peak 2 (46b) (slower eluting isomer): LCMS: MS m / z = 753.2 [M+1], t R = 1.00 min; 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.29 (dd, J = 8.7, 7.0 Hz, 2H), 7.17 (d, J = 7.8 Hz, 3H), 6.91 - 6.80 (m, 2H), 6.21 (d, J = 5.8 Hz, 1H), 5.57 (dd, J = 5.9, 3.7 Hz, 1H), 4.61 (dd, J = 4.1, 1.8 Hz, 2H), 4.40 (pd, J = 11.1, 4.2 Hz, 2H), 4.19 - 4.03 (m, 1H), 3.90 - 3.79 (m, 1H), 3.62 - 3.45 (m, 1H), 2.67 (dp, J = 24.1, 7.0 Hz, 2H), 2.39 (td, J = 12.5, 12.0, 7.1 Hz, 2H), 2.09 - 1.77 (m, 8H), 1.36 - 1.19 (m, 15H); 31 P NMR (162 MHz, Methanol-d4) δ 3.48.

[0694] ​

[0695]

[0696] To a stirred solution of (tert-butoxycarbonyl)-L-alanine (7.5 g, 39.6 mmol) and 1-propanol (2.74 mL, 36.6 mmol) in dry dichloromethane (50 mL) at 0 °C under an argon atmosphere was added N-methylmorpholine (12.1 mL, 110 mmol), 4-(dimethylamino)pyridine (90 mg, 0.73 mmol) and tripropyl phosphine acid cyclizing anhydride (T3P, 26.2 mL, 50% in ethyl acetate). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with water (2 x 50 mL) and once with brine (50 mL), dried over magnesium sulfate, filtered through 3 cm silica gel which was washed with additional dichloromethane. The combined organics were concentrated under reduced pressure and dried under high vacuum.

[0697] The residue was then dissolved in 30 mL of a 4M HCI solution in 1,4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, co-distilled with toluene to give the product which was dried under high vacuum for 1 hour. The residue was used without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 8.62 (broad s, 3H), 4.20-4.01 (m, 3H), 1.67-1.57 (m, 2H), 1.42 (d, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0698] ​ ​

[0699]

[0700] To a solution of phosphorus oxychloride (V) (0.572 mL, 6.14 mmol) in dichloromethane (20 mL) at -78 °C under an atmosphere of argon was added 4-tert-butylphenol (0.922 g, 6.14 mmol). N,N- Diisopropylethylamine (1.07 mL, 6.14 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to 0 °C. L-alanine 1-propyl ester hydrochloride (1.03 g, 6.14 mmol) was added. N,N- Diisopropylethylamine (2.14 mL, 12.3 mmol) was added over 5 minutes. After 30 minutes, 2,3,4,5,6-pentafluorophenol (1.13 g, 6.14 mmol) was added. N,N- Diisopropylethylamine (1.07 mL, 6.14 mmol) was added over 5 minutes. After 15 minutes, the reaction mixture was allowed to warm to room temperature. After 30 minutes, the reaction was acidified with acetic acid using pH paper. The reaction was washed with water (50 mL). The organics were dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give P2: (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid 1-propyl ester. LCMS: MS m / z = 1041.1 [2M+Na + ].

[0701] ​ Base) -5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoic acid 1- propyl ester

[0702]

[0703] To a suspension of (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy) phosphoryl]amino]propanoic acid 1 -propyl ester (0.332 g, 0.554 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile (prepared according to WO2017049060, 0.184 g, 0.554 mmol) and magnesium chloride (0.057 g, 0.594 mmol) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.594 mmol) at room temperature under an argon atmosphere. After 10 minutes, the reaction was heated to 50 °C. After 2 hours, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics washed with water, dried over sodium sulfate, filtered and concentrated to give (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoic acid 1 -propyl ester. LCMS: MS m / z = 657.2 [M+H + ] at 2.09 min.

[0704] (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2- dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert-butylphenoxy) phosphoryl]amino]propanoic acid 1 -propyl ester was dissolved in tetrahydrofuran (2 mL) and concentrated hydrochloric acid (1 1.7 M, 0.400 mL, 4.66 mmol) was added. After 2 hours, the reaction was diluted with ethyl acetate and neutralised with saturated aqueous sodium bicarbonate solution. The layers were separated and the organics washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product was isolated by HPLC chromatography (0-100% acetonitrile in water) to give the title compound.

[0705] Peak 1 : Compound 47a (first eluting isomer): LCMS: MS m / z = 617.2 [M+H + ] at 2.09 min. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.35 - 7.23 (m, 2H), 7.11 - 7.00 (m, 2H), 7.00 - 6.88 (m, 2H), 4.81 (d, J = 5.5 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.32 (ddd, J = 11.0, 5.6, 3.7 Hz, 1H), 4.19 (t, J = 5.5 Hz, 1H), 4.12 - 3.94 (m, 2H), 3.84 (dq, J = 9.1, 7.1 Hz, 1H), 1.73 - 1.54 (m, 2H), 1.29 (s, 9H), 1.28 - 1.21 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 3.70 (s).

[0706] Peak 2: Compound 47b (second eluting isomer): LCMS: MS m / z = 617.2 [M+H + ] of 617.2. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.35 - 7.25 (m, 2H), 7.12 - 7.00 (m, 2H), 6.97 - 6.90 (m, 2H), 4.82 (d, J = 5.4 Hz, 1H), 4.45 - 4.35 (m, 2H), 4.35 - 4.25 (m, 1H), 4.19 (t, J = 5.6 Hz, 1H), 4.10 - 3.95 (m, 2H), 3.93 - 3.82 (m, 1H), 1.67 - 1.55 (m, 2H), 1.32 - 1.28 (m, 12H), 0.92 (t, J = 7.4 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 3.67 (s).

[0707] Example 48: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-cyclobutyloxypropan-2-yl)amino)phosphoryl)oxy)methyl)-2- cyanotetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0708]

[0709] Compound 48 was prepared in a similar manner to compound 14, except that compound 48 was used instead of compound 13. The individual isomers of compound 48 were separated by preparative HPLC (Gemini 5um NX-C18 110A LC column 100 x 30 mm, 95% to 0% water / acetonitrile gradient).

[0710] Peak 1 : Compound 48a: first eluting isomer: LCMS: MS m / z = 757.3 [M+H + ] of 757.3.1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 2.9 Hz, 1H), 7.38 - 7.25 (m, 2H), 7.09 (ddd, J = 10.3, 8.7, 1.3 Hz, 2H), 6.95 - 6.83 (m, 2H), 5.56 (ddd, J = 6.0, 3.8, 2.7 Hz, 1H), 4.51 - 4.34 (m, 2H), 4.15 - 3.93 (m, 2H), 3.84 (ddd, J = 38.2, 9.4, 7.1 Hz, 1H), 2.76 - 2.56 (m, 2H), 1.71 - 1.55 (m, 2H), 1.34 - 1.09 (m, 24H), 0.93 (q, J = 7.4 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 3.57 (s).

[0711] Peak 2: Compound 48b: second eluting isomer: LCMS: MS m / z = 757.3 [M+H + ]. 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.32 - 7.26 (m, 2H), 7.10 - 7.04 (m, 2H), 6.92 - 6.84 (m, 2H), 6.16 (d, J = 5.9 Hz, 1H), 5.57 (dd, J = 5.9, 3.7 Hz, 1H), 4.70 - 4.56 (m, 1H), 4.48 - 4.32 (m, 2H), 4.11 - 3.97 (m, 2H), 3.89 (dq, J = 9.9, 7.1 Hz, 1H), 2.67 (dp, J = 24.1, 7.0 Hz, 2H), 1.64 (hept, J = 6.9 Hz, 2H), 1.36 - 1.22 (m, 21H), 1.20 (d, J = 7.0 Hz, 6H), 0.94 (t, J = 7.4 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 3.57 - 3.51 (m).

[0712] Intermediate P3: L-alanine cyclobutyl ester hydrochloride

[0713]

[0714] To a stirred solution of (tert-butoxycarbonyl)-L-alanine (4.91 g, 26.0 mmol) and cyclobutanol (1.70 g, 23.6 mmol) in anhydrous dichloromethane (50 mL) at 0 °C under an argon atmosphere was added N-methylmorpholine (7.78 mL, 70.7 mmol), 4-(dimethylamino)pyridine (57.6 mg, 0.47 mmol) and tripropyl phosphine acid cyclizing anhydride (T3P, 16.8 mL, 50% in ethyl acetate, 28.3 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with water (2 x 50 mL) and once with brine (50 mL), dried over magnesium sulfate, filtered through 3 cm silica gel which was washed with additional dichloromethane. The combined organics were concentrated under reduced pressure and dried under high vacuum overnight.

[0715] The residue was then dissolved in 30 mL of a 4M solution of HC1 in 1,4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, co-distilled with toluene to give the product which was dried under high vacuum for 1 hour. The residue was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (broad s, 3H), 5.01 (pd, J = 7.5, 7.1, 0.9 Hz, 1H), 4.08 (q, J = 7.2 Hz, 1H), 2.40 - 2.22 (m, 2H), 2.07 (dqd, J = 12.6, 10.0, 7.9 Hz, 2H), 1.87 - 1.70 (m, 1H), 1.70 - 1.54 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H).

[0716] Intermediate P4: (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino] cyclobutyl ester

[0717]

[0718] To a solution of phosphorus oxychloride (V) (0.534 mL, 5.73 mmol) in dichloromethane (20 mL) at -78 °C under an argon atmosphere was added 4-tert-butylphenol (0.769 g, 5.12 mmol). N,N- Diisopropylethylamine (1.0 mL, 5.73 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to 0 °C. L-alanine cyclopropyl ester hydrochloride (1.03 g, 6.14 mmol) was added. N,N- Diisopropylethylamine (2.0 mL, 11.5 mmol) was added over 5 minutes. After 30 minutes, 2,3,4,5,6-pentafluorophenol (1.054 g, 5.73 mmol) was added. N,N- Diisopropylethylamine (1.0 mL, 5.73 mmol) was added over 5 minutes. After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was acidified with acetic acid using pH paper. The reaction was washed with water (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The product P4 was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid cyclobutyl ester. LCMS: MS m / z = 521.8 [M+H + ].

[0719] Example 49: (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]cyclo butyl ester

[0720]

[0721] To a suspension of (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoic acid cyclobutyl ester (0.292 g, 0.477 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile (prepared according to WO2017049060, 0.158 g, 0.477 mmol) and magnesium chloride (0.049 g, 0.511 mmol) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (89 uL, 0.511 mmol) at room temperature under an argon atmosphere. After 10 minutes, the reaction was heated to 50 °C. After 2 hours, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics washed with water, dried over sodium sulfate, filtered and concentrated to give (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoic acid cyclobutyl ester. LCMS: MS m / z = 668.9 [M+H + ] at 2.2 minutes.

[0722] (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoic acid cyclobutyl ester was dissolved in tetrahydrofuran (2 mL) and concentrated hydrochloric acid (11.7 M, 0.400 mL, 4.66 mmol) was added. After 2 hours, the reaction was diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The layers were separated and the organics washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product was purified by HPLC chromatography (0-100% acetonitrile in water) to give the title compound as a mixture of stereoisomers. LCMS: MS m / z = 628.8 [M+H + ] at 2.2 minutes.

[0723] Example 50: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((((4-(tert-butyl)phenoxy)(((S)-1-oxo-cyclobutyloxypropan-2-yl)amino)phosphoryl)oxy)methyl)-2- cyanotetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0724]

[0725] Compound 50 was prepared in a similar manner to compound 14, except that compound 49 was used instead of compound 13. The individual isomers of compoun...

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; R 1 and R 2 are each H; R 3A is H or C 1- C6alkyl; wherein said C 1- C6alkyl is optionally substituted with -OH or phenyl; R 3B is H or C1-C3alkyl; and R 4 is (i) C1-C8alkyl, (ii) -(CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C3-C 10 cycloalkyl, (iv) 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, or (v) 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; wherein said C1-C8alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl optionally substituted with one or two R 4A groups; wherein Each R 4A Independently, it is a C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S; wherein the C3-C 10 cycloalkyl, C6-C 10 The aryl or 4- to 6-membered heterocyclic group is optionally substituted by one or two independent substituents selected from the group consisting of C1-C6 alkyl, haloyl, C1-C6 haloalkyl and C1-C6 alkoxy groups; The base is Ar is C6-C10aryl or a 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S; 10 Ar is C6-C10aryl or a 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S m is 1, 2, 3, 4, or 5. Each R 5 Independently, it is a halogenated group, cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, or -COOR group. 5A -SO2R 5A The C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 alkoxy group, C1-C6 alkoxy group, 4-6 heterocyclic alkyl group and 5-6 heteroaryl group are optionally separated by one or two R atoms. 5B Group substitution; or Two Rs on adjacent carbon atoms 5 Groups are linked to form C5-C6 cycloalkyl groups; Each R 5A It is independently a C1-C6 alkyl group; each R is independently -OH, -OR 5B is independently -OH, -OR 5C , -COOR 5C , and -NHCOOR 5D ; wherein R 5C is C1-C6 alkyl, and R 5D is C1-C3 alkyl optionally substituted with a phenyl group; each R 8 , R 9 , R 10 , R 11 , and R 12 is independently H or C1-C3alkyl; and 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula la:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula lb:

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 2.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein is a 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein is C6-C 10 aryl; n is 0, 1, or 2; and each R 5 is independently halo, cyano, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, or -SO2R 5A ; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein is selected from the group consisting of:

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein is C6-C 10 aryl; n is 0, 1, or 2; and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-11, wherein is C6-C 10 aryl; n is 0, 1, or 2; and each R 5 is independently C1-C6alkyl or C3-C6cycloalkyl.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein is phenyl or naphthyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein is phenyl or naphthyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein is phenyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein is phenyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein is phenyl.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein is naphthyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C5-C6cycloalkyl.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13 and 18, wherein is naphthyl; n is 0, 1, or 2; and each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13, 18, and 19, wherein is 1-naphthyl or 2-naphthyl.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-20, wherein R 3A is C1-C6 alkyl optionally substituted with -OH or phenyl.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-21, wherein R 3A is C1-C3 alkyl optionally substituted with -OH or phenyl.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R 3A is Ci-C6alkyl.

24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-23, wherein R 3A is C1-C3alkyl.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-24, wherein R 3A is methyl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R 3B is H.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein m is 2 or 3.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-26, wherein R 4 is -(CR 8 R 9 CR 10 R 11 O) m R 12 .

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is C1-C8 alkyl optionally substituted with one or two R 4A .

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R 4 is Ci-C8alkyl optionally substituted with one R 4A .

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R 4 is C1-C6 alkyl optionally substituted with one or two R 4A .

32. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-31, wherein R 4 is C1-C6 alkyl optionally substituted with one R 4A .

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl optionally substituted with one or two R 4A .

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl optionally substituted with one R 4A .

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-33, wherein R 4A is C3-C 10 cycloalkyl or 4- to 6-membered heterocyclyl having one O.

36. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-35, wherein R 4A is C3-C6cycloalkyl or 4- to 6-membered heterocyclyl with one O.

37. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-36, wherein R 4A is cyclobutyl, oxetanyl, or tetrahydropyranyl.

38. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-37, wherein R 4A is cyclobutyl.

39. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-37, wherein R 4A is oxetanyl.

40. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-37, wherein R 4A is tetrahydropyranyl.

41. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-40, wherein R 4 is selected from the group consisting of hexyl, methyl, and ethyl.

42. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-41, wherein R 4 is hexyl.

43. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-41, wherein R 4 is methyl.

44. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-41, wherein R 4 is ethyl.

45. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is C3-C8cycloalkyl.

46. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 45, wherein R 4 is cyclobutyl, cyclohexyl, or cyclooctyl.

47. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, 45, and 46, wherein R 4 is cyclobutyl.

48. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, 45, and 46, wherein R 4 is cyclohexyl.

49. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, 45, and 46, wherein R 4 is cyclooctyl.

50. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S.

51. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 50, wherein R 4 is 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S.

52. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, 50, and 51, wherein R 4 is 4- to 6-membered heterocyclyl having 1 heteroatom selected from N, O, and S.

53. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 50-52, wherein R 4 is 4- to 6-membered heterocyclyl having one O.

54. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 50-53, wherein R 4 is oxetanyl or tetrahydropyranyl.

55. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 50-54, wherein R 4 is oxetanyl.

56. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28 and 50-54, wherein R 4 is tetrahydropyranyl.

57. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is -(CR 8 R 9 CR 10 R 11 O) m R 12 ; wherein each R 8 , R 9 , R 10 , R 11 and R 12 is independently H or C1-C3 alkyl, and m is 1, 2, 3, 4, or 5.

58. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is -(CH2CH2O) m R 12 ; wherein R 12 is H or C1-C3 alkyl, and m is 1, 2, 3, 4, or 5.

59. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is -(CH2CH2O) m R 12 ; wherein R 12 is C1-C3 alkyl, and m is 1, 2, 3, 4, or 5. (i) methyl, 61. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R 4 is selected from the group consisting of: (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (xii) cyclobutyl, (v) (vi) (vii) (viii) (ix) (x) (xi) (xiii) cyclohexyl, (xiv) cyclooctyl, (i) methyl, (xv) (xvi) (xvii) (xviii) (xix) (xx) (xxi) (xxii) (xxiii) (xxiv) (xxv) (xxvi) (xxvii) (xxviii) (xxix) (xxx) (xxxi) (xxxii) (xxxiii) and (xxxiv) 62. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 28 and 61, wherein R 4 is selected from the group consisting of: (ii) ethyl, (vi) cyclobutyl, (iii) (iv) (v) (vii) cyclohexyl, (viii) cyclooctyl, 63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, wherein n is 0. (ix) (x) (xi) (xii) (xiii) (xiv) (xv) (xvi) (xvii) (xviii) and (xix) 64. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, wherein n is 1.

65. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, wherein n is 2.

70. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein:

66. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein each R 5 is independently halo, cyano, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, or C1-C6alkoxy.

67. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-66, wherein each R 5 is independently halo, cyano, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy.

68. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-67, wherein each R 5 is independently Ci-C6alkyl or C3-C6cycloalkyl.

69. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 62, wherein R 5 is t-Bu, isopropyl, methyl, or cyclopropyl. n is 0 or 1; and R 3A is H or Ci-C6alkyl; R 3B is H or Ci-C6alkyl; R 4 is C3-C 10 cycloalkyl; Ar is C6-C 10 Aryl; 71. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein: R 5 is C1-C6 alkyl. n is 0 or 1; and R 3A is H or methyl; R 3B is H or methyl; R 4 is C3-C8cycloalkyl; Ar is C6-C 10 Aryl; 72. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: R 5 is C1-C6 alkyl.

73. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

74. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

75. A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of any one of claims 1-74, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

76. The pharmaceutical formulation of claim 75, wherein the pharmaceutical formulation is for subcutaneous administration.

77. The pharmaceutical formulation of claim 75, wherein the pharmaceutical formulation is for intravenous administration.

78. The pharmaceutical formulation of claim 75, wherein the pharmaceutical formulation is for oral administration.

79. The pharmaceutical formulation of claim 75, wherein the pharmaceutical formulation is for administration by inhalation. ​ 80. Use of a compound or pharmaceutically acceptable salt thereof of any one of claims 1- 74 in the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

81. The use of claim 80, wherein the compound is administered to the human via inhalation.

82. The use of claim 80 or 81, wherein the medicament is administered with at least one additional therapeutic agent.

83. The use of any one of claims 80-82, wherein the viral infection is a coronavirus infection.

84. The use of any one of claims 80-82, wherein the viral infection is a SARS-CoV-2 infection (COVID-19).

85. The use of any one of claims 80-84, wherein the viral infection is a SARS virus infection.

86. The use of any one of claims 80-84, wherein the viral infection is a MERS virus infection.

87. The use of any one of claims 80-82, wherein the viral infection is a pneumoviridae virus infection.

88. The use of claim 87, wherein the pneumoviridae virus infection is a respiratory syncytial virus infection.

89. The use of claim 87, wherein the pneumoviridae virus infection is a human metapneumovirus infection.

90. The use of any one of claims 80-82, wherein the viral infection is a picornaviridae virus infection.

91. The use of claim 90, wherein the picornaviridae virus infection is a human rhinovirus infection.

92. The use of any one of claims 80-82, wherein the viral infection is a flaviviridae virus infection.

93. The use of claim 92, wherein the flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

94. The use of any one of claims 80-82, wherein the viral infection is a filoviridae virus infection.

95. The use of claim 94, wherein the filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

96. The use of any one of claims 80-82, wherein the viral infection is an orthomyxoviridae virus infection.

97. The use of claim 96, wherein the viral infection is an influenza virus infection.

98. The use of any one of claims 80-82, wherein the viral infection is a paramyxoviridae virus infection.

99. The use of claim 98, wherein the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

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