Methods for treating SARS cov-2 infection

Abstract

To provide a method for treating diseases.SOLUTION: Methods are provided for treating 2019 - nCoV virus (SARS-CoV-2) infections by administering nucleosides and prodrugs thereof of Formula I, wherein the 1 ' position of the nucleoside sugar is substituted.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 031,373, filed May 28, 2020, U.S. Provisional Application No. 62 / 985,194, filed March 4, 2020, U.S. Provisional Application No. 62 / 976,671, filed February 14, 2020, and U.S. Provisional Application No. 62 / 966,440, filed January 27, 2020, the entire contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention relates generally to methods and compounds for treating or preventing 2019 novel coronavirus (2019-nCoV, SARS-CoV-2) infection (COVID-19), and in particular to methods and nucleosides and prodrugs thereof for treating or preventing 2019-nCoV infection (COVID-19). [Background technology]

[0003] Coronaviruses, named for the crown-like spikes on their surface, mostly infect bats, pigs, and small mammals. Coronaviruses mutate easily and can jump from animals to humans and from one human to another. In recent years, they have been at the center of infectious disease outbreaks worldwide. Recently, a novel coronavirus was identified in Wuhan, China (Wuhan coronavirus, 2019-nCoV, SARS-CoV-2, also known as transmissible acute respiratory syndrome (TARS-CoV), clustered acute respiratory syndrome coronavirus (clustered acute respiratory syndrome coronavirus). acute respiratory syndrome coronavirus (CARS-CoV), or rapidly spreading respiratory syndrome coronavirus (RS-CoV) Rapid spread respiratory syndrome coronavirus (R Currently, a large outbreak of 2019-nCoV-associated pneumonia is occurring in China. There remains an urgent need to develop safe and effective products to protect against and / or treat 2019-nCoV infection. Summary of the Invention [Means for solving the problem]

[0004] Methods and compounds are provided for the treatment or prevention of infection caused by 2019-nCoV (COVID-19).

[0005] 1. A method for treating or preventing 2019-nCoV infection in a human in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula I [ka] or a pharmaceutically acceptable salt or ester thereof, During the ceremony, Each R 1 is H or a halogen, Each R 2 , R 3 , R 4 , or R 5 are independent, H, OR a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl; Or, any two R on adjacent carbon atoms 2 , R 3 , R 4 , or R 5 when taken together are -O(CO)O- or when taken together with the ring carbon atom to which they are attached form a double bond, R 6 But, OR a, N(R a )2, N3, CN, NO2, S(O) n R a , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 , halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl; R 7 but, a) H, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), or -SO2NR 11 R 12 , [In the formula, each R 11 or R 12 Each of (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally includes one or more of halo, hydroxy, CN, N3, N(R a )2, OR a wherein one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyls are optionally substituted with -O-, -S-, or -NR a - may be replaced by b) [ka] c) [ka] [During the ceremony, R c is phenyl, 1-naphthyl, 2-naphthyl, [ka] is selected from R d is H or CH3, R e1 and R e2 are each independently H, (C1-C6) alkyl, or benzyl; R f is selected from H, (C1-C8)alkyl, benzyl, (C3-C6)cycloalkyl, and —CH2—(C3-C6)cycloalkyl; R g is selected from (C1-C8)alkyl, —O—(C1-C8)alkyl, benzyl, —O-benzyl, —CH2—(C3-C6)cycloalkyl, —O—CH2—(C3-C6)cycloalkyl, and CF3; n' is selected from 1, 2, 3, and 4; and d) a group of the formula: [ka] [During the ceremony, Q is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2; Z 1 and Z 2 When put together, -Q 1 (C(R y )2)3Q 1 - and During the ceremony, Each Q 1 are independently O, S, or NR; Each Ry are independently H, F, Cl, Br, I, OH, R, -C(=Q 2 )R, -C(=Q 2 ) OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR,-S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 ) OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 ) OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 ) OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 or when taken together, two R on the same carbon atom y forms a carbocyclic ring of 3 to 7 carbon atoms, Each Q 2 are independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2, or Z 1 and Z 2 are each independently a group of formula Ia, [ka] During the ceremony, Each Q 3 are independently bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2; M2 is 0, 1, or 2; Each R x are independently expressed as R in the following formula: y and [ka] During the ceremony, each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 3 is Z 4 or Z 5 and Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y , or -SO2Z 5 and Z 5 is a carbocyclic or heterocyclic ring, 5 are independently 0 to 3 R y substituted with a group; R 8 But halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NNHR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C-1-C8) alkyl, (C6-C 20 )aryl(C1-C8)alkyl, OR 11 or SR 11and Each R 9 or R 10 are independently H, halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NHNR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , R 11 , OR 11 , or SR 11 and Each R 11 or R 12 are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, -C (=O)(C1-C8)alkyl, -S(O) n (C-1-C8) alkyl, or (C6-C 20 ) aryl(C1-C8) alkyl, or R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, and any one carbon atom of said heterocyclic ring is optionally selected from -O-, -S-, or -NR a - may be replaced with Each R a are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C6-C 20)aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR2, —C(═O)SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), or —SO2NR2, wherein Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C 20 ) aryl, (C6-C 20 ) substituted aryl, (C2-C 20 )heterocyclyl, (C2-C 20 ) substituted heterocyclyl, (C6-C 20 )aryl(C1-C8)alkyl, or substituted (C6-C 20 )aryl(C1-C8)alkyl; each n is independently 0, 1, or 2; In the formula, each R 2 , R 3 , R 5 , R 6 , R 11 , or R 12 Each of (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally contains one or more of halo, hydroxy, CN, N3, N(R a )2, OR a wherein one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyls is optionally substituted with -O-, -S-, or -NR a - may be replaced by a method.

[0006] In another embodiment, the method comprises administering a therapeutically effective amount of a racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, to a mammal in need thereof.

[0007] In some embodiments, a method for treating or preventing 2019-nCoV infection (COVID-19) in a human in need thereof comprises administering to a subject a therapeutically effective amount of a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Each R 1 is H or a halogen, Each R 2 , R 3 , R 4 , or R 5 are independent, H, OR a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1-C8) alkyl, (C4-C8) chlorine bocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl; Or, any two R on adjacent carbon atoms 2 , R 3 , R 4 , or R 5 when taken together are -, O(CO)O-, or when taken together with the ring carbon atom to which they are attached form a double bond, R 6 But, OR a , N(R a )2, N3, CN, NO2, S(O) n R a , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12, halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl; R 7 but, a) H, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), or -SO2NR 11 R 12 , [In the formula, each R 11 or R 12 Each of (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally includes one or more of halo, hydroxy, CN, N3, N(R a )2, OR a wherein one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyls is optionally substituted with -O-, -S-, or -NR a - may be replaced by b) [ka] c) [ka] [During the ceremony, R c is phenyl, 1-naphthyl, 2-naphthyl, [ka] is selected from R dis H or CH3, R e1 and R e2 are each independently H, (C1-C6) alkyl, or benzyl; R f is selected from H, (C1-C8)alkyl, benzyl, (C3-C6)cycloalkyl, and —CH2—(C3-C6)cycloalkyl; R g is selected from (C1-C8)alkyl, —O—(C1-C8)alkyl, benzyl, —O-benzyl, —CH2—(C3-C6)cycloalkyl, —O—CH2—(C3-C6)cycloalkyl, and CF3; n' is selected from 1, 2, 3, and 4; and d) a group of the formula: [ka] [During the ceremony, Q is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2; Z 1 and Z 2 When put together, -Q 1 (C(R y )2)3Q 1 - and During the ceremony, Each Q 1 are independently O, S, or NR; Each R y are independently H, F, Cl, Br, I, OH, R, -C(=Q 2 )R, -C(=Q 2 ) OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR,-S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 ) OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 ) OR, -SC(=Q2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 ) OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 or when taken together, two R on the same carbon atom y forms a carbocyclic ring of 3 to 7 carbon atoms, Each Q 2 are independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2, or Z 1 and Z 2 are each independently a group of formula Ia, [ka] During the ceremony, Each Q 3 are independently bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2; M2 is 0, 1, or 2; Each R x are independently expressed as R in the following formula: y and [ka] During the ceremony, each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 3 is Z 4 or Z 5 and Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y, or -SO2Z 5 and Z 5 is a carbocyclic or heterocyclic ring, 5 are independently 0 to 3 R y substituted with a group; R 8 But halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NNHR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C-1-C8) alkyl, (C6-C 20 )aryl(C1-C8)alkyl, OR 11 or SR 11 and Each R 9 or R 10 are independently H, halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NHNR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , R 11 , OR 11 , or SR 11 and Each R 11 or R 12 are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C-1-C8) alkyl, or (C6-C 20 ) aryl(C1-C8) alkyl, or R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, and any one carbon atom of said heterocyclic ring is optionally -O-, -S-, or -NR a - may be replaced with Each R a are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C6-C 20 )aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR2, —C(═O)SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), or —SO2NR2, wherein Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C 20 ) aryl, (C6-C 20 ) substituted aryl, (C2-C 20 )heterocyclyl, (C2-C 20 ) substituted heterocyclyl, (C6-C 20 )aryl(C1-C8)alkyl, or substituted (C6-C 20)aryl(C1-C8)alkyl; each n is independently 0, 1, or 2; In the formula, each R 2 , R 3 , R 5 , R 6 , R 11 , or R 12 each (C1-C8) alkyl (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally includes one or more of halo, hydroxy, CN, N3, N(R a )2, OR a wherein one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyls is optionally substituted with -O-, -S-, or -NR a - may be replaced by a method.

[0008] In another embodiment, the method comprises administering a therapeutically effective amount of a racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof. In a further embodiment, the method comprises administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof. In a further embodiment, the method comprises administering remdesivir or a pharmaceutically acceptable salt thereof to a mammal in need thereof. In another embodiment, the method comprises administering remdesivir to a mammal in need thereof. In some embodiments, the mammal is a human.

[0009] In another embodiment, a method of treating or preventing 2019-nCoV in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0010] In another embodiment, a method of treating or preventing a 2019-nCoV infection in a human being in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent.

[0011] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent, the pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or ester thereof; b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against 2019-nCoV; and Includes:

[0012] In another embodiment, the present application provides a method of inhibiting 2019-nCoV RNA-dependent RNA polymerase, comprising contacting a cell infected with 2019-nCoV with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

[0013] In another embodiment, there is provided a use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for treating a viral infection caused by 2019-nCoV.

[0014] In another embodiment, the method comprises event-driven administration of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject. DETAILED DESCRIPTION OF THE INVENTION

[0015] 1.Definition Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:

[0016] When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

[0017] As used herein, "a compound of the invention" or "a compound of Formula I" means a compound of Formula I or a pharmaceutically acceptable salt thereof. Similarly, with respect to an isolatable intermediate, the phrase "a compound of Formula (number)" means a compound of that formula and a pharmaceutically acceptable salt thereof.

[0018] An "alkyl" is a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20alkyl), or 1 to 8 carbon atoms (i.e., C1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include 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(CH 3)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 (-CH2CH 2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4 These include, but are not limited to, 2-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), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0019] "Alkoxy" means a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl portion of the alkoxy group contains 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 The alkoxy group may have 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-OC(CH3)3 or -OtBu), and the like.

[0020] A "haloalkyl" is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 haloalkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable haloalkyl groups include -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0021] "Alkenyl" refers to an alkyl group containing normal, secondary, tertiary, or cyclic carbon atoms and at least one site of unsaturation, i.e., carbon-carbon, sp 2 It is a hydrocarbon with a double bond. For example, an alkenyl group can be an alkyl group having 2 to 20 carbon atoms (i.e., C2-C 20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0022] "Alkynyl" refers to a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. For example, an alkynyl group can be any group having 2 to 20 carbon atoms (i.e., C2-C20 The alkynyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkyne), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0023] "Alkylene" refers to a saturated, branched, or straight-chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH-), 1,1-ethyl (-CH(CH)-), 1,2-ethyl (-CHCH-), 1,1-propyl (-CH(CHCH)-), 1,2-propyl (-CHCH(CH)-), 1,3-propyl (-CHCHCHCH-), 1,4-butyl (-CHCHCHCHCH-), and the like.

[0024] "Alkenylene" refers to an unsaturated, branched, or straight-chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0025] "Alkynylene" refers to an unsaturated, branched, or straight-chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CHC≡C-), and 4-pentynyl (-CHCHCHC≡C-).

[0026] "Amino" generally refers to a nitrogen radical that can be considered a derivative of ammonia having the formula -N(X)2, where each "X" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. The hybridization of the nitrogen is approximately sp 3 Non-limiting examples of amino include -NH, -N(alkyl), -NH(alkyl), -N(carbocyclyl), -NH(carbocyclyl), -N(heterocyclyl), -NH(heterocyclyl), -N(aryl), -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like. The term "alkylamino" refers to an amino group substituted with at least one alkyl group. Non-limiting examples of alkylamino groups include -NH, -NH(CH), -N(CH), -NH(CHCH), -N(CHCH), -NH(phenyl), -N(phenyl), -NH(benzyl), -N(benzyl). Substituted alkylamino generally refers to an alkylamino group having at least one substituted alkyl, as defined herein, attached to the amino nitrogen atom. Non-limiting examples of substituted alkylamino include -NH(alkylene-C(O)-OH), -NH(alkylene-C(O)-O-alkyl), -N(alkylene-C(O)-OH), -N(alkylene-C(O)-O-alkyl), and the like.

[0027] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group 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, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0028] "Arylalkyl" refers to an alkyl group consisting of a carbon atom, typically a terminal or sp 3 "(Aryl)" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom of the alkyl group is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. The arylalkyl group can contain 7 to 20 carbon atoms, e.g., the alkyl portion thereof is 1 to 6 carbon atoms and the aryl portion thereof is 6 to 14 carbon atoms.

[0029] "Arylalkenyl" refers to an aryl group having a carbon atom, typically a terminal or sp 3 carbon atoms, but sp 2 "arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom that is also a carbon atom is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl can include 8 to 20 carbon atoms, e.g., the alkenyl portion is 2 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0030] "Arylalkynyl" refers to an aryl group consisting of a carbon atom, typically a terminal or sp 3(S) refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom that is also an sp carbon atom is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. The arylalkynyl can include 8 to 20 carbon atoms, e.g., the alkynyl portion is 2 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0031] The term "substituted," with respect to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, and the like, e.g., "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl," refers to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Exemplary substituents include -X, -R b , -O - , =O, -OR b , -SR b , -S - , -NR b 2, -N + R b 3, =NR b , -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NHC(=O)R b , -OC(=O)R b , -NHC (=O)NR b 2, -S(=O)2-, -S(=O)2OH, -S(=O)2R b , -OS(=O)2OR b , -S(=O)2NR b 2. -S(=O)R b ,-OP(=O)(OR b )2, -P(=O)(OR b )2, -P(=O)(O -)2, -P(=O)(OH)2, -P(O)(OR b )(O - ), -C(=O)R b , -C(=O)X, -C(S)R b , -C(O)OR b , -C(O)O - , -C(S)OR b , -C(O)SR b , -C(S)SR b , -C(O)NR b 2. -C(S)NR b 2. -C(=NR b )NR b 2, wherein each X is independently a halogen, F, Cl, Br, or I; and each R b are independently H, alkyl, aryl, arylalkyl, heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups can be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group such as arylalkyl having two or more moieties capable of substitution, the substituents may be attached to the aryl portion, the alkyl portion, or both. The term "C1-C8 substituted alkyl" refers to an alkyl group having 1 to 8 carbons substituted as defined herein. Similarly, the term "C2-C8 substituted alkenyl" refers to an alkenyl having 2 to 8 carbons substituted as defined herein, and the term "C2-C8 substituted alkynyl" refers to an alkynyl group having 1 to 8 carbons substituted as defined herein. Similarly, "(C6-C 20 The term "substituted aryl" refers to an aryl having 6 to 20 carbons substituted as defined herein, including (C-C 20 ) The term substituted heterocyclyl refers to a heterocyclyl having 2 to 20 carbons substituted as defined herein.

[0032] A "prodrug" is defined in the pharmaceutical arts as a biologically inactive derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug by some chemical or enzymatic pathway.

[0033] Those skilled in the art will recognize that substituents and other moieties for compounds of Formulas I-IV should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptably stable pharmaceutical compositions. Compounds of Formulas I-IV having such stability are considered to be within the scope of the present invention.

[0034] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom, such as O, N, or S. For example, when a carbon atom of an alkyl group that is attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH), an amine (e.g., -NHCH, -N(CH), or a thioalkyl group (e.g., -SCH), respectively. When a non-terminal carbon atom of an alkyl group that is not attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CHCH-O-CH), an alkylamine (e.g., -CHNHCH, -CHN(CH), or a thioalkyl ether (e.g., -CH-S-CH), respectively. When the terminal carbon atom of an alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., -CHCH-OH), an aminoalkyl group (e.g., -CHNH), or an alkylthiol group (e.g., -CHCH-SH), respectively. The heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0035] As used herein, "heterocycle" or "heterocyclyl" refers to any heterocyclic ring or heterocyclic ring as described, by way of example and not limitation, in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; The Ch "The term "heterocycle" includes heterocycles described in "Emistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), particularly volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one particular embodiment of the present invention, "heterocycle" includes "carbocycle" as defined herein, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclyls are: [ka]

[0036] Examples of heterocyclic rings include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidyl, and the like. Dinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiyl yl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, furan phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and the following bis-tetrahydrofuranyl: [ka]

[0037] By way of example and not limitation, carbon-bonded heterocycles may be bonded to positions 2, 3, 4, 5, or 6 of pyridine, 3, 4, 5, or 6 of pyridazine, 2, 4, 5, or 6 of pyrimidine, 2, 3, 5, or 6 of pyrazine, 2, 3, 4, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, 2, 4, or 5 of oxazole, imidazole, or thiazole, isoxazole, pyridine, or pyridine. The carbon-bonded heterocycle is bonded at the 3, 4, or 5 position of the thiazole or isothiazole, the 2 or 3 position of the aziridine, the 2, 3, or 4 position of the azetidine, the 2, 3, 4, 5, 6, 7, or 8 position of the quinoline, or the 1, 3, 4, 5, 6, 7, or 8 position of the isoquinoline. Even more typically, the carbon-bonded heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0038] By way of example and not limitation, nitrogen-bonded heterocycles are bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0039] "Heterocyclylalkyl" refers to a heterocyclyl group consisting of a carbon atom, typically a terminal or sp 3

[0033] "Heterocyclyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom of the alkyl group is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene moiety). Typical heterocyclylalkyl groups include, but are not limited to, heterocyclyl-CH2-, 2-(heterocyclyl)ethan-1-yl, and the like, and the "heterocyclyl" moiety includes any of the heterocyclyl groups described above, including those described in "Principles of Modern Heterocyclic Chemistry." Those skilled in the art will also recognize that a heterocyclyl group can be attached to the alkyl portion of a heterocyclylalkyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. Heterocyclylalkyl groups contain 3 to 20 carbon atoms; for example, the alkyl portion of an arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl portion is 2 to 14 carbon atoms. Examples of heterocyclylalkyl include, by way of example and not limitation, 5-membered sulfur-, oxygen-, and / or nitrogen-containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and 6-membered sulfur-, oxygen-, and / or nitrogen-containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyrididylmethyl, pyrimidylmethyl, pyrazinylmethyl, and the like.

[0040] "Heterocyclylalkenyl" refers to a heterocyclyl group consisting of a carbon atom, typically a terminal or sp 3 carbon atoms, but sp 2This refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom that is also a carbon atom has been replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the heterocyclylalkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclylalkenyl group includes any of the alkenyl groups disclosed herein. Those skilled in the art will also understand that a heterocyclyl group can be attached to the alkenyl portion of a heterocyclylalkenyl by a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. The heterocyclylalkenyl group contains 4 to 20 carbon atoms; for example, the alkenyl portion of the heterocyclylalkenyl group is 2 to 6 carbon atoms and the heterocyclyl portion is 2 to 14 carbon atoms.

[0041] "Heterocyclylalkynyl" refers to a heterocyclyl group consisting of a carbon atom, typically a terminal or sp 3 (i.e., a heterocyclyl-alkynylene-moiety) in which one of the hydrogen atoms bonded to a carbon atom that is also an sp carbon atom is replaced with a heterocyclyl radical. The heterocyclyl portion of the heterocyclylalkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclylalkynyl group includes any of the alkynyl groups disclosed herein. Those skilled in the art will also understand that a heterocyclyl group can be attached to the alkynyl portion of the heterocyclylalkynyl by a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. The heterocyclylalkynyl group contains 4 to 20 carbon atoms; for example, the alkynyl portion of the heterocyclylalkynyl group is 2 to 6 carbon atoms and the heterocyclyl portion is 2 to 14 carbon atoms.

[0042] "Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all aromatic rings listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

[0043] "Carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.), or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 7 ring atoms, and even more typically 5 or 6 ring atoms. Bicyclic carbocycles have, for example, 7 to 12 ring atoms arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclic carbocycles include naphthyl, tetrahydronaphthalene, and decalin.

[0044] "Carbocyclylalkyl" refers to an acyclic alkyl radical, as described herein, in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a carbocyclyl radical. Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0045] "Arylheteroalkyl" refers to a heteroalkyl, as defined herein, in which a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is replaced with an aryl group, as defined herein. The aryl group may be attached to a carbon atom of the heteroalkyl group or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety. For example, arylheteroalkyl groups can be represented by the general formulas -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S -aryl, -alkylene-S-alkylene-aryl, etc. Additionally, any of the alkylene moieties in the above general formulas can be further substituted with any of the substituents defined or exemplified herein.

[0046] "Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom is replaced with a heteroaryl group, as defined herein. Non-limiting examples of heteroarylalkyl include -CH-pyridinyl, -CH-pyrrolyl, -CH-oxazolyl, -CH-indolyl, -CH-isoindolyl, -CH-purinyl, -CH-furanyl, -CH-thienyl, -CH-benzofuranyl, -CH-benzothiophenyl, -CH-carbazolyl, -CH-imidazolyl, -CH-thiazolyl, -CH-isoxazolyl, -CH-pyrazolyl, -CH-isothiazolyl, -CH-quinolyl, -CH-isoquinolyl, -CH-pyridazyl, -CH-pyrimidyl, -CH-pyrazyl, -CH(CH)-pyridinyl, -CH(CH)-pyrrolyl, -CH(CH)- H3)-oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-purinyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl, -CH(CH3)-pyrazyl and the like.

[0047] The term "optionally substituted" with respect to a particular moiety in a compound of Formula I-IV (e.g., an optionally substituted aryl group) means that all of the substituents may be hydrogen, or one or more of the hydrogens on the moiety may be replaced with a substituent as listed under the definition of "substituted."

[0048] The term "optionally replaced" in reference to a particular moiety of a compound of Formulas I-IV (e.g., a carbon portion of a (C1-C8) alkyl group above can be replaced with -O-, -S-, or -NR a-) is defined as a group in which one or more of the methylene groups of the (C1-C8) alkyl is replaced with a specified group (e.g., -O-, -S-, or -NR a -) can be replaced with 0, 1, 2 or more of the following:

[0049] The term "non-terminal carbon atom(s)" with respect to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to a carbon atom in the moiety that is intervening between the first carbon atom of the moiety and the last carbon atom in the moiety. Thus, by way of example and not limitation, the alkyl moiety -CH(C * )H2(C * )H2CH3, or the alkylene moiety -CH2(C * )H2(C * )H2CH2-, C * The atom is considered a non-terminal carbon atom.

[0050] Certain Q and Q 1 An alternative to is, for example, + N(O)(R) or + Nitrogen oxides such as N(O)(OR). Here, as attached to carbon atoms, these nitrogen oxides also [ka] It can also be expressed as a charge-separated group such as Each is intended to be equivalent to the preceding expression for purposes of describing the present invention.

[0051] "Linker" or "linkage" means a chemical moiety comprising a covalent bond or a chain of atoms. Linkers include alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™) repeating units, diacid esters and amides including succinate, succinamide, diglycolic acid, malonic acid, and caproamide.

[0052] Terms such as "oxygen bond," "nitrogen bond," "carbon bond," "sulfur bond," or "phosphorus bond" refer to cases where a bond between two moieties can be formed using more than one type of atom within the moieties, and thus the bond formed between the moieties is through the specified atom. For example, a nitrogen-linked amino acid will be bonded through the nitrogen atom of the amino acid, rather than through an oxygen or carbon atom of the amino acid.

[0053] In some embodiments of the compounds of Formulas I-IV, Z 1 or Z 2 are independently nitrogen-linked naturally occurring α-amino acid ester radicals. Examples of naturally occurring amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine, and taurine. Esters of these amino acids include any of those described for the substituent R, particularly those where R is optionally substituted (C1-C8) alkyl.

[0054] The term "purine" or "pyrimidine" base includes adenyl, N 6 -Alkylpurines, N 6 -acylpurine, where acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -Benzylpurine, N 6 -Haloprin, N 6 -vinylpurine, N 6 -acetylene purine, N 6 -Acylpurines, N 6 -Hydroxyalkylpurine, N 6 -Alkylaminopurine, N 6 -Thioallylpurine, N 2 -Alkylpurines, N 2-Alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidines including 6-azacytosine, 2- and / or 4-mercaptopyrimidines, uracil, 5-halouracils including 5-fluorouracil, C 5 -Alkylpyrimidines, C 5 -benzylpyrimidine, C 5 -halopyrimidines, C 5 -vinylpyrimidine, C 5 -acetylene pyrimidine, C 5 -Acylpyrimidine, C 5 -Hydroxyalkylpurine, C 5 -Amidopyrimidine, C 5 -cyanopyrimidine, C 5 -5-iodopyrimidine, C 6 -Iodopyrimidine, C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyrrinidine, C 5 -Nitropyrimidine, C 5 -aminopyrimidine, N 2 -Alkylpurines, N 2 Examples of suitable protecting groups include, but are not limited to, 6-alkyl-thiopurine, 5-azacytidinyl, 5-azauracil, thiazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The purine and pyrimidine bases of Formulas I-III are linked to the ribose sugar or its analogue through the nitrogen atom of the base. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

[0055] Unless otherwise specified, the carbon atoms of the compounds of Formulas I-IV are intended to have a valence of four. In some chemical structure representations where a carbon atom does not have a sufficient number of variables to produce a valence of four, the remaining carbon substituents necessary to provide a valence of four should be assumed to be hydrogen. For example, [ka] teeth [ka] has the same meaning as

[0056] A "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the compound as a whole. The chemical structures of protecting groups vary widely. One function of a protecting group is to serve as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, "Protective Groups in Organic Chemistry," by Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often utilized to mask the reactivity of particular functional groups to aid in the efficiency of desired chemical reactions, for example, to create and break chemical bonds in an orderly and planned manner. Protection of a functional group in a compound alters other physical properties beyond the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. A "hydroxy-protecting group" refers to a protecting group useful for protecting hydroxy groups (-OH).

[0057] Protected compounds may also exhibit altered, and in some cases optimized, properties in vitro and in vivo, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert a parent drug into a prodrug, whereby the parent drug is released upon in vivo conversion of the prodrug. Because an active prodrug may be absorbed more effectively than the parent drug, the prodrug may have greater in vivo efficacy than the parent drug. Protecting groups are removed in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. In the case of chemical intermediates, it is not particularly important that the product obtained after deprotection, such as an alcohol, is physiologically acceptable, although it is generally more desirable if the product is pharmacologically harmless.

[0058] The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that possess the property of non-superimposability of their mirror image partners. Refers to a molecule that can be superimposed on a partner.

[0059] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0060] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, reactivity, and biological properties. For example, compounds of Formulas I-IV may have R 7 but, [ka] and Z 1 and Z 2 When Z is different from Z, it may have a chiral phosphorus atom. 1 or Z 2 When at least one of the groups has a chiral center, for example, Z1 or Z 2 When is attached to nitrogen, is chiral, or is a naturally occurring α-amino acid ester, the compounds of Formulas I-IV exist as diastereomers due to the two centers of chirality in the molecule. All such diastereomers and their uses described herein are encompassed by the present invention. Mixtures of diastereomers may separate under high-resolution analytical procedures such as electrophoresis, crystallization, and / or chromatography. Diastereomers may have different physical properties, including, but not limited to, solubility, chemical stability, and crystallinity, and may also have different biological properties, including, but not limited to, enzymatic stability, absorption, and metabolic stability.

[0061] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0062] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

[0063] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0064] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of Formulas I-IV used herein required to provide a desired level of drug in the secretory and pulmonary tissues of a subject, or alternatively, in the bloodstream of a treated subject, that will produce an expected physiological response or desired biological effect when such composition is administered by a selected route of administration. The exact amount will depend on numerous factors, including the particular compound of Formulas I-IV, the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state and patient interaction, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0065] The term "normal saline" refers to an aqueous solution containing 0.9% (w / v) NaCl. means.

[0066] The term "hypertonic saline" means an aqueous solution containing more than 0.9% (w / v) NaCl. For example, 3% hypertonic saline would contain 3% (w / v) NaCl.

[0067] "Forming a reaction mixture" refers to the process of contacting at least two different species so that they can mix and react together. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate derived from one or more of the added reagents that may be produced in the reaction mixture.

[0068] "Coupling agent" refers to an agent capable of linking two dissimilar compounds. Coupling agents can be catalytic or stoichiometric. For example, coupling agents can be lithium-based coupling agents or magnesium-based coupling agents such as Grignard reagents. Exemplary coupling agents include, but are not limited to, n-BuLi, MgCl, iPrMgCl, tBuMgCl, PhMgCl, or combinations thereof.

[0069] "Silane" refers to a silicon-containing group having the formula SiR4, where each R group can be alkyl, alkenyl, cycloalkyl, phenyl, or other silicon-containing group. When the silane is linked to another compound, the silane is called a "silyl" and has the formula -SiR3.

[0070] "Halo-silane" refers to a silane having at least one halogen group bonded to the silicon atom. Representative halo-silanes have the formula halo-SiR, where each R group can be alkyl, alkenyl, cycloalkyl, phenyl, or other silicon-containing group. Specific halo-silanes include Cl-Si(CH), and Cl-Si(CH)CHSi(CH)-Cl.

[0071] "Non-nucleophilic base" refers to Lewis bases that are electron donors, such as nitrogen bases including triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine.

[0072] A "leaving group" refers to a group that maintains the bonding electron pair during heterolytic bond cleavage. For example, a leaving group is easily displaced during a nucleophilic substitution reaction. Suitable leaving groups include chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, pentafluorophenoxy, and the like. Those skilled in the art will recognize other leaving groups useful in the present invention.

[0073] "Deprotecting agent" refers to any agent capable of removing a protecting group. The deprotecting agent depends on the type of protecting group used. Representative deprotecting agents are known in the art and can be found in Protective Groups in Organic Chemistry, Peter G.M.Wuts and Theodora W. Greene, 4th Ed., 2006.

[0074] A "pharmaceutically acceptable salt" is a non-toxic salt of the free base form of a compound that possesses the desired pharmacological activity of the free base. In some embodiments, these salts are derived from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, disulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, etc. , iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate salts. Lists of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0075] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + Also included are salts derived from appropriate bases, such as: (wherein X is C1-C4 alkyl). Base addition salts, such as sodium or potassium salts, are also included.

[0076] Pharmaceutically acceptable esters of the compounds of formula I include esters of a hydroxy group, for example in vivo hydrolysable esters of a hydroxy group. Examples of in vivo hydrolysable esters of a hydroxyl group include those provided by C alkyl carboxylic acids. 2. Compounds of the Present Invention

[0077] Reference will now be made in detail to specific embodiments of the invention, examples of which are illustrated in the accompanying description, structures, and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention.

[0078] 1. A method for treating a 2019-nCoV infection in a human in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula I [ka] or a pharmaceutically acceptable salt or ester thereof, During the ceremony, Each R 1 is H or a halogen, Each R 2 , R 3 , R 4 , or R 5 But independently, H, OR a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1-C8) alkyl, (C4-C8) carboxy or (C-C) substituted alkyl, (C-C) alkenyl, (C-C) substituted alkenyl, (C-C) alkynyl, or (C-C) substituted alkynyl; Or, any two R on adjacent carbon atoms 2 , R 3 , R 4 , or R 5when taken together are -O(CO)O- or when taken together with the ring carbon atom to which they are attached form a double bond, R 6 But, OR a , N(R a )2, N3, CN, NO2, S(O) n R a , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 , halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl; R 7 but, a) H, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), or -SO2NR 11 R 12 , [In the formula, each R 11 or R 12 Each of (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally includes one or more of halo, hydroxy, CN, N3, N(R a )2, OR aand one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyls is substituted with -O-, -S-, or -NR a - optionally replaced by b) [ka] c) [ka] [During the ceremony, R c is phenyl, 1-naphthyl, 2-naphthyl, [ka] is selected from R d is H or CH3, R e1 and R e2 are each independently H, (C1-C6) alkyl, or benzyl; R f is selected from H, (C1-C8)alkyl, benzyl, (C3-C6)cycloalkyl, and —CH2—(C3-C6)cycloalkyl; R g is selected from (C1-C8)alkyl, —O—(C1-C8)alkyl, benzyl, —O-benzyl, —CH2—(C3-C6)cycloalkyl, —O—CH2—(C3-C6)cycloalkyl, and CF3; n' is selected from 1, 2, 3, and 4; and d) a group of the formula: [ka] [During the ceremony, Q is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2; Z 1 and Z 2 When put together, -Q 1 (C(R y )2)3Q1 - and During the ceremony, Each Q 1 are independently O, S, or NR; Each R y are independently H, F, Cl, Br, I, OH, R, -C(=Q 2 )R, -C(=Q 2 ) OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR,-S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 ) OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 ) OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 ) OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 or when taken together, two R on the same carbon atom y forms a carbocyclic ring of 3 to 7 carbon atoms, Each Q 2 are independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2, or Z 1 and Z 2 are each independently a group of formula Ia, [ka] During the ceremony, Each Q 3 are independently bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2; M2 is 0, 1, or 2; Each R x are independently expressed as R in the following formula: y and [ka] During the ceremony, each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 3 is Z 4 or Z 5 and Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y , or -SO2Z 5 and Z 5 is a carbocyclic or heterocyclic ring, 5 are independently 0 to 3 R y substituted with a group; R 8 But halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NNHR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n (C-1-C8) alkyl, (C6-C 20 )aryl(C1-C8)alkyl, OR 11 or SR 11 and Each R 9 or R 10 are independently H, halogen, NR 11 R 12 , N(R 11 ) OR 11 , N.R. 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NHNR 11 , -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 , -C(=S)NR 11 R 12 , -C(=O)OR 11 , R 11 , OR 11 , or SR 11 and Each R 11 or R 12 are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C-1-C8) alkyl, or (C6-C 20 ) aryl(C1-C8) alkyl, or R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, and any one carbon atom of said heterocyclic ring is optionally selected from -O-, -S-, or -NR a - may be replaced with Each R a are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C6-C 20)aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR2, —C(═O)SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), or —SO2NR2, wherein Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C 20 ) aryl, (C6-C 20 ) substituted aryl, (C2-C 20 )heterocyclyl, (C2-C 20 ) substituted heterocyclyl, (C6-C 20 )aryl(C1-C8)alkyl, or substituted (C6-C 20 )aryl(C1-C8)alkyl; each n is independently 0, 1, or 2; In the formula, each R 2 , R 3 , R 5 , R 6 , R 11 , or R 12 each (C1-C8) alkyl (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20 )aryl(C1-C8)alkyl independently optionally contains one or more of halo, hydroxy, CN, N3, N(R a )2, OR a and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyls is substituted with -O-, -S-, or -NR a - may be optionally replaced by -.

[0079] In another embodiment, a method of treating 2019-nCoV infection in a human in need thereof comprises the step of administering to a subject a therapeutically effective amount of a compound of formula I represented by formula II [ka] or a pharmaceutically acceptable salt or ester thereof, During the ceremony, R 1 , R 3 , R 5 , R 7 , R 8 , and R 9 is as defined above for formula I; Each R 2 But, OR a or a halogen, R 6 But, OR a , N(R a )2, N3, CN, S(O) n R a , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 , halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl.

[0080] In one embodiment of the method of treating 2019-nCoV infection by administering a compound of Formula II, R 1 is H. In another aspect of this embodiment, R of Formula II 6 is N3, CN, halogen, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl. In another aspect of this embodiment, R of Formula II 6 is CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R of formula II 6In another aspect of this embodiment, R of Formula II is 6 In another aspect of this embodiment, R of Formula II is methyl. 5 is H. In another aspect of this embodiment, R of Formula II 2 is OR a In another aspect of this embodiment, R of Formula II is 2 In another aspect of this embodiment, R of Formula II is 2 is F. In another aspect of this embodiment, R of Formula II 3 is OR a In another aspect of this embodiment, R of Formula II is 3 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of Formula II is 3 In another aspect of this embodiment, R of Formula II is 8 is NR 11 R 12 In another aspect of this embodiment, R of Formula II is 8 In another aspect of this embodiment, R of Formula II is 8 is OR 11 In this embodiment, In another embodiment, R of Formula II 8 In another aspect of this embodiment, R of Formula II is 9 is H. In another aspect of this embodiment, R of Formula II 9 is NR 11 R 12 In another aspect of this embodiment, R of Formula II is 9 In another aspect of this embodiment, R of Formula II is 7 is H, -C(=O)R 11 , -C(=O)OR 11 , or [ka] is. In another aspect of this embodiment, R of Formula II 7 is H. In another aspect of this embodiment, R of Formula II 7 teeth, [ka] is.

[0081] In another embodiment, a method of treating 2019-nCoV infection in a human in need thereof comprises administering to a subject a therapeutically effective amount of a compound of formula I represented by formula III [ka] or a pharmaceutically acceptable salt or ester thereof, During the ceremony, R 6 , R 7 , R 8 , and R 9 is as defined above for formula II; Each R 2 But, OR a or F, Each R 3 But, OR a is.

[0082] In one embodiment of the method of treating 2019-nCoV infection comprising administering to a compound of formula III, R 6 is N3, CN, halogen, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl. In another aspect of this embodiment, R of Formula III 6 is CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R of formula III 6 In another aspect of this embodiment, R of formula III is 6 In another aspect of this embodiment, R of formula III is methyl. 2 teeth, OR a In another aspect of this embodiment, R of formula III is 2 In another aspect of this embodiment, R of formula III is 2is F. In another aspect of this embodiment, R of formula III 3 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of formula III is 3 In another aspect of this embodiment, R of formula III is 8 is NR 11 R 12 In another aspect of this embodiment, R of formula III is 8 In another aspect of this embodiment, R of Formula III is 8 is OR 11 In another aspect of this embodiment, R of formula III is 8 In another aspect of this embodiment, R of formula III is 9 is H. In another aspect of this embodiment, R of formula III 9 is NR 11 R 12 In another aspect of this embodiment, R of formula III is 9 In another aspect of this embodiment, R of Formula III is 7 is H, -C(=O)R 11 , -C(=O)OR 11 , or [ka] is. In another aspect of this embodiment, R of Formula III 7 is H. In another aspect of this embodiment, R of formula III 7 teeth, [ka] is.

[0083] In another embodiment of the method of treating 2019-nCoV infection comprising administering to a compound of formula III, R 6is N3, CN, halogen, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl; R 8 In another aspect of this embodiment, R of Formula III is 6 is CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R of formula III 6 In another aspect of this embodiment, R of formula III is 6 In another aspect of this embodiment, R of formula III is methyl. 2 is OR a In another aspect of this embodiment, R of formula III is 2 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of formula III is 2 In another aspect of this embodiment, R of formula III is 2 is F. In another aspect of this embodiment, R of formula III 3 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of formula III is 3 In another aspect of this embodiment, R of formula III is 9 is H. In another aspect of this embodiment, R of formula III 9 is NR 11 R 12 In another aspect of this embodiment, R of formula III is 9 In another aspect of this embodiment, R of Formula III is 7 is H, -C(=O)R 11 , -C(=O)OR 11 , or [ka] is. In another aspect of this embodiment, R of Formula III 7 is H. In another aspect of this embodiment, R of formula III7 teeth, [ka] is.

[0084] In another embodiment of the method of treating 2019-nCoV infection comprising administering a compound of formula III, R 6 is CN, methyl, ethenyl, or ethynyl, and R 8 is NH2 and R 9 is H. In another aspect of this embodiment, R of formula III 6 In another aspect of this embodiment, R of formula III is CN. 6 In another aspect of this embodiment, R of formula III is methyl. 2 is OR a In another aspect of this embodiment, R of formula III is 2 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of formula III is 2 In another aspect of this embodiment, R of formula III is 2 is F. In another aspect of this embodiment, R of formula III 3 OH, -OC(=O)R 11 , or -OC(=O)OR 11 In another aspect of this embodiment, R of formula III is 3 In another aspect of this embodiment, R of formula III is 7 is H, -C(=O)R 11 , -C(=O)OR 11 , or [ka] is. In another aspect of this embodiment, R of Formula III 7 is H. In another aspect of this embodiment, R of formula III 7 teeth, [ka] is.

[0085] In another embodiment, a method of treating 2019-nCoV infection in a human in need thereof comprises administering to a subject a therapeutically effective amount of a compound of formula I represented by formula IV. [ka] or a pharmaceutically acceptable salt or ester thereof, In the formula, R 7 is as defined above for Formula I.

[0086] In some embodiments of the compound of Formula I or Formula IV, Z 4 is R, -C(Q 2 )Z 5 , or SO2Z 5 and Z 5 is a carbocyclic or heterocyclic ring, Each R 11 or R 12 are independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, (C6-C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C1-C8) alkyl, or (C6-C 20 ) aryl(C1-C8) alkyl, or R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, any one carbon atom of which may be optionally replaced by -O-, -S-, or -NH-, wherein Each R 2 , R 3 , R 5 , R 6 , R 11 , or R 12 Each of (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or (C6-C 20) aryl(C1-C8)alkyl are independently optionally substituted with one or more halo, hydroxy, CN, N3, NH2, or OH, and one or more of the non-terminal carbon atoms of each of said (C1-C8)alkyl may optionally be replaced with -O-, -S-, or -NH-.

[0087] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 is H. In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 is selected from the group consisting of a), b), or c) as defined for Formula I.

[0088] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and In the formula, Z 1 and Z 2 are each independently a group having the structure [ka] Z 3 Z 5 is.

[0089] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and In the formula, Z 1 and Z 2 are each independently a group having the structure [ka] Z 3 Z5 is.

[0090] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] where each Q 3b is independently O or N(R). In another embodiment, each Q 3b is O, and each R x became independent, [ka] wherein M12c is 1, 2, or 3, and each Q 3 is independently a bond, O, CR2, or S.

[0091] In some embodiments, R e1 and R e2 may each independently be H, C1-C6 alkyl, or benzyl. In some embodiments, R e1 can be H, C-C alkyl, or benzyl; R e2 can be H or C1-C6 alkyl. In some embodiments, R e1 and R e2 may each independently be H or C1-C6 alkyl. In some embodiments, R e1 and R e2 may each independently be H or benzyl. In some embodiments, R e1 can be H, methyl, or benzyl, and R e2 can be H or methyl. In some embodiments, R e1 can be H or methyl, R e2 can be H or methyl. In some embodiments, R e1 can be methyl, R e2 can be H or methyl. In some embodiments, R e1 can be H or benzyl, R e2can be H or methyl.

[0092] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] is.

[0093] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] is.

[0094] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and In the formula, R f is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl. In another embodiment of the compound of formula IV, R f is C1-C8 alkyl. In another embodiment of the compound of formula IV, R f is 2-ethylbutyl.

[0095] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and During the ceremony, R f is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl; Rg is selected from C1-C8 alkyl, —O—C1-C8 alkyl, benzyl, —O-benzyl, —CH2—C3-C6 cycloalkyl, —O—CH2—C3-C6 cycloalkyl, and CF3.

[0096] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and In the formula, R f is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl. In another embodiment of the compound of formula IV, R f is C1-C8 alkyl. In another embodiment of the compound of formula IV, R f teeth, In another embodiment of the compound of formula IV, R f is 2-ethylbutyl.

[0097] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] and In the formula, R g is selected from C1-C8 alkyl, —O—C1-C8 alkyl, benzyl, —O-benzyl, —CH2-C3-C6 cycloalkyl, —O—CH2-C3-C6 cycloalkyl, and CF3. In another embodiment of the compound of Formula IV, R f is C1-C8 alkyl. In another embodiment of the compound of formula IV, R f is C1-C6 alkyl.

[0098] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7is selected from the group: [ka]

[0099] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, R 7 teeth, [ka] is.

[0100] In another embodiment of the method of treating 2019-nCoV infection comprising administering a compound of formula IV, Z 1 and Z 2 are, respectively [ka] It could be.

[0101] In another embodiment, there is provided a method of treating a 2019-nCoV infection in a human being in need thereof, comprising administering a therapeutically effective amount of a compound of Formulas I-IV, wherein R 11 or R 12 are independently H, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C-C)alkyl, —S(O) n (C1C8) alkyl, or aryl(C1C8) alkyl. In another embodiment, R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, and any one carbon atom of said heterocyclic ring is optionally selected from -O-, -S-, or -NR a -. Thus, by way of example and not limitation, the moiety -NR 11 R 12 is a heterocycle: [ka] It can be expressed as follows:

[0102] In another embodiment, there is provided a method of treating a 2019-nCoV infection in a human being in need thereof, comprising administering a therapeutically effective amount of a compound of Formulas I-IV, wherein each R 3 , R 4 , R 5 , R 6 , R 11 , or R 12 are independently (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or aryl(C1-C8) alkyl, wherein the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or aryl(C1-C8) alkyl independently and optionally contain one or more of halo, hydroxy, CN, N, N(R a )2, OR a Thus, by way of example and not limitation, R 3 , R 4 , R 5 , R 6 , R 11 , or R 12 may represent moieties such as -CH(NH2)CH3, --CH(OH)CH2CH3, -CH(NH2)CH(CH3)2, -CH2CF3, -(CH2)2CH(N3)CH3, -(CH2)6NH2, etc.

[0103] In another embodiment, there is provided a method of treating a 2019-nCoV infection in a human being in need thereof, comprising administering a therapeutically effective amount of a compound of Formulas I-IV, wherein R 3 , R 4 , R 5 , R 6 , R 11 , or R 12 is (C1-C8) alkyl, and one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyl is optionally -O-, -S-, or -NR a- may be replaced by. Thus, by way of example and not limitation, R 3 , R 4 , R 5 , R 6 , R 11 , or R 12 may represent moieties such as -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2SCH3, -(CH2)6OCH3, -(CH2)6N(CH3)2, etc.

[0104] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula I, the compound is [ka] or a pharmaceutically acceptable salt or ester thereof.

[0105] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula I, the compound is [ka] [ka] or a pharmaceutically acceptable salt or ester thereof.

[0106] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, the compound is [ka] or a pharmaceutically acceptable salt or ester thereof.

[0107] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of formula IV, the compound is [ka] or a pharmaceutically acceptable salt or ester thereof.

[0108] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of Formulas I-IV, the compound is [ka] [ka] or a pharmaceutically acceptable salt or ester thereof.

[0109] In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of Formulas I-IV, the compound is [ka] or a pharmaceutically acceptable salt or ester thereof. In another embodiment of the method of treating a 2019-nCoV infection comprising administering a compound of Formulas I-IV, the compound is: [ka] or a pharmaceutically acceptable salt or ester thereof.

[0110] The methods described herein can be used to detect C caused by any strain of SARS-CoV-2. For example, in some embodiments, the methods described herein are useful for treating an infection caused by SARS-CoV-2 L-type or S-type. In some embodiments, the methods described herein are useful for treating an infection caused by SARS-CoV-2 L-type. In some embodiments, the methods described herein are useful for treating an infection caused by SARS-CoV-2 S-type. In some embodiments, the methods described herein are useful for treating an infection caused by SARS-CoV-2 UK-type B.1.1.7 or SARS-CoV-2 South African-type 501.V2.

[0111] The methods described herein can be used to treat viral infections caused by viruses having polymerases homologous to SARS polymerase. For example, the methods can be used to treat viral infections caused by viruses having at least about 60% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by viruses having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by viruses having at least 90% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by viruses having at least 92% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by viruses having at least 94% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 96% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 98% sequence homology to SARS polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 99% sequence homology to SARS polymerase. In some embodiments, the polymerase is an RNA-dependent RNA polymerase.

[0112] In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 90% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 92% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 94% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 96% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 98% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 99% sequence homology to the L-type SARS-CoV-2 polymerase. In some embodiments, the polymerase is an RNA-dependent RNA polymerase.

[0113] In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 90% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 92% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 94% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 96% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 98% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 99% sequence homology to the S-type SARS-CoV-2 polymerase. In some embodiments, the polymerase is an RNA-dependent RNA polymerase.

[0114] In some embodiments, the methods may be used to treat viral infections caused by viruses with at least about 60% sequence identity to the entire genomic sequence of SARS-CoV-2. For example, the methods described herein are used to treat viral infections caused by viruses with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the entire genomic sequence of SARS-CoV-2. In some embodiments, the methods described herein are used to treat viral infections caused by viruses with at least 90% sequence identity to the entire genomic sequence of SARS-CoV-2. In some embodiments, the methods described herein are used to treat viral infections caused by viruses with at least 92% sequence identity to the entire genomic sequence of SARS-CoV-2. In some embodiments, the methods described herein are used to treat viral infections caused by viruses with at least 94% sequence identity to the entire genomic sequence of SARS-CoV-2. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 96% sequence homology to the entire genomic sequence of SRAS-CoV-2. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 98% sequence homology to the entire genomic sequence of SRAS-CoV-2. In some embodiments, the methods described herein are used to treat a viral infection caused by a virus having at least 99% sequence homology to the entire genomic sequence of SRAS-CoV-2.

[0115] The names of the compounds of the present disclosure are provided using ACD / Name software (Advanced Chemistry Development, Inc., Toronto, Canada) for naming chemical compounds. Other compounds or radicals may be designated using common names, or systematic or non-systematic names. The naming and numbering of the compounds of the present disclosure is illustrated by a representative compound of Formula I. [ka] It is named 2-ethylbutyl (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramino)propionate. Other compounds of the present invention include: [ka] This is named 2-ethylbutyl (S)-2-(((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)amino)propionate. [ka] This is named 2-ethylbutyl (S)-2-(((R)-(((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)propionate.

[0116] Any reference to a compound of the invention described herein also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include alkali metal or alkaline earth salts (e.g., Na + , Li + , K.+ , Ca +2 , and Mg +2 ), ammonium and NR4 + and the like. Examples of suitable bases include salts derived from appropriate bases such as: Physiologically acceptable salts of nitrogen atoms or amino groups include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; (b) salts formed with, for example, 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-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, (c) salts formed from elemental anions such as chlorine, bromine, and iodine. Physiologically acceptable salts of compounds with hydroxy groups include Na + and NR4 + Examples of suitable cations include the anions of the above compounds in combination with suitable cations such as:

[0117] The compounds of Formulas I-IV and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystalline structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of hydrates or solvates of a compound to exist in different crystalline structures. Pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of the compounds of Formulas I-III and their pharmaceutically acceptable salts.

[0118] The compounds of Formulas I-IV and their pharmaceutically acceptable salts can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to create the amorphous forms of the present invention. The present invention includes all amorphous forms of the compounds of Formulas I-IV and their pharmaceutically acceptable salts.

[0119] For therapeutic use, salts of the active ingredients of the compounds of the present invention are physiologically acceptable. That is, they are salts derived from physiologically acceptable acids or bases. However, salts of physiologically unacceptable acids or bases may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0120] Finally, it should be understood that the compositions herein include compounds of the present invention in their non-ionized as well as zwitterionic forms, as well as combinations with stoichiometric amounts of water in hydrates.

[0121] It should be noted that all enantiomers, diastereomers, and racemic mixtures, polymorphs, pseudopolymorphs, and pharmaceutically acceptable salts of compounds within the scope of Formulas I-IV are encompassed by the present invention, and all mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0122] The compounds of the present invention, as exemplified by Formulas I-IV, may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers apparent from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual isolated optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures can be resolved into their individual, substantially optically pure isomers through well-known techniques, for example, separation of diastereomeric salts formed with optically active auxiliaries, such as acids or bases, followed by conversion to optically active materials. In most cases, the desired optical isomer is synthesized by stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

[0123] The stereochemical definitions and rules used herein are generally those of S.P. Parker, E. d., 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. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, D and L, or (+) and (-) are used to indicate the rotation of plane-polarized light by the compound; S, (-), or 1 means that the compound is levorotatory, while compounds with the R, (+), or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0124] The compounds of the present invention may also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention. For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0125] Any formula or structure given herein, including compounds of Formula I, is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include: 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 Isotopically labeled compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. 3 H, 13 C and 14 These are compounds into which a radioactive isotope, such as C, has been incorporated. Such isotopically labeled compounds are suitable for use in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays. or in the radioactive treatment of patients.

[0126] The present disclosure also includes compounds of Formula I in which 1 to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0127] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure exhibit improved drug kinetics (DMPK) with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0128] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have that hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0129] The compounds described herein may be, for example, "R" or "R 1 It will be understood that whenever a group is substituted with more than one of the same groups, the groups may be the same or different, i.e., each group is independently selected. [ka] indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom.

[0130] Selected substituents, including compounds of Formulas I-IV, exist to a recursive degree. In this context, "recursive substituent" means that the substituent can list other instances of itself. Due to the recursive nature of such substituents, theoretically, multiple compounds can exist for any given embodiment. For example, R x is R y Contains substituents. y can be R. R is Z 3 It can be. Z 3 is Z 4 Z 4 can be R or R y Alternatively, Z may include a substituent comprising 3 is R y Z may contain substituents including 5 Those skilled in the art of medicinal chemistry will understand that the total number of such substituents will be reasonably limited by the desired properties of the intended compound. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility, or log P; application properties such as activity against the intended target; and practical properties such as ease of synthesis.

[0131] By way of example and not limitation, Z 3 and R y is a recursive substituent in certain embodiments. Typically, in a given embodiment, each recursive substituent may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 times. More typically, each recursive substituent may independently occur 12 or fewer times in a given embodiment. Even more typically, each recursive substituent may independently occur 3 or fewer times in a given embodiment. For example, in a given embodiment, Z 3 occurs 0 to 8 times, R y occurs 0 to 6 times. Even more typically, in a given embodiment, Z 3 occurs 0 to 6 times, R y occurs 0 to 4 times.

[0132] Recursive substituents are an intended aspect of the present invention. One of ordinary skill in the art of medicinal chemistry will appreciate the versatility of such substituents. To the extent that recursive substituents are present in one embodiment of the present invention, the total number is determined as described above.

[0133] The compounds of the present disclosure can be prepared by any method known to those skilled in the art. For example, the compounds of the present invention can be prepared according to the methods described in U.S. Patent No. 8,008,264 and U.S. Patent Application Publication No. US2012 / 0027752. 1. Substitution patterns of compounds

[0134] Compounds of formula I-IV are R 7 may contain a phosphate group as R 7 is selected from the group consisting of: a) H, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O)2R 11 , -S(O)(OR 11 ), -S(O)2(OR 11 ), or -SO2NR 11 R 12 , [During the ceremony, Each R 11 or R 12 are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O) n (C1-C8) alkyl, or aryl(C1-C8) alkyl, or R 11 and R 12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring, and any one carbon atom of said heterocyclic ring is optionally selected from -O-, -S-, or -NR a - may be replaced with Each R a are independently H, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, aryl(C-C)alkyl, (C-C)carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR, —C(═O)SR, —S(O)R, —S(O)R, —S(O)(OR), —S(O)(OR), or —SONR; wherein each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, C6-C 20 Aryl, C6-C 20 Substituted Aryl, C2-C 20 Heterocyclyl, C2-C 20 substituted heterocyclyl, arylalkyl, or substituted arylalkyl; In the formula, each R 11 or R 12 Each (C-C) alkyl, (C-C) alkenyl, (C-C) alkynyl, or aryl(C-C) alkyl independently optionally contains one or more halo, hydroxy, CN, N, N(R a )2, OR a wherein one or more of the non-terminal carbon atoms of each of said (C1-C8) alkyls is optionally substituted with -O-, -S-, or -NR a - may be replaced by b) [ka] c) [ka] [During the ceremony, R c is phenyl, 1-naphthyl, 2-naphthyl, [ka] is selected from R dis H or CH3, R e1 and R e2 are each independently H, C1-C6 alkyl, or benzyl; R f is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl; R g is selected from C1-C8 alkyl, —O—C1-C8 alkyl, benzyl, —O-benzyl, —CH2-C3-C6 cycloalkyl, —O—CH2-C3-C6 cycloalkyl, and CF3; n' is selected from 1, 2, 3, and 4; and d) a group of the formula: [ka] [During the ceremony, Q is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2; Z 1 and Z 2 When put together, -Q 1 (C(R y )2)3Q 1 - and During the ceremony, Each Q 1 are independently O, S, or NR; Each R y are independently H, F, Cl, Br, I, OH, R, -C(=Q 2 )R, -C(=Q 2 ) OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR,-S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 2 )R, -OC(=Q 2 ) OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 ) OR, -SC(=Q 2)(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 ) OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 or when taken together, two R on the same carbon atom y forms a carbocyclic ring of 3 to 7 carbon atoms, Each Q 2 are independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR2, or Z 1 and Z 2 are each independently a group of formula Ia, [ka] During the ceremony, Each Q 3 are independently bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2; M2 is 0, 1, or 2; Each R x are independently expressed as R in the following formula: y and [ka] During the ceremony, each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 3 is Z 4 or Z 5 and Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y , or -SO2Z5 and Z 5 is a carbocyclic or heterocyclic ring, 5 are independently 0 to 3 R y substituted with a group.

[0135] Z 5 Carbocycle and Z 5 The heterocycle may independently contain 0 to 3 R y may be substituted with a Z group. 5 Z may be a saturated, unsaturated, or aromatic ring, including a monocyclic or bicyclic carbocyclic or heterocyclic ring. 5 may have 3 to 10 ring atoms, for example 3 to 7 ring atoms. 5 The ring is saturated if it contains 3 ring atoms, saturated or monounsaturated if it contains 4 ring atoms, saturated or monounsaturated or diunsaturated if it contains 5 ring atoms, and saturated, monounsaturated or diunsaturated or aromatic if it contains 6 ring atoms.

[0136] Z 5 The heterocycle of Z can be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), or 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). 5 A heterocyclic monocycle may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), or may contain 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). Z 5 Heterocyclic bicyclic hydrocarbons have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclic [4,5], [5,5], [5,6], or [6,6] system, or arranged as a bicyclic [5,6] or [6,6] system. Contains 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S). Z 5 Heterocycles are rings that are connected to Q by a stable covalent bond through a carbon, nitrogen, sulfur, or other atom. 2can bind to

[0137] Z 5 Heterocycles include, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. 5 Examples include, but are not limited to, the following: [ka]

[0138] Z 5 Carbocycles and heterocycles may be independently substituted with 0 to 3 R groups as defined above. For example, substituted Z 5 Carbocycles include: [ka]

[0139] Examples of substituted phenyl carbocycles include: [ka]

[0140] In another embodiment, Z of the compounds of Formulas I-IV 5 is a carbocyclic or heterocyclic ring, 5 are independently 0 to 3 R z groups, wherein each R z are independently H, F, Cl, Br, I, OH, R, -C(=Q 2 )R, -C(=Q 2 ) OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR,-S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 ) OR, -OC(=Q 2)(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 ) OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 ) OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, or -OR.

[0141] Compounds of Formulas I-IV [ka] Embodiments of include the following substructures: [ka] In the formula, each Q 3b is independently O or N(R). In another aspect of this embodiment, each Q 3b is O, and each R x became independent, [ka] wherein M12c is 1, 2, or 3, and each Q 3 is independently a bond, O, CR2, or S. In another aspect of this embodiment, one Q 3b -R x is NH(R), and other Q 3b -R x is OR x , where R x is [ka] wherein M is 2. In another aspect of this embodiment, each Q 3b is O and each R x are independently: [ka] wherein M is 2. In another aspect of this embodiment, each Q3b is O, and each R x became independent, [ka] wherein M12c is 1 and Q 3 is a bond, O, or CR2.

[0142] Compounds of Formulas I-IV [ka] Other embodiments of include the following moieties: [ka] In the formula, each Q 3 is independently O or N(R). In another aspect of this embodiment, each Q 3 is O. In another aspect of this embodiment, the moiety is [ka] where R y is defined herein as Z 5 is.

[0143] Formulas I-IV [ka] Another embodiment of includes the following structure: [ka] In the formula, each Q 2c are independent, O, N(R y ), or S.

[0144] Compounds of Formulas I-IV [ka] Another embodiment of the present invention is 1 or Z 2 One of them is R 3or R 4 -Q with one of 3 - and Z 1 or Z 2 and the other is formula Ia. Such an embodiment is [ka] The compound is represented by a compound of formula Ib selected from:

[0145] In another aspect of the embodiment of Formula Ib, each Q and Q 3 is O. In another aspect of the embodiment of Formula Ib, Z 1 or Z 2 Q 3b -R x and each Q, Q 3 , and Q 3b is O and R x teeth, [ka] wherein M12c is 1, 2, or 3, and each Q 3 is independently a bond, O, CR2, or S. In another aspect of the embodiment of Formula Ib, Z 1 or Z 2 Q 3b -R x and each Q, Q 3 , and Q 3b is O and R x teeth, [ka] wherein M12c is 2. In another aspect of the embodiment of Formula Ib, Z 1 or Z 2 Q 3b -R x and each Q, Q 3 , and Q 3b is O and R x teeth, [ka] wherein M12c is 1 and Q 3is a bond, O, or CR2.

[0146] Compounds of Formula I-IV [ka] Another embodiment of includes the following substructure: [ka] In the formula, Z 5 is a carbocycle such as phenyl or substituted phenyl. In another aspect of this embodiment, the moiety is [ka] where Q 3b is O or N(R), and the phenyl carbocycle is substituted with 0 to 3 R groups. In another aspect of the embodiment of the moiety, R x teeth, [ka] wherein M12c is 1, 2, or 3, and each Q 3 is independently a bond, O, CR2, or S.

[0147] Formulas I-IV [ka] Another embodiment of the formula includes the substructure: [ka]

[0148] The chiral carbons of the amino acid and lactic acid moieties can be in either the R or S configuration, or can be a racemic mixture.

[0149] Formulas I-IV [ka] Another embodiment of the moiety [ka] where each Q 3 is independently -O- or -NH. In another aspect of this embodiment, R y is (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl. In another aspect of this embodiment, R y is (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl, and R is CH3. In another aspect of this embodiment, R y is (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl; R is CH3; and each Q 3 is -NH-. In another aspect of this embodiment, Z 1 and Z 2 are independently a nitrogen-linked naturally occurring amino acid or a naturally occurring amino acid ester. 1 and Z 2 is independently a naturally occurring 2-hydroxycarboxylic acid or a naturally occurring 2-hydroxycarboxylic acid ester, the acid or ester being attached to P through the 2-hydroxy group.

[0150] Formulas I-IV [ka] Another embodiment of the moiety [ka] is.

[0151] In one aspect of this embodiment, each R xis independently (C-C) alkyl. In one aspect of this embodiment, each R x independently, C-6-C 20 Aryl or C-6-C 20 It is a substituted aryl.

[0152] In one embodiment, [ka] teeth, [ka] is selected from.

[0153] R x Embodiments of the present invention include ester, carbamate, carbonate, thioester, amide, thioamide, and urea groups. [ka] Includes: 2. Metabolites of the Compounds of the Present Invention

[0154] In vivo metabolic products of the compounds described herein are also within the scope of the invention to the extent that such products are novel and not apparent over the prior art. Such products may result from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily through enzymatic processes. Accordingly, the invention includes novel and unidentified compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are not contemplated as being related to the radiolabeled (e.g., 14 C or 3 H) Compounds are prepared and identified by parenteral administration to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolites). The metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products may be useful in diagnostic assays for therapeutic administration of the compounds of the invention, even if they have no anti-2019-nCoV activity of their own, unless otherwise found in vivo.

[0155] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as being stable in the gastrointestinal tract when less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids upon incubation at 37°C for 1 hour. Simply because a compound is stable to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. The prodrugs of the present invention are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, or other metabolic organs, or cells in general. 3. Pharmaceutical preparations

[0156] The compounds of the present invention are formulated with conventional carriers and additives selected in accordance with ordinary practice. Tablets include excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and, if intended for delivery by routes other than oral administration, are generally isotonic. All formulations optionally contain additives such as those listed in the "Handbook of Pharmaceutical Excipients" (1986). Additives include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulations ranges from about 3 to about 11, but is typically about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5, but is typically about 3 to 4.

[0157] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and optionally other additional therapeutic ingredients as discussed herein, particularly additional therapeutically active ingredients as discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0158] Formulations include those suitable for the aforementioned routes of administration. Formulations may be presented in unit dosage form or may be conveniently prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally 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, formulations 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.

[0159] Formulations of the present invention suitable for oral administration may 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 suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0160] 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, surfactant, 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. Tablets can optionally be coated or scored, and can optionally be formulated to provide slow or controlled release of the active ingredient therefrom.

[0161] For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount, for example, of 0.075 to 20% w / w (containing active ingredient(s) in 0.1% w / w increments ranging from 0.1% to 20%, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0162] Optionally, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, 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. Topical formulations may 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 dimethyl sulfoxide and related analogues.

[0163] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply comprise an emulsifier (otherwise known as an emulgent), but desirably comprises a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that functions as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0164] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Additional emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 80.

[0165] The selection of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Creams should preferably be non-greasy, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, monobasic or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, may also be used, the last three being preferred esters. These may be used alone or in combination depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0166] The pharmaceutical formulations according to the invention comprise a combination according to the invention in one or more pharmaceutically acceptable It includes a carrier or additive and optionally other therapeutic agents. Pharmaceutical preparations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral administration can be 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 sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable additives suitable for tablet manufacture are acceptable. These additives can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0167] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0168] Aqueous suspensions of the present invention contain the active ingredient in admixture with additives suitable for the manufacture of aqueous suspensions. Such additives include suspending agents such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacin, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins and Captisol (= sulfobutyl ether beta-cyclodextrin, SEB-beta-CD).

[0169] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0170] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional additives, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0171] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or Arabica oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as acacia gum and tragacanth gum, natural 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. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain adhesives, preservatives, flavorings, or coloring agents.

[0172] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparation may 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 may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any solventless, fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, may also be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0173] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain about 1 to 1,000 mg of active ingredient (weight:weight), combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution, for infusion of a suitable volume at a rate of about 30 mL / hour.

[0174] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0175] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and gum acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0176] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0177] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for pulmonary or nasal administration have particle sizes ranging from, for example, 0.1 to 500 micrometers, e.g., 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used in the treatment or prevention of 2019-nCoV infection, as described below. In some embodiments, the compounds used herein are 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 a spray formulation. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face tent.

[0178] Formulations suitable for vaginal administration may 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.

[0179] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0180] The formulations are presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a lyophilized (lyophilized) condition requiring only the addition of a sterile liquid, for example, water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of an active ingredient, as herein above recited.

[0181] It will be understood that, in addition to the above ingredients, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0182] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0183] Veterinary carriers are materials useful for the purpose of administering the compositions and may be solid, liquid, or gaseous materials that are otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0184] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present invention as the active ingredient, in which release of the active ingredient is controlled and regulated to allow less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient. 4. Route of Administration

[0185] One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0186] In some embodiments, the compounds provided herein are administered by inhalation or IV infusion. In some embodiments, the compounds provided herein are administered by a combination of inhalation and IV infusion, e.g., one or more doses of a compound disclosed herein are administered by inhalation and one or more doses are administered by IV infusion.

[0187] In the methods of the present invention for treating 2019-nCoV infection, the compounds of the present invention can be administered at any time to a human who may have come into contact with a human suffering from 2019-nCoV infection or who already has 2019-nCoV infection. In some embodiments, the compounds of the present invention can be administered prophylactically to a human, such as a healthcare provider, who has come into contact with a human suffering from 2019-nCoV infection or is at risk of coming into contact with a human suffering from 2019-nCoV infection. In some embodiments, the compounds of the present invention can be administered to a human who has tested positive for 2019-nCoV infection but has not yet shown symptoms of 2019-nCoV infection. In some embodiments, the compounds of the present invention can be administered to a human at the onset of symptoms of 2019-nCoV infection.

[0188] In some embodiments, the methods disclosed herein include event-driven administration of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, to a subject.

[0189] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event) that exposes the individual to 2019-nCoV (or otherwise increases the individual's risk of infection with 2019-nCoV); and / or (2) during an event (or two or more recurring events) that exposes the individual to 2019-nCoV (or otherwise increases the individual's risk of infection with 2019-nCoV), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the individual to 2019-nCoV (or otherwise increases the individual's risk of infection with 2019-nCoV). In some embodiments, event-driven administration occurs prior to the subject's exposure to 2019-nCoV. In some embodiments, the event-driven administration occurs after the subject's exposure to 2019-nCoV. In some embodiments, the event-driven administration occurs before the subject's exposure to 2019-nCoV and after the subject's exposure to 2019-nCoV.

[0190] In certain embodiments, the methods disclosed herein include administering a 2019-nCoV antibody to a subject before and / or after an event that exposes the subject to 2019-nCoV or that otherwise increases the subject's risk of becoming infected with 2019-nCoV, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0191] In some embodiments, the compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is administered prior to the subject's exposure to 2019-nCoV.

[0192] In some embodiments, a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is administered before and after the subject's exposure to 2019-nCoV.

[0193] In some embodiments, the compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is administered after the subject's exposure to 2019-nCoV.

[0194] An example of an event-driven dosing regimen includes administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, within 24 hours prior to 2019-nCoV exposure, followed by administration of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by administration of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, after the last exposure. and V, or a pharmaceutically acceptable salt thereof, followed 24 hours later by one final administration of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

[0195] A further example of an event-driven dosing regimen includes administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 24 hours before 2019-nCoV exposure, then daily for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0196] The effective dose of active ingredient will depend, at least, on the nature of the condition being treated, its toxicity, whether the compound is being used prophylactically or against an active viral infection, the delivery method, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose-escalation studies. It can be expected to be about 0.0001 to about 100 mg / kg of body weight per day, typically about 0.01 to about 10 mg / kg of body weight per day, more typically about 0.01 to about 5 mg / kg of body weight per day, and most typically about 0.05 to about 0.5 mg / kg of body weight per day. For example, the daily candidate dose for an adult weighing about 70 kg will range from 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can take the form of single or multiple doses.

[0197] The effective dose of a compound of the invention for treating 2019-nCoV infection may depend on whether the dose is used prophylactically or to treat a person already suffering from 2019-nCoV infection. Furthermore, the dose may depend on whether the person suffering from 2019-nCoV infection has not yet shown symptoms of 2019-nCoV infection or is already showing symptoms. Larger doses may be required to treat people who test positive for 2019-nCoV infection and people who show symptoms of 2019-nCoV infection compared to people receiving prophylactic treatment.

[0198] Any suitable period for administering the compounds of the present invention is contemplated. For example, administration can be from 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 from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer administration periods are also contemplated. The time of administration can depend on whether the compound is being administered prophylactically or to treat a human suffering from 2019-nCoV infection. For example, prophylactic administration can be during the period in which a human is in regular contact with other humans suffering from 2019-nCoV infection, as well as a suitable period after the last contact with a human suffering from 2019-nCoV infection. For humans already suffering from 2019-nCoV infection, the administration period may be any time necessary to treat the patient and a suitable period following a negative test for 2019-nCoV infection to ensure that the 2019-nCoV infection does not recur.

[0199] In some embodiments, the compounds disclosed herein are administered once a day. In some embodiments, the compounds disclosed herein are administered once every other day. In some embodiments, the compounds disclosed herein are administered once a week. In some embodiments, the compounds disclosed herein are administered twice a week.

[0200] In some embodiments, the methods described herein include administering a loading dose of one or more compounds disclosed herein on day 1, followed by a maintenance dose of one or more compounds once daily each day thereafter. The once-daily maintenance dose of one or more compounds can be administered as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, the once-daily maintenance dose is administered for about 6-12 days, e.g., about 8-10 days. In some embodiments, the once-daily maintenance dose is administered for about 4 days. In some embodiments, the once-daily maintenance dose is administered for about 5 days. In some embodiments, the once-daily maintenance dose is administered for about 9 days. In some embodiments, the once-daily maintenance dose is administered for about 10 days. The loading dose may be equal to, less than, or greater than the maintenance dose. In some embodiments, the loading dose is greater than the maintenance dose.

[0201] In some embodiments, the methods disclosed herein comprise administering a loading dose of 150-250 mg on day 1, followed by once-daily maintenance doses of about 50-150 mg on subsequent days. In some embodiments, the once-daily maintenance dose is administered for about 6-12 days, e.g., about 8-10 days. In some embodiments, the once-daily maintenance dose is administered for about 9 days. In some embodiments, the once-daily maintenance dose is administered for about 2-6 days, e.g., about 3-5 days. In some embodiments, the once-daily maintenance dose is administered for about 4 days. In some embodiments, the compound is remdesivir.

[0202] In some embodiments, the methods disclosed herein comprise administering a loading dose of about 200 mg on day 1, followed by once-daily maintenance doses of about 100 mg on subsequent days. In some embodiments, the once-daily maintenance dose is administered for about 6-12 days, e.g., about 8-10 days. In some embodiments, the once-daily maintenance dose is administered for about 9 days. In some embodiments, the once-daily maintenance dose is administered for about 2-6 days, e.g., about 3-5 days. In some embodiments, the once-daily maintenance dose is administered for about 4 days. In some embodiments, the compound is remdesivir.

[0203] In some embodiments, the methods disclosed herein comprise administering a loading dose of about 50-250 mg (e.g., about 100 mg) on ​​day 1, followed by once-daily maintenance doses of about 10-100 mg (e.g., about 50 mg) on ​​subsequent days. In some embodiments, the once-daily maintenance dose is administered for about 6-12 days, e.g., about 8-10 days. In some embodiments, the once-daily maintenance dose is administered for about 9 days. In some embodiments, the once-daily maintenance dose is administered for about 10 days. In some embodiments, the once-daily maintenance dose is administered for about 2-6 days, e.g., about 3-5 days. In some embodiments, the once-daily maintenance dose is administered for about 4 days. In some embodiments, the compound is remdesivir.

[0204] In some embodiments, the loading dose is equal to the maintenance dose, and the methods disclosed herein include administering a dose of one or more compounds disclosed herein once daily. The once-daily dose can be administered as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, the once-daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0205] In some embodiments, one or more compounds disclosed herein are administered once daily for about 6-12 days, e.g., about 8-10 days. In some embodiments, one or more compounds are administered once daily for about 9 days. In some embodiments, one or more compounds are administered once daily for about 10 days. In some embodiments, about 50-150 mg of one or more compounds disclosed herein are administered once daily for about 6-12 days, e.g., about 10 days. In some embodiments, about 100 mg of one or more compounds disclosed herein are administered once daily for about 6-12 days, e.g., about 10 days. In some embodiments, the compound is remdesivir.

[0206] In some embodiments, one or more compounds disclosed herein are administered once daily for about 1-5 days, e.g., about 1-3 days. In some embodiments, one or more compounds are administered once daily for about 5 days. In some embodiments, one or more compounds are administered once daily for about 4 days. In some embodiments, one or more compounds are administered once daily for about 3 days. In some embodiments, one or more compounds are administered once daily for about 2 days. In some embodiments, one or more compounds are administered once daily for about 1 day. In some embodiments, about 50-300 mg of one or more compounds disclosed herein are administered once daily for about 3 days, e.g., about 1 day, about 2 days, or about 3 days. 5. Combination therapy

[0207] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, provided herein is a method for treating 2019-nCoV virus infection (COVID-19), the method comprising administering to a subject in need thereof a compound of the present disclosure and a therapeutically effective amount of one or more additional therapeutic agents.

[0208] In some embodiments, the additional therapeutic agent comprises 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 a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A inhibitor, an NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, and combinations thereof.

[0209] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0210] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is vidarabine, entecavir (ETV), or the like. ), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof In some embodiments, the additional therapeutic agent is selected from the group consisting of: Favipiravir, Ribavirin, Galidesivir, or a combination thereof. In some embodiments, the additional therapeutic agent is β-D-N4-hydroxycytidine.

[0211] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0212] 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. In some embodiments, the additional therapeutic agent is sangivamycin, β-d-N4-hydroxycytidine (NHC), EIDD-2801, EIDD-1931, or combinations thereof. In some embodiments, the antiviral agent is MK-4482 (EIDD-2801).

[0213] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is nevirapine, delravidine, efavirenz , etravirine, rilpivirine, and combinations thereof.

[0214] 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, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0215] 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.

[0216] 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, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], varicella zoster immune globulin [VariZIG], varicella zoster immune globulin [VZIG], and combinations thereof.

[0217] 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.

[0218] 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, rilpivirine, 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, TDF, and combinations thereof.

[0219] In some embodiments, the additional therapeutic agent is an inhibitor of HCV NS5A or NS5B. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-based 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.

[0220] 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, lanamivir 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, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, 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. In some embodiments, the additional therapeutic agent is DAS-181 or XC-221.

[0221] 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 alfacon1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof. In some examples, the additional therapeutic agent is interferon beta. For example, the additional therapeutic agent is interferon beta-1a, such as SNG-001. In some embodiments, the additional therapeutic agent is an interferon inducer, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent is an IL-17 antagonist, such as ixekizumab. In some embodiments, the additional therapeutic agent is an interferon alpha 2 ligand, secukinumab, IMU-838, or bidofludimus.

[0222] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof. In some embodiments, the additional therapeutic agent is azeoximer bromide or IMM-101.

[0223] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN 2222, travirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0224] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0225] In some embodiments, the antiviral agent is DFV890. In some embodiments, the antiviral agent is MAS825. In some embodiments, the antiviral agent is emetine. In some embodiments, the antiviral agent is protoporphyrin IX, SnPP protoporphyrin, and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivermectin.

[0226] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0227] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria. For example, the additional therapeutic agent is dihydroartomisinin piperaquine. In some embodiments, the additional therapeutic agent is Pyramax.

[0228] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemisone, and combinations thereof.

[0229] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus, hi some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, and combinations thereof.

[0230] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), 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-dimethylquinolino[8,7- h]quinolone-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.

[0231] In some embodiments, the additional therapeutic agent is an agent for the treatment of 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, ladarbuvir, 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, vedroprevir, voxilaprevir, and combinations thereof.

[0232] 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.

[0233] 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 α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, 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, oleanolic acid, 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, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, and U.S. Patent Application Publication No. 20150210 682 (Roche), 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 16128335(A1) (Roche), WO 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), WO 16107833(A1) ) (Roche), U.S. Patent Application Publication No. 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and U.S. Patent Application Publication No. 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBV Examples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, and entecavir. In some embodiments, the additional therapeutic agent includes, but is not limited to, HBV capsid inhibitors, such as HBV cyclosporine, ...

[0234] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0235] In some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immunomodulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modulating agent, a gene editing agent (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and a cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy). In some embodiments, the additional therapeutic agent is an immunotherapeutic peptide such as tertomotide. In some embodiments, the additional therapeutic agent is a CCL26 gene inhibitor such as mocedipimod.

[0236] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. In some embodiments, the additional therapeutic agent is a PI3K inhibitor, e.g., idelalisib or duvelisib.

[0237] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® bictegravir, emtricitabine; tricitabine, and tenofovir alafenamide; COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFS EY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate; CIMDU™ (doravirine, lamivudine, and tenofovir disoproxil fumarate); tenofovir tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA (registered trademark) Trademarks) (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, 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; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine These include, but are not limited to, lopinavir + 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;

[0238] 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, and cobicistat. In some examples, 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.

[0239] 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, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, 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.

[0240] 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. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (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).

[0241] 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.

[0242] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, ethozidovudine lavirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0243] In some examples, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilp (VM-1500), and combinations thereof.

[0244] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC ); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir; Adefovir dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRI UMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir 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; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine;Selected from indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir and abacavir sulfate;

[0245] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovyne, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0246] 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 (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, 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 receptor tyrosine kinase inhibitor (RTKI). In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9). In some embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor. In some embodiments, the additional therapeutic agent is abivertinib maleate (STI-5656). In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor such as masitinib.

[0247] In some embodiments, the additional therapeutic agent is a sphingosine kinase-2 (sk2) inhibitor, such as opaganib. In some embodiments, the additional therapeutic agent is a kinase inhibitor, such as pacritinib. In some embodiments, the additional therapeutic agent is an Axl tyrosine kinase receptor inhibitor, such as bemcentinib. In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor. In some embodiments, the additional therapeutic agent is a checkpoint kinase inhibitor, such as prexasertib. In some embodiments, the additional therapeutic agent is a MAP kinase inhibitor, such as KTH-222 or ATI-450. In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus. In some embodiments, the additional therapeutic agent is a pi3k / mTOR inhibitor, such as dactolisib. In some embodiments, the additional therapeutic agent is an Hsp90 inhibitor, such as ganetespib or ADX-1612. In some embodiments, the additional therapeutic agent is a MEK inhibitor, such as ATR-002. In some embodiments, the additional therapeutic agent is a topoisomerase II inhibitor, such as etoposide. In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor or veldinexor. In some embodiments, the additional therapeutic agent is a dual inhibitor of PARP1 / 2 and tankyrase1 / 2, e.g., 2X-121. In some embodiments, the additional therapeutic agent is a cyclin-dependent kinase inhibitor, such as CYC-065 or CYC-202. In some embodiments, the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine. In some embodiments, the additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments, the additional therapeutic agent is a small ubiquitin-related modifier inhibitor, such as TAK-981. In some embodiments, the additional therapeutic agent is an integrin agonist, such as 7HP-349. In some embodiments, the additional therapeutic agent is a BET inhibitor, such as apabetalone. In some embodiments, the additional therapeutic agent is a BRD4 inhibitor, such as CPI-0610 or ABBV-744.In some embodiments, the additional therapeutic agent is an ER1 inhibitor, such as tolmifen.

[0248] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is a KRAS inhibitor, including 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, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), MRTX-84 9(G12C) and K-Ras(G12D) selective inhibitory peptides, and combinations thereof.

[0249] In some embodiments, the additional therapeutic agent is an alkylating agent, such as melphalan.

[0250] 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.

[0251] 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, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., a monovalent influenza A [H5N1] virus vaccine and a monovalent influenza A [H1N1] 2009 virus vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Flude, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (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 (eg, 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., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MM-RII 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 variola virus (smallpox) 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. In some embodiments, the additional therapeutic agent is Ad5-nCoV. In some embodiments, the additional. The therapeutic agent is the mRNA vaccine BNT-162. In some embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the additional therapeutic agent is a Pfizer-BioNTech COVID-19 vaccine. In some embodiments, the additional therapeutic agent is a Moderna Covid-19 vaccine. In some embodiments, the additional therapeutic agent is AZD1222 (astrazeneca Covid-19 vaccine). In some embodiments, the additional therapeutic agent is a poliovirus vaccine, e.g., OPV.

[0252] In some embodiments, the additional therapeutic agent is BNT162a1, BNT162b1, BNT162b2, or BNT162c2 (prime / boost, single or multiple doses). In some embodiments, the additional agent is AZD1222 (ChAdOx1 nCov-19). In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 prime-boost), Covax-19, or NasoVAX. In some embodiments, the additional therapeutic agent is LUNAR-COV19 (ARCT-021). In some embodiments, the additional agent is TerraCoV2. In some embodiments, the additional agent is COVID-19 S-Trimer. In some embodiments, the additional agent is TNX-1810, TNX-1820, or TNX-1830. In some embodiments, the additional agent is VaxiPatch COVID-19 vaccine. In some embodiments, the additional agent is VBI-2901. In some embodiments, the additional agent is VLA-2001. In some embodiments, the additional agent is exoVACC-SARS-CoV2CoV-2. In some embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-M, or NVX-CoV2373. In some embodiments, the additional agent is BBV152A, B, C, PicoVacc, KBP-COVID-19, MF59-adjuvanted SARS-CoV-2Sclamp, MVC-COV1901, SCB-2019 (COVID-19S-Trimer+CpG1018+AS03), TMV-083, V-591, VPM1002, or V-SARS.

[0253] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (a 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 an aPD-1 antibody. In some embodiments, the additional therapeutic agent is an anti-IL-6R mAb. For example, the additional therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic agent is an antibody targeting a specific site on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide targeting the SARS-CoV-2 spike protein (S-protein). In some embodiments, the additional therapeutic agent is a viral suppressor factor (VSF, HzVSFv13).

[0254] In some embodiments, the additional therapeutic agent is an anti-CD147 antibody, e.g., the additional therapeutic agent is meplasmab.

[0255] In some embodiments, the additional therapeutic agent is a phosphodiesterase type 4 (PDE4) or phosphodiesterase type 5 (PDE5) inhibitor. In some embodiments, the additional therapeutic agent is a PDE5 inhibitor, e.g., the additional therapeutic agent is sildenafil. In some embodiments, the additional therapeutic agent is a PDE4 inhibitor, e.g., the additional therapeutic agent is brilacidin.

[0256] In some embodiments, the additional therapeutic agent is an agent that targets NKGA2. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is an NKG2 AB-activating NK receptor antagonist, such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor, such as BPI-002.

[0257] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as CPI-006.

[0258] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0259] 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 lamivudine. 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. In some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, pimodivir, and combinations thereof.

[0260] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, avidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0261] In some embodiments, the additional therapeutic agent is a β-catenin inhibitor, e.g., the additional therapeutic agent is tetradrine.

[0262] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, e.g., the additional therapeutic agent is urinastatin. In some embodiments, the additional therapeutic agent is TAK-671.

[0263] In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, sapanisertib, rapamycin, zotatifin, veldinexor, chloroquine, dabrafenib, WDB002, sanglifehrin A, FK-506, pevonedistat, ternatin 4, 4E2RCat, tomivosertib, PS3061, IHVR-19029, captopril, lisinopril, camostat, nafamostat, chloramphenicol, tigecycline, linezolid, and combinations thereof.

[0264] In some embodiments, the additional therapeutic agent is JQ-1, RVX-208, silmitasertib, TMCB, apicidin, valproic acid, bafilomycin A1, E-52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, metformin, ponatinib, H-89, merimepodib, migalastat, mimetformin, thiazolinone ... cophenolic acid, ribavirin, XL413, CCT365623, midostaurin, ruxolitinib, ZINC1775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, daunorubicin, GB110, S-verapamil, AZ3451, and combinations thereof.

[0265] In some embodiments, the additional therapeutic agent is selected from the group consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof.

[0266] In some embodiments, the additional therapeutic agent is a drug that targets coronavirus main protease 3CL (e.g., lopinavir). In some embodiments, the additional therapeutic agent is a drug that targets papain-like protease PL (e.g., lopinavir). In some examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells (e.g., arbidol). In some embodiments, the additional therapeutic agent is a TMPRSS2 inhibitor (e.g., camostat mesylate).

[0267] In some embodiments, the additional therapeutic agent is a serine protease inhibitor such as LB1148, upamostat, RHB-107, or alpha-1 antitrypsin.

[0268] In some embodiments, the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonoderestat.

[0269] In some embodiments, the additional therapeutic agent is an α-ketoamide.

[0270] In some examples, the additional therapeutic agent is a poly ADP-ribose polymerase 1 (PARP1) inhibitor, for example, the additional therapeutic agent is CVL218.

[0271] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a vananin and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, dihydrotanshinones E-64-C and E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, a hydroxybenzoate, a benzocaine, a benzodiazepine ... rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0272] 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, e.g., an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus in a 2019-nCoV study. It is an antibody against the virus.

[0273] In some embodiments, the additional therapeutic agent is LY-CoV555. In some embodiments, the additional therapeutic agent is S309. In some embodiments, the additional therapeutic agent is SAB-185. In some embodiments, the additional therapeutic agent is CB6. In some embodiments, the additional therapeutic agent is STI-1499. In some embodiments, the additional therapeutic agent is JS016. In some embodiments, the additional therapeutic agent is VNAR. In some embodiments, the additional therapeutic agent is VIR-7832 and / or VIR-7831. In some embodiments, the additional therapeutic agent is REGN-COV2 (REGN10933 + RGN10987). In some embodiments, the additional therapeutic agent is BAT2020, BAT2019. In some embodiments, the additional therapeutic agent is 47D11. In some embodiments, the additional therapeutic agent is COVI-SHIELD. In some embodiments, the additional therapeutic agent is BRII-196, BRII-198. In some embodiments, the additional therapeutic agent is INM-005, SCTA01, TY-027, XAV-19.

[0274] The compositions of the invention may also be used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably, the other active therapeutic agent is active against coronavirus infection, e.g., 2019-nCoV viral infection. The compounds and compositions of the invention may also be used in combination with 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 prophylaxis, fever and analgesics, 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 agents (e.g., interferons), other small molecule or biological antibiotics targeting 2019-nCoV, and other suitable antiviral agents. The present invention is intended for use in conjunction with the general care provided to patients with 2019-nCoV virus infection, including antivirals (including, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and drugs for other common illnesses in the patient population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoids (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is a corticosteroid, for example, the additional therapeutic agent is ciclesonide. In some embodiments, the compounds disclosed herein are used in combination with amoxicillin / clebranate, trimethoprim / sulfamethoxazole, cholecalciferol, vitamin C, prednisone, mometasone, or budenoside.

[0275] In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as Panaphix (PAX-1), which inhibit the production of pro-inflammatory cytokines. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as NCP-112, which inhibit excessive immune responses, such as cytokine storm.

[0276] In some embodiments, the additional therapeutic agent is an antifungal agent, such as itraconazole or 17-OH-itraconazole.

[0277] In some examples, the additional therapeutic agent is an immune modulator. Examples of immune-based therapies include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Ill-like receptor modulators; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives, mycophenolate mofetil (MMF); ribavirin; polymeric polymers Examples of additional therapeutic agents include triethyleneimine (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, normferon, pegylated interferon α-2a, pegylated interferon α-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 is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide. In some embodiments, the additional therapeutic agent is CD24Fc. In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra. In some embodiments, the additional therapeutic agent is a TLR4 antagonist, such as EB-05.

[0278] In some embodiments, the additional therapeutic agent is nivolumab, efineptakine alfa, lactoferrin, ozanimod, astegolimab (MSTT1041A, RG-6149), or UTTR1147A. In some embodiments, the additional therapeutic agent is ampligen. In some embodiments, the additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor, such as MEDI3506. In some embodiments, the additional therapeutic agent is an IL-5 receptor antagonist, such as mepolizumab. In some embodiments, the additional therapeutic agent is an IL-12 inhibitor, such as apilimod. In some embodiments, the additional therapeutic agent is an IL-15 receptor agonist, such as N-803.

[0279] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.

[0280] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof. In some embodiments, the additional therapeutic agent is tocilizumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, olokizumab, sirukumab, clazakizumab, revilimab, or a combination thereof.

[0281] In some embodiments, the additional therapeutic agent is a nicotinamide phosphoribosyltransferase inhibitor, e.g., the additional therapeutic agent is enamptcumab.

[0282] In some embodiments, the additional therapeutic agent is a dipeptidase 1 (DPEP-1) inhibitor. For example, the additional therapeutic agent is Metablok (LSALT peptide).

[0283] 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. In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor, such as XPro1595.

[0284] In some embodiments, the additional therapeutic agent is a JAK inhibitor, e.g., the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof. In some examples, the additional therapeutic agent is jactinib. In some embodiments, the additional therapeutic agent is tofacitinib or TD-0903.

[0285] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, e.g., pirfenidone. In some embodiments, the additional therapeutic agent is LYT-100.

[0286] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as dosiparstat sodium. In some embodiments, the additional therapeutic agent is used to treat septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a CCR1 antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent targets IKKβ and NFκβ, such as OP-101. In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone or dexamethasone. In some embodiments, the additional therapeutic agent is an immunosuppressant, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, or M-5049. In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758. In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8). In some embodiments, the additional therapeutic agent is a CD14 inhibitor, such as IC-14. In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar or PCT-299. ... In some embodiments, the additional therapeutic agent is an anti-fibrotic agent, such as RT-1840, nintedanib, GB-0139, nintedanib, or pamrevlumab. In some embodiments, the additional therapeutic agent is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777).

[0287] In some embodiments, the additional therapeutic agent is an A3 adenosine receptor (A3AR) antagonist, e.g., the additional therapeutic agent is piclidenoson. is.

[0288] 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. In some embodiments, the coronavirus therapeutic agent is XEL 1004. In some embodiments, the additional therapeutic agent is eravacycline.

[0289] In some embodiments, the compounds disclosed herein are used in combination with standard of care treatments for pneumonia (e.g., Pediatric Community Pneumonia). Guidelines, CID 2011:53 (1 October). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the individual. Options include: (i) antibiotics, (ii) cough medicine, and (iii) antipyretics / 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.

[0290] In some embodiments, the compounds disclosed herein are used in combination with immune globulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusions. In some examples, the compounds disclosed herein are used in combination with TAK-888 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)). In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immune globulin. In some embodiments, the compounds described herein are used in combination with COVID-EIG or COVID-HIG. In some embodiments, the compounds disclosed herein are used in combination with stem cells. For example, in some embodiments, the compounds disclosed herein are used in combination with MultiStem or Remestemcel-L (mesenchymal stem cells). In some embodiments, the compounds described herein are used in combination with allogeneic mesenchymal cells, e.g., PLX cells. In some embodiments, the compounds described herein are used in combination with allogeneic cell therapy, e.g., CK-0802. In some embodiments, the compounds described herein are used in combination with Pluristem or ACT-20.

[0291] In some examples, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531. In some embodiments, the additional therapeutic agent is PUL-042. In some embodiments, the additional therapeutic agent is polyinosinic-polycytidylic acid (Poly I:C).

[0292] In some examples, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof. In some examples, the additional therapeutic agent is simvastatin or rosuvastatin.

[0293] In some examples, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. 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).

[0294] In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2), e.g., APN-01. In some embodiments, the additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the additional therapeutic agent is an AT2 partial agonist or an AT1 partial antagonist. In some embodiments, the additional therapeutic agent is L-163491. In some embodiments, the additional therapeutic agent is an ACE2-Fc fusion protein, e.g., the additional therapeutic agent is STI-4398. In some embodiments, the additional therapeutic agent is valsartan, losartan, candesartan, eprosartan, irbesartan, or olmesartan. In some embodiments, the additional therapeutic agent is VP-01 or TXA-127. In some embodiments, the additional therapeutic agent is telmisartan.

[0295] In some embodiments, the additional therapeutic agent is ramipril, captopril, enalapril or lisopril. In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as AT-001.

[0296] In some embodiments, the additional therapeutic agent is a platelet inhibitor, e.g., the additional therapeutic agent is dipyridamole.

[0297] In some embodiments, the additional therapeutic agent is an anticoagulant such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux. In some embodiments, the additional therapeutic agent is a tissue factor inhibitor such as AB-201. In some embodiments, the additional therapeutic agent is a factor XIIa antagonist such as galadacumab. In some embodiments, the additional therapeutic agent is a VE-PTP inhibitor such as razuprotafib. In some embodiments, the additional therapeutic agent is a VIP2 receptor agonist such as PB-1046. In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tranexamic acid. In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, bentaprost, bazegepant, angiotensin I-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301, sodium nitrite, or TRV-027. In some embodiments, the additional therapeutic agent is a coagulation modulator, such as lanadelumab. In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone. In some embodiments, the additional therapeutic agent is an antihypoxic agent, such as trans-sodium crocetinate. In some embodiments, the additional therapeutic agent is MK-5475.

[0298] In some embodiments, the additional therapeutic agent is a hypoxia-inducible factor (HF) prolyl hydroxylase-2 (PHD-2) inhibitor, such as desidustat or vadadustat. In some embodiments, the additional therapeutic agent is a renin inhibitor, such as aliskiren. In some embodiments, the additional therapeutic agent is a calcium channel inhibitor, such as nifedipine. In some embodiments, the additional therapeutic agent is a chelating agent, such as desferal, deferiprone, or deferoxamine. In some embodiments, the additional therapeutic agent is a retinoic acid receptor agonist, such as isotretinoin or fenrenide. In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurosin. In some embodiments, the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i. In some embodiments, the additional therapeutic agent is a microbiome modulator, such as EDP-1815 or KB-109. In some embodiments, the additional therapeutic agent is an estrogen receptor antagonist, such as tamoxifen. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide or enzalutamide.

[0299] In some embodiments, the additional therapeutic agent is a GNRH receptor antagonist, such as degarelix. In some embodiments, the additional therapeutic agent is a sex hormone modulator, such as dutasteride. In some embodiments, the additional therapeutic agent is a calpene inhibitor, such as BLD-2660. In some embodiments, the additional therapeutic agent is a GM-CSF ligand inhibitor, such as gimsilumab, lenzilumab, namilumab, TJM2, or otilimab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as mavrilimumab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim. In some embodiments, the additional therapeutic agent is an alpha 1 adrenergic receptor antagonist, such as prazosin. In some embodiments, the additional therapeutic agent is a neuropilin inhibitor, such as ATYR-1923. In some embodiments, the additional therapeutic agent is a calcium activated agonist (CRAC) channel inhibitor, such as CM-4620. In some embodiments, the additional therapeutic agent is a proto-oncogene Mas agonist, such as BIO101. In some embodiments, the additional therapeutic agent is a DPP4 inhibitor, such as saxagliptin, sitagliptin, alogliptin, or linagliptin. In some embodiments, the additional therapeutic agent is a glucose cotransporter type 2 (SGLT-2) inhibitor, such as dapagliflozin propanediol. In some embodiments, the additional therapeutic agent is a fractalkine receptor inhibitor, such as KAND-567.

[0300] In some embodiments, the additional therapeutic agent is an alpha 2 receptor agonist, e.g., the additional therapeutic agent is dexmedetomidine.

[0301] In some embodiments, the additional therapeutic agent is a mCBM40 (multivalent carbohydrate binding module family 40 domain) product, for example, the additional therapeutic agent is pneumifil.

[0302] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist such as ebastine. In some embodiments, the additional therapeutic agent is tranilast. In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist. In some embodiments, the additional therapeutic agent is famotidine. In some embodiments, the additional therapeutic agent is an antihistamine. In some embodiments, the additional therapeutic agent is chloroperastine or clemastine.

[0303] In some embodiments, the additional therapeutic agent is a vasoactive intestinal peptide receptor 1 agonist, such as aviptadil.

[0304] In some embodiments, the additional therapeutic agent is a drug that treats respiratory distress syndrome (ARDS).

[0305] In some embodiments, the additional therapeutic agent is a peptide, e.g., the additional therapeutic agent is BIO-11006. In some embodiments, the additional therapeutic agent is a liposomal formulation, e.g., the additional therapeutic agent is LEAF-4L6715, LEAF-4L7520. In some embodiments, the additional therapeutic agent is a respiratory stimulant, such as almitrine. In some embodiments, the additional therapeutic agent is a bronchodilator, such as brensocatib or formoterol. In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as CERC-002. In some embodiments, the additional therapeutic agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE.

[0306] In some embodiments, the compounds described herein are used in combination with respiratory-specific small interfering RNA therapies, which in some embodiments are delivered by a nebulizer.

[0307] In some embodiments, the additional therapeutic agent is a vimentin modulator. For example, the additional therapeutic agent is pritumumab. In some embodiments, the additional therapeutic agent is hzVSF-v13.

[0308] In some embodiments, the additional therapeutic agent is a modulator of Nsp15 (nonstructural protein 15), such as benzopurpurin B, C-467929, C-473872, NSC-306711, and N-65828.

[0309] In some embodiments, the additional therapeutic agent is a xanthine dehydrogenase inhibitor, such as oxypyrinol (XRx-101).

[0310] In some embodiments, the additional therapeutic agent is a cathepsin-L inhibitor. In some embodiments, the additional therapeutic agent is a cathepsin inhibitor such as VBY-825 or ONO-5334.

[0311] In some embodiments, the additional therapeutic agent is a transforming growth factor beta (TGF-β) inhibitor, e.g., the additional therapeutic agent is OT-101.

[0312] In some embodiments, the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor antagonist, e.g., the additional therapeutic agent is ifenprodil.

[0313] In some embodiments, the additional therapeutic agent is a glycogenolysis inhibitor, e.g., the additional therapeutic agent is WP-1122.

[0314] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast. In some embodiments, the additional therapeutic agent is a leukotriene BLT receptor antagonist, such as ebselen. In some embodiments, the additional therapeutic agent is a tubulin inhibitor, such as VERU-111 or colchicine. In some embodiments, the additional therapeutic agent is a glucosylceramide synthase inhibitor, such as miglustat. In some embodiments, the additional therapeutic agent is an Nrf2 activator, such as PB125. In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as ABX464. In some embodiments, the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV-15). In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as PPP003. In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide. In some embodiments, the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, or aspirin / dipyridamole. In some embodiments, the additional therapeutic agent is an antitoxin such as CAL02. In some embodiments, the additional therapeutic agent is a nitric oxide stimulator such as GLS-1200. In some embodiments, the additional therapeutic agent is an apelin receptor agonist such as CB-5064. In some embodiments, the additional therapeutic agent is a complement inhibitor such as ravulizumab. In some embodiments, the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSF1R) inhibitor such as abdolalimab. In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor such as eculizumab or zilucoplan, or a complement C5a factor inhibitor such as BDB-001, IFX-1, or advallimab. In some embodiments, the additional therapeutic agent is a complement C1s inhibitor such as conestat. In some embodiments, the additional therapeutic agent is a C3 inhibitor such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody such as advolalimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor 1 alpha 2 inhibitor, such as plitidepsin.In some embodiments, the additional therapeutic agent is an angiopoietin ligand-2 inhibitor, such as LY-3127804. In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 inhibitor, such as bafidemstat. In some embodiments, the additional therapeutic agent is a hyaluronic acid inhibitor. In some embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole.

[0315] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is The therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO 2004112687, WO 2006135978, WO 2018145148, and WO 2009018609.

[0316] In some embodiments, the compounds disclosed herein are used in combination with cell therapy such as allogeneic natural killer cells, BM-Allo.MSCs, CAStem, IL-15-NK cells, NKG2D-CAR-NK cells, ACE 2 CAR-NK cells, partially HLA-matched virus-specific T cells (VSTs), RAPA-501, or SARS-CoV-2-specific T cells.

[0317] Any compound of the present invention 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. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0318] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound disclosed herein and the one or more other active therapeutic agents are present in the patient's body.

[0319] Co-administration includes administration of a unit dose of a compound of the invention before or after administration of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of a compound of the invention. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by 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 a unit dose of a compound of the invention. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more other active therapeutic agents. In other embodiments, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound of the invention.

[0320] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination.

[0321] In another embodiment, the present application provides a method of inhibiting 2019-nCoV polymerase, comprising contacting a cell infected with 2019-nCoV with an effective amount of a compound of Formulas I-IV or a pharmaceutically acceptable salt or solvate thereof, and / or an ester thereof, thereby inhibiting 2019-nCoV polymerase.

[0322] In another embodiment, the present application provides a method for treating cells infected with 2019-nCoV by administering an effective amount of a compound of Formula I-IV or a pharmaceutically acceptable salt or solvate thereof, and / or an ester thereof, and at least one additional active therapeutic agent, thereby inhibiting the 2019-nCoV polymerase.

[0323] In yet another embodiment, the present application provides a method of treating 2019-nCoV infection in a human, comprising administering to a patient a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

[0324] In another embodiment, the present application provides a method of treating 2019-nCoV infection in a human, comprising administering to a patient a therapeutically effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional active therapeutic agent, whereby 2019-nCoV polymerase is inhibited.

[0325] In yet another embodiment, the present application provides a method of treating 2019-nCoV infection in a human, comprising administering to a patient a therapeutically effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional active therapeutic agent.

[0326] Kits are also provided that include a compound of Formula I, or a pharmaceutically acceptable salt, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers, or tautomers thereof. In separate embodiments, individual kits are provided that include a compound selected from each group of formulas herein, Formula II, Formula II, Formula IV, and each subgroup and embodiment thereof, including individual compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32 (Compounds 1-32), or a pharmaceutically acceptable salt, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers, or tautomer thereof. In one aspect, the kit includes a compound of Formula I, or a pharmaceutically acceptable salt thereof. Each of the individual kits described herein may include a label and / or instructions for use of the compound in treating a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a human 2019-nCoV infection. In other embodiments, each separate kit may also include instructions for use of an additional medicinal agent in combination with the compound of Formula I in treating a disease or condition in a subject (e.g., a human) in need thereof. In certain of these embodiments, the disease or condition is a human 2019-nCoV infection. In each of the kits herein, there are further embodiments in which the kit includes individual dosage units of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. Examples of individual dosage units include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, etc., each of which may contain a therapeutically effective amount of the compound of interest, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. In some embodiments, the kit may contain a single dosage unit and other multiple dosage units, such as the number of dosage units needed for a particular regimen or time period.

[0327] Also provided are articles of manufacture comprising a compound of Formula I, or a pharmaceutically acceptable salt, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In one aspect, the article of manufacture comprises a compound of Formula I, Formula II, Formula II, Formula IV, and individual compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32 (Compounds 1-32), or a pharmaceutically acceptable salt thereof, and a container. In a separate embodiment, the article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, bottle, or other container. It may be a lister package, tin, can, bottle, box, or intravenous bag.

[0328] Also provided is the use of a compound selected from each of the formulas herein, as well as each subgroup and embodiment thereof, including one of the specific compounds of the Examples herein, including a compound selected from the group of Formula (I), Formula (II), Formula (III), Formula (IV), Compounds 1-32, or pharmaceutically acceptable salts, solvates, and / or esters thereof, in the preparation of a medicament for use in treating 2019-nCoV infection in a human. 6. Methods for Inhibition of 2019-nCOV Polymerase

[0329] Another aspect of the invention relates to a method of inhibiting the activity of 2019-nCoV polymerase comprising treating a sample suspected of containing 2019-nCoV with a compound or composition of the invention.

[0330] The compositions of the present invention can act as inhibitors of 2019-nCoV polymerase, serving as intermediates for such inhibitors or having other utilities as described below. The inhibitors bind to locations on surfaces or within the cavity of 2019-nCoV polymerase that have geometries unique to the 2019-nCoV polymerase. Compositions that bind to 2019-nCoV polymerase can bind with varying degrees of reversibility. These compounds bind substantially irreversibly, making them ideal candidates for use in this method of the present invention. When labeled, compositions that bind substantially irreversibly are useful as probes for detecting 2019-nCoV polymerase. Accordingly, the present invention relates to a method for detecting 2019-nCoV polymerase in a sample suspected of containing 2019-nCoV polymerase, comprising treating the sample suspected of containing 2019-nCoV polymerase with a composition comprising a compound of the present invention conjugated to a label and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostic arts and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds herein are labeled in conventional manner using functional groups such as hydroxyl, carboxyl, sulfhydryl, or amino.

[0331] Within the context of the present invention, samples suspected of containing 2019-nCoV polymerase include natural or artificial materials such as living organisms, tissue or cell cultures, biological samples such as biomaterial samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.), laboratory samples, food, water, or air samples, biological product samples such as extracts of cells, particularly recombinant cells that synthesize the desired glycoprotein, etc. Typically, the sample is suspected of containing an organism that produces 2019-nCoV polymerase, often a pathogenic organism such as the 2019-nCoV virus. The sample can be contained in any medium, including water and organic solvent / water mixtures. Samples include organisms such as humans, and artificial materials such as cell cultures.

[0332] The treating step of the present invention comprises adding a composition of the present invention to the sample, or it comprises adding a precursor of the composition to the sample. The adding step includes any of the administration methods described above.

[0333] If desired, the activity of the 2019-nCoV polymerase after application of the composition can be monitored by any method, including direct and indirect methods for detecting 2019-nCoV polymerase activity. Quantitative, qualitative, and semi-qualitative methods for determining 2019-nCoV polymerase activity are all contemplated. Typically, one of the screening methods described above is used, although any other method, such as observing the physiological characteristics of an organism, is also applicable.

[0334] Organisms containing the 2019-nCoV polymerase are known to contain the 2019-nCoV virus. The compounds of the invention are useful for treating or preventing 2019-nCoV infection in animals or humans.

[0335] However, in screening for compounds that can inhibit the human 2019-nCoV virus, it should be kept in mind that the results of enzyme assays may not correlate with those of cell culture assays, and therefore, cell-based assays should be the primary screening tool.

[0336] In another embodiment, the present application provides a method of treating a 2019-nCoV infection in a human, comprising administering to the patient a therapeutically effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In some embodiments, the 2019-nCoV infection is caused by 2019-nCoV. In some embodiments, 2019-nCoV polymerase is inhibited.

[0337] The compounds of the present invention can be used to treat humans already infected with 2019-nCoV, or can be administered prophylactically to reduce or prevent the likelihood of 2019-nCoV infection. Physical examination of patients infected with 2019-nCoV after the onset of fever may reveal purulent pharyngitis, bilateral conjunctival hemorrhages, facial edema, and generalized abdominal tension. Gross pathological changes may include pleural effusion, pulmonary edema, ascites, and hemorrhagic manifestations of the gastrointestinal mucosa. 7.2019-NCOV polymerase inhibitor screening.

[0338] Compositions of the invention are screened for inhibitory activity against 2019-nCoV polymerase by any conventional technique for assessing enzymatic activity. Within the context of the present invention, typically, compositions are first screened for inhibition of 2019-nCoV polymerase in vitro, and those that demonstrate inhibitory activity are then screened for activity in vivo.

[0339] Useful in vitro screens will not be detailed here, however the Examples describe suitable in vitro assays. [Example]

[0340] 8. Working Example 1. Compound Preparation The compounds described herein can be prepared by known methods, for example, by the methods disclosed in WO 2017 / 049060. The following are exemplary compounds that have been prepared: i. (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (Compound 1) [ka] ii. (2R,3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (compound 2) [ka] iii. (2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-2-(hydroxymethyl)-5-methyltetrahydrofuran-3-ol (compound 3) [ka] iv. 2R)-2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoramino)propionic acid isopropyl (compound 4) [ka] v. (2R)-2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramino)ethyl propionate (Compound 5) [ka] vi. ((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methyl tetradiene triphosphate (compound 6) [ka] vii. (2R,3R,5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile (Compound 7) [ka] viii. (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)propionic acid isopropyl ester (compound 8) [ka] ix. 2-Ethylbutyl (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramino)propionate (Compound 9) [ka] x. (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramino)ethyl propionate (Compound 10) [ka] xi. (2S)-2-((((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramino)ethyl propionate (Compound 11) [ka] xii. (2S,2'S)-2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropionate diethyl ester (Compound 12) [ka] xiii. (2S,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-2-ethynyl-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 13) [ka] xiv. (2R,3R,4R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-1,3,4-tris(benzyloxy)hexane-2,5-diol (Compound 14) [ka] xv. S,S'-2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate) (Compound 15) [ka] xvi. S,S'-2,2'-((((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate) (Compound 16) [ka] xvii. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetradiene triphosphate (Compound 17) [ka] xviii. ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetradiene triphosphate (Compound 18) [ka] xix. ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)methyl tetradiene triphosphate (Compound 19) [ka] xx. ((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl tetradiene triphosphate (Compound 20) [ka] xxi. (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)-3-phenylpropionic acid ethyl ester (21) [ka] xxii. (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)-3-methylbutanoate ethyl butanoate (22) [ka] xxiii. (S)-2-(((R)-(((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)propionic acid isopropyl (23) [ka] xxiv. (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)cyclobutyl propionate (24) [ka] xxv. (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)-3-phenylpropionic acid isopropyl ester (25) [ka] xxvi. (S)-2-(((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) Methyl aminopropionate (26) [ka] xxvii. (S)-2-(((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)amino)propionic acid neopentyl ester (27) [ka] xxviii. (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)propionic acid cyclopentyl ester (28) [ka] xxix. (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)propionic acid cyclohexyl (29) [ka] xxx. Ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-methylpropionate (30) [ka] xxxi. 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-methylpropionic acid isopropyl ester (31) [ka] xxxii. 2-Ethylbutyl (S)-2-(((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)amino)propionate (32) [ka] 2. Antiviral activity

[0341] Another aspect of the present invention relates to a method of inhibiting 2019-nCoV infection, comprising treating a sample or subject suspected of needing such inhibition with a composition of the present invention.

[0342] Within the context of the present invention, samples suspected of containing viruses include natural or artificial materials such as living organisms, tissue or cell cultures, biological samples such as biomaterial samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, bronchoalveolar lavage fluid, nasal swabs, nasal washes, saliva, tissue samples, etc.), laboratory samples, food, water, or air samples, biological product samples such as cell extracts, particularly recombinant cells that synthesize the desired glycoprotein, etc. Typically, the sample is suspected of containing an organism that induces a viral infection, often a pathogenic organism such as a tumor virus. The sample can be contained in any medium, including water and organic solvent / water mixtures. Samples include organisms such as humans, and artificial materials such as cell cultures.

[0343] If necessary, the antiviral activity of the compound of the present invention after applying the composition can be observed by any method, including direct and indirect methods for detecting such activity.All quantitative, qualitative, and semi-qualitative methods for determining such activity are contemplated.Typically, one of the screening methods described herein is applied, but any other method, such as observing the physiological characteristics of an organism, can also be applied.

[0344] The antiviral activity of the compounds of the invention can be determined using suitable screening protocols. Example 1: 2019-nCoV Antiviral Assay

[0345] Vero E6 cells were seeded into 384-well plates, and serial dilutions of compound 32 or compound 9 were added to the assay plates by direct titration using an HP D300 digital dispenser (Hewlett-Packard, Palo Alto, CA). The plates were infected with 2019-nCoV at a multiplicity of infection of 0.5 plaque-forming units (pfu) per cell. The infected cultures were incubated for 48 hours. The level of viral replication in compound-treated and control vehicle-treated cultures was determined by quantifying the level of virus-specific antigen after immunostaining with an antibody against the 2019-nCoV spike (S) protein. The primary antibody was diluted 1:1000 in blocking buffer (1x phosphate-buffered saline (PBS) containing 3% BSA) and added to each well of the assay plate. The assay plate was incubated for 60 minutes at room temperature. The primary antibody was removed, and the cells were washed three times with 1x PBS. The secondary detection antibody is anti-rabbit IgG conjugated with Dylight488 (Thermo Fisher Scientific, Waltham, MA, Cat. No. 405310). The secondary antibody is diluted 1:1000 in blocking buffer and added to each well in the assay plate. The assay plate is incubated at room temperature for 60 minutes. Nuclei are stained using Draq5 (Biostatus, Shepshed Leicestershire, UK, Cat. No. DR05500) diluted in 1x PBS. Cells are counterstained with CellMask Deep Red (Thermo Fisher Scientific, Waltham, MA, Cat. No. C10046) to enhance detection of the cytoplasmic compartment. Cell images are captured using a Perkin EUV1000 microscope using a 10x air objective to collect five images per well. Images are acquired using an Elmer Opera confocal microscope (Perkin Elmer, Waltham, MA). Virus-specific antigens are quantified by measuring fluorescence at a wavelength of 488 nm, and nuclei are quantified by measuring fluorescence at a wavelength of 640 nm. High-content image analysis is performed to quantify the percentage of infected cells and cell survival. EC 50Dose-response analysis to determine values ​​is performed using GeneData Screener software, which applies the Levenberg-Marquardt algorithm in a curve-fitting strategy. Example 2: 2019-nCoV Antiviral Assay

[0346] HAE cell cultures isolated from lung tissue are cultured at the air-liquid interface for up to 6 weeks to promote differentiation (Zhu et al., NEJM, January 24, 2020). The apical surface of the HAE cultures is washed with 1x PBS at 37°C for over 1 hour 24 hours and 1 hour before infection. Differentiated HAE cultures are infected apically with recombinant 2019-nCoV expressing red fluorescent protein (2019-nCoV RFP) at a multiplicity of infection of 0.1 pfu per cell. To infect HAE cultures, the apical wash is removed, the virus inoculum is added, and the inoculated culture is incubated at 37°C for 2.5 hours. The inoculum is removed, and the apical surface of the HAE culture is washed three times with 500 μL of 1x PBS to remove residual virus. Five 3-fold serial dilutions of compound 9, starting at 10 μM, are prepared and added to the HAE ALI medium on the basolateral side of the culture approximately 30 minutes before infection. Viral replication is assessed by fluorescent imaging of cell cultures after 48 hours of incubation, and is further quantified by measuring infectious virus production in the apical lavage of HAEs by plaque assay on Vero cell monolayers and quantifying viral RNA production from total cellular RNA by real-time PCR assay. Example 3: 2019-nCoV Real-Time PCR Assay

[0347] At 48 hours post-infection, primary HAE cultures from the antiviral assay described above were harvested in 500 μL of TRIzol. RNA was purified using the Direct-zol RNA MiniPrep Kit (Zymo Research Corporation, Irvine, CA, USA). First-strand cDNA was generated for each sample using SuperScript III (Life Technologies, Grand Island, NY, USA) and incubated at 55°C. After first-strand cDNA generation, 2019-nCoV subgenomic RNA was quantified by real-time PCR using appropriate primers. Reads were normalized to GAPDH using the following primers: GAPDH forward (5'-TGC ACC AAC TGC TTA GC-3') and GAPDH reverse (5'-GGC ATG GAC TGT GGT CAT Results are expressed as log10 fold change in copy number of viral 2019-nCoV encoding RNA in treated versus untreated cells using the ΔΔCt method. Example 4: In vitro efficacy in Calu-3 2B4 cells

[0348] Forty-eight hours before infection, Calu-3 2B4 cells were cultured at 5 × 10 4Cells were seeded at 1000 cells / well into 96-well black-walled, clear-bottom plates. 24 h prior to infection, the culture medium was changed. A 20 mM stock of compound 32 was serially diluted in 3-fold increments with 100% DMSO to obtain a 10-point dilution series. 2019-nCoV-nLUC was diluted in DMEM 10% FBS and 1% antibiotic / antimycin to achieve a multiplicity of infection (MOI) of 0.08. Cells were infected in triplicate for 1 h per drug dilution, after which the virus was aspirated, the cultures were rinsed once, and fresh medium containing drug or vehicle was added. At 48 h postinfection, viral replication was quantified on a Spectramax (Molecular Devices) plate reader via a nanoluciferase assay (Promega) according to the manufacturer's protocol. For our 100% inhibition control, diluted 2019-nCoV-nLUC is exposed to shortwave UV light (LLC, Upland, CA) for 6 minutes to inhibit the virus's ability to replicate. For our 0% inhibition control, cells are infected in the presence of vehicle. DMSO is kept constant across all conditions at 0.05% (v / v). Values ​​from triplicate wells per condition are averaged and compared to the control to generate a percent inhibition value for each drug dilution. EC 50 The EC value is defined as the concentration at which viral replication is reduced by 50%. Data were analyzed using GraphPad Prism 6.0 (La Jolla, CA). 50 and CC 50 Values ​​are dose-response (variable gradient) Calculate by nonlinear regression analysis using the formula (four-parameter logistic equation): Y = trough (ceiling-trough) / (1 + 10^(LogEC 50 -X) * Hill slope). The "floor" and "ceiling" values ​​are defined by the minimum and maximum Y values. Hill slope is a parameter used to define the steepness of a dose-response curve. EC 50 and CC 50 Values ​​are calculated as the mean of two to four independent experiments. Example 5: Evaluation of Subcutaneous Compound 32 Against 2019-nCoV in Esterase-Deficient (Ces1c- / -) Mice

[0349] Male and female mice (25–28 weeks old) were genetically deficient in carboxylesterase 1C (Ces1c− / −) (Jackson Laboratories stock 014096). Ces1c− / − mice were used because rodents express high levels of carboxylesterase activity in plasma compared to other animal species, which reduces the plasma half-life of compound 32. Genetic deletion of carboxylesterase 1C improved the plasma stability of compound 32 and produced a pharmacokinetic profile similar to that observed in humans and other animal species.

[0350] The study design is shown in Table 1. Efficacy studies will be conducted in an Animal Biosafety Level 3 (ABSL3) facility. [Table 1]

[0351] Groups 1 (vehicle), 2 (compound 32 BID 25 mg / kg), and 3 (compound 32 QD 50 mg / kg) were anesthetized with ketamine / xylazine and administered 10 mg / kg via the intranasal route. 4 Groups 4 (vehicle) and 5 (Compound 32 BID 25 mg / kg) were left uninfected and used as controls for whole-body plethysmography evaluation. Vehicle consisted of 12% sulfobutylether-β-cyclodextrin in water (with HCl / NaOH), pH 5.0. On day 0, animals were exposed to virus. On days 2 and 5 post-infection, groups were euthanized by isofluorane overdose, and the left lung lobe was placed in a 2 mL screw-cap tube with 1 mL of DPBS containing glass beads and frozen at -80°C until analyzed by plaque assay. The lower right lobe was placed in 10% buffered formalin and stored at 4°C until histological analysis.

[0352] Changes in pulmonary function are determined by whole-body plethysmography (WBP, Buxco Pulmonary Function Testing System, Data Sciences International). After 30 minutes of acclimation in the plethysmograph chamber, 11 respiratory responses and several quality control metrics are measured continuously every 2 seconds for 5 minutes for a total of 150 data points. The mean value of each parameter is determined within DSI Finepoint software.

[0353] Histological analysis is performed on formalin-fixed samples and 5 μm paraffin-embedded tissues. Sections are stained with hematoxylin and eosin to assess lung pathology. Viral antigens in the lungs are stained using a polyclonal anti-nucleocapsid antibody (Imgenex). Slides are evaluated blinded to the assessor for virus-associated lung pathology, as well as the spatial location and prevalence of viral antigens. Images are taken using an Olympus BX41 microscope equipped with an Olympus DP71 camera.

[0354] Quantify infectious virus from frozen lung tissue using a viral plaque assay. Vero E6 cells were cultured at 5 x 10 in a 6-well plate. 5 Lung tissue is thawed and homogenized using a Roche Magnalyzer, the tissue suspension is serially diluted, and the dilutions are used to infect Vero E6 cells. At 72 hours post-infection, plates are fixed, stained, and the number of plaques quantified by visual inspection.

[0355] The primary endpoint of this study is the viral load in lung tissue at day 5 post-infection. Additional endpoints include changes in animal weight and lung function. Animal weight will be recorded daily throughout the survival period. Whole-body plethysmography will be performed to assess lung function on days -1, 1, 2, 3, and 5 post-inoculation. Scheduled necropsies will be performed on all remaining animals on day 5. Gross lung pathology will be evaluated by a board-certified veterinary pathologist. Lung tissue will be collected for histopathological and virological analysis.

[0356] Changes in body weight and viral load: Changes in body weight and tissue viral load for each study group on day 5 are recorded.

[0357] Pulmonary function measurements: The effect of compound 32 treatment on pulmonary function in 2019-nCoV-infected mice will be assessed by whole body plethysmography (WBP). Example 6: Blinded, Randomized, Vehicle-Controlled Evaluation of Intravenous Compound 32 Against 2019-nCoV in Rhesus Macaques

[0358] The 2019-nCoV isolate will be used for virus challenge in the testing facility. The 2019-nCoV will be propagated in VeroE6 cells in DMEM (Sigma) supplemented with 2% (vol / vol) FCS (Logan), 1 mM L-glutamine (Lonza), 50 U / mL penicillin, and 50 μg / mL streptomycin (Gibco). Naive male rhesus macaques will be randomly assigned to treatment groups and balanced by weight.

[0359] The study design is shown in Table 2. [Table 2]

[0360] All animals were treated with 7 × 10 PBS diluted in 0.9% sodium chloride for inoculation. 6 Animals are exposed to a target dose of 2019-nCoV virus of plaque-forming units. Animals are inoculated by multiple routes, including intranasal, ocular, and intrapulmonary administration. The day on which this occurs is designated as day 0.

[0361] Methods to control bias include experimental blinding. Specifically, study personnel administering Compound 32 or vehicle treatments or routinely assessing animal health will be experimentally blinded to the group assignment of all animals throughout their survival. Unblinded personnel not involved in assessing animal health will prepare individual doses from ready-to-use bulk formulations provided by the sponsor. Vehicle and Compound 32 formulations will be identical in physical appearance.

[0362] Groups 1 and 2 receive vehicle treatment once daily for 7 days, beginning on Day -1 (1 day before virus challenge). Group 3 receives vehicle treatment once daily for 7 days, beginning on Day 1 (12-24 hours after virus challenge). Each dose of Compound 32 or vehicle is administered as a single bolus, delayed IV injection in the saphenous vein over 1-2 minutes at a volume of 2.0 mL / kg body weight. Doses are administered to anesthetized animals using an IM injection of a solution containing ketamine (100 mg / mL) and acepromazine (10 mg / mL) at a volume of 0.1 mL / kg body weight. Weights of each animal are obtained on Day -7, and these weights are used to determine dose volume for all administered doses of Compound 32 or vehicle.

[0363] The primary endpoint of this study is the viral load in lung tissue on day 6 postinfection. Animal health will be monitored at least twice daily throughout the survival period, and clinical disease signs will be recorded. On days -7, 0, 1, 3, 5, and 6 postinoculation, all animals will undergo clinical examination to determine body weight, temperature, and breaths per minute (under anesthesia), and X-rays, nasal, and throat swabs will be collected. Whole blood and serum will be collected for hematology, biochemistry, and cytokine analysis. On day 6, scheduled necropsies will be performed on all animals. Gross lung pathology will be scored (as the percentage of lung lobes affected by gross lesions) by a board-certified veterinary pathologist, and lung weights will be recorded to determine lung weight / body weight ratios. Nineteen tissues will be collected for histopathological and virological analysis.

[0364] The disease symptoms in the vehicle-treated animals were attributed to 2019-nCoV infection. The cumulative clinical score was significantly higher in the vehicle-treated animals compared to the Compound 32-treated animals. These disease symptoms were less pronounced in the Compound 32-treated animals.

[0365] Body weight and viral load: Changes in body weight, temperature, and respiration are recorded.

[0366] Tissue viral load: Viral RNA is measured in lung tissue or other organs taken at necropsy. Example 7: SARS-CoV-2 Antiviral Assay

[0367] The antiviral activity of the compound against SARS-CoV-2 was evaluated by Xue, Xi et al. 2020 (Xie, X. et al. (2020) A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19. Nat.Comm.bioRxiv 2020.06.22.165712; doi: https: / / doi.org / 10.1101 / 2020.06.22.165712). Briefly, human alveolar epithelial cell line (A549) was maintained in high-glucose DMEM supplemented with 10% fetal bovine serum, 1% P / S, and 1% HEPES (ThermoFisher Scientific). A549-hACE2 cells stably expressing human angiotensin-converting enzyme 2 (hACE2) were grown in culture medium supplemented with 10 μg / mL blasticidin S (Mossel, EC et al. (2005). Exogenous ACE2 expression allows refractory cell l ines to support severe acute respiratory syndrome coronavirus replication. J Virol 79, 3846-3850, doi:10.1128 / JVI.79.6.3846-3850.2005). Cells were grown at 37°C with 5% CO2. All culture media and antibiotics were purchased from ThermoFisher Scientific (Waltham, MA). All cell lines were tested negative for mycoplasma. A549-hACE2 cells (12,000 cells per well in phenol red-free medium containing 2% FBS) were seeded into white opaque 96-well plates (Corning). The following day, two-fold serial dilutions of compounds were prepared in DMSO. Compounds were further diluted 100-fold in phenol red-free culture medium containing 2% FBS. Cell culture medium was removed and incubated with 50 μL of diluted compound solution and 50 μL of SARS-CoV2-Nluc virus (MOI 0.025). At 48 hours post-infection, 50 μL of nanoluciferase substrate (Promega) was added to each well. Luciferase signals were measured using a Synergy™ Neo2 microplate reader. Relative luciferase signals were calculated by normalizing the luciferase signals of the compound-treated groups to those of the DMSO-treated group (set as 100%). The logarithm of compound concentration (X-axis) was used to calculate the relative luciferase signal. 10 The relative luciferase signal (Y-axis) versus EC values ​​was plotted using the software Prism 8. 50 The compound concentration required to reduce the luciferase signal by 50% was calculated using a nonlinear regression model (four parameters). Two experiments were performed in technical replicates. Example 8: A549 Cytotoxicity Assay

[0368] The cytotoxicity of compounds was determined in A549 cells as follows: Compounds (200 nL) were spotted onto 384-well Grenier plates, and then 5000 A549 cells / well were seeded in a volume of 40 μL of culture medium. The plates were incubated at 37°C and 5% CO2 for 48 hours. On the second day, 40 μL of CellTiter-Glo (Promega) was added and mixed five times. The plates were read for luminescence on an Envision (PerkinElmer) and CC 50 The compound concentration required for a 50% reduction in luminescence signal (as a measure of cell viability) was calculated using a nonlinear regression model (four parameters). [Table 3]

[0369] Example 9: Combination Therapy

[0370] Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir and baricitinib or remdesivir and placebo. Randomization was stratified according to study site and disease severity at enrollment (Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19; The New England Journal of Medicine, December 11, 2020, DOI: 10.1056 / NEJMoa2031994). Patients received remdesivir intravenously as a 200 mg loading dose on day 1, followed by a 100 mg maintenance dose administered daily from days 2 to 10, or until discharge or death. Baricitinib was administered as a 4 mg daily dose (orally [two 2 mg tablets] or via a nasogastric tube) for 14 days or until discharge. Patients with an estimated glomerular filtration rate of less than 60 ml per minute received baricitinib at a 2 mg dose once daily. A matching oral placebo was administered according to the same schedule as the active drug. All patients received standard supportive care at the study site hospital. Venous thromboembolism prophylaxis was recommended for all patients without major contraindications. If the hospital had a written policy for the treatment of Covid-19, patients could receive those treatments. In the absence of a written policy, other experimental treatments and off-label use of marketed drugs intended as specific treatments for Covid-19 were prohibited. This included glucocorticoids, which were permitted only for standard indications such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute respiratory distress syndrome.

[0371] All patients were assessed daily during their hospital stay from days 1 to 29. All data queries were resolved and the database remained locked and unaware of study group allocation.

[0372] Patients treated with the combination of baricitinib and remdesivir recovered a median of 1 day faster than patients receiving remdesivir and placebo (median 7 days vs. 8 days; recovery rate 1.16, 95% confidence interval [CI] 1.01-1.32, P = 0.03, by log-rank test stratified according to actual baseline severity). When analyzed according to the severity level entered at randomization (moderate vs. severe), the hazard ratio was 1.15 (95% CI, 1.00-1.31, P = 0.047). The median time to recovery among patients receiving noninvasive ventilation or high-flow oxygen (baseline ordinal score 6) was 10 days in the combination group and 18 days in the control group (recovery rate 1.51, 95% CI, 1.10-2.08). Among patients with baseline scores of 4 (no oxygen) and 5 (supplemental oxygen), the rate ratios of recovery were 0.88 (95% CI, 0.63 to 1.23) and 1.17 (95% CI, 0.98 to 1.39), respectively. For patients receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio of recovery was 1.08 (95% CI, 0.59 to 1.97). Among the 223 patients receiving glucocorticoids for clinical indications during the study, the rate ratio of recovery was 1.06 (95% CI, 0.75 to 1.48). A random-effects sensitivity analysis for hospital site yielded similar results (conditional random-effects estimate of rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.33; restricted maximum likelihood-based random-effects variance estimate, 0.0305).

[0373] Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating clinical improvement, particularly in patients receiving high-flow oxygen or noninvasive mechanical ventilation. The combination was associated with fewer serious adverse events.

[0374] All publications, patents, and patent documents cited herein are incorporated by reference herein, as though individually incorporated by reference.

[0375] Although the present invention has been described with reference to various specific preferred embodiments and techniques, those skilled in the art will recognize that many variations and modifications can be made while remaining within the spirit and scope of the disclosure.

[0376] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) 1. A method for treating or preventing 2019-nCoV infection in a human in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula I [ka] or a pharmaceutically acceptable salt or ester thereof, During the ceremony, Each R 1 is H or a halogen, Each R 2 、R 3 、R 4 , or R 5 But independently, H, OR a , N(R a ) 2 、N 3 , CN, NO 2 , S(O) n R a , halogens, (C 1 -C 8 ) alkyl, (C 4 -C 8 ) carbocyclylalkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, or (C 2 -C 8 ) substituted alkynyl; Or, any two R on adjacent carbon atoms 2 、R 3 、R 4 , or R 5 when taken together are -O(CO)O- or when taken together with the ring carbon atoms to which they are attached form a double bond, R 6 But, OR a , N(R a ) 2 、N 3 , CN, NO 2 , S(O) n R a , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O) 2 R 11 , -S(O)(OR 11 ), -S(O) 2 (OR 11 ), -SO 2 NR 11 R 12 , halogens, (C 1 -C 8 ) alkyl, (C 4 -C 8 ) carbocyclylalkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, or (C 6 -C 20 )Aryl(C 1 -C 8 ) alkyl, R 7 but, a) H, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)SR 11 , -S(O)R 11 , -S(O) 2 R11 , -S(O)(OR 11 ), -S(O) 2 (OR 11 ), or -SO 2 NR 11 R 12 、 [In the formula, each R 11 or R 12 Each (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, or (C 6 -C 20 )Aryl(C 1 -C 8 ) alkyl independently optionally includes one or more of halo, hydroxy, CN, N 3 , N(R a ) 2 OR a and (C 1 -C 8 ) One or more of the non-terminal carbon atoms of each alkyl is optionally —O—, —S—, or —NR a - may be replaced by b)

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Claims

[Claim 1] The invention described in the specification.

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