WO2022232919A1

WO2022232919A1 - Viral rna polymerase inhibitors and uses thereof

Info

Publication number: WO2022232919A1
Application number: PCT/CA2022/050683
Authority: WO
Inventors: Sheng-Xiang Lin; Stephen PREYESH; Guy Boivin; Mariana BAZ
Original assignee: UNIVERSITé LAVAL
Priority date: 2021-05-03
Filing date: 2022-05-03
Publication date: 2022-11-10

Abstract

The present application relates to compounds, and uses thereof for example for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease. In an embodiment, the virus is a respiratory virus, and the viral disease is a viral respiratory disease. In embodiments, the viral infection is a SARS or respiratory syncytial virus (RSV) infection. In embodiments, the viral infection is a SARS infection, e.g., a SARS-CoV-2 infection. In embodiments, the disease is COVID-19. In embodiments the compounds may also be used for inhibiting a viral nucleic acid polymerase, e.g., a viral RNA-dependent RNA polymerase (RdRp). In embodiments, the compound is a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof.

Description

TITLE OF INVENTION

VIRAL RNA POLYMERASE INHIBITORS AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application 63/183,208, filed May 3, 2021. The contents of the referenced application are incorporated into the present application by reference.

SEQUENCE LISTING

[0002] This application contains a Sequence Listing in computer readable form entitled “G11229_452_SeqList.txt”, created on April 28, 2022 and having a size of about 16 KB. The computer readable form is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0003] The present disclosure generally relates to prevention and treatment of viral infection and disease, such as a respiratory viral infection and disease.

BACKGROUND ART

[0004] Severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in Wuhan, China in December 2019. SARS-CoV-2 infection causes a respiratory disease that can progress to viral pneumonia and acute respiratory distress syndrome (ARDS). Based on its onset in December 2019, the associated disease is called coronavirus disease 2019 (COVID-19). As of May 1^st, 2022, there have been 453 million cases of COVID-19 worldwide which have led to more than 6 million deaths.

[0005] Historically, humans have been infected with several common cold-causing coronaviruses, including hCoV-229E, OC43, NL63, and HKU1 (Hossain et al., 2020). However, in the last 20 years some highly pathogenic coronaviruses have emerged, including SARS-CoV in 2002-2003 (SARS = severe acute respiratory syndrome; 8000 cases and mortality of about 10%) and MERS-CoV in 2012 (MERS = Middle East respiratory syndrome; 2,500 confirmed cases and 36% mortality). SARS-CoV, MERS-CoV and now SARS-CoV-2 viruses are beta-coronaviruses with a single-stranded RNA genome. These viruses trigger an acute, sometimes fatal respiratory distress syndrome, which can cause long-term reduction in lung function as well as arrhythmia and neurological effects (Aguilar et al. , 2020; Chatterjee et al., 2020; Gordon et al. , 2020bc; Huang et al. , 2020; Mathew et al., 2020; Tang et al., 2020).

[0006] An example of a repurposed drug approved for the treatment of COVID-19 is remdesivir, which for example reduces the time to recovery of hospitalized patients who require supplemental oxygen (Beigel et al., 2020

[0007] However, there exists an urgent need for further drugs and therapies for such infections and associated diseases.

[0008] The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.

SUMMARY OF THE DISCLOSURE

[0009] The present disclosure generally relates to prevention and treatment of viral infection and disease, such as a respiratory viral infection and disease. In embodiments, such prevention and treatment are based on viral nucleic acid polymerase inhibition, such as RNA-dependent-RNA polymerase (RdRp) inhibition.

[0010] In various aspects and embodiments, the present disclosure relates to the following items:

1. A compound of Formula I:

Formula I wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R³ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸;

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl; R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

A is chosen from CO, SO, SO2 or CH2, or is absent;

B¹ and B² are independently chosen from CH or N;

G¹ is chosen from CH2, NH, O or S;

G² is chosen from CH or N;

G³ is chosen from CH or N; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 1, having the structure:

wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R³ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸;

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 1 or 2, having the structure:

F

A compound of Formula II:

Formula II wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R³ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸;

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

A¹ and A² are independently chosen from CH or N;

B¹ and B² are independently chosen from CH or N;

Y is O, S or NH;

wherein: each R⁹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R¹⁰ is independently chosen from H, alkyl or aryl; and W¹ is chosen from O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 9, having the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl; each R⁹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 9, having the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 9 or 10, having the structure:

The compound of item 9 or 11, having the structure:

The compound of item 9, having the structure:

A compound of Formula III:

Formula III wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁴, OCOR⁵, OCONR⁶R⁷, 0S0₂NR⁶R⁷ or NR⁶R⁷; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁴, OCOR⁵, OCONR⁶R⁷, 0S0₂NR⁶R⁷ or NR⁶R⁷;

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

A is chosen from CO, SO, S0₂ or CH₂, or is absent;

B¹ and B² are independently chosen from CH, N or S;

G¹ is chosen from CH₂, NH, O or S;

G² is chosen from CH or N;

G³ is chosen from CH or N; and

wherein:

W¹ is chosen from O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; each R⁸ is independently chosen from H, alkyl, alkylnitrile or aryl; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. The compound of item 16, having the structure:

wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁴, OCOR⁵, OCONR⁶R⁷, 0S0₂NR⁶R⁷ or NR⁶R⁷; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁴, OCOR⁵, OCONR⁶R⁷, 0S0₂NR⁶R⁷ or NR⁶R⁷;

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl; R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; each R⁸ is independently chosen from H, alkyl, alkylnitrile or aryl; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

The compound of item 16 or 17, having the structure:

The compound of item 16 or 18, having the structure:

The compound of item 16, having the structure:

A composition comprising the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21, and a pharmaceutically acceptable carrier. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21 or the composition of item 22 for the preparation of a medicament. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21 or the composition of item 22 for use as a medicament. A method of preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject, said method comprising administering the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21 or the composition of item 22 to the subject. The method of item 25, wherein the viral infection is a coronavirus infection. The method of item 25 or 26, wherein the viral disease is a viral respiratory disease. The method of any one of items 25 to 27, wherein the viral infection is a SARS or respiratory syncytial virus (RSV) viral infection. The method of item 28, wherein the viral infection is a SARS-CoV viral infection. The method of item 29, wherein the viral infection is a SARS-CoV-2 viral infection. The method of any one of items 25 to 30, wherein the viral disease is COVID-19. The method of item 28, wherein the infection is an RSV infection. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21 or the composition of item 22 for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21 or the composition of item 22 for the preparation of a medicament for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject. The use of item 33 or 34, wherein the viral infection is a coronavirus infection. The use of any one of items 33 to 35, wherein the viral disease is a viral respiratory disease. The use of any one of items 33 to 36, wherein the viral infection is a SARS or respiratory syncytial virus (RSV) viral infection. The use of item 37, wherein the viral infection is a SARS-CoV viral infection. The use of item 38, wherein the viral infection is a SARS-CoV-2 viral infection. The use of any one of items 33 to 39, wherein the viral disease is COVID-19. The use of item 37, wherein the infection is an RSV infection. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of items 1 to 21, or the composition of item 22, for use in preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject.

43. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of item 42, wherein the viral infection is a coronavirus infection.

44. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of item 42 or 43, wherein the viral disease is a viral respiratory disease.

45. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of any one of items 42 to 44, wherein the viral infection is a SARS or respiratory syncytial virus (RSV) viral infection.

46. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of item45, wherein the viral infection is a SARS-CoV viral infection.

47. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of item 46, wherein the viral infection is a SARS-CoV-2 viral infection.

48. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of any one of items 42 to 47, wherein the viral disease is COVID-19.

49. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of item 45, wherein the infection is an RSV infection.

[0010] Other objects, advantages and features of the present disclosure will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In the appended drawings:

[0012] Fig. 1 : EM-COV-A (A) and EM-COV-B (B) inhibition efficiency on SARS-CoV-2. PRA in triplicates has demonstrated that two of the selected molecules showed potency in vitro inhibition.

The EC50s obtained are shown in each graph. [0013] Fig. 2: Structural analysis of EM-COV-A and EM-COV-B binding on RdRp. The 2D structure of EM-COV-A (A) and EM-COV-B (B) are shown. C and D show the interactions established between RdRp and Remdesivir, EM-CO-VA (C) and EM-COV-B (D). RdRp (green), RNA (orange), Remdesivir (stick; blue), EM-COV-A (stick; yellow) and EM-COV-B (stick; Orange). E, F show the Ligplot representation of interaction by EM-COV-A and EM-COV-B with aminoacids on RdRp. There are hydrogen bonds (dotted lines) and hydrophobic interactions.

[0014] Fig. 3: Intrinsic fluorescence titration of SARS-CoV-2 RdRp complex with NTP and EM-CoV-A. (A) Titration of the RdRp complex with EM-COV-A (5-40 mM). AF= -11.97 AF/ [EM-COV- A]+ 386900; (B) Titration of the RdRp complex with 1-17 mM of NTP and then titrated with 5-40 mM of EM-CoV-A. AF = -3.10 AF/ [EM-COV-A] + 157900. Inserted plot on the upper right of each figure shows the fluorescence change with the addition of EM-COV-A.

[0015] Fig. 4: Pharmacological properties of EM-COV-A and EM-COV-B. (A) Cytotoxicity of inhibitors in Vero E6 cells by WST-8 assy. The metabolic stability of EM-COV-A (B) and EM-COV- B (C) in human whole blood, human plasma and rat liver are plotted.

DETAILED DISCLOSURE

[0011] The use of the terms "a", "an" and "the" and similar referents in the context of describing the technology (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0012] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e. , meaning "including, but not limited to") unless otherwise noted.

[0013] The term “alkyl” or “alk” as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon comprising, unless otherwise specified, from 1 to 15 carbon atoms and is exemplified by methyl, ethyl, n- and /so-propyl, n-, sec-, iso- and tert- butyl, neopentyl and the like, and may be optionally substituted with one, two, three or, in the case of alkyl groups comprising two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) 0C(0)R^A, where R^A is selected from the group consisting of (a) substituted or unsubstituted Ci-₆ alkyl, (b) substituted or unsubstituted C₆ or Cio aryl, (c) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C1-9 heterocyclyl, and (e) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(0)R^B, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C₆ or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CC>2R^b, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted Ce or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(0)NR^cR^D, where each of R^c and R^D is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(0)R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(0)₂R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(0)₂NR^FR^G, where each of R^F and R^G is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) -NR^HR', where each of R^H and R' is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, 0 alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (I) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

[0014] The terms “alkoxy” or “alkyloxy,” as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom.

[0015] The term “alkylsulfinyl” as used herein, represents an alkyl group attached to the parent molecular group through an S(O) group. [0016] The term “alkylsulfonyl,” as used herein, represents an alkyl group attached to the parent molecular group through a S(0)₂ group.

[0017] The term “alkylthio” as used herein, represents an alkyl group attached to the parent molecular group through a sulfur atom.

[0018] The term “alkylene” as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.

[0019] The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 15 carbons, such as, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms, containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like, and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1 ) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) OC(0)R^A, where R^A is selected from the group consisting of (a) substituted or unsubstituted Ci-₆ alkyl, (b) substituted or unsubstituted C₆ or Cio aryl, (c) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C1-9 heterocyclyl, and (e) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(0)R^B, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C₆ or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CC>2R^b, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted Ce or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(0)NR^cR^D, where each of R^c and R^D is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(0)R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(0)₂R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(0)₂NR^FR^G, where each of R^F and R^G is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) -NR^HR', where each of R^H and R' is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms; (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, 0 alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (I) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

[0020] The term “alkynyl” as used herein, represents monovalent straight or branched chain groups of from two to six carbon atoms comprising a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl and the like, and may be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) OC(0)R^A, where R^A is selected from the group consisting of (a) substituted or unsubstituted Ci-₆ alkyl, (b) substituted or unsubstituted C₆ or Cio aryl, (c) substituted or unsubstituted C_7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C_1-9 heterocyclyl, and (e) substituted or unsubstituted C_2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(0)R^B, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C_1-6 alkyl, (c) substituted or unsubstituted Ce or C₁₀ aryl, (d) substituted or unsubstituted C_7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CC^R⁶, where R^B is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted Ce or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(0)NR^cR^D, where each of R^c and R^D is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(0)R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(0)₂R^E, where R^E is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(0)₂NR^FR^g, where each of R^F and R^G is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) -NR^HR', where each of R^H and R' is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, (j) alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (I) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

[0021] The term “aryl” as used herein, represents mono- and/or bicyclic carbocyclic ring systems and/or multiple rings fused together and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like, and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups are independently comprised of one to six carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group comprises one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group comprises one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group comprises one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms and the alkylene group comprises one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group comprises one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (36) (CH2)_qCC>2R^A, where q is an integer ranging from zero to four and R^A is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (37) (CH₂)_qC(0)NR^BR^c, where R^B and R^c are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (38) (CH₂)_qS(0)₂R^D, where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (39) (CH₂)_qS(0)₂NR^ER^F, where each of R^E and R^F is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (40) (CH2)_qNR^GR^H, where each of R^G and R^H is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, and (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

[0022] The term “alkaryl” represents an aryl group attached to the parent molecular group through an alkyl group.

[0023] The term “alkheterocyclyl” represents a heterocyclic group attached to the parent molecular group through an alkyl group.

[0024] The term “aryloxy” as used herein, represents an aryl group that is attached to the parent molecular group through an oxygen atom.

[0025] The term "alkoxyalkyl" as used herein means alkyl-O-alkyl-, wherein alkyl is defined above.

[0026] The term "alkoxyaryl" as used herein means alkyl-O-aryl-, wherein alkyl is defined above.

[0027] The term "alkthioalkyl" as used herein means alkyl-S-alkyl-, wherein alkyl is defined above.

[0028] The term "alkthioaryl" as used herein means alkyl-S-aryl-, wherein alkyl is defined above.

[0029] The terms “aryloyl” or “aroyl” as used interchangeably herein, represent an aryl group that is attached to the parent molecular group through a carbonyl group.

[0030] The term “carbonyl” as used herein, represents a C(O) group, which can also be represented as C=0.

[0031] The terms “carboxy” or “carboxyl,” as used interchangeably herein, represents a CO2H group.

[0032] The term “cycloalkyl” as used herein, represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of three to eight carbon atoms, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl, and the like. The cycloalkyl groups of the present disclosure can be optionally substituted with: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group comprises one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group comprises one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group comprises one to six carbon atoms; 20) cycloalkyl of three to eight carbon atoms; (21) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms and the alkylene group comprises one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group comprises one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (36) (CH2)_qCC>2R^A, where q is an integer ranging from zero to four and R^A is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (37) (CH₂)_qC(0)NR^BR^c, where each of R^B and R^c is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (38) (CH₂)_qS(0)₂R^D, where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (39) (CH₂)_qS(0)₂NR^ER^F, where each of R^E and R^F is independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (40) (CH2)_qNR^GR^H, where each of R^G and R^H is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

[0033] The term “halogen” or “halo” as used interchangeably herein, represents F, Cl, Br, and I.

[0034] The term “heteroaryl” as used herein, represents that subset of heterocycles, as defined herein, which is aromatic: (/.e., containing 4n+2 pi electrons within a mono- or multicyclic ring system).

[0035] The terms “heterocycle” or “heterocyclyl” as used interchangeably herein represent a 5-, 6- or 7-membered ring, unless otherwise specified, comprising one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has from zero to two double bonds and the 6- and 7-membered rings have from zero to three double bonds. The term “heterocycle” also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like. Heterocycles include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroinidolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, and the like. Heterocyclic groups also include compounds of the formula

ΪΎ , where F' is selected from the group consisting of CH2, CH2O and O, and G' is selected from the group consisting of C(O) and (C[R'][R"])_V, where each of R' and R" is independently selected from the group consisting of hydrogen and alkyl of one to four carbon atoms, and v is an integer ranging from one to three, and includes groups such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Any of the heterocyclic groups mentioned herein may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group comprises one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group comprises one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group comprises one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) alkcycloalkyl, where the cycloalkyl group comprises from three to eight carbon atoms and the alkylene group comprises from one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group comprises from one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (36) (CH2)_qCC>2R^A, where q is an integer ranging from zero to four and R^A is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises from one to six carbon atoms; (37) (CH₂)_qC(0)NR^BR^c, where each of R^B and R^c is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises from one to six carbon atoms; (38) (CH₂)_qS(0)₂R^D, where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises from one to six carbon atoms; (39) (CH₂)_qS(0)₂NR^ER^F, where each of R^E and R^F is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises from one to six carbon atoms; (40) (CH2)_qNR^GR^H, where each of R^G and R^H is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises from one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, and (i) alkcycloalkyl, where the cycloalkyl group comprises from three to eight carbon atoms, and the alkylene group comprises from one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

[0036] The terms “heterocyclyloxy” or “(heterocycle)oxy” as used interchangeably herein, represents a heterocyclic group, as defined herein, attached to the parent molecular group through an oxygen atom.

[0037] The term “heterocyclyloyl” or “(heterocycle)oyl” as used interchangeably herein, represents a heterocyclic group, as defined herein, attached to the parent molecular group through a carbonyl group.

[0038] The term “heteroatom”, as used herein, is understood as being oxygen, sulfur, or nitrogen.

[0039] The term “alkyl nitrile”, as used herein, is understood as being a compound of the formula RCN, wherein R is a linear, branched chain or cyclic aliphatic substituent or an aryl sunstituent. Typical examples of such materials are acetonitrile and propionitrile.

[0040] The term “sulfinyl” as used herein, represents an S(O) group.

[0041] The term “sulfonyl” as used herein, represents an S(0)₂ group.

[0042] The term “thioalkoxy” as used herein, represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted thioalkoxy groups comprise from 1 to 6 carbon atoms.

[0043] The term “thiocarbonyl” as used herein, represents a C(S) group, which can also be represented as C=S. [0044] Prodrugs and solvates are also contemplated herein. The term “prodrug”, as used herein, is understood as being a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present disclosure or a salt and/or solvate thereof. Non limiting examples of prodrugs include conversion of a hydroxy

group. Solvates are preferably hydrates.

[0045] The term “derivative” as used herein, is understood as being a substance which comprises the same basic carbon skeleton and carbon functionality in its structure as a given compound, but can also bear one or more substituents or rings.

[0046] The term “analogue” as used herein, is understood as being a substance similar in structure to another compound but differing in some slight structural detail.

[0047] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0048] The use of any and all examples, or exemplary language (“e.g", "such as") provided herein, is intended merely to better illustrate embodiments of the claimed technology and does not pose a limitation on the scope unless otherwise claimed.

[0049] No language in the specification should be construed as indicating any non-claimed element as essential to the practice of embodiments of the claimed technology.

[0050] Herein, the term "about" has its ordinary meaning. The term “about” is used to indicate that a value includes an inherent variation of error for the device or the method being employed to determine the value, or encompass values close to the recited values, for example within 10% of the recited values (or range of values).

[0051] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein.

[0052] Where features or aspects of the disclosure are described in terms of Markush groups or list of alternatives, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member, or subgroup of members, of the Markush group, or list of alternatives. [0053] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning, as commonly understood by one of ordinary skill in the art (e.g., in stem cell biology, cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry).

[0054] The present disclosure generally relates to prevention and treatment of viral infection and disease, such as a respiratory viral infection and disease. In embodiments, such prevention and treatment is based on viral nucleic acid polymerase inhibition.

[0055] The disclosure thus provides compounds, uses, methods and compositions for preventing or treating viral infection and disease in subjects, and also for inhibition of viral nucleic acid polymerases, such as RNA and DNA polymerases.

[0056] In an embodiment, a compound or inhibitor described herein is an inhibitor of Formula I:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

A is chosen from CO, SO, S0₂ or CH₂, or is absent;

B¹ and B² are independently chosen from CH or N;

G¹ is chosen from CH₂, NH, O or S;

G² is chosen from CH or N;

G³ is chosen from CH or N; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

[0057] In an embodiment, the compound or inhibitor has the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

[0058] In embodiments, the compound or inhibitor has the structure:

[0059] In an embodiment, a compound or inhibitor described herein is an inhibitor of Formula II:

R⁴ is chosen from H, alkyl or aryl; R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl; A¹ and A² are independently chosen from CH or N;

B¹ and B² are independently chosen from CH or N;

Y is O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

[0060] In an embodiment, the compound or inhibitor has the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl; R⁷ and R⁸ are independently chosen from H, alkyl or aryl; each R⁹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

[0061] In an embodiment, the compound or inhibitor has the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

[0062] In embodiments, the compound or inhibitor has the structure:

[0063] In an embodiment, a compound or inhibitor described herein is an inhibitor of Formula III:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl; A is chosen from CO, SO, SO2 or CH2, or is absent;

B¹ and B² are independently chosen from CH, N or S; G¹ is chosen from CH2, NH, O or S;

G² is chosen from CH or N;

G³ is chosen from CH or N; and

wherein:

W¹ is chosen from O, S or NH;

[0064] In an embodiment, the compound or inhibitor has the structure:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

W², W³ and W⁴ are independently chosen from CH, C or N; each R⁸ is independently chosen from H, alkyl, alkylnitrile or aryl; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof. [0065] In an embodiment, the compound or inhibitor has the structure:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

[0066] In embodiments, the compound or inhibitor has the structure:

[0067] The term "pharmaceutically acceptable salt" refers to a salt of a compound described herein that is pharmacologically acceptable and substantially non-toxic to the subject to which it is administered. More specifically, these salts retain the biological effectiveness and properties of the compound, and are formed from suitable non-toxic organic or inorganic acids or bases.

[0068] For example, these salts include acid addition salts which are sufficiently basic to form such salts. Such acid addition salts include acetates, adipates, alginates, lower alkanesulfonates such as a methanesulfonates, trifluoromethanesulfonatse or ethanesulfonates, arylsulfonates such as a benzenesulfonates, 2-naphthalenesulfonates, or toluenesulfonates (also known as tosylates), ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cinnamates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydrogen sulphates, 2- hydroxyethanesulfonates, itaconates, lactates, maleates, mandelates, methanesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, perchlorates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates, tartrates, thiocyanates, undecanoates, and the like.

[0069] Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et ai, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0070] Such salts can be formed quite readily by those skilled in the art using standard techniques. Indeed, the chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists, (See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems [6^th Ed. 1995] at pp. 196 and 1456-1457). Salts of a compound described herein may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0071] In embodiments, the present disclosure relates to preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease. Provided are compounds, uses, methods, and compositions for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease.

[0072] In embodiments, the disclosure provides compounds, uses, methods and compositions for inhibition of viral nucleic acid polymerases, such as RNA and DNA polymerases.

[0073] In an aspect, the present disclosure relates to a method of preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (such as COVID-19), said method comprising administering a compound or inhibitor described herein to the subject.

[0074] The present disclosure also relates to a use of a compound or inhibitor described herein for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (such as COVID-19) in a subject.

[0075] The present disclosure also relates to a use of a compound or inhibitor described herein for the preparation of a medicament for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (such as COVID-19) in a subject.

[0076] The present disclosure also relates to a compound or inhibitor described herein for use in preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease, such as COVID-19 and RSV (Respiratory synthitia virus) caused disease) in a subject.

[0077] In a further aspect, the present disclosure also relates to a method of inhibiting a viral RdRp, said method comprising administering a compound or inhibitor described herein to the subject.

[0078] The present disclosure also relates to a use of a compound or inhibitor described herein for in inhibiting a viral RdRp.

[0079] The present disclosure also relates to a use of a compound or inhibitor described herein for the preparation of a medicament for in inhibiting a viral RdRp.

[0080] The present disclosure also relates to a compound or inhibitor described herein for use in inhibiting a viral RdRp.

[0081] In an embodiment, the viral RNA polymerase is an RdRp.

[0082] As used herein, “inhibition” of viral RdRp activity refers to a reduction in activity level of at least 5% as compared to a reference viral nucleic acid polymerase activity (e.g., a measurement of viral nucleic acid polymerase activity in a cell or tissue of the subject before treatment with the inhibitor). In an embodiment, the reduction in viral nucleic acid polymerase activity level is of at least 10% lower, in a further embodiment, at least 15% lower, in a further embodiment, at least 20% lower, in a further embodiment of at least 30% lower, in a further embodiment of at least 40% lower, in a further embodiment of at least 50% lower, in a further embodiment of at least 60% lower, in a further embodiment of at least 70% lower, in a further embodiment of at least 80% lower, in a further embodiment of at least 90% lower, in a further embodiment of 100% lower (complete inhibition).

[0083] Preferably, a viral nucleic acid polymerase inhibitor is a compound having a low level of cellular toxicity.

[0084] In an embodiment, the viral nucleic acid polymerase inhibitor is for administration in the form of a prodrug, which is converted to its active metabolite.

[0085] In an embodiment, the virus is an RNA virus.

[0086] In an embodiment the virus is of the realm Ribovaria.

[0087] In an embodiment, the virus is of the kingdom Orthornavirae.

[0088] In an embodiment, the virus is a positive-strand RNA virus.

[0089] In an embodiment, the virus is of the phylum Pisuviricota or Negarnaviricota.

[0090] In an embodiment, the virus is of the class Pisoniviricetes or Monjiviricetes.

[0091] In an embodiment, the virus is of the order Nidovirales or Mononegavirales.

[0092] In an embodiment, the virus is of the sub-order Cornidovirineae.

[0093] In an embodiment, the virus is of the family Coronaviridae or Pneumoviridae.

[0094] In an embodiment, the virus is a coronavirus, of the sub-family Orthocoronavirinae.

[0095] In an embodiment, the virus is of the genus Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Deltacoronavirus , in a further embodiment, of the genus Betacoronavirus.

[0096] In embodiments, the virus is Human coronavirus 229E, Human coronavirus NL63, Human coronavirus OC43, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), or Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2).

[0097] In embodiments, the virus is a SARS coronavirus. In a further embodiment, it is a SARS- CoV-2 coronavirus. [0098] In an embodiment, the virus is a respiratory virus, which is a virus that can infect the respiratory tissue or system of a subject ( e.g nasal epithelium, trachea, bronchi, lungs, upper respiratory tract, lower respiratory tract).

[0099] In embodiments, the virus is a SARS virus or Respiratory syncytial virus (RSV; such as RSV-A2 or RSV-B1).

[00100] In an embodiment, the virus is of the genus Orthopneumovirus, which in embodiments includes RSV (such as RSV-A2 or RSV-B1).

[00101] In a further embodiment the coronavirus is a SARS coronavirus 2 virus (SARS-CoV-2). In embodiments, the SARS-CoV-2 is a variant selected from: B.1.1.7 (also known as VOC-202012/01 or alpha), 501Y.V2 (B.1.351 , Beta), P.1 (B.1.1.28.1, Gamma), Delta (B.1.617.2) and B.1.1.529 (Omicron).

[00102] In an embodiment, the disease is a respiratory disease, in a further embodiment, a severe acute respiratory disease. In a further embodiment, the disease is COVID-19.

[00103] SARS-CoV-2 was first identified from an outbreak in Wuhan, China. As of March 2021, there were about 125 million cases worldwide, resulting in 2.75 million deaths. Clinical features of COVID-19 include fever, dry cough, and fatigue, and the disease can cause respiratory failure resulting in death. For example, the following SARS-CoV-2 RdRp polypeptide sequence has been reported (Accession no. YP_009725307; SEQ ID NO: 1):

1 sadaqsflnr vcgvsaarlt pcgtgtstdv vyrafdiynd kvagfakflk tnccrfqekd

61 eddnlidsyf w krhtfsny qheetiynll kdcpavakhd ffkfridgdm vphisrqrlt

121 kytmadlvya lrhfdegncd tlkeilvtyn ccdddyfnkk dwydfvenpd ilrvyanlge

181 rvrqallktv qfcdamrnag ivgvltldnq dlngnwydfg dfiqttpgsg vpw dsyysl

241 lmpiltltra ltaeshvdtd ltkpyikwdl lkydfteerl klfdryfkyw dqtyhpncvn

301 clddrcilhc anfnvlfstv fpptsfgplv rkifvdgvpf vvstgyhfre lgw hnqdvn

361 lhssrlsfke llvyaadpam haasgnllld krttcfsvaa ltnnvafqtv kpgnfnkdfy

421 dfavskgffk egssvelkhf ffaqdgnaai sdydyyrynl ptmcdirqll fvvew dkyf

481 dcydggcina nqvivnnldk sagfpfnkwg karlyydsms yedqdalfay tkrnviptit

541 qmnlkyaisa knrartvagv sicstmtnrq fhqkllksia atrgatvvig tskfyggwhn

601 mlktvysdve nphlmgwdyp kcdrampnml rimaslvlar khttccslsh rfyrlaneca

661 qvlsemvmcg gslyvkpggt ssgdattaya nsvfnicqav tanvnallst dgnkiadkyv

721 rnlqhrlyec lyrnrdvdtd fvnefyaylr khfsmmilsd davvcfnsty asqglvasik

781 nfksvlyyqn nvfmseakcw tetdltkgph efcsqhtmlv kqgddyvylp ypdpsrilga

841 gcfvddivkt dgtlmierfv slaidayplt khpnqeyadv fhlylqyirk lhdeltghml 901 dmysvmltnd ntsrywepef yeamytphtv lq

[00104] The SARS-CoV-2 ORFlab gene contains overlapping open reading frames that encode polyproteins PP1ab and PP1a. Ribosomal frameshifting results in production of either the longer (PP1ab) or shorter (PP1a) protein. The polyproteins are cleaved to yield 16 nonstructural proteins, NSP1-16, including: papain-like proteinase protein (NSP3), 3C-like proteinase (NSP5), RNA- dependent RNA polymerase (NSP12, RdRp), helicase (NSP13, HEL), endoRNAse (NSP15), 2'-0- Ribose-Methyltransferase (NSP16).

[00105] SEQ ID NO: 1 corresponds to the RdRp polypeptide produced by PP1ab. SEQ ID NO: 2, which corresponds to the sequence of positions 5-932 of SEQ ID NO: 1, corresponds to the RdRp polypeptide produced by PP1a.

[00106] In embodiments, the RdRp comprises an amino acid sequence that is substantially identical to the amino acid sequence of SEQ ID NO: 1 or 2.

[00107] In embodiments, the RdRp comprises an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% identical to the amino acid sequence of SEQ ID NO: 1 or 2.

[00108] In embodiments, the RdRp comprises one or more polymerase regions defined in Table 1 :

Table 1 : Polymerase regions within RdRp (Accession no. YP_009725307)

[00109] In embodiments, a compound described herein interacts with at least 4, 5, 6, 7, 8, 9, 10, 11 or 12 residues of an RdRp, for example via a hydrogen bond and/or a hydrophobic interaction. In embodiments, a compound described herein interacts with one or more of the following residues of an RdRp (numbering based on SEQ ID NO: 1): Pro620, Lys621, Arg553, Cys622, Thr687, Thr680, Asn691, Ser682, Asp623, Asp760, Tyr619, Asp618, for example via a hydrogen bond and/or a hydrophobic interaction.

[00110] "Homology" and “homologous” refers to sequence similarity between two peptides or two nucleic acid molecules. Homology can be determined by comparing each position in the aligned sequences. A degree of homology between nucleic acid or between amino acid sequences is a function of the number of identical or matching nucleotides or amino acids at positions shared by the sequences. As the term is used herein, a sequence is "substantially homologous" to another sequence if the two sequences are substantially identical and the functional activity of the sequences is conserved (as used herein, the term “homologous” does not infer evolutionary relatedness, but rather refers to substantial sequence identity, and thus is interchangeable with the terms “identityTidentical”). Two sequences are considered substantially identical if, when optimally aligned (with gaps permitted), they share at least about 50% sequence similarity or identity, or if the sequences share defined functional motifs. In alternative embodiments, sequence similarity in optimally aligned substantially identical sequences may be at least 60%, 70%, 75%, 80%, 85%, 90% or 95%. For the sake of brevity, the units {e.g., 66, 67...81, 82...91, 92%...) have not systematically been recited but are considered, nevertheless, within the scope of the present disclosure.

[00111] Substantially complementary nucleic acids are nucleic acids in which the complement of one molecule is substantially identical to the other molecule. Two nucleic acid or protein sequences are considered substantially identical if, when optimally aligned, they share at least about 70% sequence identity. In alternative embodiments, sequence identity may for example be at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 98% or at least 99%. Optimal alignment of sequences for comparisons of identity may be conducted using a variety of algorithms, such as the local homology algorithm of Smith and Waterman, 1981 , Adv. Appl. Math 2: 482, the homology alignment algorithm of Needleman and Wunsch, 1970, J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (Pearson and Lipman 1988), and the computerized implementations of these algorithms (such as GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wl, U.S.A.). Sequence identity may also be determined using the BLAST algorithm, described in Altschul et al. (Altschul et al. 1990) (using the published default settings). Software for performing BLAST analysis may be available through the National Center for Biotechnology Information (NCBI). The BLAST algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence that either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold. Initial neighborhood word hits act as seeds for initiating searches to find longer HSPs. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Extension of the word hits in each direction is halted when the following parameters are met: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. One measure of the statistical similarity between two sequences using the BLAST algorithm is the smallest sum probability (P[N], which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. In alternative embodiments of the disclosure, nucleotide or amino acid sequences are considered substantially identical if the smallest sum probability in a comparison of the test sequences is less than about 1, preferably less than about 0.1 , more preferably less than about 0.01, and most preferably less than about 0.001.

[00112] An alternative indication that two nucleic acid sequences are substantially complementary is that the two sequences hybridize to each other under moderately stringent, or preferably stringent, conditions. Hybridization to filter-bound sequences under moderately stringent conditions may, for example, be performed in 0.5 M NaHP04, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65°C, and washing in 0.2 x SSC/0.1% SDS at 42°C (Ausubel 2010). Alternatively, hybridization to filter-bound sequences under stringent conditions may, for example, be performed in 0.5 M NaHP04, 7% SDS, 1 mM EDTA at 65°C, and washing in 0.1 x SSC/0.1% SDS at 68°C (Ausubel 2010). Hybridization conditions may be modified in accordance with known methods depending on the sequence of interest (Tijssen 1993). Generally, stringent conditions are selected to be about 5°C lower than the thermal melting point for the specific sequence at a defined ionic strength and pH.

[00113] The present disclosure also relates to a kit comprising a compound or inhibitor described herein, or a composition comprising the compound or inhibitor described herein and a pharmaceutically acceptable carrier, for use in preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (e.g., COVID-19)) in a subject. The present disclosure also relates to a kit comprising a compound or inhibitor described herein, or a composition comprising the compound or inhibitor described herein and a pharmaceutically acceptable carrier, for use in inhibiting a viral nucleic acid polymerase (e.g., a viral RdRp). The arrangement and construction of such kits is conventionally known to one of skill in the art. Such kits may include, for example, container(s) (e.g., a syringe and/or vial and/or ampoule) for containing the agent or combination of agents or compositions, other apparatus for administering the therapeutic agent(s) and/or composition(s) and/or diluent(s). The kit may optionally further include instructions. The instructions may describe how the agent(s) and the diluent should be mixed to form a pharmaceutical formulation. The instructions may also describe how to administer the resulting pharmaceutical formulation to a subject. In an embodiment, the above-mentioned kit comprises instructions for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (e.g., COVID-19)), or for inhibiting a viral nucleic acid polymerase (e.g., a viral RNA polymerase).

[00114] “Progression” as used herein refers to an advancement or worsening of a disease or condition (e.g., a viral respiratory disease such as COVID-19) over time.

[00115] The disclosure further provides a (pharmaceutical) composition comprising a compound or inhibitor described herein. Such a composition may be used in the methods and uses described herein, e.g., for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease (e.g., a viral respiratory disease (e.g., COVID-19)), or for in inhibiting a viral nucleic acid polymerase (e.g., a viral RNA polymerase, e.g., a viral RdRp).

[00116] In addition to the active ingredients (e.g., a compound or inhibitor described herein, such as a compound having Formula I or II, or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof), pharmaceutical compositions may contain suitable pharmaceutically acceptable excipients. “Pharmaceutically acceptable excipient” as used herein has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself. Excipients include for example binders, lubricants, diluents, bulking agents (fillers), thickening agents, disintegrants, plasticizers, coatings, barrier layer formulations, lubricants, stabilizing agent, release-delaying agents, and other components. "Pharmaceutically acceptable excipient" as used herein refers to any excipient that does not interfere with the effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of excipient and/or is for use in an amount which is not toxic to the subject. Excipients are well known in the art, and the present composition is not limited in these respects. In certain embodiments, the pharmaceutical composition comprises one or more excipients, including for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants/dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents and any combinations thereof. As those of skill would recognize, a single excipient can fulfill more than two functions at once, e.g., can act as both a binding agent and a thickening agent. As those of skill will also recognize, these terms are not necessarily mutually exclusive. Therapeutic formulations are prepared using standard methods known in the art by mixing the active ingredient having the desired degree of purity with one or more optional pharmaceutically acceptable carriers, excipients, and/or stabilizers. The excipient(s) may be suitable, for example, for intravenous, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, epidural, intracisternal, intraperitoneal, intranasal, or pulmonary (e.g., aerosol) administration (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22nd edition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7th edition, Pharmaceutical Press). In an embodiment, the pharmaceutical composition is for intranasal or pulmonary (e.g., aerosol) administration.

[00117] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, lecithin, phosphatidylcholine, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propyl hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the disclosure can be formulated to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[00118] Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose (e.g., preventing and/or ameliorating and/or inhibiting a disease). The determination of an effective dose is well within the capability of those skilled in the art. For any compounds, the therapeutically effective dose can be estimated initially either in cell culture assays (e.g., cell lines) or in animal models, usually mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. An effective dose or amount refers to that amount of one or more active ingredient(s), for example a compound or inhibitor described herein, which is sufficient for treating a specific disease or condition (e.g., a viral infection or disease (e.g., a viral respiratory disease such as COVID-19). Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions, which exhibit large therapeutic indices, are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account, include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. In embodiments, dosages of an active ingredient (e.g., a compound or inhibitor described herein, such as a compound having Formula I or II, or a pharmaceutically acceptable salt, a prodrug, an N-oxide, or a solvate thereof) of between about 0.01 and about 100 mg/kg body weight (in an embodiment, per day) may be used. In further embodiments, dosages of between about 0.5 and about 75 mg/kg body weight may be used. In further embodiments, dosages of between about 1 and about 50 mg/kg body weight may be used. In further embodiments, dosages of between about 10 and about 50 mg/kg body weight in further embodiments about 10, about 25 or about 50 mg/kg body weight, may be used.

[00119] In an embodiment, an active ingredient (e.g., a compound or inhibitor described herein, such as a compound having Formula I or II, or a pharmaceutically acceptable salt, a prodrug, an N- oxide, or a solvate thereof) described herein is administered or is for administration such that it comes into contact with respiratory tissue, e.g., via intranasal or pulmonary (e.g., aerosol) administration. As such, in embodiments an active ingredient (e.g., a compound or inhibitor described herein, such as a compound having Formula I or II, or a pharmaceutically acceptable salt, a prodrug, an N-oxide, or a solvate thereof) described herein can be administered to treat respiratory tissue in vivo via intranasal or pulmonary (e.g., aerosol) administration.

[00120] A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as preventing or inhibiting the rate of onset or progression of the above-noted conditions. A prophylactically effective amount can be determined as described above for the therapeutically effective amount.

[00121] As used herein, the terms "subject" or "patient" are used interchangeably and are used to mean any animal, such as a mammal, including humans and non-human primates. In an embodiment, the above-mentioned subject is a mammal. In a further embodiment, the above- mentioned subject is a human.

[00122] In an embodiment, the kit according to the present disclosure may be divided into separate packages or compartments containing the respective reagent components explained above.

[00123] In addition, such a kit may optionally comprise one or more of the following: (1) instructions for using the reagents for performing the methods described herein and/or for interpreting the results obtained; (2) one or more containers; and/or (3) appropriate controls/standards.

[00124] Informational material included in the kits can be descriptive, instructional, marketing, or other material that relates to the methods described herein and/or the use of the reagents for the methods described herein. For example, the informational material of the kit can contain contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about performing the method described herein and interpreting the results.

MODE(S) FOR CARRYING OUT THE INVENTION

[00125] The present disclosure is illustrated in further details by the following non-limiting examples.

Example 1 : Study compounds

[00126] The compounds EM-COV-A (Life Chemicals No. F2967-0682) and EM-COV-B (Life Chemicals No. F2647-0997), shown in Table 2, were used in the studies described herein. Remdesivir is also shown. (Life Chemicals Inc., Niagara-on-the-Lake, ON, Canada)

Table 2: Study compounds

Example 2: Assessment of solubility of study compounds

[00127] The solubility of EM-COV-A (F2967-0682) and EM-COV-B (F2647-0997) was assessed in different solvents. The compounds were dissolved in different solvents, shaken overnight, and centrifuged at 12k rpm for 1 min. 300 mI of supernatant were taken for testing in LC/MS. A calibration curve of 7 concentrations (1, 5, 10, 50, 250, 500 and 1000 ng/ml) was prepared in 80: 20 (v/v) MeOH: H₂0. The samples were diluted 1/100 or 1/1000 in 10:90 (v/v) H₂0: MeOH. 15 ul of each diluted solution was injected into the LC/MS/MS system. The chromatographic separation of the 2 analytes was achieved using a HPLC at ambient temperature on a Nexera system with a run duration of 3.5 min. Analyst software version 1.6.2 (Sciex) was used for system control and data analysis.

[00128] The compounds showing no visible precipitation or aggregation was tested for its soluble/insoluble proportion by LC/MS experiments. Canola oil is found to be the best solvent for EM-CoV-A while a combination of either isopropyl alcohol and ethanol or acetic acid and ethanol are shown to dissolve the EM-CoV-B to a sufficiently high concentration. For EM-COV-A, we could reach a concentration of 200 mM in 1% DMSO and 0.1% methylcellulose, while EM-COV-B could be solubilized to 90.7 pM in 1% Acetic acid plus 5% Ethanol. Results are shown in Table 3.

Table 3: Solubility test for new RdRp inhibitors

Example 3: Methods

A. Determination of ECso of compounds against SARS-CoV-2 using Plaque reduction assay (PRA) method.

[00129] Confluent VERO E6 cells were seeded in 12-well plates, inoculated with 30-40 plaque forming units (PFUs) of SARS-CoV- 2 (SARS-CoV-2/Quebec/21697/2020) and incubated for 1 hour at 37°C in a 5% CO2 atmosphere. The viral supernatants were aspirated.

[00130] The overlay was prepared by two-fold serial dilutions of each drug. The compound F2967-0682 was started at 200 pM final concentration, the compound F6247-0997 was started at 100 pM final concentration and remdesivir was started at 20 pM final concentration in Minimum Essential Medium (MEM) 2X in addition to 10 % FBS (Fetal Bovine Serum) and 1 % of antibiotics (GVF). Then, agarose was added to an initial concentration of 1.2 % to each drug concentrations. Triplicate wells of infected cells were covered by two-fold serial dilutions of each drug overlay and incubated for 3 days at 37°C in a 5% CO2 atmosphere.

[00131] Plates were inactivated for 1 hour with formalin solution at 3.7%. The overlay was removed and plates were colored with crystal violet 0.8 %. Then, the number of plaque forming units was counted under a binocular for each drug concentration.

[00132] The 50% effective concentration (EC50) values of the different antiviral agents were calculated for SARS- CoV- 2 using Microsoft Excel (2016).

B. Determination of EC50 of compounds against respiratory syncytium virus (RSV)-A2 using Plaque reduction assay (PRA) method

[00133] Confluent Hep-2 cells were seeded in 24-well plates, inoculated with 30-40 plaque forming units (PFUs) of RSV-A2 and incubated for 90 min at 37°C in a 5% CO2 atmosphere. The viral supernatants were aspirated.

[00134] The overlay was prepared by two-fold serial dilutions of each drug. The compound F2967-0682 was started at 20 mM final concentration, the compound F6247-0997 was started at 100 pM final concentration and remdesivir was started at 2.5 pM final concentration in Minimum Essential Medium (MEM) 2X in addition to 4 % FBS (Fetal Bovine Serum). Then, agarose was added to an initial concentration of 1.2 % to each drug concentration. Triplicate wells of infected cells were covered by two-fold serial dilutions of each drug overlay and incubated for 4 days at 37°C in a 5% CO2 atmosphere.

[00135] Plates were inactivated for 1 hour with formaline solution at 3.7 %. The overlay was removed and plates were immunostained by using a goat anti-respiratory syncytial virus antibody (Cedarlane, cat. # MD-05-0391) as first antibody and a Rabbit Anti-Goat IgG HRP Affinity Purified antibody (Cedarlane, cat. # HAF017) as second antibody. Then, the number of plaque forming unit was revealed with TrueBlue peroxidase substrate and counted under a binocular for each drug concentration.

[00136] The 50% effective concentration (EC50) values of the different antiviral agents were calculated for RSV-A2 using Microsoft Excel (2016).

Example 4: Infection of Vero cells by SARS-CoV-2 [00137] The effect of EM-COV-A, EM-COV-B and Remdesivir on the infection of Vero E6 cells by SARS-CoV-2 was assessed. Experimental methods (A) are described above. Results are shown in Table 4. Table 4: Infection of Vero cells by SARS-CoV-2

Example 5: Effect of compounds on respiratory viruses

[00138] The effect of EM-COV-A, EM-COV-B, and Remdesivir on the infection of Hep-2, LLC MK2, and ST6-Gall-MDCK cells by various respiratory viruses was assessed Experimental methods (B, C and D) are described above. Results are shown in Table 5.

Table 5: Effect of compounds on respiratory viruses

RSV: Respiratory syncytial virus

[00139] Certain compounds were further tested via a plaque reduction assay (PRA) for their in vitro inhibition efficiency against SARS-CoV-2. The SARS-CoV-2 virus for these studies was collected during the first wave of COVID-19 (SARS-CoV-2/Quebec City/9771 /2020) and underwent two passages in Vero E6 cells to generate a high-titer viral stock for the experiments. In brief, confluent Vero E6 cells were seeded in 6-well plates. Cells were infected with about 40 plaque forming units (PFUs) of SARS-CoV-2 for 60 min at 37°C in a 5% CO2 atmosphere. After the incubation period, the inoculum was discarded and infected cells were incubated for three days with two-fold serial dilutions of EM-COV-A and -B leads in 2X Minimum Essential Medium (2X MEM) supplemented with 2% fetal bovine serum containing 0.6% SeaPlaque agarose. After 3 days of incubation, cells were fixed with formaldehyde 4% and stained with crystal violet. The number of PFUs were counted under an inverted microscope and plotted against the logarithm of antiviral concentrations.

[00140] PRA studies performed in triplicate revealed the efficiency for in vitro inhibition of EM- COV-A and EM-COV-B. Fitting the dose response curve for EM-COV-A and EM-COV-B demonstrated EC50s of 6.10±1.21 mM and 18.5±4.7 mM, respectively (Fig. 1). Remdesivir EC50 value in Vero E6 cells has been reported to be in the range of 8 and 12 pM (Jeon et al., 2020; Ko et al. , 2021; Jang et al. 2021). These EC50s obtained for EM-COV-A and EM-COV-B in Vero E6 cells are comparable to those obtained for Remdesivir.

Example 6: Inhibitor-RdRp interactions

[00141] Initial analysis of the binding site and the binding mechanism were studied by taking the docked poses of EM-COV-A and EM-COV-B in Ligplot software (Wallace et al., 1995) and the interaction plot in MOE (Molecular Operating Environment, 2019.01.). When comparing with Remdesivir, both molecules showed a significantly different binding pose and interactions. EM-CoV- A established 2 hydrogen bonds and 10 hydrophobic interactions with the RdRp, while EM-CoV-B established 1 hydrogen bond and 9 hydrophobic interactions (Fig. 2). Remdesivir makes only 4 hydrophobic contacts with RdRp (Hillen et al., 2020). These are Asp623, Ser682, Asn691, and Asp760. EM-COV-A overlaps with these interactions, and makes 8 additional contacts with RdRp. EM-COV-B overlaps only at 2 of the Remdesivir interactions. Though the docking process did not include RNA interactions, the pharmacophore created may have helped to preserve such interactions, as seen in Remdesivir. Details of interactions of certain compounds described herein with RdRp are also provided in Table 6.

Table 6: Interactions between inhibitors and RdRp

Example 7: Binding affinity

[00142] We further used intrinsic fluorescence titration to evaluate the direct binding of EM-COV- A on RdRp. The titrations were performed on a Fluorolog-3-21 JOBIN YVON-SPEX equipped with a temperature-regulated cell compartment. A 0.5 cm* 0.5 cm square quartz cuvette with a sample volume of 350 mI was used to perform measurements. The RdRp/nsp7/nsp8 complex was purchased from BPS BioScience (Catalog number: 100839). The excitation wavelength was 285 nm when the titration was first initiated with inhibitors and 290 nm when the titration was first initiated with NTPs. The emission wavelength was 340 nm. To minimize the enzyme photobleaching, a small excitation- slit width of 2 nm was chosen, while a large emission-slit width of 8 nm was chosen for a significant signal-to-noise ratio. A water bath was used to maintain the temperature of the sample compartment at 23 ± 0.1 °C. RdRp complex solution at 83 nM was used for the titration. The EM-COV-A concentration used in the titration was from 1.1 mM to 50 mM , in the presence of saturating NTP (16.4 mM). The inner filter correction was carried out using:

[00143] Where f, h and / are the correction factor, the corrected fluorescence and observed fluorescence, respectively; Po and DA stands for the sample absorption before and the change with substrate addition.

[00144] The KD plot is carried out using the Eadie plot:

AF

AF = -K_D — + AF_¥

L'-’J

[00145] Where AF, AF and KD denote the fluorescence change at the substrate concentration [S], the fluorescence change when all enzymes are complexed with substrates, and the dissociation constant, respectively.

[00146] These studies showed direct binding of EM-COV-A on RdRp, demonstrating a KD of 11.97±0.79 mM (p<0.001). This KD is significantly reduced to 3.10 ± 0.28 mM (p<0.001) in the presence of saturating Nucleoside triphosphates (NTP) (Fig. 3), indicating stronger binding. This demonstrates that NTP can induce change in enzyme conformation that can enhance inhibitor binding. This result demonstrates the close implication of NTP in viral replication, as well as the evident involvement of inhibitors described herein in the interaction with the critical RdRp enzyme. Example 8: Cytotoxicity

[00147] A wide range of toxicity profiles, including hepatotoxicity, respiratory toxicity, cardiovascular toxicity, reproductive toxicity etc. in Remdesivir has restricted its use only in emergency situations (Fan et al., 2020). The cytotoxicity of the EM-COV-A and EM-COV-B were studied in Vero cells. The effect of concentrations of compounds from 1 mM to 1 mM on Vero E6 viability was assessed by incubating cultured cells in 96-well plates for 3 days in an MEM culture medium and 2% serum. Then, 10 pL of “CellTiter 96 aqueous one solution cell proliferation assay” (#G3580 Promega) that contains tetrazolium [3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) was added to each plate and incubated for 3 h. Absorbance at 490 n is proportional to the quantity of the formazan product and directly proportional to the number of living cells in culture. On fitting the value into a non-linear regression curve, the CC50 of EM-COV-A and EM-COV-B were calculated to be 61.9 mM and 98.5 mM, respectively (Fig. 4A). The selectivity index (SI) obtained for EM-COV-A and EM-COV-B obtained were 10.1 and 5.3, demonstrating acceptable toxicity profile and efficacy in human cells for the first-round leads.

Example 9: Pharmacological properties

[00148] EM-COV-A has a molecular mass of 462 Da and cLogP is 4.42. EM-COV-B has a molecular mass of 420 Da and cLogP of 2.19. Absorption, Distribution, Metabolism and Excretion (ADME) studies are designed to investigate how the proposed lead molecule may be processed by a living organism. An initial computational ADME prediction was performed using Qikprop in Schrodinger software. Except for oral absorption, all the other characteristics of EM-COV-A and EM- COV-B are within the accepted range of ADME (Table 7).

[00149] We further performed a series of in vitro experiments to test the pharmacological properties of EM-COV-A and B (Figs. 4B, 4C).

[00150] For studies of metabolic stability in human whole blood and plasma, 140 pl_ of human whole blood or plasma (BiolVT) were homogenized and mixed with a final concentration of 10 mM ligand solution. The mixture was incubated in a thermostatized shaker at 37 °C and 1000 rpm for each timepoint. After incubation, the mixture was quenched with 3 volumes of ice-cold quenching solution, vortexed for 15-20 seconds and kept in ice. The mixture was centrifuged at 5,000 x g for 15 minutes at 4 °C. Following this the concentration ligand in the supernatant of each mixture was quantified using HPLC-MS using Agilent 1260 Infinity HPLC coupled with single quad MSD. For t=0 controls, samples are immediately quenched after addition of the ligand (diluted to 2 imM). Quenching solution consists of acetonitrile containing 25 mM Glyburide as internal standard. (10 mM) propantheline bromide was used as a positive control. The data were derived based on duplicate of each experiment.

[00151] For studies of metabolic stability in rat liver microsomes, 776 mI_ of 0.5 mg/ml_ rat liver microsomes (BiolVT) in PBS was mixed with 8 mI_ of 100 mM NADPH. The ligand molecules diluted in DMSO, and acetonitrile was added to the liver microsomes and NADPH mixture to a final concentration of 10 mM. The sample tubes were pre-incubated for 5 minutes at 37°C while shaking at 950 rp on orbital shaker. At predefined time points, 100 mI_ aliquots were extracted and added over 3 volumes of quenching solution containing Glyburide as internal standard at 2.5 mM concentration. Time zero samples were extracted just after initial homogenization of test article. The tubes containing the quenched samples were centrifuged at 5000 x g for 5 minutes at 4°C. The remaining percentage of ligand and internal standard were quantified in the supernatant by HPLC- MS using Agilent 1260 Infinity HPLC coupled with single quad MSD with a flow rate of 0.4 l/ in. The mobile phase comprised 0.1% formic acid in water and 0.1% formic acid in ACN. The mixture containing all but not NADPH was taken as negative control. The reference sample was dissolved in PBS.

[00152] For lipophilicity studies, ligand solutions (10 mI, 1 mM) were added to 1-octanol and phosphate buffer (pH 7.4, 1:1 v/v) in a 96-well plate. The plate was agitated at 25°C, 2,000 rpm for 2 hours. The buffer and 1-octanol layers were removed separately by centrifugation at 3,220 g at 25°C for 30 minutes and transferred into 96-well plates. H₂0 and acetonitrile (1:1) were added making a dilution of 100-fold octanol in the samples and vortexed for 5 minutes at 1,000 rpm. Internal standards, a mixture of H₂0 and acetonitrile (1:1) were mixed with 50 mI of 100-fold octanol and 50 mI of PBS and vortexed for 5 minutes at 1 ,000 rpm. The concentration of ligands and internal standard were quantified in the supernatant by LCMS/MS.

[00153] For studies of plasma protein binding, ligand solutions prepared in DMSO were diluted in phosphate buffer (final concentration = 5 mM) and were spiked into human plasma (total volume = 1 ml_). Aliquots were then transferred in duplicate to: (i) a final concentration plate that was immediately quenched with 5 mM of reference control (ketoconazole) in ACN, (ii) the remaining spiked plasma solution sample in the plastic plate was incubated for 6 hours at 37°C with 5% C0₂ in the C0₂ incubator. At T=6 hours, 50 mI_ of the original spiked plasma solution were taken for analysis. Cells with plasma sample were dialyzed against PBS at 37 °C at 100 rpm. The samples from both chambers were taken for analysis. 50 mI_ of plasma solution in equal volume of PBS were shaken at 1000 rpm for 2 minutes and 400 mI_ of acetonitrile containing reference control, Ketoconazole was used to precipitate protein and release the compound. The mixture was vortexed at 1000 rpm for 10 minutes and centrifuged for 30 minutes at 3,220 g. 250 pL of the supernatant were taken to a 96-well plate and centrifuged again (3,220 g, 30 minutes). 100 pl_ of supernatant in equal volume of water in a 96-well plate was taken for analysis in an LC/MS equipped with XSelect HSS T3 column at a flow rate of 0.8 mL/min.

[00154] EM-COV-A and EM-COV-B did not show significant decomposition in both human blood and plasma, and EM-COV-A was relatively stable in rat liver microsomes. The Percentage plasma protein binding of EM-COV-A and EM-COV-B was 103.91% and 99.75% respectively, indicating probability of a lower unbound drug fractions in the circulatory system. Binding to plasma proteins assures hydrophobic drugs to be transported in the aqueous environment of the human organism. LogD values, which indicates lipophilicity was obtained in an octanol/PBS partitioning assay. LogD value is interpreted in relation with molecular weight (Waring et al., 2009). LogD values of 5.36 for EM-COV-A (mw: 461 g/mol) and 3.38 for EM-COV-B (mw: 420 g/mol) were obtained, which indicate EM-COV-A may preferably be tested for non-oral administration.

Table 7: Computational report of AMDE

*· aromatic OH oxidation · enol oxidation · benzylic-like H alcohol · allylic H alcohol · secondary alcohol ketone · primary alcohol acid · tertiary alcohol E1 or SN1 · amine dealkylation · ether dealkylation · pyridine C2 hydroxylation · aniline NH NOH or NCOR · low IP — easily oxidized · alpha hydroxylation of cyclic ether · sulfoxide sulfone · alpha hydroxylation of carbonyl · alpha, beta dehydrogenation at carbonyl · thiol SH SSR, SR · para hydroxylation of aryl · aryl sulfide S=0 · reduction of aryl nitro to amine · oxidative deamination of primary amine

[00155] Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims. In the claims, the word "comprising" is used as an open- ended term, substantially equivalent to the phrase "including, but not limited to". The singular forms "a", "an" and "the" include corresponding plural references unless the context clearly dictates otherwise.

REFERENCES

Aguilar RB, P, et al. (2020). Current understanding of COVID-19 clinical course and investigational treatments. Front Med 7: 555301.

Beigel, JH, et al. (2020) Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020; 383:1813-1826.

Chatterjee SK, et al. (2020) Molecular pathogenesis, immunopathogenesis and novel therapeutic strategy against COVID-19. Front Mol Biosci 7: 196.

Fan Q, Zhang B, Ma J, Zhang S. Safety profile of the antiviral drug remdesivir: An update. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2020, 130: 110532.

Gordon DE, et al. (2020a). A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583: 459-468.

Gordon CJ, et al. (2020b). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 295: 4773-4779.

Gordon CJ, et al. (2020c). Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 295: 6785-6797.

Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Structure of replicating SARS- CoV-2 polymerase. Nature 2020, 584(7819): 154-156.

Hossain MF, et al. (2020) COVID-19 outbreak: pathogenesis, current therapies, and potentials for future management. Front Pharmacol. 11: 563478.

Huang J, et al. (2020). Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: from mechanistic studies to clinical trials for COVID-19. J Clin Med 9: 1131.

Jang WD, Jeon S, Kim S, Lee SY. Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proceedings of the National Academy of Sciences of the United States of America 2021, 118(30).

Jeon S, Ko M, Lee J, Choi I, Byun SY, ParkS, etal. Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs. Antimicrobial agents and chemotherapy 2020, 64(7).

Ko M, Jeon S, Ryu WS, Kim S. Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells. Journal of medical virology 2021, 93(3): 1403-1408.

Mathew D, et al. (2020). Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 369: eabc8511.

MOE. Molecular Operating Environment, 2019.01. Chemical Computing Group ULC. Montreal, QC, Canada, H3A 2R7; 2021. Tang D, P Cornish, and R Kang (2020). The hallmarks of COVID-19 disease. PLoS Pathog 16: e1008536.

Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein engineering 1995, 8(2): 127-134.

Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower logD limits based on permeability. Bioorganic & medicinal chemistry letters 2009, 19(10): 2844-2851.

Claims

1. A compound of Formula I:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

A is chosen from CO, SO, SO2 or CH2, or is absent;

B¹ and B² are independently chosen from CH or N;

G¹ is chosen from CH2, NH, O or S;

G² is chosen from CH or N;

2. The compound of claim 1 , having the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

3. The compound of claim 1 or 2, having the structure:

4. The compound of claim 1 or 2, having the structure:

5. The compound of claim 1 or 2, having the structure:

6. The compound of claim 1 or 2, having the structure:

7. The compound of claim 1 or 2, having the structure:

8. The compound of claim 1 or 2, having the structure:

F

9. A compound of Formula II:

Formula II wherein: each R¹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R² is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; each R³ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

B¹ and B² are independently chosen from CH or N; Y is O, S or NH;

10. The compound of claim 9, having the structure:

R⁴ is chosen from H, alkyl or aryl; R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl; each R⁹ is independently chosen from H, OH, halogen, alkyl, aryl, OR⁵, OCOR⁶, OCONR⁷R⁸ or 0S0₂NR⁷R⁸; and each n is independently chosen from 0, 1, 2 or 3; or a pharmaceutically acceptable salt, a prodrug, an N-oxide or a solvate thereof.

11. The compound of claim 9, having the structure:

R⁴ is chosen from H, alkyl or aryl;

R⁵ is chosen from alkyl or aryl;

R⁶ is chosen from H, alkyl or aryl;

R⁷ and R⁸ are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

13. The compound of claim 9 or 11 , having the structure:

14. The compound of claim 9, having the structure:

15. The compound of claim 9, having the structure:

16. A compound of Formula III:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

A is chosen from CO, SO, S0₂ or CH₂, or is absent;

B¹ and B² are independently chosen from CH, N or S;

G¹ is chosen from CH₂, NH, O or S;

G² is chosen from CH or N;

G³ is chosen from CH or N; and

wherein:

W¹ is chosen from O, S or NH;

17. The compound of claim 16, having the structure:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl;

R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

18. The compound of claim 16, having the structure:

R³ is chosen from H, alkyl or aryl;

R⁴ is chosen from alkyl or aryl; R⁵ is chosen from H, alkyl or aryl;

R⁶ and R⁷are independently chosen from H, alkyl or aryl;

W¹ is chosen from O, S or NH;

19. The compound of claim 16 or 17, having the structure:

20. The compound of claim 16 or 18, having the structure:

21. The compound of claim 16, having the structure:

22. A composition comprising the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21, and a pharmaceutically acceptable carrier.

23. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21 or the composition of claim 22 for the preparation of a medicament. 24. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21 or the composition of claim 22 for use as a medicament.

25. A method of preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject, said method comprising administering the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21 or the composition of claim 22 to the subject.

26. The method of claim 25, wherein the viral infection is a coronavirus infection.

27. The method of claim 25 or 26, wherein the viral disease is a viral respiratory disease.

28. The method of any one of claims 25 to 27, wherein the viral infection is a SARS or respiratory syncytial virus (RSV).

29. The method of claim 28, wherein the viral infection is a SARS-CoV viral infection.

30. The method of claim 29, wherein the viral infection is a SARS-CoV-2 viral infection.

31. The method of any one of claims 25 to 30, wherein the viral disease is COVID-19.

32. The method of claim 28, wherein the infection is an RSV infection.

33. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21 or the composition of claim 22 for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject.

34. Use of the compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21 or the composition of claim 22 for the preparation of a medicament for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject.

35. The use of claim 33 or 34, wherein the viral infection is a coronavirus infection.

36. The use of any one of claims 33 to 35, wherein the viral disease is a viral respiratory disease.

37. The use of any one of claims 33 to 36, wherein the viral infection is a SARS or respiratory syncytial virus (RSV) viral infection.

38. The use of claim 37, wherein the viral infection is a SARS-CoV viral infection.

39. The use of claim 38, wherein the viral infection is a SARS-CoV-2 viral infection.

40. The use of any one of claims 33 to 39, wherein the viral disease is COVID-19.

41. The use of claim 37, wherein the infection is an RSV infection.

42. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof of any one of claims 1 to 21, or the composition of claim 22, for use in preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a viral infection or disease in a subject.

43. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of claim 42, wherein the viral infection is a coronavirus infection.

44. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of claim 42 or 43, wherein the viral disease is a viral respiratory disease.

45. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of any one of claims 42 to 44, wherein the viral infection is a SARS or respiratory syncytial virus (RSV) viral infection.

46. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of claim 45, wherein the viral infection is a SARS-CoV viral infection.

47. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of claim 46, wherein the viral infection is a SARS-CoV-2 viral infection.

48. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of any one of claims 42 to 47, wherein the viral disease is COVID- 19.

49. The compound or pharmaceutically acceptable salt, prodrug, N-oxide or solvate thereof for use, or the composition for use, of claim 45, wherein the infection is an RSV infection.