Antiviral compounds

Abstract

The present disclosure provides compounds compound of Formula (II): [Image available in PDF document] and pharmaceutically acceptable salts thereof, for treating a variety of diseases, such as respiratory syncytial vims (RSV), HRV, hMPV, Ebola, Zika, West Nile, Dengue, and HCV.

Description

ANTIVIRAL COMPOUNDS CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 977,881 filed 18 February 2020, titled ANTIVIRAL COMPOUNDS. SEQUENCE LISTING [0001.1] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format. Said ASCII copy, created on February 17, 2021, is named 1223-WO-PCT_SL.txt and is 800 bytes in size. BACKGROUND OF THE INVENTION

[0002] Pneumoviridae viruses are negative-sense, single-stranded, RNA viruses that are responsible for many prevalent human and animal diseases. The Pneumoviridae family of viruses includes human respiratory syncytial virus (HRSV) and human metapneumovirus. Almost all children will have had an HRSV infection by their second birthday. HRSV is the major cause oflower respiratory tract infections in infancy and childhood with 0.5% to 2% of those infected requiring hospitalization.

[0003] No vaccine to prevent HRSV infection is currently available. The monoclonal antibody palivizumab is available for immunoprophylaxis, but its use is restricted to infants at high risk, e.g., premature infants or those with either congenital heart or lung disease, and the cost for general use is often prohibitive. In addition, nucleoside analog ribavirin has been approved as the only antiviral agent to treat HRSV infections but has limited efficacy. Therefore, there is a need for anti-Pneumoviridae therapeutics.

[0004] Examples of pyrrolo[2,3-d]pyrimidine compounds useful for treating viral infections are described in U.S. 2012 / 0009147 Al (Cho et al.), U.S. 2012 / 0020921 Al (Cho et al.), WO 2008 / 089105 A2 (Babu et al.), WO 2008 / 141079 Al (Babu et al.), WO 2009 / 132135 Al (Butler et al.), WO 2010 / 002877 A2 (Francom), WO 2011 / 035231 Al (Cho et al.), WO 2011 / 035250 Al (Butler et al.), WO 2011 / 150288 Al (Cho et al.), WO 2012 / 012465 (Cho et al.), WO 2012 / 012776 Al (Mackman et al.), WO 2012 / 037038 (Clarke et al.), WO 2012 / 087596 Al (Delaney et al.), and WO 2012 / 142075 Al (Girijavallabhan et al.). 1 Date Re9ue / Date Received 2024-02-02 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0005] Thus, there is a need for compositions and methods for treating Pneumoviridae viral infections, such as HRS V infections, that are effective and have acceptable toxicity profiles, Flaviviridae infections, including dengue, and EBOV infections. The present disclosure addresses these and other needs. BRIEF SUMMARY OF THE INVENTION

[0006] In some embodiments, the present disclosure provides a compound of Formula (II): R4A 11 R4BI _p-QXO : / Ba se R4C _..- / 2''' N81 / j \ oyd byo R2 A R1 A Formula (II) or a pharmaceutically acceptable salt thereof, wherein: Base is N ) N or R1A and R2A are each independently: (A) C1.12 alkyl optionally substituted with 1 to 3 R18, (B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R1c, or (C) phenyl, wherein each R 18 is independently halogen, -OH, -NH2, C1-6 alkoxy, methoxyethoxy, C3.s cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, and each R1c is independently C1.3 alkyl; R3 is -N(H)R3A or -N=C(R38)(R3c); R3A is H, -CH2OP(O)(OH)2, or -C(O)R30, wherein R30 is C1- 6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1. 3 alkyl; R38 is Hor C1.3 alkyl; R3c is -N(R3c1)(R3c2); R3c1 and R3c2 are each 2 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 independently Hor C1-6 alkyl; or R3c1 and R3c2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1-6 alkyl; R4A is O or S· ' R4B and R4c are each independently (A) -OH; (B) -OR4B1, wherein R4B1 is C1-6 alkyl optionally substituted with 1 to 3 R4B2 groups, or C6-12 aryl, wherein each R4B2 group is independently C1-6 alkoxy, -S-R4B3, (C) or -S(O)2-R4B3, and each R4B3 group is independently C1-6 alkyl; , wherein mis 0, 1, 2, 3, 4, or 5; and each R40 is independently C1.3 alkyl optionally substituted with 1 to 3 R401 groups, C1.3 alkoxy optionally substituted with 1 to 3 R402 groups, or - C(O)N(R403)2, wherein each R401 group is independently -NH2 or -C(O)OR403, each R402 is independently C1.3 alkoxy, and each R403 is independently C1.3 alkyl; R4E2 R4E1 R4GO~~,\ (D) R 4 F 2 R4 F 1 , wherein R4E1 and R4E2 are each independently Hor C1-6 alkyl, R4F1 and R4F2 are each independently Hor C1-6 alkyl, or R4F1 and R4F2 together are oxo, R 40 is C 1-12 alkyl optionally substituted with 1 to 3 R 401 , C3.7 cycloalkyl optionally substituted with 1 to 3 R402, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, 0 and S, optionally substituted with 1 to 3 R403, or -C(O)R404, each R401 is independently -OH, C1-6 alkyl, C1.3 alkoxy, - (CH2OCH2)1-s-CH3, -N(R408)2, -OP(O)(OH)2, C3.7 cycloalkyl optionally substituted withl to 3 R409, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with 1 to 3 R4010, or phenyl, each R402 is independently C1-6 alkyl, C1.3 haloalkyl, -OH or -NH2, each R403 is independently halogen or C1.3 alkyl, each R404 is independently C1-12 alkyl, each R408 is independently C1-6 alkyl, each R409 is independently C1.3 haloalkyl, -OH or -NH2, and each R4010 is independently C1.3 haloalkyl; or (E) -(OP(O)(OH))1-2-OH; and 3 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 R5A and R58 are each C1-6 alkyl substituted with -OP(O)(OH)2.

[0007] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0008] In another embodiment, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, the present disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0010] In another embodiment, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0013] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating a Picornaviridae virus infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0014] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating a Flaviviridae virus infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used reof. 4 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0015] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating a Filoviridae virus infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0016] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Pneumoviridae virus infection.

[0017] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Picornaviridae virus infection.

[0018] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a F1aviviridae virus infection.

[0019] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Filoviridae virus infection.

[0020] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Pneumoviridae virus infection in a human in need thereof.

[0021] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Picornaviridae virus infection in a human in need thereof.

[0022] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Flaviviridae virus infection in a human in need thereof.

[0023] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Filoviridae virus infection in a human in need thereof.

[0024] In another embodiment, the present disclosure provides a method for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of 5 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0025] In another embodiment, the present disclosure provides a method for manufacturing a medicament for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0026] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis in a human of an exacerbation of a respiratory condition by a viral infection, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0027] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. DETAILED DESCRIPTION OF THE INVENTION I. GENERAL

[0028] The present disclosure provides 2' ,3 '-diester-4' -cyano nucleoside compounds for the treatment of viral infections, such as Ebola, Zika, West Nile, Yellow Fever, Dengue, HCV, RSV, and others. II. DEFINITIONS

[0029] "Alkyl" is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., C1-1s alkyl) or 1 to 8 carbon atoms (i.e., C1-s alkyl) or 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., Ci-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), I-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sbutyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (npentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- 6 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH( CH3 )CH( CH3 )CH2CH3 ), 4-methyl-2-pentyl (-CH( CH3 )CH2CH(CH3 )2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3_ Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl.

[0030] "Alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted.

[0031] "Alkoxy-alkoxy" refers an alkoxy group linked to a second alkoxy group which is linked to the remainder of the compound. Alkoxy is as defined above, and can include, but is not limited to, methoxy-methoxy (CH3OCH2O-), methoxy-ethoxy (CH3OCH2CH2O-) and others.

[0032] "Hydroxy" refers to -OH.

[0033] "Halo" or "halogen" as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-1).

[0034] "Haloalkyl" as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different. For example, C1.4 haloalkyl is a C1.4 alkyl wherein one or more of the hydrogen atoms of the C1.4 alkyl have been replaced by a halo substituent. Examples of haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1, 1,1-trifluoroethyl and pentafluoroethyl.

[0035] "Cycloalkyl" refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3.20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term "cycloalkyl" also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as 7 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 bicyclo[3. 1.0]hexane and bicyclo[2.1. l]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, l-cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, l-cyclohex-1-enyl, l-cyclohex-2-enyl and l-cyclohex-3-enyl.

[0036] "Heterocyclyl" or "heterocycle" or "heterocycloalkyl" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The rings of the multiple condensed ring (e.g., bi cyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine,, 2-oxa-6- azaspiro[3 .3 ]heptan-6-yl, 6-oxa-1-azaspiro[3 .3 ]heptan-1-yl, 2-thia-6-azaspiro[3 .3]heptan-6-yl, 2,6-diazaspiro[3 .3]heptan-2-yl, 2-azabicyclo[3 .1. 0]hexan-2-yl, 3-azabicyclo[3. l .0]hexanyl, 2- azabicyclo[2. l. l ]hexanyl, 2-azabicyclo[2.2. l ]heptan-2-yl, 4-azaspiro[2.4 ]heptanyl, 5- azaspiro[2.4 ]heptanyl, and the like.

[0037] "Aryl" as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged 8 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl and a IOmembered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0038] "Heteroaryl" as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes single aromatic rings of from about 1 to 6 carbon atoms and about 1- 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, 9 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b ]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

[0039] A "compound of the present disclosure" includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) and (Iln), including the compounds of the Examples.

[0040] "Pharmaceutically effective amount" refers to an amount of a compound of the present disclosure in a formulation or combination thereof, that provides the desired therapeutic or pharmaceutical result.

[0041] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0042] "Treatment" or "treat" or "treating" as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more symptoms associated with the disease or condition ( e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and (c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0043] "Prophylaxis" refers to preventing or retarding the progression of clinical illness in patients suffering from a viral infection.

[0044] "Respiratory condition" refers to a disease or condition such as a respiratory infection caused by a viral infection, allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary disease (COPD), chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyperreactivity consequent to other drug therapy, pulmonary vasulcar disease (including pulmonary arterial hypertension), acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis or atopic dermatitis, particularly asthma or allergic rhinitis or atopic dermatitis or allergic conjunctivitis.

[0045] "Exacerbation of a respiratory condition" refers to exacerbations induced by viral infections. Representative viral infections include, but are not limited to, respiratory syncytial virus (RSV), rhinovirus and metapneumovirus.

[0046] "Therapeutically effective amount" or "effective amount" as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0047] "Co-administration" as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed 11 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

[0048] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0049] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts or when appropriate as a free base. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possess the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propyl sulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, yhydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0050] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX4 + (wherein Xis C1-C4 alkyl). Also included are base addition salts, such as sodium or potassium salts. 12 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0051] Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 ton hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0052] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, uc, 13C, 14C, 13N, 15N, 150, 170, 180, 31P, 32P, 35 S, 18F, 36Cl, 1231, and 1251, respectively. Substitution with positron emitting isotopes, such as uc, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (I), can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0053] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active(+) and(-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral fom1, it is understood that the embodiment encompasses, but is not 13 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality ls not spec.:ified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomericaliy enriched form; or a racemlc or scalemic mixture of such compound(s). As used herein, "scalemic mixture" is a mixture of stereoisomers at a ratio other than 1: 1.

[0054] "Racemates" refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

[0055] "Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0056] "Tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group "-S02CH2-" is equivalent to "-CH2S02-" and both may be connected in either direction. Similarly, an "arylalkyl" group, for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as "Cu-v" or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, "C1-6alkyl" and "C1-C6 alkyl" both indicate that the alkyl group has from 1 to 6 carbon atoms. 14 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0058] "Solvate" as used herein refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0059] "Prodrug" as used herein refers to a derivative of a drug that upon administration to the human body is converted to the parent drug according to some chemical or enzymatic pathway. III. COMPOUNDS

[0060] The present disclosure provides compounds of Formula (II), (Ila), (Ilb ), (Ile), (IId), (Ile), (IIf), (Ilg), (IIh), (Iii), (IIj), (Ilk), (IIm) and (IIn).

[0061] In some embodiments, the present disclosure provides a compound of Formula (II): R4A 11 R4Is _p-oXO Ysa se R4C / / 4''' N~ l \. oy6 byo R2 A R1 A Formula (II) or a pharmaceutically acceptable salt thereof, wherein: Base is N ) N or R1A and R2A are each independently: (A) C1-12 alkyl optionally substituted with 1 to 3 R18 , (B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R1c, or (C) phenyl, wherein each R18 is independently halogen, -OH, -NH2, C1-6 alkoxy, methoxyethoxy, C3.s cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, and each R1c is independently C1.3 alkyl; 15 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 R3 is -N(H)R3A or -N=C(R38)(R3c); R3A is H, -CH2OP(O)(OH)2, or -C(O)R30, wherein R30 is C1- 6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1- 3 alkyl; R38 is Hor C1-3 alkyl; R3c is -N(R3c1)(R3c2); R3c1 and R3c2 are each independently Hor C1-6 alkyl; or R3c1 and R3c2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1-6 alkyl; R4A is O or S· ' R48 and R4c are each independently (A) -OH; (B) -OR48 1, wherein R481 is C1-6 alkyl optionally substituted with 1 to 3 R482 groups, or C6-12 aryl, wherein each R482 group is independently C1-6 alkoxy, -S-R48 3, (C) or -S(O)2-R483, and each R483 group is independently C1-6 alkyl; , wherein mis 0, 1, 2, 3, 4, or 5; and each R40 is independently C1-3 alkyl optionally substituted with 1 to 3 R401 groups, C1-3 alkoxy optionally substituted with 1 to 3 R402 groups, or - C(O)N(R403)2, wherein each R401 group is independently -NH2 or -C(O)OR403, each R402 is independently C1-3 alkoxy, and each R403 is independently C1-3 alkyl; R4E2 R4E1 R,Go0N,\ (D) R 4 F 2 R4 F 1 , wherein R4E1 and R4E2 are each independently Hor C1-6 alkyl, R4F1 and R4F2 are each independently Hor C1-6 alkyl, or R4F1 and R4F2 together are oxo, R4G is C1-12 alkyl optionally substituted with 1 to 3 R4Gl, C3-7 cycloalkyl optionally substituted with 1 to 3 R4m, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, 0 and S, optionally substituted with 1 to 3 R4G3, or -C(O)R4G4, each R4Gl is independently -OH, C1-6 alkyl, C1-3 alkoxy, - (CH2OCH2}i-s-CH3, -N(R 4G 8)2, -OP(O)(OH)2, C3-7 cycloalkyl optionally substituted withl to 3 R4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with 1 to 3 R4G10, or phenyl, each R4G2 is independently C1-6 alkyl, C1-3 haloalkyl, -OH or -NH2, each R4G3 is independently halogen or C1-3 alkyl, each R4G4 is 16 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 independently C1-12 alkyl, each R4G8 is independently C1-6 alkyl, each R4G9 is independently C1-3 haloalkyl, -OH or -NH2, and each R4mo is independently C1-3 haloalkyl; or (E) -(OP(O)(OH))1-2-0H; and R5A and R5B are each C1-6 alkyl substituted with -OP(O)(OH)2.

[0062] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein Base is ) N or N I R5B In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein Base is ) N In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein Base is In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein Base is 17 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0063] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Uh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently: (A) C1.12 alkyl optionally substituted with 1 to 3 R18 , (B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with I to 3 R1c, or (C) phenyl, wherein each R 18 is independently -OH, -NH2, C1-6 alkoxy, methoxyethoxy, C3.s cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, and each R1c is independently C1.3 alkyl.

[0064] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1 A and R2 A are C1-12 alkyl optionally substituted with I to 3 R18. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Uh), (Iii), (Ilj), (Ilk), (Um) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each selected from the group consisting of methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert-butyl, and isopentyl, each optionally substituted with I to 3 R18 . In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R18 can independently be methoxy, methoxyethoxy, morpholinyl, -OH, or -NH2. In some embodiments, the compound can be represented by Formula (11), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Uh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1 A and R2 A are each independently methyl optionally substituted with methoxy, methoxyethoxy, or morpholinyl, ethyl optionally substituted with methoxy, n-propyl, isopropyl, n-butyl, isobutyl optionally substituted with -OH or -NH2, tert-butyl, or isopentyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), 18 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (Iii), (IIj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein RiA and R2 A are each independently methyl, ethyl, or isopropyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (IId), (Ile), (IIf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each ethyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (IId), (Ile), (IIt), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R2A are each isopropyl.

[0065] In some embodiments, the compound can be represented by Formula (II), (Ila), (IIb ), (Ile), (IId), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (IIj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each 3 to 6 membered heterocyclyl having I to 3 heteroatoms independently selected from N, 0 and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 Ric, wherein each Ric is independently Ci-3 alkyl, hydroxy, or halogen. In some embodiments, the compound can be represented by Formula (11), (Ila), (IIb), (Ile), (Ild), (Ile), (IIt), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each 4 to 6 membered heterocyclyl having I heteroatom selected from N and 0, wherein the 4 to 6 membered heterocyclyl is optionally substituted with 1 Ric, wherein each Ric is independently Ci-3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (IId), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each oxetanyl, tetrahydropyranyl or piperidinyl, each optionally substituted with 1 Ric, wherein each Ric is independently Ci-3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each Ric is methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each independently oxetanyl, tetrahydropyranyl, or piperidinyl optionally substituted with methyl.

[0066] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein RiA and R 2A are each phenyl. 19 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0067] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3 is -N(H)R3A or -N=C(R38)(R3c), R3A is H, -CH20P(O)(OH)2, or -C(O)R30, wherein R30 is C1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1-3 alkyl, R38 is Hor C1-3 alkyl, R3c is -N(R3c1)(R3c2), R3c1 and R3c2 are each independently Hor C1-6 alkyl, or R3c1 and R3c2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1-6 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3 is -N(H)R3A, and R3A is H, -CH20P(O)(OH)2, or -C(O)R30, wherein R30 is C1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with C1-3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3 is -N(H)R3A and R3A is H, -CH20P(O)(OH)2, or -C(O)R30, wherein R30 is C1-3 alkyl optionally substituted with 1 methoxy, or piperidine optionally substituted with methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3A is H. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3 is -NH2. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R3 is -N=C(R38)(R3c), wherein R38 is Hor methyl, R3c is -N(R3c1)(R3c2), R3c1 and R3c2 are each independently H or methyl, or R3c1 and R3c2 together with the atom to which they are attached form piperazine, optionally substituted with methyl.

[0068] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 A is O or S. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 A is 0. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilrn) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4A is S. 20 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0069] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one of R 48 and R 4c is -OH.

[0070] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is -OR481, wherein R481 is C1-6 alkyl optionally substituted with I to 3 R482 groups, or C6-12 aryl, wherein each R482 group is independently C1-6 alkoxy, -S-R483 , or -S(O)2-R483, and each R483 group is independently C1-6 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R481 is C1-6 alkyl optionally substituted with 1 to 3 R482 groups. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (II±), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R482 group is independently C1-6 alkoxy, -S-R483 , or -S(O)2-R483, and each R483 group is independently C1-6 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (II±), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R481 is C1-6 alkyl optionally substituted with 1 to 3 R482 groups, wherein each R482 group is independently C1-6 alkoxy, -S-R483 , or -S(O)2- R483, and each R483 group is methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (II±), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is -O-C1-6 alkyl optionally substituted with methoxy, methylthio or methylsulfonyl.

[0071] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is wherein mis 0, 1, 2, 3, 4, or 5; and each R40 is independently C1-3 alkyl optionally substituted with I to 3 R401 groups, C1-3 alkoxy optionally substituted with I to 3 R402 groups, or - C(O)N(R403 )2, wherein each R401 group is independently -NH2 or -C(O)OR403 , each R402 is independently C1-3 alkoxy, and each R403 is independently C1-3 alkyl. 21 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0072] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein mis 0, 1 or 2; and each R40 is independently C1.3 alkyl optionally substituted with 1 R401 group, C1.3 alkoxy optionally substituted with methoxy, or - C(O)N(R403 )2, wherein each R401 group is independently -NH2 or -C(O)OR403, and each R403 is independently C1.3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein m is O or 1. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein mis 0.

[0073] In some embodiments, the compound can be represented by Formula (II), (Ila), (IIb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is: ...-0- R41R4E1\,. R4G ~Y 'N / \ R4F2 R4F1 H wherein R 4El and R 4Ez are each independently H or C 1-6 alkyl, R 4Fl and R 4Fz are each independently Hor C1-6 alkyl, or R4F1 and R4F2 together are oxo, R40 is C1-12 alkyl optionally substituted with 1 to 3 R401, C3.7 cycloalkyl optionally substituted with 1 to 3 R402, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, 0 and S, optionally substituted with 1 to 3 R403, or -C(O)R404, each R401 is independently -OH, C1-6 alkyl, C1.3 alkoxy, -(CH2OCH2)1-s-CH3, -N(R408)2, -OP(O)(OH)2, C3.7 cycloalkyl optionally substituted withl to 3 R409, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with 1 to 3 R4010, or phenyl, each R402 is independently C1-6 alkyl, C1.3 haloalkyl, -OH or -NH2, each R403 is independently halogen or C1.3 alkyl, each R404 is independently C1-12 alkyl, each R408 is independently C1-6 alkyl, each R409 is independently C1.3 haloalkyl, or -NH2; and each R4010 is independently C1.3 haloalkyl.

[0074] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is: 22 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 ; and the other ofR4B and R4c is:

[0075] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 E 1 and R4 E 2 are each independently Hor C1-6 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 E 1 and R4 E 2 are each independently Hor methyl.

[0076] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4Fl and R 4Fz are each independently Hor C1-6 alkyl, or R 4Fl and R4 F 2 together are oxo. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 F 1 and R4 F 2 are each independently Hor methyl, or R4 F 1 and R4 F 2 together are oxo. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 F 1 and R4 F 2 together are oxo.

[0077] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR4 B and R4c is: "- NH R4G ~o T 0

[0078] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR4 B and R4c is: 23 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 R4"G- . ~oTN H 0

[0079] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is C1-12 alkyl optionally substituted with 1 to 3 R4m. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (IIj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or 2-ethylbutyl, each optionally substituted with 1 to 3 R4m.

[0080] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4Gl is independently -OH, C1-6 alkyl, C1.3 alkoxy, - (CH20CH2)1-s-CH3, -N(R4G 8)2, -OP(O)(OH)2, C3.7 cycloalkyl optionally substituted withl to 3 R4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, 0 and S, optionally substituted with 1 to 3 R4G 10 , or phenyl, wherein each R4G 8 is independently C1- 6 alkyl, each R4G9 is independently C1.3 haloalkyl, or -NH2, and each R4G10 is independently C1.3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4Gl is independently -OH, C1-6 alkyl, C1.3 alkoxy, -(CH20CH2)1-s-CH3, - N(R4G 8)2, -OP(O)(OH)2, C4-6 cycloalkyl optionally substituted withl to 3 R4G 9 , 4 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from N and 0, optionally substituted with 1 to 3 R4G10 , or phenyl, wherein each R4G8 is independently C1-6 alkyl, each R4G9 is independently C1.3 haloalkyl or -NH2, and each R4GI 0 is independently C1.3 haloalkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4G1 is independently -OH, methyl, OMe, -(CH20CH2)2-CH3, -N(iPr)2, - OP(O)(OH)2, cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or CF3, oxetanyl, piperidinyl optionally substituted with CF3 or CH2CF3, tetrahydropyranyl, morpholinyl, or phenyl.

[0081] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4G is methyl optionally substituted with R 4G1, ethyl optionally substituted with morpholinyl or -N(R4G8)2, n-propyl optionally substituted with methoxy or 24 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 morpholinyl, isopropyl, n-butyl optionally substituted with C1-3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, wherein R4 Gl is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with R4G9, oxetanyl, piperidinyl optionally substituted with R4010, tetrahydropyranyl, or phenyl.

[0082] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R408 is C1-3 alkyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R408 is isopropyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G9 is C1-3 haloalkyl or -NH2. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R409 is -CF3 or -NH2. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4mo is C1- 3 haloalkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4Gl0 is -CF3 or 2,2,2-trifluoroethyl.

[0083] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R40 is methyl optionally substituted with R4m, ethyl optionally substituted with morpholinyl or -N(C1-3 alkyl)2, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C1-3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, wherein R4m is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or C1-3 haloalkyl, oxetanyl, piperidinyl optionally substituted with C1-3 alkyl or C1-3 haloalkyl, tetrahydropyranyl, or phenyl.

[0084] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R40 is C3_7 cycloalkyl optionally substituted with 1 to 3 R402 . In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R40 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1 to 3 R402 . In some embodiments, the compound can be represented by 25 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4 G2 is independently C1-6 alkyl, C1.3 haloalkyl or -NH2. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4G2 is tert-butyl, -CF3 or -NH2.

[0085] In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Hf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4 G is 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, 0 and S, optionally substituted with 1 to 3 R4m_ In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 G is 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from N, 0 and S, optionally substituted with 1 to 3 R4m_ In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4 G is a 4-6 membered heterocyclyl having 1 to 2 heteroatoms selected from N and 0, optionally substituted with 1 to 3 R4m_ In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Hf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with 1 to 3 R4m. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4m is independently halogen or C1.3 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4m is independently F, methyl or ethyl.

[0086] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Hf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is -C(O)R4G4 _ In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein each R4G4 is independently C1.12 alkyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Hf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 G is -C(O)C1-6 alkyl. In some embodiments, the compound can be 26 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 represented by Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 G is -C(O)-tert-butyl.

[0087] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is -(OP(O)(OH))1-2-0H. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein one ofR48 and R4c is -(OP(O)(OH))1-2-0H and one ofR48 and R4c is -OH

[0088] In some embodiments, the compound can be represented by Formula (II), (Ila) or (lib), or a pharmaceutically acceptable salt thereof, wherein RsA and Rs8 are each -CH20P(O)(OH)2. In some embodiments, the compound can be represented by Formula (II) or (Ila), wherein RsA is -CH20P(O)(OH)2. In some embodiments, the compound can be represented by Formula (II) or (lib), or a pharmaceutically acceptable salt thereof, wherein Rs8 is -CH20P(O)(OH)2.

[0089] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (Ila): Formula (Ila), wherein RsA is -CH20P(O)(OH)2.

[0090] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (lib): 27 CA 03171497 2022-08-16 WO 2021 / 168038 Formula (Ilb) wherein R58 is-CH2OP(O)(OH)2. PCT / 0S2021 / 018458

[0091] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl optionally substituted with methoxy, methoxyethoxy, or morpholinyl, ethyl optionally substituted with methoxy, npropyl, isopropyl, n-butyl, isobutyl optionally substituted with -OH or -NH2, tertbutyl, isopentyl, oxetanyl, tetrahydropyranyl, piperidinyl optionally substituted with methyl, or phenyl; R3 is -N(H)R3 A or -N=C(R38 ) (R3c); R3 A is H, -C(H)2OP(O)(OH)2, or -C(O)R30 ; R30 is methyl, ethyl optionally substituted with methoxy, isopropyl, or piperidinyl optionally substituted with methyl; R38 is Hor methyl; R3c is -N(R3c1)(R3c2); R3c1 and R3c2 are independently Hor methyl; or R3c1 and R3c2 together with the atom to which they are attached form a piperazinyl optionally substituted with methyl; R4A is O or S· and ' R 48 and R 4c are each independently (A) -OH; (B) -O-C1-6 alkyl optionally substituted with methoxy, methylthio or methylsulfonyl; (C) 28 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 wherein mis 0, 1 or 2; and each R4D is independently C1.3 alkyl optionally substituted with 1 R4m group, C1.3 alkoxy optionally substituted with methoxy, or - C(O)N(R4D3)2, wherein each R4D1 group is independently -NH2 or -C(O)OR4D3, and each R4 D3 is independently C1.3 alkyl; or (D) ,..0- R41R4E1 \... R4G X "N / \ R4F2 R4F1 H wherein R4E1 and R4E2 are each independently Hor methyl, R4F1 and R4F2 are each independently Hor methyl, or R4F1 and R4F2 together are oxo, R4G is methyl optionally substituted with R4m, ethyl optionally substituted with morpholinyl or -N(C1.3 alkyl)2, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C1.3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently -NH2, C1-6 alkyl, or C1.3 haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C1.3 alkyl, tetrahydrofuranyl, tetrahydropyranyl, or -C(O)C1-6 alkyl, and R4m is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or C1.3 haloalkyl, oxetanyl, piperidinyl optionally substituted with C1.3 haloalkyl, tetrahydropyranyl, or phenyl.

[0092] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ile): ) N Formula (Ile).

[0093] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ild): 29 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 NH2 N J N Formula (lid).

[0094] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (lid): ) N Formula (Ile).

[0095] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (lit): N J N Formula (lit).

[0096] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ilg): 30 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 N J N Formula (Ilg) wherein m is O or 1.

[0097] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ilh): N J N Formula (Ilh).

[0098] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Iii): N J N Formula (Iii).

[0099] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ilj): 31 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 N ) N Formula (Ilj).

[0100] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ilk): N ) N Formula (Ilk).

[0101] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Ilm): N ) N Formula (Ilm).

[0102] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (Iln): 32 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 N ) N Formula (Iln).

[0103] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Hf), (Ilg), (Ilh), (IIi), (Ilj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (lib), (Ile), (Ild), (Ile), (IIf), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1 A and R2 A are each independently methyl, ethyl, or isopropyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (IIf), (Ilg), (IIh), (Iii), (IIj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1 A and R2 A are each independently methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently ethyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (IIg), (Ilh), (Iii), (IIj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently isopropyl.

[0104] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (IIk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4 G is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2- ethyl-butyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (Ilb), (Ile), (Ild), (IIe), (Ilf), (Ilg), (IIh), (Iii), (IIj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4G is methyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (IIf), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is ethyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (IIc), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4G is n-propyl. In some embodiments, the compound can be represented by Formula 33 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4 G is isopropyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilt), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 G is nbutyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R 4 G is t-butyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R4 G is 2-ethyl-butyl.

[0105] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl, R 4 G is methyl optionally substituted with R4Gl, ethyl optionally substituted with morpholinyl or -N(C1.3 alkyl)2, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C1.3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently -NH2, C1-6 alkyl, or C1.3 haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C1.3 alkyl, tetrahydrofuranyl, tetrahydropyranyl, or -C(O)C1-6 alkyl, and R4Gl is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or C1.3 haloalkyl, oxetanyl, piperidinyl optionally substituted with C1.3 alkyl or C1.3 haloalkyl, tetrahydropyranyl, or phenyl.

[0106] In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, R4 G is methyl optionally substituted with R4m, ethyl optionally substituted with morpholinyl or - N(C1.3 alkyl)2, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C1.3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently -NH2, C1-6 alkyl, or C1.3 haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C1.3 alkyl, tetrahydrofuranyl, tetrahydropyranyl, or -C(O)C1-6 alkyl, and R4Gl is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or C1.3 haloalkyl, oxetanyl, piperidinyl optionally substituted with C1.3 alkyl or C1.3 haloalkyl, tetrahydropyranyl, or phenyl. 34 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0107] In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl, and R40 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2-ethyl-butyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, and R40 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2-ethyl-butyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each methyl, and R40 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2-ethyl-butyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each ethyl, and R 40 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2-ethylbutyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb ), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each isopropyl, and R40 is methyl, ethyl, npropyl, isopropyl, n-butyl, t-butyl or 2-ethyl-butyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, and R40 is methyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, R40 is ethyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, R40 is n-propyl. In some embodiments, the compound can be represented by Formula (11), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, R 40 is isopropyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each independently methyl, ethyl, or isopropyl, R40 is n-butyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), 35 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (Iii), (IIj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R1A and R2 A are each independently methyl, ethyl, or isopropyl, R4 G is t-butyl. In some embodiments, the compound can be represented by Formula (II), (Ila), (IIb), (Ile), (IId), (Ile), (IIt), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln), or a pharmaceutically acceptable salt thereof, wherein R1 A and R2A are each independently methyl, ethyl, or isopropyl, R4G is 2-ethyl-butyl.

[0108] The compounds of the present disclosure include the compounds of Table IA, Table IB, Table IC, Table ID, Table IE, Table IF, Table IG, Table IH, and Table II. In some embodiments, the compound can be represented by Formula (II), (Ila), (IIb), (Ile), (IId), (Ile), (IIf), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds in Table IA, Table IB, Table IC, Table ID, Table IE, Table IF, Table IG, Table lH, and Table 11: Table lA. Compounds 36 WO 2021 / 168038 N N N ) CA 03171497 2022-08-16 N ) 37 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 = 0 : II O~N-P-0 II \-? H I ,. O NH NC' . O 6 i / ~ 38 CA 03171497 2022-08-16 39 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 Q 0 II O-P-0 Q O I . 0 )l_ ~ O / NH 4,' _ , _ff o J N d o \ ;=o NH, N N ~ = 0 : II O~N-P-0 II k.,.,~H NC''" 0 o I - , ~ ~ ,10 0 ) NH, 40 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Table lB. Compounds 41 WO 2021 / 168038 °'--0 / 0 \__ • .- II ~N-P-0 0 I . 0 ,. ~ ~- v ~6 ~o\ __• / .- oII II ~-P-0 O 0 I . 0 ~,,. 0-5,6 CA 03171497 2022-08-16 42 PCT / 0S2021 / 018458 WO 2021 / 168038 N N ) CA 03171497 2022-08-16 43 PCT / 0S2021 / 018458 l Q 0II (l ~o o-~-o ,,· NH~' . O N .:: F F HO Q 0 11 oo-~-o A_..,..NH ,,' 'o I ~ 6 by-o o~~ CA 03171497 2022-08-16 44 PCT / 0S2021 / 018458 WO 2021 / 168038 Q 0 II O-P-O CA 03171497 2022-08-16 0 0 I ,. )l__ / NH 4,'' . , _ / / 0 0 IN O ()\_ <O NH, N N ) 45 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 N N ) Q o II Q Q-pb-0 o~ A__,.,~H Ne''._. o '-----'---o T o~0 b--{_ \ NH2 N / 4 N ~o / ' o \__.-' II I / ~-P-0 0 I . vrrY~0 ~y\ ,, N J N 46 PCT / 0S2021 / 018458 WO 2021 / 168038 Q 0 II o-P-0 0 : . Q 0 A,..I.N Hy NoC'':: 0 Q II 011••P-O Q 1--~H NC''., 0 I yo CA 03171497 2022-08-16 47 PCT / 0S2021 / 018458 WO 2021 / 168038 Q o II O O-J?-O oc:r'o~N~d >-0 --~ 0 \.__.-' II ~N-P-0 o o1 ,. ~H2 N 4 ''. ,,o~ ~t 0 = 0 : II O~N-P-O 0 Y 119H I ,,. I O A...--NH 4' . :. 0 ~ I N 6 °f ~o / = 0 : II O~N-P-0 r 11 9H I , .. I O A.,,.NH 4' . :. 0 '( I N 6 °f ~o / CA 03171497 2022-08-16 48 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Table lC. Compounds 49 CA 03171497 2022-08-16 WO 2021 / 168038 Table lD. Com pounds Q -.-: ---:N OII ~ N,NJ O ► P-0 0 O ~H o / ,,,·. , >--0 '••o N -(g NH2 NH2 ---:N O\_ / '; / ~.::_N) I / ~N••·P-0 0 0 ' ,. 0 4'' v,:x 50 PCT / 0S2021 / 018458 WO 2021 / 168038 CA 03171497 2022-08-16 X 51 PCT / 0S2021 / 018458 WO 2021 / 168038 Q 0 II O-P-0 Q O I ,. CA 03171497 2022-08-16 Jl..✓NH q:-'' . , ----f_O OINc50;-- --t0 NH2 Q 0 II O•·P-O 9✓-"-, JI.__ / ~ H 4 / . , ----f_O ~o I N c5 o / -to NH, 52 PCT / 0S2021 / 018458 WO 2021 / 168038 Q 0 'Q 0-PII -O ~O I ,,· 0 CA 03171497 2022-08-16 NH o / ' . , -{ O N cj Q / ~O NH2 Q 0 II O ► P-O -----~-------, JL~H o / ''' . ' ----f._° l....._,,).._o I N d o / -to NH, 'NQ o I - ~ 11 o II O•·P-O 0 0 ' . NH ~,,, _ -:. )-a O N -ti 53 PCT / 0S2021 / 018458 WO 2021 / 168038 Q 0 11 0 O-P-O 0~ ~~H Ne''' . \_-J-__o ~6 CA 03171497 2022-08-16 54 PCT / 0S2021 / 018458 WO 2021 / 168038 CA 03171497 2022-08-16 55 PCT / 0S2021 / 018458 WO 2021 / 168038 Q o II o o-~-o . NH ,, NC orf"0 ):d CA 03171497 2022-08-16 N N ,) N N ,) :( 56 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Table lE. Compounds -< --< ~o / o \ \__.: 11 d~N-P-0 0I ~,,.. v5: 57 CA 03171497 2022-08-16 N N ) N N ) 58 PCT / 0S2021 / 018458 -o / ' 0 \.__.·• II / / ~N-P-0 0 I . ~H2 nY0 ,,o~)~--:-· · 0 N CA 03171497 2022-08-16 N J 59 PCT / 0S2021 / 018458 WO 2021 / 168038 CA 03171497 2022-08-16 ~N O\._ / \? ~~-✓ 0I I ~-PI -0 0 HO 0 ,, .. Nr ~ X -o .--:~ 0 \__:' II 0I / ~-P-0 I HO N N J 60 PCT / 0S2021 / 018458 WO 2021 / 168038 N CA 03171497 2022-08-16 N ) N N ) N N ) 61 PCT / 0S2021 / 018458 WO 2021 / 168038 \_o .:\__.-- 0 f / \ II 0 HN-P-0 I Vo~,,·· NV .: X X -0 .:\__. ·' 0 f / \ II 0 HN-P-0 6 ,. -q:;>' N .. CA 03171497 2022-08-16 100 XX 62 PCT / 0S2021 / 018458 WO 2021 / 168038 N CA 03171497 2022-08-16 N N J N J 63 PCT / 0S2021 / 018458 WO 2021 / 168038 = 0 : II O~N-P-0 ( II~O~H I / 4,,. . 0 NH~ . :. 0 l ~ / X N N _) N CA 03171497 2022-08-16 N _) H ,...H 'N 64 PCT / 0S2021 / 018458 CA 03171497 2022-08-16 WO 2021 / 168038 Table lF. Compounds = 0 : II O~N-P-0 N N ) '-...,.,.- II!.,-!~OH ~ HNC''' . 0 0 •• -{ J / / '--\__ Q 0 II O-P-0 0 9-"-, JL~H 4-''' . , --1<..° ~o I N ci o {\"" --to NH2 Q 0 II N ) N 0 ~O O• -~-0 ,. NH 4-'' . , -- / (__O o N ci b (\"" --!:O NH2 N N ) 65 PCT / 0S2021 / 018458 WO 2021 / 168038 Table lG. C o mpounds N J N N N J CA 03171497 2022-08-16 66 PCT / 0S2021 / 018458 WO 2021 / 168038 CA 03171497 2022-08-16 67 PCT / 0S2021 / 018458 WO 2021 / 168038 Table l H · Compounds N ) N CA 03171497 2022-08-16 68 PCT / 0S2021 / 018458 WO 2021 / 168038 Table 11. Compounds -0 ~ \._:' 0 f / \ II 0 HN-P-0 I . ~ N .: 000 ~I :::::::,..., 0 HN~ 0 HN~ ''X, NH ,,,,·· 'o oold olo CA 03171497 2022-08-16 PCT / 0S2021 / 018458 69 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 J NH 70 WO 2021 / 168038 N CA 03171497 2022-08-16 N ~ 71 PCT / 0S2021 / 018458 WO 2021 / 168038 CA 03171497 2022-08-16 0 HN~O....__ PCT / 0S2021 / 018458

[0109] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure: NH 0 II . / "'-... .... P,-OH N O OH ~ N ~I 'N~

[0110] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure: 72 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0111] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is: X 73 CA 03171497 2022-08-16 WO 2021 / 168038 74 PCT / 0S2021 / 018458 NH2 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 , or

[0112] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0113] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is: 75 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0114] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is: Q o II 0 O ► P-0 , 0~NH / 2,--· N~ -.::: ox X

[0115] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0116] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is: 76 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0117] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0118] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0119] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0120] Also falling within the scope herein are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., 14c or 3H) compound, administering it parenterally in a detectable dose (e.g., greater than about 0.5 77 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 mg / kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled ( others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds even if they possess no HSV antiviral activity of their own.

[0121] Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for I hour at 37 °C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The prodrugs typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver, lung or other metabolic organ, or within cells in general. As used herein, a prodrug is understood to be a compound that is chemically designed to efficiently liberate the parent drug after overcoming biological barriers to oral delivery. IV. PHARMACEUTICAL FORMULATIONS

[0122] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical formulation comprising a pharmaceutically effective amount ofa compound of Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) and (Iln), or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient.

[0123] The compounds herein are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents 78 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.

[0124] While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0125] The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0126] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[0127] A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0128] For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active 79 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including active ingredient(s) in a range between 0.1 % and 20% in increments of 0.1 % w / w such as 0.6% w / w, 0. 7% w / w, etc.), preferably 0.2 to 15% w / w and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-inwater cream base.

[0129] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[0130] The oily phase of the emulsions may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

[0131] Emulgents and emulsion stabilizers suitable for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

[0132] The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol di ester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used. 80 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0133] Pharmaceutical formulations herein comprise a combination together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0134] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0135] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride ( e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. 81 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0136] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0137] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0138] The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0139] The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparations, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable or intravenous preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. 82 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0140] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 3 0 mL / hr can occur.

[0141] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w / w.

[0142] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid earner.

[0143] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0144] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Pneumoviridae infections as described below.

[0145] Another embodiments provides a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising a compound of Formula (II), (Ila), (lib), (Ile), (IId), (Ile), (IIf), (Ilg), (IIh), (Ili), (IIj), (Ilk), (IIm) or (IIn), or a pharmaceutically 83 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 acceptable salt thereof, suitable for treating Pneumoviridae infections and potentially associated bronchiolitis. Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation. Preferably, the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 μm. Preferably, the compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).

[0146] Non-limiting examples ofnebulizers include atomizing,jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S 10). A jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets. A vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.

[0147] In a preferred embodiment, the formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 μm and about 5 μmusing a nebulizer able to aerosolize the formulation of the compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (lit), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) into particles of the required MMAD. To be optimally therapeutically effective and to avoid upper respiratory and systemic side effects, the majority of aerosolized particles should not have a MMAD greater than about 5 μm. If an aerosol contains a large number of particles with a MMAD larger than 5 μm, the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 μm, then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.

[0148] When formulated and delivered according to the method herein, the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) to the site of Pneumoviridae infection sufficient to treat the Pneumoviridae infection. The amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), 84 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (Iii), (IIj), (Ilk), (IIm) or (IIn). In a preferred embodiment, a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (IIf), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (IIm) or (IIn) into the airways. In a preferred embodiment, at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.

[0149] In another embodiment, a compound of Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (Ilf), (Ilg), (IIh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compounds are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers. For delivery by DPI, the compound of Formula (11), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) is processed into particles with, predominantly, MMAD between about 1 μm and about 5 μm by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 μm and about 5 μm are well known in the art. In one embodiment, excipients are added to the compound of Formula (II), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) before processing into particles of the required sizes. In another embodiment, excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.

[0150] Particle size determinations are made using devices well known in the art. For example a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.

[0151] In another preferred embodiment, a compound of Formula (11), (Ila), (Ilb), (Ile), (Ild), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices. Non-limiting examples of dry powder inhalers and devices include those disclosed in USS,458, 135; USS, 740,794; US5775320; USS,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; USS,522,385; US4,668,218; US4,667,668; US4,805,81 l and USS,388,572. There are two major designs of dry powder inhalers. One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber. The second design is a factory-metered device in which each individual dose has been 85 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 manufactured in a separate container. Both systems depend on the formulation of the drug into small particles ofMMAD from 1 μm and about 5 μm and often involve co-formulation with larger excipient particles such as, but not limited to, lactose. Drug powder is placed in the inhalation chamber ( either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs. In preferred embodiments, a compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (lit), (Ilg), (Ilh), (Ili), (Ilj), (Ilk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 μm to about 5 μm.

[0152] In another embodiment, a compound of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (lit), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) is delivered as a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in USS,261,538; USS,544,647; USS,622,163; US4,955,371; US3,565,070; US3,361306 and US6,l 16,234. In preferred embodiments, a compound ofFormula (II), (Ila), (lib), (Ile), (IId), (Ile), (lit), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (IIn), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 μm.

[0153] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0154] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0155] The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are 86 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0156] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0157] Further provided are veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

[0158] Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0159] Compounds herein are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more of the compounds ("controlled release formulations") in which the release of the active ingredient is controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0160] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg / kg body weight per day; typically, from about 0.01 to about 10 mg / kg body weight per day; more typically, from about .01 to about 5 mg / kg body weight per day; most typically, from about .05 to about 0.5 mg / kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to I 000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses. V. ROUTES OF ADMINISTRATION

[0161] One or more of the compounds of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (IIf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including 87 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be dosed orally.

[0162] The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0163] A compound of the present disclosure, may be administered to an individual in accordance with an effective dosing regimen for a desired period oftime or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.

[0164] The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0165] The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0166] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0167] A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per 88 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100,125,150, 175,200,225,250,275,300,325,350,375,400,425,450,475,or about 500 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In some embodiments, a single dose can be administered once every week. A single dose can also be administered once every month.

[0168] Other therapeutically effective amounts of the compound of the present disclosure are about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.

[0169] The frequency of dosage of the compound of the present disclosure are will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the viral infection. For example, a compound can be administered to a human being infected with a virus for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.

[0170] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day, or three times per week. Again by way of example, a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

[0171] In one embodiment, pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided. 89 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0172] In one embodiment, kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents are provided.

[0173] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0174] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0175] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0176] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0177] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of a compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending a compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of a compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable 90 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 formulations are also prepared by entrapping a compound in liposomes or microemulsions that are compatible with body tissues. VI. COMBINATION THERAPY

[0178] The compounds of Formula (II), (Ila), (lib), (Ile), (lid), (Ile), (Ilf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) and compositions provided herein are also used in combination with other active therapeutic agents for the treatment of virus infections, such as Pneumoviridae, Picornaviridae, Flaviviridae, or Filoviridae virus infections. Combination Therapy for the treatment of Pneumoviridae

[0179] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, preferably, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents active against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT- 637, BMS-433771, ALN-RSV0, ALX-0171 and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infections include respiratory syncytial virus protein F inhibitors, such as AK-0529; RV-521, ALX-0171, JNJ- 53718678, BTA-585, and presatovir; RNA polymerase inhibitors, such as lumicitabine and ALS-8112; anti-RSV G protein antibodies, such as anti-G-protein mAb; viral replication inhibitors, such as nitazoxanide.

[0180] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI- 8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-IA, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0181] Non-limiting examples of other active therapeutic agents active against metapneumovirus infections include sialidase modulators such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for the treatment of Metapneumovirus infections, such as EV-046113.

[0182] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infections, including but not limited to mRNA- 1653 and rHMPV-Pa vaccine. 91 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Combination Therapy for the treatment of Picornaviridae

[0183] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infections, preferably, the other active therapeutic agent is active against Picornaviridae virus infections, particularly Enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu, et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase protein such as DAS- 181; a capsid protein VPl inhibitor such as VVX-003 and AZN-001; a viral protease inhibitor such as CW-33; a phosphatidylinositol 4 kinase beta inhibitor such as GSK-480 and GSK-533; anti-EV71 antibody.

[0184] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infections, including but not limited to EV71 vaccines, TAK-021, and EV-D68 adenovector-based vaccine. Combination Therapy for Respiratory Infections

[0185] Many of the infections of the Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds provided herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids

[0186] Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids. Non-limiting examples of corticosteroids that 92 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 may be used in combinations with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone , AZD-7594, ciclesonide; or a pharmaceutically acceptable salts thereof. Anti-inflammatory agents

[0187] Other anti-inflammatory agents working through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. Applying "anti-inflammatory signal transduction modulators" (referred to in this text as AISTM), like phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFKB through IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to switching off inflammation as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-lisobutyl- lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4- difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4- methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-l-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol- 3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281 ); 8-Methoxy-2-trifluoromethyl-quinoline- 5-carboxylic acid (3,5-dichloro-l-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5- ( 4-Fluorophenyl)-2-( 4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB- 203850); 4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3- yn-l-ol (P38 inhibitor RWJ-67657); 4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-ylpropoxy)- quinazolin-4-yl]-amine (Gefitinib, EGFR inhibitor); and 4-(4-Methyl-piperazin-lylmethyl)- N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (Imatinib, EGFR inhibitor). 93 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 02-adrenoreceptor agonist bronchodilators

[0188] Combinations comprising inhaled J32-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds provided herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.

[0189] Combinations of inhaled J32-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively). The combinations comprising these ICS and J32-adrenoreceptor agonist combinations along with the compounds provided herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.

[0190] Other examples of Beta 2 adrenoceptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arfom1oterol, levalbuterol, fenoterol, and TD-5471. Anticholinergics

[0191] For the treatment or prophylaxis of pulmonary broncho-constriction, anticholinergics are of potential use and, therefore, useful as an additional therapeutic agent in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); 1-{ 4-Hydroxy-l-[3,3,3-tris-(4-fluoro-phenyl)propionyl ]-pyrrolidine-2-carbonyl }-pyrrolidine-2-carboxylic acid ( 1-methy 1-pi peridin-4- ylmethyl )-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy ]-8-isopropyl-8-methyl- 8-azonia-bicyclo[3 .2.1 ]octane (Ipratropium-N,N-diethylglycinate ); l-Cyclohexyl-3,4-dihydrolH- isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin); 2- Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid l-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate ); 2-{ 1-[2-(2,3-Dihydro-benzofuran-5-yl )-ethyl ]-pyrrolidin-3-yl }-2,2-diphenylacetamide (Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2- Di ethy lamino-acetoxy )-2-pheny 1-propi ony loxy ]-9-ethy 1-9-methy l-3-oxa-9-azoniatri cycl o[3. 3 .1. 02, 4 ]nonane (Oxitropium-N,N-diethylglycinate); 7-[2-(2-Diethylamino-acetoxy)- 2,2-di-thiophen-2-yl-acetoxy ]-9, 9-dimethyl-3-oxa-9-azonia-tricyclo[3. 3 .1. 02, 4 ]nonane (Tiotropium-N,N-diethylglycinate ); Dimethylamino-acetic acid 2-(3-diisopropylamino-1- phenyl-propyl )-4-methyl-phenyl ester (Tolterodine-N,N-dimethylglycinate); 3-[4,4-Bis-(4- fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium; 1-[ 1-(3-Fluoro-benzyl )-pi peridin-4-yl ]-4, 4-bis-( 4-fluoro-phenyl )-imidazolidin-2-one; 1- 94 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2- Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-l-(3-phenoxy-propyl)-1-azoniabicyclo[ 2.2.2]octane (Aclidinium-N,N-diethylglycinate); or (2-Diethylamino-acetoxy)-dithiophen- 2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl )-piperidin-4-yl ester; revefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencycloquidium bromide. Mucolytic agents

[0192] The compounds provided herein and the compositions provided herein may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds of Formula (I), (Ia), (lb), (le), (Id), (le), (If), (lg), (Ih), (Ij), (Ik), (Im) or (In) may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A nonlimiting example of an expectorant is guaifenesin.

[0193] Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266). Thus, the compounds provided herein may also be combined with nebulized hypertonic saline particularly when the Pneumoviridae virus infection is complicated with bronchiolitis. The combination of the compounds of Formula (I) or Formula (II) with hypertonic saline may also comprise any of the additional agents discussed above. In one embodiment, nebulized about 3% hypertonic saline is used. Combination Therapy for the Treatment of COPD

[0194] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of respiratory exacerbations of COPD, the other active therapeutic agents include other active against COPD. Non-limiting examples of these other active therapeutic agents include anti-ILS antibodies, such as benralizumab, mepolizumab; dipeptidyl peptidase I (DPPI) inhibitors, such as AZD-7986 (INS-1007); DNA gyrase inhibitor / topoisomerase IV inhibitors, such as ciprofloxacin hydrochloride; MDR associated protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors, such as RPL-554; CFTR stimulators, such as ivacaftor, QBW-251; MMP-9 / MMP-12 inhibitors, such as RBx-10017609; Adenosine Al receptor antagonists, such as PBF-680; GATA 3 transcription factor inhibitors, such as SB-010; muscarinic receptor modulator / nicotinic acetylcholine receptor agonists, such as ASM-024; MARCKS protein inhibitors, such as BIO-11006; kit tyrosine kinase / PDGF inhibitors such as masitinib; phosphodiesterase (PDE) 4 inhibitors, such as roflumilast, CHF- 95 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 6001; phosphoinositide-3 kinase delta inhibitors, such as nemiralisib; 5-Lipoxygenase inhibitors, such as TA-270; muscarinic receptor antagonist / beta 2 adrenoceptor agonist, such as batefenterol succinate, AZD-887, ipratropium bromide; TRN-157; elastase inhibitors, such as erdosteine; metalloprotease-12 inhibitors such as FP-025; interleukin 18 ligand inhibitors, such as tadekinig alfa; skeletal muscle troponin activators, such as CK-2127107; p38 MAP kinase inhibitors, such as acumapimod; IL-17 receptor modulators, such as CNTO-6785; CXCR2 chemokine antagonists, such as danirixin; leukocyte elastase inhibitors, such as POL-6014; epoxide hydrolase inhibitors, such as GSK-2256294; HNE inhibitors, such as CHF-6333; VIP agonists, such as aviptadil; phosphoinositide-3 kinase delta / gamma inhibitors, such as RV-1729; complement C3 inhibitors, such as APL-I; and G-protein coupled receptor-44 antagonists, such as AM-211.

[0195] Other non-limiting examples of active therapeutic agents also include budesonide, adipocell, nitric oxide, PUR-1800, YLP-001, LT-4001, azithromycin, gamunex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxofylline, TEV-46017, OligoG-COPD-5 / 20, Stempeucel®, ZP-051, lysine acetylsalicylate.

[0196] In some embodiments, the other active therapeutic agent may be a vaccine that is active against COPD, including but not limited to MV-130 and GSK-2838497A. Combination Therapy for the treatment of Dengue

[0197] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae virus infections, preferably, the other active therapeutic agent is active against Flaviviridae virus infections, particularly dengue infections. Non-limiting examples of these other active therapeutic agents are host cell factor modulators, such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase I inhibitors, such as celgosivir; platelet activating factor receptor (P AFR) antagonists, such as modipafant; cadherin-5 / Factor Ia modulators, such as FX-06; NS4B inhibitors, such as JNJ-8359; viral RNA splicing modulators, such as ABX-202; a NS5 polymerase inhibitor; a NS3 protease inhibitor; and a TLR modulator.

[0198] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue, including but not limited to Tetra Vax-DV, Dengvaxia ®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue fever vaccine, tetravalent DNA vaccine, rDEN2delta30-7169; and DENV-1 PIV. 96 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Combination Therapy for the treatment of Ebola

[0199] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae virus infections, preferably, the other active therapeutic agent is active against Filoviridae virus infections, particularly Marburg virus, Ebola virus and Cueva virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI- 557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5Hpyrrolo[ 3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol ), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3- ( dimethyl amino )propyl ]-3, 9-dimethylquinolino[S, 7-h ]quinolone-1, 7-diamine ), rNAPc2, OS- 2966, brincidofovir, remdesivir; RNA polymerase inhibitors, such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators, such as GMV-006; cadherin-5 / factor la modulators, such as FX-06; and antibodies for the treatment of Ebola, such as REGN-3470-3471-3479 and ZMapp.

[0200] Other non-limiting active therapeutic agents active against Ebola include an alphaglucosidase I inhibitor, a cathepsin B inhibitor, a CD29 antagonist, a dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, an estrogen receptor antagonist, a factor VII antagonist HLA class II antigen modulator, a host cell factor modulator, a Interferon alpha ligand, a neutral alpha glucosidase AB inhibitor, a niemann-Pick CI protein inhibitor, a nucleoprotein inhibitor, a polymerase cofactor VP35 inhibitor, a Serine protease inhibitor, a tissue factor inhibitor, a TLR- 3 agonist, a viral envelope glycoprotein inhibitor, and an Ebola virus entry inhibitors (NPC I inhibitors).

[0201] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+ Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB Vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, Filo Vax vaccine, GOVX-E301, and GOVX-E302.

[0202] The compounds and compositions provided herein may also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with translational processes by forming base-pair 97 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 duplexes with specific RNA sequences. Examples of PMOs include but are not limited to AVI- 7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0203] The compounds and compositions provided herein are also intended for use with general care provided to patients with Filoviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including Vitamin Kand zinc sulfate), anti-inflammatory agents ( such as ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or shigellosis. VII. METHODS OF TREATING VIRAL INFECTIONS

[0204] The present disclosure provides methods for treating a variety of diseases, such as respiratory syncytial virus (RSV), ebola, Zika, West Nile, Dengue, and HCV using compounds of Formula (I), (Ia), (lb), (le), (Id), (le), (If), (lg), (Ih), (Ij), (Ik), (Im) or (In). Paramyxoviridae

[0205] In some embodiments, the present disclosure provides methods for treating a Paramyxoviridae infection, comprising administering to an individual (e.g., a human) infected with Paramyxoviridae virus a therapeutically effective amount a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Paramyxoviridae viruses include, but are not limited to Nipah virus and parainfluenze virus. Pneumoviridae

[0206] In some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Pneumoviridae viruses include, but are not limited to, respiratory snycytial virus, and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is human metapneumovirus infection. 98 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0207] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a human in need thereof, characterized in that the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Pneumoviridae virus infection. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is human metapneumovirus infection.

[0208] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is human metapneumovirus infection.

[0209] In some embodiments, the present disclosure provides methods for treating a RSV infection, comprising administering to an individual (e.g., a human) infected with respiratory syncytial virus a therapeutically effective amount a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Typically, the individual is suffering from a chronic respiratory syncytial viral infection, although it is within the scope of the present disclosure to treat people who are acutely infected with RSV.

[0210] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual ( e.g., a human).

[0211] In some embodiments, the present disclosure provides a method for reducing the viral load associated with RSV infection, wherein the method comprises administering to an individual (e.g., a human) infected with RSV a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to reduce the RSV viral load in the individual.

[0212] As described more fully herein, compounds of the present disclosure can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with RSV. The additional therapeutic agent(s) can be administered to the infected individual (e.g., a human) at the same time as a compound of the present disclosure or before or after administration of a compound of the present disclosure. 99 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0213] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a RSV infection is provided. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (Ia), (lb), (le), (Id), (le), (If), (lg), (Ih), (Ij), (Ik), (Im) or (In)), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a RSV infection is provided.

[0214] As described more fully herein, compounds of the present disclosure can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with RSV. Further, in some embodiments, when used to treat or prevent RSV, a compound of the present disclosure may be administered with one or more (e.g., one, two, three, four or more) additional therapeutic agent(s) selected from the group consisting of RSV combination drugs, RSV vaccines, RSV DNA polymerase inhibitors, immunomodulators tolllike receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, respiratory syncytial surface antigen inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, RSV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA)and ddRNAi endonuclease modulators, ribonucelotide reductase inhibitors, RSV E antigen inhibitors, covalently closed circular DNA ( cccDNA) inhibitors, famesoid X receptor agonists, RSV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PBK) inhibitors, indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-Ll inhibitors, recombinant thymosin alpha-I, bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, RSV replication inhibitors, arginase inhibitors, and other RSV drugs. Picornaviridae

[0215] In some embodiments, the present disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Picornaviridae viruses are eneteroviruses causing a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome (human rhinovirus infection), a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-footmouth syndrome, pediatric and adult pancreatitis and serious myocarditis. In some embodiments, the Picornaviridae virus infection is human rhinovirus infection. 100 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0216] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Picornaviridae virus infection in a human in need thereof, characterized in that the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Picornaviridae virus infection. In some embodiments, the Picornaviridae virus infection is human rhinovirus infection.

[0217] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Picornaviridae virus infection in a human in need thereof. In some embodiments, the Picornaviridae virus infection is human rhinovirus infection. Flaviviridae

[0218] In some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Representative Flaviviridae viruses include, but are not limited to, dengue, Yellow fever, West Nile, Zika, Japanese encephalitis virus, and Hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow fever virus infection. In some embodiments, theFlaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the P1aviviridae virus infection is a Japanese ensephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0219] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Flaviviridae virus infection in a human in need thereof, characterized in that the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Flaviviridae virus infection. In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is 101 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0220] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection. Filoviridae

[0221] In some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Representative Filoviridae viruses include, but are not limited to, Ebola and Marburg. In some embodiments, the Filoviridae virus infection is an Ebola virus infection.

[0222] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Filoviridae virus infection in a human in need thereof, characterized in that the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Filoviridae virus infection. In some embodiments, the Filoviridae virus infection is an Ebola virus infection.

[0223] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. 102 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 VIII. METHODS OF TREATMENT OR PROPHYLAXIS OF AN EXACERBATION OF A RE SPIRA TORY CONDITION BY A VIRUS INFECTION

[0224] The compounds of Formula (II), (Ila), (lib), (Ile), (Ild), (Ile), (IIf), (Ilg), (Ilh), (Iii), (Ilj), (Ilk), (Ilm) or (Iln) can also be used for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof.

[0225] In some embodiments, the present disclosure provides a method for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

[0226] In some embodiments, the present disclosure provides a method for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enteroviruses or metapneumovirus.

[0227] In some embodiments, the present disclosure provides a method for manufacturing a medicament for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

[0228] In some embodiments, the present disclosure provides a method for manufacturing a medicament for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, characterized in that the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enteroviruses or metapneumovirus.

[0229] In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis in a human of an exacerbation of a respiratory 103 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 condition by a viral infection, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

[0230] In some embodiments, the present disclosure provides use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis in a human of an exacerbation of a respiratory condition by a viral infection, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enteroviruses or metapneumovirus.

[0231] In some embodiments, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

[0232] In some embodiments, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enteroviruses or metapneumovirus. IX. EXAMPLES

[0233] Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 2 contains a list of many of these abbreviations and acronyms. Table 2. List of abbreviations and acronyms. Abbreviation Meaning Ac acetate ACN acetoni tril e AIBN azobi si sobutyroni tril e Bn benzyl Bu butyl 104 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Bz benzoyl BzCl benzoyl chloride CDI 1, l '-carbonyldiimidazole DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5 .4.0]undec-7-ene DCE 1,2-di chloroethane DCM dichloromethane DIC N,N' -diisopropylcarbodiimide DIPEA N ,N-dii sopropy 1 ethy lamine DMAP 4-dimethylamiopyridine DMDO dimethydioxirane DMSO dimethylsulfoxide DMF dimethylformamide DMTrCl 4,4' -dimethoxytritylchloride DMTr 4,4'-dimethoxytrityl EDCI N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride Et ethyl EtOAc ethyl acetate Imid imidazole KOtBu potassium tert-butoxide LC liquid chromatography MCPBA meta-chloroperbenzoic acid Me methyl m / z mass to charge ratio MS orms mass spectrum NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone Ph phenyl Ph3P triphenylphosphine PMB para-methoxybenzyl PMBCl para-methoxybenzyl chloride PhOC(S)Cl phenylchlorothionoformate (PhO)3PMel methyltriphenoxyphosphonium iodide Pyr pyridine 105 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 RT room temperature SFC supercritical fluid chromatography TBAF tetrabutylammonium flouride TBME tert-butyl methyl ether TBS tert-butyldimethylsilyl TBSCl tert-Butyldimethylsilyl chloride TMSN3 trimethylsilyl azide TEA triethylamine TES triethylsilane TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl TMSCl trimethylsilyl chloride tR retention time Ts 4-tol uenesulfony 1 TsOH tosylic acid 8 parts per million referenced to residual non-deuterated solvent peak

[0234] Compounds can be subjected to preparatory HPLC (Phenomenex Gemini lOu Cl8 I lOA AXIA 250 x 21.2 mm column, 30-70% acetonitrile / water gradient with 0.1% TFA). Some compounds are afforded as the TF A salt following this preparatory HPLC process.

[0235] Compound structures using a "P3 " or "Pb" designation refers to the (R)- or (S)-isomer where the specific stereochemistry at that position is unassigned. A. Intermediates Intermediate 1. (2R,3S,4R,5S)-5-( 4-aminopyrrolo[2,1-fl [1,2,4]triazin-7-yl}-3,4-dihydroxy- 2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile 106 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0236] The product can be prepared according WO2015 / 069939. For example, pages 43-54 of WO2015 / 069939 provide a process for preparing the compound, identified as compound 1 in WO2015 / 069939. Intermediate 2. tert-butyl (7-((3aS,4S,6R,6aS)-6-cyano-6-(hydroxymethyl}-2,2- dimethyltetrahydrofuro [3,4-d] [1,3Jdioxol-4-yl}pyrrolo [2,1-fl [1,2,4 J triazin-4-yl}carbamate Boe, NH

[0237] Compound 14j from WO2015 / 069939 (21.79 g, 39.93 mmol) in THF (400 mL) was cooled in an ice bath. TBAF 1.0 Min THF (50.0 mL, 50.0 mmol) was added in one portion. The mixture was allowed to come to ambient temperature and stirred for about 30 min. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water and the organics were removed under reduced pressure. The crude was partitioned between EtOAc and Water. The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over sodium sulfate. The solids were filtered off and the solvent removed under reduced pressure. The crude was purified by silica gel chromatography 330 g column 30-100% EtOAc in Hexanes to afford the product. MS mlz = 431.74 [M+l]. 1HNMR (400 MHz, DMSO-d6) 8 10.53 (s, lH), 8.25 (s, lH), 7.21 (s, lH), 7.03 (d, J = 4.6 Hz, lH), 5.77 (t, J = 6.1 Hz, IH), 5.59 (d, J = 4.0 Hz, IH), 5.27 (dd, J = 6.7, 4.1 Hz, 1H), 4.94 (d, J = 6.7 Hz, lH), 3.66 (dd, J = 6.1, 2.4 Hz, 2H), 1.62 (s, 3H), 1.50 (s, 9H), 1.33 (s, 3H). Intermediate 3. (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-fl [1,2,4]triazin-7-yl}-4-(((tertbutyldimethylsilyl) oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3Jdioxole-4- carbonitrile 107 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0238] The product can be prepared according to WO2015 / 069939. For example, pages 127- 138 of WO2015 / 069939 provide a process for preparing the compound, identified as compound 14k in WO2015 / 069939. Intermediate 4. (3aS,4R,6S,6aS)-6-( 4-aminopyrrolo[2,1-f1 [1,2,4]triazin-7-yl}-4- (hydroxymethyl}-222-dimethyltetrahydrofuro[3,4-d] [l,3] dioxole-4-carbonitrile ox°

[0239] Took up Intermediate 3 (8.41 g, 18.87 mmol) in THF (100 mL). Added TBAF 1.0 Min THF (28.31 mL, 28.31 mmol) in one portion at ambient temperature. Allowed to stir at ambient temperature for 10 min. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water and the organics were removed under reduced pressure. The crude was partitioned between EtOAc and Water. The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over sodium sulfate. The solids were filtered off and the solvent removed under reduced pressure. The crude was purified by silica gel chromatography 120 g column 0-10% CH3OH in CH2Ch to afford the product. LC / MS: tR = 0.76 min, MS mlz = 332.14 [M+ 1]; LC system: Thermo Accela 1250 UHPLC. MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 l00A, 50 x 3.00 mm. Solvents: Acetonitrile with 0.1 % formic acid, Water with 0.1 % formic acid. Gradient: 0 min-2.4 min 2- 100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8 mL / min. 1HNMR (400 MHz, DMSO-d6) 8 7.87-7.80 (m, 3H), 6.85 (d, J = 4.5Hz, lH), 6.82 (d, J = 4.5Hz, lH), 5.74 (t, J = 5.8 Hz, lH), 5.52 (d, J = 4.2 Hz, lH), 5.24 (dd, J= 6.8, 4.2 Hz, lH), 4.92 (d, J= 6.8 Hz, lH), 3.65 (dd, J= 6.1, 1.7 Hz, 2H), 1.61 (s, 3H), 1.33 (s, 3H). Intermediate 5. (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f1[1,2,4]triazin-7-yl)-2-(((tertbutyldimethylsilyl) oxy)methyl)-324-dihydroxytetrahydrofuran-2-carbonitrile TBDMSO HO OH 108 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0240] Dissolved Intermediate 1 (2 g, 6.18 mmol) in 50 mL DMF, to the solution were added tert-butylchlorodimethylsilane (1 g, 7 mmol) and imidazole (1.26 g, 19 mmol). The resulting mixture was stirred at RT for 2 hand the reaction was diluted with EtOAc, washed with NH4Cl solution, the organic solvent was evaporated and the residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in hexane to afford the product. LCMS: MS mlz = 406.36 [M+ 1], tR = 1.45 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min- 3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.25 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex Cl8, 2.6u ll0A, 100 x 4.6 mm; Solvents: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 - 98% B with 8.5 min gradient at 1.5 mL / min. Intermediate 6. (2R,3S,4S,5S)-5-( 4-aminopyrrolo[2,1-f1 [1,2,4Jtriazin-7-yl}-2-(((tertbutyldimethylsilyl) oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2-methylpropanoate) TBDMSO

[0241] Dissolved Intermediate 5 (1.8 g, 4.44 mmol) in 15 mL THF, to the solution were added isobutyric anhydride (1.54 g, 9.8 mmol) and DMAP (179 mg, 1.45 mmol). The resulting mixture was stirred at RT for 5 min and the reaction was quenched with MeOH and then diluted with EtOAc, washed with brine, the organic solvent was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in hexane to afford the product. LCMS: MS mlz = 546.16 [M+l], tR = 1.92 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C 18 1 00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.88 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex C18, 2.6u 110A, 100 x 4.6 mm; Solvents: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 - 98% B with 8.5 min gradient at 1.5 mL / min. 109 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 7. (2R,3S,4S,5S)-5-( 4-aminopyrrolo[2,1-fl [1,2,4]triazin-7-yl}-2-cyano-2- (hydroxymethyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)

[0242] Dissolved Intermediate 6 (3.2 g, 5.86 mmol) in 25 mL THF in a 100 mL plastic bottle, to the solution was added HF-pyridine (10 g, 0.35 mmol). The resulting mixture was stirred at RT for 3 hand the reaction was quenched with NaHCO3 and then diluted with EtOAc, washed with brine, the organic solvent was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in hexane to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) o 7.90 (s, lH), 6.83 - 6.74 (m, 2H), 6.33 (s, 2H), 5.84 - 5.74 (m, 2H), 5.62 (d, J = 5.4 Hz, lH), 4.31 (dd, J = 8.4, 5.2 Hz, IH), 3.94 (dd, J = 12.2, 5.0 Hz, IH), 3.87 (dd, J = 12.2, 8.4 Hz, IH), 2.70 (hept, J = 7.0 Hz, IH), 2.56 (hept, J = 7.0 Hz, IH), 1.28-1.17 (m, 6H), 1.12 (dd, J = 15.1, 7.0 Hz, 6H). LCMS: MS mlz = 432.24 [M+l], tR = 1.47 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min- 3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 2.74 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex Cl 8, 2.6u ll0A, 100 x 4.6 mm; Solvents: A: Water with 0.1 % TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 - 98% B with 8.5 min gradient at 1.5 mL / min. Intermediate 8. cyclopentyl L-alaninate HCI salt

[0243] To a mixture of (tert-butoxycarbonyl)-L-alanine (3.95 g, 20.9 mmol), cyclopentanol (1.5 g, 17.4 mmol) and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (3.5 g, 22.6 mmol) in acetonitrile (100 mL) was added 4-(Dimethylamino)pyridine (DMAP, 3.2 g, 26.1 mmol). Then the mixture was stirred at room temperature for 2 h, and then the reaction mixture was diluted with EtOAc, washed with brine, dried organic solvent over sodium sulfate, and then concentrated in vacuum. The obtained residue was purified by silica gel chromatography eluting 110 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 with 0-100% ethyl acetate in hexanes to afford intermediate which was dissolved in 10 mL DCM, to the solution was added 4 N HCl in dioxane (3 mL). The reaction mixture was stirred at RT for 30 min, the solvent was then evaporated and the residue was dried over high vacuum to afford crude product. 1HNMR (400 MHz, Chloroform-cl) 8 8.75 8.42 (m, 2H), 5.20 (tt, J = 5.6, 2.5 Hz, lH), 4.22 - 4.07 (m, lH), 1.87 - 1.58 (m, 8H), 1.54 (dd, J = 12.6, 7.2 Hz, 3H). Intermediate 9. cyclopropyl L-alaninate HCI salt

[0244] To a mixture of (tert-butoxycarbonyl)-L-alanine (5.86 g, 31 mmol), cyclopropanol (1.5 g, 25.8 mmol) and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (5.2 g, 33.6 mmol) in acetonitrile (100 mL) was added 4-(Dimethylamino)pyridine (DMAP, 4.7 g, 38.7 mmol). Then the mixture was stirred at room temperature for 2 h, and then the reaction mixture was diluted with EtOAc, washed with brine, dried organic solvent over sodium sulfate, and then concentrated in vacuum. The obtained residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford intermediate which was dissolved in 10 mL DCM, to the solution was added 4 N HCl in dioxane (3 mL). The reaction mixture was stirred at RT for 30 min, the solvent was then evaporated and the residue was dried over high vacuum to afford crude product. 1HNMR (400 MHz, Chloroform-cl) 8 8.68 (s, 2H), 4.22 (tt, J = 6.3, 3.2 Hz, lH), 1.68 (d, J = 7.3 Hz, 3H), 1.42 (s, lH), 0.86- 0.69 (m, 2H), 0.70 (dd, J = 7.1, 3.6 Hz, 2H). Intermediate 10. formacetal 1 and 2: 1,1-Dimethoxy-N,N-dimethylmethanamine and 1- (dimethoxymethyl)-4-methylpiperazine '- / formacetal 1: R = ~ I N formacetal 2: R = ( ) N "'1"'

[0245] A mixture of N-methylpiperazine (1.5 mL, 15.93 mmol) and DMF-dimethylacetal (1 mL, 7.50 mmol) was heated in a sealed tube at 100 °C for 3 days, concentrated under high vacuum at 60 °C to remove excess N-methyl piperazine, and then used in next reaction. Based on the next reaction's product compositions, the product was a mixture of formacetal 1 and formacetal 2 with ca 1 :2 ratio. 111 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 11. (S)-cyclohexyl 2-aminopropanoate hydrochloride QO~NH,·HCI

[0246] To a mixture ofL-alanine (5 g, 56.12 mmol) and cyclohexanol (56 g, 561 mmol) was added TMSCl (20 mL ). The resulting mixture was stirred at about 70 °C for about 15 h and concentrated in vacuo at about 80 °C, co-evaporated with toluene, dissolved in hexanes, and stirred at about room temperature, during which solid was precipitated. The solid was collected by filtration and the filter cake was washed with 5% EtOAc in hexanes several times, and dried under high vacuum for about 15 h to give the product. 1H NMR (400 MHz, Chloroform-cl) 8 8.76 (s, 3H), 4.85 (tt, J = 8.7, 3.8 Hz, lH), 4.17 (p, J = 6.5 Hz, lH), 1.84 (dd, J = 9.9, 5.5 Hz, 2H), 1.70 (d, J= 7.3 Hz, SH), 1.57 - 1.42 (m, 3H), 1.32 (ddddd, J= 20.3, 12.8, 9.9, 6.4, 3.1 Hz, 3H). Intermediate 12. (S)-2-ethylbutyl 2-{(tert-butoxycarbonyl)amino)-4-methylpentanoate

[0247] Took up (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid (1.09 g, 4.71 mmol) in acetonitrile (10 mL) and added 2-ethyl-1-butanol (2.88 mL, 23.56 mmol) followed by EDCI (878 mg, 5.66 mmol) and DMAP (863 mg, 7.07 mmol) in one portion. Allowed to stir at room temperature overnight. Concentrated and diluted with CH2Ch. Purified by silica gel chromatography 0-40% EtOAc / Hex to afford the product. 1HNMR (400 MHz, DMSO-d6) 8 7.19 (d, J = 8.7 Hz, lH), 4.00-3.84 (m, 3H), 1.67-1.22 (m, 17H), 0.91-0.80 (m, 12H). Intermediate 13. (S)-2-ethylbutyl 2-amino-4-methylpentanoate hydrochloride HCI

[0248] Took up (S)-2-ethylbutyl 2-((tert-butoxycarbonyl)amino)-4-methylpentanoate in CH2Ch (10 mL) and 4 N HCl in dioxane (10 mL, 40 mmol). Stirred at ambient temperature for 1 h. Concentrated under reduced pressure and co-evaporated with hexanes. Placed under high vacuum for 1 hand the product was used as is without purification for the next step. 1H NMR 112 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (400 MHz, DMSO-d6) 8 8.43 (s, 3H), 4.08 (d, J = 5.6 Hz, 2H), 3.92 (m, lH), 1.69 (m, lH), 1.61 (m, 2H), 1.47 (m, lH), 1.34 (m, 4H), 0.83 (m, 12H). Intermediate 14. 2-(Benzyloxy)-2-methylpropyl ((4-nitrophenoxy){phenoxy)phosphoryl}-Lalaninate 0 BnrO~NH / l> 0 Cl

[0249] To a mixture ofBoc-L-alanine (1.26 g, 6.66 mmol), 2-benzyloxy-2-methylpropanol (1.0 g, 5.55 mmol), and EDCI (1.12 g, 7.21 mmol) in acetonitrile (20 mL) was added DMAP (2.04 g, 8.32 mmol). Then the mixture was stirred at room temperature for 2 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc Oto 60% in hexanes) to give a BocL- alanine propyl ester, which was dissolved in DCM (10 mL) and 4 N HCl in dioxane (5.5 mL, 22.19 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h, concentrated in vacuo, re-dissolved in ACN (10 mL), lyophilized overnight to afford the product. 1H NMR (400 MHz, Chloroform-d) 8 8.82 (s, 3H), 7.42-7.07 (m, SH), 4.44 (s, 2H), 4.24 (m, 2H), 4.08 (d, J= 11.2 Hz, lH), 1.70 (d, J= 7.0 Hz, 3H), 1.28 (d, J= 2.4 Hz, 6H). LCMS mlz = 251.97 (freebase M +H), 1R = 0.85 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 IO0A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min- 2.00 min 2% ACN at 1800 μL / min.

[0250] 2-(Benzyloxy )-2-methyl propyl ( ( 4-nitrophenoxy )(phenoxy )phosphoryl)-Lalaninate. To a solution of 2-(Benzyloxy)-2-methylpropyl L-alaninate HCl salt (832 mg, 2.89 mmol) in DCM (20 mL) was added phenyl phosphorodichloridate (0.43 mL, 2.89 mmol) in one portion at -78 °C and triethylamine (0.80 mL, 5.76 mmol) was added dropwise over 5 min at-78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and p-nitrophenol (402 mg, 2.89 mmol) was added in one portion and triethylamine (0.40 mL, 2.89 mmol) added over 5 min at -78 °C. The resulting mixture was stirred for 50 min after 113 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 removal of dry ice bath, then diluted with DCM, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc Oto 60% in hexanes) to give the product. 1HNMR (400 MHz, Chloroform-cl) o 8.23- 8.13 (m, 2H), 7.41- 7.27 (m, 3H), 7.28 7.14 (m, 4H), 4.45 (m, 2H), 4.27 4.15 (m, 2H), 4.07 (m, lH), 3.89 (m, lH), 1.41 (m, 3H), 1.27 (m, 6H). 31P NMR (162 MHz, Chloroform-cl) o -3.10, -3.18. LCMS mlz = 528.78 (M+H), tR = 1.70 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 15. cyclobutylmethyl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate Q~ oO-P-0 [j'o~~Ho N02

[0251] L-Alanine cyclobutylmethyl ester-HCl (1.2 g, 7.16 mmol) was suspended in methylene chloride (10 mL), cooled to -78 °C, and phenyl dichlorophosphate (1.07 mL, 7.16 mmol) added quickly. Triethylamine (2.0 mL, 14.32 mmol) was added over 60 min at -78 °C and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and 4- nitrophenol (996 mg, 7.16 mmol) was added in one portion. Then triethylamine (1.0 mL, 7.16 mmol) was added over 60 min. Then the mixture was stirred for 3 hat room temperature, filtered, the filtrate concentrated to one third volume, and filtered again. The filtrate was concentrated and the residue purified by silica gel column chromatography (EtOAc Oto 35% in hexanes) to give the product. 1H NMR (400 MHz, chloroform-d) o 8.28 - 8.16 (m, 2H), 7.45 - 7.32 (m, 4H), 7.29 7.16 (m, 3H), 4.23 4.01 (m, 3H), 3.95 3.83 (m, lH), 2.59 (m, lH), 2.03 (m, 2H), 1.98 - 1.80 (m, 2H), 1.73 (m, 2H), 1.42 (d, J= 3.2 Hz, 1.5H), 1.40 (d, J= 3.3 Hz, 1.5H). 31P NMR (162 MHz, chloroform-d) o -3.06, -3.11. 114 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 16. 2-ethylbutyl ((benzyloxy}(4-nitrophenoxy)phosphoryl}-L-alaninate

[0252] 4-Nitrophenyl phosphorodichloridate (2.00 g, 7.81 mmol) and triethylamine (2.18 mL, 15.6 mmol) were sequentially added to a suspension of 2-ethylbutyl L-alaninate hydrochloride (1.091 g, 18.9 mmol) in dichloromethane (23 mL) at 0 °C under an argon atmosphere. After 1 h, benzyl alcohol (0.810 mL, 7.81 mmol) and triethylamine (1.09 mL, 7.81 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to rt. After 1 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated an aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1 H NMR (400 MHz, chloroform-d1) o 8.30- 8.07 (m, 2H), 7.42-7.28 (m, 7H), 5.18 - 5.09 (m, 2H), 4.70 (s, lH), 4.08- 3.95 (m, 2H), 3.68 (q, J= 9.4 Hz, lH), 1.55- 1.18 (m, 8H), 0.87 (t, J= 7.4 Hz, 6H). 31P NMR (162 MHz, chloroform-d1) o 2.32 (s), 2.28 (s). LCMS: MS mlz = 463.00 [M-1], tR = 1.56 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 IO0A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. Intermediate 17. 2-ethylbutyl ((S)-(4-nitrophenoxy}(phenoxy}(phosphoryl}-L-alaninate

[0253] Prepared as described in WO 2016 / 069825. 115 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 18. isopropyl ((S)-( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate

[0254] Prepared as described in Cho et al., J. Med. Chem. 2014, 57, 1812-1825. Intermediate 19. ethyl {(S)-( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate

[0255] Prepared as described in US20120009147Al. Intermediate 20. Cyclopropylmethyl ((4-nitrophenoxy}(phenoxy)phosphoryl)-L-alaninate Q o II oO-P-0 vo~~Ho N02

[0256] L-Alanine cyclopropylmethyl ester-HCI (1.0 g, 5.57 mmol) was suspended in methylene chloride (10 mL), cooled to -78 °C, and phenyl dichlorophosphate (0.83 mL, 5.57 mmol) was added quickly. Triethylamine (1.54 mL, 11.13 mmol) in DCM (1.5 mL) was added over 30 min at -78 °C and stirred 30 min. 4-Nitrophenol (774 mg, 5.57 mmol) was added in one portion at -78 °C. Then triethylamine (0. 77 mL, 7.16 mmol) in DCM (2 mL) was added over 30 min. Then the mixture was stirred for 30 min at the same temperature, washed with water, saturated Na2CO3 solution, and brine, and dried with sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc Oto 20% in hexanes) to give the product. 1HNMR (400 MHz, chloroform-d) o 8.22 (m, 2H), 7.58-7.29 (m, 4H), 7.32- 7.14 (m, 3H), 4.25 -4.07 (m, lH), 4.07 -3.80 (m, 3H), 1.44 (d, J = 2.9 Hz, I.SH), 1.42 (d, J= 2.9 Hz, I .SH), 1.26 - 1.01 (m, lH), 0.66 - 0.49 (m, 2H), 0.42 - 0.15 (m, 2H). 31P NMR (162 MHz, chloroform-d) o -3.07, -3.11. MS mlz = 420.97. 116 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 21. 2-(((4-nitrophenoxy){phenoxy)phosphoryl)amino)ethyl pivalate r0 0 ~NH2·HCI

[0257] 2-aminoethyl pivalate hydrochloride. Pivaloyl chloride (3.82mL,31.0 mmol) was added to a solution oftert-butyl (2-hydroxyethyl)carbamate (4.8 mL, 31.0 mmol) and diisopropylethylamine ( 5.4 mL, 31.0 mmoL) in dichloromethane (150 mL) at RT. After 4 h, the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (150 mL) and brine (150 mL), was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The crude colorless oil was taken up into a solution of hydrochloric acid in dioxane ( 4 M, 50 mL), and was stirred at RT and white solids slowly precipitated from the solution. After 3 h, The solids were collected by vacuum filtration to afford the product. 1H NMR ( 400 MHz, CD3OD) o 4.32 - 4.25 (m, 2H), 3.26 (t, J = 5.4 Hz, 2H), 1.23 (s, 9H). Q II o O-P-0 rO~~Ho N02

[0258] 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)ethyl pivalate. To a solution of 2- aminoethyl pivalate hydrochloride (0.861 g, 4.74 mmol) and phenyl dichlorophosphate (0.705 mL, 4.74 mmol) in dichloromethane (23 mL) was added triethylamine (1.2 mL, 9.4 mmol) at 0 °C under and argon atmosphere. The resulting mixture was allowed to warm to RT and was stirred for 1.5 h. 4-Nitrophenol (660 mg, 4.74 mmol) and triethylamine (0.66 mL, 4.7 mmol) were then added. After I h, the reaction mixture was diluted with dichloromethane (50 mL) and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (40 g SiO2 CombiflashHP Gold Column, 0-100% ethyl acetate / hexanes) to afford the product. 1HNMR (400 MHz, CDCh) o 8.23 (d, J = 9.2 Hz, 2H), 7.47 - 7.31 (m, 4H), 7.29 - 7.16 (m, 3H), 4.18 - 4.06 (m, 2H), 3.45 - 3.31 (m, 2H), 1.17 (s, 9H). 31P NMR (162 MHz, DMSO-d6) o -1.48 (s). MS mlz = 422.95 [M+l]. 117 CA 03171497 2022-08-16 WO 2021 / 168038 Intermediate 22. (2S)-tetrahydro-2H-pyran-4-yl 2-((( 4- nitrophenoxy)(phenoxy)phosphoryl)amino )propanoate 0o\NH2·HCI PCT / 0S2021 / 018458

[0259] (S)-tetrahydro-2H-pyran-4-yl 2-aminopropanoate hydrochloride. To a mixture ofLalanine (500 mg, 5.61 mmol) and tetrahydro-2H-pyran-4-ol (5 g, 49.0 mmol) was added TMSCl (2 mL). The resulting mixture was stirred at 70 °C for 15 hand concentrated in vacuo and the resulting solid was tritulated with 5% EtOAc in hexanes, filtered, and washed with 5% EtOAc in hexanes several times, and dried under high vacuum for 15 h to give the product which was used in next reaction without any characterization.

[0260] (2S)-tetrahydro-2H-pyran-4-yl 2-((( 4- nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate. (S)-tetrahydro-2H-pyran-4-yl 2- aminopropanoate hydrochloride (1.33 g, 6.34 mmol) was dissolved in methylene chloride (15 mL), cooled to-78 °C, and phenyl dichlorophosphate (1.137 mL, 7.61 mmol) added quickly. Triethylamine (2.2 mL, 15.2 mmol) was added over 30 min at -78 °C and the resulting mixture was stirred for 30 min at -78 °C. Then 4-nitrophenol (882 mg, 6.34 mmol) was added in one portion and triethylamine (1. 1 mL, 7 .61 mmol) was added over 30 min at -78 °C. The mixture was stirred for 30 min at -78 °C, washed with water twice and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc Oto 70% in hexanes) to give the product. 1H NMR (400 MHz, Chloroform-d) 8 8.22 (m, 2H), 7.49- 7.06 (m, 7H), 4.95 (m, lH), 4.14 (m, lH), 4.07 - 3.80 (m, 3H), 3.52 (m, 2H), 1.95 - 1.81 (m, 2H), 1.64 m, 2H), 1.42 (m, 3H). 31P NMR (162 MHz, Chloroform-d) 8 -3.09, -3.13. MS mlz = 45 l (M+Ht. 118 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 23. (S)-1-methylpyrrolidin-3-yl (( 4-nitrophenoxy){phenoxy)phosphoryl}-Lalaninate -N / "'-i O H V·,,o~N,Boc

[0261] (S)-1-methylpyrrolidin-3-yl (tert-butoxycarbonyl)-L-alaninate. Boc-L-Alanine (2.1 g, 11 rnrnol) and (R)-3-hydroxy-l-rnethylpyrrolidine (I.I mL, 10 rnrnol) were dissolved in anhydrous THF (20 rnL). Triphenylphosphine (3.4 g, 13 rnrnol) was added in one portion. Diisopropyl azodicarboxylate (2.4 mL, 12 mmol) was added dropwise. Reaction was stirred for 2 hrs. More diisopropyl azodicarboxylate (240 uL, 1.2 mrnol) was added dropwise, and the reaction was stirred for 16 hrs. Reaction was diluted with EtOAc (10 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). Organic was then extracted with 5% aqueous citric acid solution (30 mL). Citric acid extract was washed with EtOAc (2x5 mL). Citric acid portion was basified with 1 N aqueous NaOH solution to give pH of 9 and extracted with EtOAc (2x10 mL). Organic extracts were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the product. 1H NMR ( 400 MHz, chloroform-d) 8 5.24 (rn, IH), 5.01 (m, IH), 4.27 (m, IH), 2.88 - 2.69 (rn, 2H), 2.64 (m, IH), 2.37 (s, 3H), 2.29 (m, IH), 1.96 1.80 (rn, IH), 1.44 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H). N02 Q~P 0 00-P-O -N .,,0~NH

[0262] (S)-1-methylpyrrolidin-3-yl ( ( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. (S)-1-methylpyrrolidin-3-yl (tert-butoxycarbonyl)-L-alaninate (545 mg, 2 mmol) was mixed with 10 rnL of 4 N HCl in dioxane and stirred for 1 hr. Reaction was concentrated under reduced pressure to give foam which was then mixed with 20 mL anhydrous DCM and stirred under atmospheric nitrogen in an ice bath. Phenyl dichlorophosphate (298 uL, 2 mrnol) was added to reaction in one portion. Reaction was stirred for 15 mins. Triethylamine (837 uL, 6 mmol) was added to the reaction dropwise. Reaction was stirred for 1 hr. Triethylamine (279 μL, 2 mmol) was added to the reaction dropwise and then stirred for 30 mins. p-Nitrophenol (250 mg, 1.8 mmol) was added in one portion. Reaction mixture was stirred for 16 hrs. Reaction was diluted with DCM (20 mL) and washed with water (5 x 20 mL). Organic was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-10% 119 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 methanol / DCM). Fractions were combined and concentrated under reduced pressure to give the product. 1HNMR (400 MHz, chloroform-d) 8 8.28-8.15 (m, 2H), 7.46-7.28 (m, 4H), 7.28- 7.13 (m, 3H), 5.17 (m, lH), 4.21 - 4.04 (m, lH), 4.01 - 3.85 (m, lH), 2.81 (m, lH), 2.70-2.55 (m, 2H), 2.35 (s, 3H), 2.33 2.21 (m, 2H), 1.84 1.70 (m, lH), 1.39 (m, 3H). 31P NMR (162 MHz, chloroform-d) 8-3.16, -3.21. LCMS: MS mlz = 450.3 [M+l]; 448.1 [M-1], tR = 1.15 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; Column: Phenomenex Kinetex 2.6μ C18 l00A, 50 x 3 mm; Solvents: A: Water with 0.1 % acetic acid, B: Acetonitrile with 0.1 % acetic acid; Gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min- 2.2 min 100-5% B at 2 mL / min. HPLC: tR = 2.61 min; HPLC system: Agilent 1100 series; Column: Phenomenex Gemini 5μ C18 110A, 50 x 4.6 mm; Solvent: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2-98% Bin 5 min at 2 mL / min. Intermediate 24. (R)-1-methylpyrrolidin-3-yl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-Lalaninate N_r-., O H - ~o~N'Boc

[0263] (R)-1-methylpyrrolidin-3-yl (tert-butoxycarbonyl)-L-alaninate. Boc-L-Alanine (5.2 g, 27.5 mmol) and (R)-3-hydroxy-l-methylpyrrolidine (2.74 mL, 25 mmol) were dissolved in anhydrous THF (25 mL). N,N'- Diisopropylcarbodiimide (4.67 mL, 30 mmol) was added dropwise. Reaction was stirred for 2 hrs. More N,N'- diisopropylcarbodiimide (467 uL, 3 mmol) was added dropwise, and the reaction was stirred for 2 hrs. More N,N'- diisopropyl carbodiimide (467 uL, 3 mmol) was added dropwise, and the reaction was stirred for 16 hrs.

[0264] Reaction was diluted with EtOAc (25 mL) and stirred for 10 mins. Solid was filtered off and washed with small amount of EtOAc. Filtrate was washed with saturated aqueous sodium bicarbonate solution (3x10 mL). Organic was then extracted with 5% aqueous citric acid solution (50 mL). Citric acid extract was washed with EtOAc (5 mL). Citric acid portion was basified with 1 N aqueous NaOH solution to give pH of 9 and then extracted with EtOAc (3x15 mL). Organic extracts were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the product. 1H NMR (400 MHz, chloroform-d) o 5.28 - 5.18 (m, lH), 5.02 (m, lH), 4.28 (m, lH), 2.84- 2.75 (m, lH), 2.69 (d, J= 4.2 Hz, 2H), 2.36 (s, 3H), 2.34- 2.22 (m, 2H), 1.87- 1.76 (m, lH), 1.44 (s, 9H), 1.37 (d, J= 7.2 Hz, 3H). 120 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 N02 Q~P !\ 00-P-O -N~0~NH

[0265] (R)-1-methylpyrrolidin-3-yl ( ( 4-nitrophenoxy)(phenoxy )phosphoryl)-L-alaninate. (R)-1-methylpyrrolidin-3-yl (tert-butoxycarbonyl)-L-alaninate (3.9 g, 14.3 mmol) was mixed with 30 mL of 4 N HCl in dioxane and stirred for 3 hrs. Reaction was concentrated under reduced pressure to give foam which was then mixed with 30 mL anhydrous DCM and stirred under atmospheric nitrogen in an ice bath. Phenyl dichlorophosphate (2.34 mL, 15.75 mmol) was added to reaction in one portion. Reaction was stirred for 15 mins. Triethylamine (4.4 mL, 31.5 mmol) was mixed with anhydrous DCM (5 mL) and added to the reaction dropwise. Reaction was stirred for 1 hr. Triethylamine (2.2 mL, 15.75 mmol) was mixed with anhydrous DCM (3 mL) and added to the reaction dropwise. Reaction was stirred for 15 mins. pNitrophenol (1.8 g, 12.87 mmol) was added in one portion. Reaction mixture was stirred for 2 hrs.

[0266] Reaction was diluted with DCM (20 mL) and washed with aqueous sodium bicarbonate solution (3x20 mL). Organic was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (40 g SiO2 Combiflash HP Gold Column, 0-10% methanol / DCM). Fractions were combined and concentrated under reduced pressure to give the product. 1H NMR ( 400 MHz, chloroform-d) 8 8.29 - 8.15 (m, 2H), 7.48 - 7.29 (m, 4H), 7.29 - 7.13 (m, 3H), 5.20 (m, lH), 4.21 4.07 (m, lH), 3.99 (m, lH), 2.86 (m, lH), 2.70 (m, lH), 2.63 (m, lH), 2.37 (m, 3H), 2.35 -2.21 (m, 2H), 1.86 - 1.73 (m, lH), 1.40 (m, 3H). 31P NMR (162 MHz, chloroform-d) 8 - 3.12, -3.14. LCMS: MS mlz = 450.3 [M+ 1]; 448.1 [M-1], tR = 1.24 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; Column: Phenomenex Kinetex 2.6μ C18 l00A, 50 x 3 mm; Solvents: A: Water with 0.1 % acetic acid, B: Acetonitrile with 0.1 % acetic acid; Gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% Bat 2 mL / min. HPLC: tR = 2.63 min; HPLC system: Agilent 1100 series; Column: Phenomenex Gemini 5μ C18 110A, 50 x 4.6 mm; Solvent: A: Water with 0.1 % TFA, B: Acetonitrile with 0.1 % TFA; Gradient: 2-98% B in 5 min at 2 mL / min. 121 CA 03171497 2022-08-16 WO 2021 / 168038 Intermediate 25. (2S)-cyclohexyl 2-(((4- nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate Q~ ()_o~J:Q N02 PCT / 0S2021 / 018458

[0267] Intermediate 11 (3.4 g, 16.37 mmol) was dissolved in methylene chloride (45 mL), cooled to -78 °C, and phenyl dichlorophosphate (2.45 mL, 16.37 mmol) added quickly. Triethylamine (4.54 mL, 32.74 mmol) was added over 60 min at -78 °C and then 4-nitrophenol (2277 mg, 16.37 mmol) was added in one portion. Triethylamine (2.27 mL, 16.37 mmol) was added over 60 min at -78 °C. The resulting mixture was stirred for 2 hat -78 °C, diluted with methylene chloride (100 mL), washed with water twice and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc 0 to 20% in hexanes) to give the product. 1H NMR (400 MHz, Chloroform-d) o 8.22 (m, 2H), 7.46 - 7.30 (m, 4H), 7.29- 7.09 (m, 3H), 4.76 (m, lH), 4.20 -4.02 (m, lH), 3.92 (m, lH), 1.87 - 1.64 (m, 4H), 1.54 (m, 2H), 1.46 1.18 (m, 7H). 31P NMR (162 MHz, Chloroform-d) o -2.94, - 3.00. MS mlz = 449 (M+Ht. Intermediate 26. tert-butyl 4-(((2S)-2-((( 4- nitrophenoxy)(phenoxy)phosphoryl}amino )propanoyl)oxy)piperidine-1-carboxylate Boe~~ 0 ~O~NH2

[0268] tert-butyl 4-((L-alanyl)oxy)piperidine-l-carboxylate. To a mixture of ((benzyloxy)carbonyl)-L-alanine (1.26 g, 5.65 mmol), tert-butyl 4-hydroxypiperidine-1- carboxylate (5.68 g, 28.22 mmol), and EDCI (1.05 g, 6.77 mmol) in acetonitrile (15 mL) was added DMAP (1.03 g, 8.47 mmol). Then the mixture was stirred at room temperature for 15 h, diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc Oto 100% in hexanes) to give a Cbz-L-alanine piperidyl ester, which was dissolved in THF (10 mL) and 20% palladium hydroxide ( 400 mg) on carbon was added. The resulting mixture was stirred under H2 gas for 2 h, filtered, and the filtrate concentrated in vacuo. The obtained residue was dried under high vacuum to afford the product. 1HNMR (400 MHz, Chloroform-d) o 4.95 (tt, J= 7.9, 3.8 Hz, lH), 3.79 3.62 (m, 2H), 3.56 (q, J = 7.0 Hz, lH), 3.25 (ddd, J = 13.6, 8.5, 3.7 Hz, 2H), 122 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 1.85 (ddd, J= 13.4, 6.4, 3.4 Hz, 2H), 1.73 (s, 2H), 1.62 (ddq, J= 12.7, 8.7, 4.3, 3.9 Hz, 2H), 1.46 (s, 9H), 1.34 (d, J = 7.0 Hz, 3H). MS mlz = 273 [M+H].

[0269] tert-butyl 4-(((2S)-2-(((4- nitrophenoxy )(phenoxy )phosphoryl)amino )propanoyl)oxy )piperidine-1-carboxylate. tertbuty l 4-((L-alanyl)oxy)piperidine-l-carboxylate (0.9 g, 3.31 mmol) was dissolved in methylene chloride (10 mL), cooled to -78 °C, and phenyl dichlorophosphate (0.49 mL, 3.31 mmol) added quickly. Triethylamine (0.46 mL, 3.31 mmol) was added over 30 min at -78 °C and 4- nitrophenol (460 mg, 3.31 mmol) was added in one portion. Then triethylamine (0.49 mL, 3.31 mmol) was added over 30 min at -78 °C. The resulting mixture was stirred for 2 hat -78 °C, diluted with methylene chloride, washed with water twice and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc Oto 70% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-cl) & 8.23 (m, 2H), 7.42 - 7.31 (m, 4H), 7.25 - 7.16 (m, 3H), 4.93 (m, lH), 4.26 - 4.03 (m, lH), 3.85 (m, lH), 3.75 - 3.56 (m, 2H), 3.21 (m, 2H), 1.91 - 1.75 (m, 2H), 1.66- 1.48 (m, 2H), 1.46 (s, 9H), 1.44-1.38 (m, 3H). 31P NMR (162 MHz, Chloroform-cl) & -3.07, -3.13. MS mlz = 550 (M+Ht. Intermediate 27. trans-4-(trifluoromethyl)cyclohexyl ((4- nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate F3CYl V·-·0J.NH2

[0270] trans-4-(trifluoromethyl)cyclohexyl L-alaninate. The product was prepared from Cbz-1-alanine (900 mg, 4.03 mmol) and trans-4-(trifluoromethyl)cyclohexan-l-ol (1.02 g, 6.05 mmol) in a manner similar to that described for Intermediate 26. MS mlz = 240 [M+H]. 123

[0271] trans-4-(trifluoromethyl)cyclohexyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-Lalaninate. The product (840 mg) was prepared as isomeric mixture from trans-4- (trifluoromethyl)cyclohexyl L-alaninate (974 mg, 4.07 mmol) in a manner similar to that described for Intermediate 25. 1H NMR (400 MHz, Chloroform-d) 6 8.27 - 8.19 (m, 2H), 7.43 - 7.31 (m, 4H), 7.26 - 7.16 (m, 3H), 4.68 (m, lH), 4.11 (m, lH), 3.84 (m, lH), 2.02 (m, 4H), 1.50 - 1.27 (m, 8H). 19F NMR (377 MHz, Chloroform-d) 6 -73.91 (d, J = 7.7 Hz). 31P NMR (162 MHz, Chloroform-d) 6 -3.08, -3.12. MS mlz = 517 [M+H].

[0272] The product was separated by Chiralpak:™ SFC (Chiralpak IF 20X250 mm column, 30% isopropanol) to afford Intermediate 28 and Intermediate 29: Intermediate 28. trans-4-(trifluoromethyl)cyclohexyl ((R)-( 4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. First eluting diastereomer of Intermediate 27: 1H NMR (400 MHz, Chloroform-cl) o 8.22 (d, J= 9.1 Hz, 2H), 7.42- 7.31 (m, 4H), 7.29- 7.16 (m, 3H), 4.69 (tt, 10.7, 4.2 Hz, lH), 4.19-4.04 (m, lH), 3.90 (dd, J= 11.9, 9.5 Hz, lH), 2.12-1.97 (m, 5H), 1.52-1.21 (m, 7H). 19FNMR (376 MHz, Chloroform-cl) o -73.90 (d, J= 7.7 Hz). 31P NMR (162 MHz, Chloroform-cl) o -3.07. Intermediate 29. trans 4-(trifluoromethyl)cyclohexyl ((S)-(4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. Second eluting diastereomer of Intermediate 27: 1H NMR (400 MHz, Chloroform-cl) o 8.21 (d, J = 9.08 Hz, 2H), 7.42- 7.31 (m, 4H), 7.26- 7.13 (m, 3H), 4.67 (tt, J = 10.8, 4.2 Hz, lH), 4.11 (ddt, J = 15.8, 8.9, 7.1 Hz, lH), 3.97 (dd, J = 12.0, 9.4 Hz, lH), 2.07 - 1.91 (m, 5H), 1.51 -1.19 (m, 7H). 19F NMR (376 MHz, Chloroformd) 6 -73.90 (d, J = 7.9 Hz). 31P NMR (162 MHz, Chloroform-cl) 6 -3.08. Intermediate 30. 1-Methylpiperidin-4-yl((4-nitrophenoxy) (phenoxy)phosphoryl)-Lalaninate 't:J~ 0 l.._,,.)-.0~ NH2

[0273] 1-Methylpiperidin-4-yl L-alaninate. To a mixture ofN-Cbz-L-alanine (1.047 g, 4.688 mmol), 4-hydroxy-N-methylpiperidine (450 mg, 3.907 mmol), and EDCI (788 mg, 5.079 124 Date Re9ue / Date Received 2024-02-02 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 mmol) in acetonitrile (20 mL) was added DMAP (716 mg, 5.861 mmol). Then the mixture was stirred at room temperature for 15 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (MeOH Oto 10% in DCM) to give an Cbz-L-alanine 4-piperidyl ester, which was dissolved in THF (10 mL) and 20% Pd(OH)2 ( 300 mg, 0.427 mmol) was added at room temperature. The resulting mixture was stirred under H2 gas at room temperature for 2 h, filtered, concentrated in vacuo, co-evaporated with DCM several times, and dried under high vacuum overnight to afford the product. 1HNMR (400 MHz, Chloroform-d) 8 4.81 (td, J= 8.3, 7.7, 3.8 Hz, lH), 3.52 (q, J= 7.0 Hz, lH), 2.63 (s, 2H), 2.29 (s, SH), 2.14- 1.86 (m, 4H), 1.73 (ddt, J = 12.9, 8.8, 4.5 Hz, 2H), 1.32 (d, J = 7.0 Hz, 3H). LCMS: MS mlz = 187.09 [M+ l]; tR = 0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Q \I --00~~:o N02

[0274] 1-Methylpiperidin-4-yl((4-nitrophenoxy) (phenoxy)phosphoryl)-L-alaninate. To a solution of 1-Methylpiperidin-4-yl L-alaninate (360 mg, 1.706 mmol) in DCM (10 mL) was added phenyl phosphorodichloridate (0.255 mL, 1.706 mmol) in one portion at -78 °C and then triethylamine (0.24 mL, 1.706 mmol) in DCM (2.76 mL) was added over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and then recooled to -78 °C. p-Nitrophenol (0.237 g, 1.706 mmol) was added in one portion and triethylamine (0.237 mL, 1.706 mmol) added over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath, then diluted with EtOAc, washed with water and brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (MeOH 0 to 10% in DCM) to afford the product. 1H NMR (400 MHz, Chloroform-d) 8 8.28 - 8.15 (m, 2H), 7.36 (m, 4H), 7.25-7.17 (m, 3H), 4.80 (s, lH), 4.19-4.04 (m, lH), 3.93 (m, lH), 2.64 (s, 2H), 2.31 (m, SH), 1.90 (m, 2H), 1.78 - 1.67 (m, 2H), 1.47 - 1.33 (m, 3H). 31P NMR (162 MHz, Chloroform-d) 8 -3.04, -3.07. LCMS: MS mlz = 464.32 [M+l]; tR = 0.74 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1 % 125 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 31. (tetrahydro-2H-pyran-4-yl)methyl ((4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate Cr )'.,)yo__D H 0

[0275] (tetrahydro-2H-pyran-4-yl)methyl ((benzyloxy)carbonyl)-L-alaninate. Cbz-L-Ala (446 mg, 2 mmol) was dissolved in anhydrous MeCN (10 mL). EDCI (422 mg, 2.2 mmol) was added in one portion and the reaction was stirred for 15 mins. Tetrahydropyran-4-methanol (279 uL, 2.4 mmol) was added. DMAP (269 mg, 2.2 mmol) was then added in one portion. Reaction was stirred for 16 hrs.

[0276] Reaction was diluted reaction with EtOAc (30 mL) and washed with 5% aqueous citric acid solution (10 mL), followed with saturated aqueous sodium bicarbonate solution (10 mL) and finally with brine (10 mL). Organic was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-80% ethyl acetate / hexanes). Fractions were combined and concentrated under reduced pressure to afford the product. 1H NMR (400 MHz, Chloroform-d) 8 7.40 - 7.28 (m, SH), 5.28 (d, J = 7.9 Hz, lH), 5.11 (s, 2H), 4.39 (t, J= 7.4 Hz, lH), 4.07 -3.84 (m, 4H), 3.38 (t, J= 11.7 Hz, 2H), 1.92 (s, lH), 1.68 - 1.50 (m, 3H), 1.39 (m, 4H).

[0277] (tetrahydro-2H-pyran-4-yl)methyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-Lalaninate. (tetrahydro-2H-pyran-4-yl)methyl ((benzyloxy)carbonyl)-L-alaninate (530 mg, 1.65 mmol) was dissolved in anhydrous THF (12 mL). 10% Pd / C Degussa type was added and the reaction mixture was stirred under atmospheric hydrogen for 2 hrs. Catalyst was filtered and the filtrate was used without purification. 126 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0278] Phenyl dichlorophosphate (294 uL, 1.98 mmol) was dissolved in anhydrous DCM (10 mL) and stirred in an ice bath under atmospheric nitrogen. Above THF solution was added to the reaction dropwise and then stirred for 10 mins. Triethylamine (300 uL, 2.15 mmol) was added dropwise and then stirred for 30 mins. p-Nitrophenol (207 mg, 1.49 mmol) and triethylamine (300 uL, 2.15 mmol) were added. Ice bath was removed and the reaction mixture was stirred for 14 hrs at RT.

[0279] Reaction was diluted with EtOAc (30 mL) and washed with 0.2 M sodium carbonate solution (2 x 10 mL) and followed with brine (10 mL). Organic was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-50% ethyl acetate / hexanes). Fractions were combined and concentrated under reduced pressure to afford the product. 1HNMR (400 MHz, Chloroform-d) cS 8.23 (d, J = 9.0 Hz, 2H), 7.45 -7.30 (m, 4H), 7.30 - 7.16 (m, 3H), 4.23 - 4.07 (m, 2H), 3.97 (m, 4H), 3.85 (t, J = 10.5 Hz, IH), 3.35 (t, J = 11.8 Hz, 2H), 1.99 - 1.79 (m, lH), 1.56 (d, J = 8.4 Hz, 3H), 1.48 - 1.29 (m, 4H). 31P NMR (162 MHz, Chloroform-d) cS -3.13(s), -3.16 (s). MS mlz = 464.9 [M+ I]; 463.1 [M-1]. Intermediate 32. trans-4-(tert-butyl}cyclohexyl ((S)-(4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate

[0280] trans-4-(tert-butyl)cyclohexyl L-alaninate. The product (845 mg) was prepared from Cbz-1-alanine (960 mg, 4.03 mmol) and trans-4-(tert-butyl)cyclohexanol (1.0 g, 6.45 mmol) in a manner similar to that described for Intermediate 26. 1H NMR ( 400 MHz, Chloroform-d) cS 4.65 (tt, J= 11.2, 4.5 Hz, lH), 3.51 (q, J= 7.1 Hz, lH), 2.07- 1.93 (m, 2H), 1.87- 1.73 (m, 4H), 1.40 -1.23 (m, 4H), 1.19 - 0.94 (m, 4H), 0.85 (d, J= 2.6 Hz, 9H). MS mlz = 228 [M+H].

[0281] trans-4-(tert-butyl)cyclohexyl (( 4-nitrophenoxy)(phenoxy) phosphoryl)-Lalaninate. The product (520 mg) was prepared as isomeric mixture from trans-4-(tertbutyl )cyclohexyl L-alaninate ( 420 mg, 1. 85 mmol) in a manner similar to that described for Intermediate 25. 1HNMR (400 MHz, Chloroform-d) cS 8.27 - 8.19 (m, 2H), 7.37 (m, 4H), 7.28- 127 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 7.16 (m, 3H), 4.62 (m, lH), 4.17 - 4.00 (m, lH), 3.88 (m, lH), 1.95 (m, 2H), 1.80 (m, 2H), 1.39 (m, 3H), 1.35 - 1.22 (m, 2H), 1. 15 - 0.92 (m, 3H), 0.85 (s, 9H). 31P NMR (162 MHz, Chloroform-cl) 8 -2.98, -3.04. MS mlz = 505 [M+H]. Intermediate 33. (Or, 4S)-4-(trifluoromethyl}cyclohexyl)methyl ((4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate F F F~·-,,,--OH

[0282] ((ls, 4s)-4-(trifluoromethyl)cyclohexyl)methanol. To an ice cold solution of (ls,4s)- 4-(trifluoromethyl)cyclohexane carboxylic acid (3 g, 15.29 mmol) in anhydrous tetrahydrofuran (40 mL) was added lithium aluminum hydride (0.871 g, 22.94 mmol) portion wise in 30 min. The reaction mixture was stirred at room temperature for 3 h. Cooled to O °C and quenched with water (0.8 mL), 5 N aqueous sodium hydroxide (0.8 mL) followed by water (2.4 mL). Solids separated were filtered and filtrate was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. Organic layer was separated, washed with brine and dried over sodium sulfate. Ethyl acetate was filtered and concentrated under reduced pressure to afford the product. The residue obtained was dried at high vacuum for 1 h and is used as such in subsequent reactions. 1HNMR (400 MHz, Chloroform-cl) 8 3.47 (dd, J = 6.3, 1.9 Hz, 2H), 2.08 - 1.77 (m, SH), 1.62 - 1. 18 (m, 4H), 0.99 (qd, J = 13.0, 3.2 Hz, 2H). 19F NMR (376 MHz, Chloroform-cl) 8 -74.33 (d, J = 8.2 Hz). ~ F3C~ oANH l___) .. ,,,,,,o--(' 0

[0283] ((lr, 4S)-4-(trifluoromethyl)cyclohexyl)methyl (tert-butoxycarbonyl)-L-alaninate. The product (1.48 g) was prepared in a manner similar to that described for Intermediate 12. 1H NMR (400 MHz, Chloroform-cl) 8 5.00 (s, lH), 4.30 (s, lH), 4.04 - 3.89 (m, 2H), 2.08 - 1.79 (m, SH), 1.74 - 1.57 (m, lH), 1.44 (s, 9H), 1.38 (d, J = 7.2 Hz, 3H), 1.30 (m, 2H), 1.12 - 0.93 (m, 2H). 19F NMR (376 MHz, Chloroform-cl) 8 -74.38 (d, J = 7.8 Hz). 128 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0284] (S)-1-oxo-1-( ( (lr, 4S)-4-(trifluoromethyl)cyclohexyl)methoxy )propan-2-aminium chloride. The product (1.184 g) was prepared in a manner similar to that described for Intermediate 13. 1HNMR (400 MHz, DMSO-d6) o 8.55 (s, 3H), 4.17- 3.88 (m, 3H), 2.21 (dtd, J = 12.2, 8.8, 3.3 Hz, lH), 1.83 (ddd, J = 29.5, 13.4, 3.4 Hz, 4H), 1.63 (tdd, J = 11.9, 6.0, 3.3 Hz, lH), 1.41 (d, J = 7.2 Hz, 3H), 1.32 - 0.93 (m, 4H). 19F NMR (377 MHz, DMSO-d6) o -72.84 (d, J= 8.8 Hz).

[0285] ((lr, 4S)-4-(trifluoromethyl)cyclohexyl)methyl ((4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. The product (1.4 g) was prepared in a manner similar to that described for Intermediate 35. 1HNMR (400 MHz, DMSO-d6) o 8.37 - 8.22 (m, 2H), 7.56 - 7.31 (m, 4H), 7.30 - 7.14 (m, 2H), 6.72 (ddd, J = 13.7, 10.1, 8.6 Hz, lH), 4.10 - 3.91 (m, lH), 3.88 - 3.75 (m, 2H), 2.20- 1.99 (m, lH), 1.86 - 1.63 (m, 4H), 1.54 - 1.41 (m, lH), 1.29 - 1.06 (m, 5H), 0.98 (td, J = 12.7, 3.2 Hz, 2H). MS mlz = 531.02 [M+l]. Intermediate 34. Ethyl ((S)-(perfluorophenoxy}(phenoxy)phosphoryl}-L-alaninate Q F. F O 0 1 -~-0* / / F / '--o~NH F F

[0286] To a solution ofL-alanine ethyl ester-HCl (631 mg, 2.465 mmol) in DCM (15 mL) was added phenyl phosphorodichloridate (0.368 mL, 2.465 mmol) in one portion at -78 °C and triethylamine (0.68 mL, 4.93 mmol) was added dropwise over 5 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and then cooled to -78 °C. Pentafluorophenol (454 mg, 2.465 mmol) was added in one portion and triethylamine (0.34 mL, 2.465 mmol) added over 5 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with DCM, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc Oto 60% in hexanes) to give a diastereomeric mixture, to which diisopropyl ether (4 mL) was added. The suspension was sonicated and filtered. 1H NMR of the filter cake showed it is 3: 1 ratio of mixture. Diisopropyl ether (5 mL) was added to the filter cake and the suspension was heated at 70 °C to a clear solution. Upon removal of heating bath, needle like crystals started to form and after 10 129 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 min, the mixture was filtered and the filter cake was dried under high vacuum for 30 min to afford the Sp isomer.

[0287] Diastereomeric mixture: 1H NMR (400 MHz, Chloroform-d) cS 7.43 - 7.30 (m, 2H), 7.32 - 7.17 (m, 3H), 4.29 - 4.11 (m, 3H), 3.94 (m, lH), 1.52 - 1.42 (m, 3H), 1.28 (q, .J = 7.0 Hz, 3H).

[0288] Sp isomer: 1H NMR (400 MHz, Acetonitrile-d3) cS 7.50 - 7.36 (m, 2H), 7.32 - 7.21 (m, 3H), 4.75 (t, J= 11.5 Hz, lH), 4.17-3.98 (m, 3H), 1.37 (dd,.J= 7.1, 1.1 Hz, 3H), 1.22 (t, .J = 7.1 Hz, 3H). 31P NMR (162 MHz, Acetonitrile-d3) cS -0.51. 19F NMR (376 MHz, Acetonitriled3) cS -155.48- -155.76 (m), -162.73 (td, .J= 21.3, 3.7 Hz), -165.02- -165.84 (m). LCMS mlz = 440.5 (M-ethyl+H), tR = 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 IO0A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2- 100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 35. (2S)-2-ethylbutyl 2-cyclohexyl-2-((( 4-nitrophenoxy) (phenoxy)phosphoryl)amino )acetate

[0289] (S)-2-ethylbutyl 2-amino-2-cyclohexylacetate hydrochloride. Took up Lcyclohexylglycine (0.90 g, 5.75 mmol) in 2-ethyl-1-butanol (20 mL) and added chlorotimethylsilane (1.31 mL, 10.30 mmol) in one portion. Placed in a preheated 60 °C oil bath for 16 h. Concentrated and co-evaporated with toluene 5 times in a 60 °C rotary evaporator bath. Placed under high vacuum overnight to afford the product. The material was used as is for the next step. 1H NMR (400 MHz, DMSO-d6) cS 8.38 (s, 3H), 4.17 - 3.96 (m, 2H), 3.84 (d, .J = 4.5 Hz, lH), 1.90- 1.40 (m, 5H), 1.41 - 0.88 (m, 1 lH), 0.83 (t, J= 7.3 Hz, 6H). 130 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0290] (2S)-2-ethylbutyl 2-cyclohexyl-2-((( 4-nitrophenoxy) (phenoxy)phosphoryl)amino )acetate. To a solution of (S)-2-ethylbutyl 2-amino-2- cyclohexylacetate hydrochloride (1.50 g, 5.39 mmol) and phenyl dichlorophosphate (0.803 mL, 5.39 mmol) in dichloromethane (50 mL) was added triethylamine (1.56 mL, 11.16 mmol) at 0 °C under an argon atmosphere. The resulting mixture was allowed to warm to RT and was stirred for 1 h. 4-Nitrophenol (713 mg, 5.13 mmol) and triethylamine (0.81 mL, 5.63 mmol) were then added. After 2 h, the reaction mixture was diluted with Et2O (100 mL) and the solids were filtered off. The crude was concentrated under reduced pressure and was purified by silica gel chromatography (120 g SiO2 Combiflash HP Gold Column, 0-50% ethyl acetate / hexanes), followed by purification by reverse phase HPLC without modifier 20-100% ACN in Water to afford the product. 1HNMR (400 MHz, DMSO-d6) o 8.28 (br d, J= 9.3 Hz, 2H), 7.55 -7.28 (m, 4H), 7.28 7.01 (m, 3H), 6.61 6.52 (m, lH), 3.85 (d, J = 4.0 Hz, 2H) 3.75 3.53 (m, lH), 1.67 -1.31 (m, 7H), 1.25 (m, 6H), 1.16-0.67 (m, 9H). LC / MS: tR = 1.48 min, MS mlz = 519.03 [M+ l]; LC system: Thermo Accela 1250 UHPLC. MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.00 mm. Solvents: Acetonitrile with 0.1 % formic acid, Water with 0.1% formic acid. Gradient: 0 min-2.4 min 2-100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8 mL / min. Intermediate 36. O-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl (( 4- nitrophenoxy)(phenoxy)phosphoryl)alaninate 0 ~ 0~NHBoc F3C..._.,.N.__)

[0291] (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl (tert-butoxycarbonyl)alaninate. The product (3.8 g) was prepared in a manner similar to that described for Intermediate 12. 1H NMR (400 MHz, DMSO-d6) o 7.25 (d, J = 7.4 Hz, lH), 4.08 - 3.72 (m, 3H), 3.10 (q, J = 10.3 Hz, 2H), 2.88 (d, J = 11.0 Hz, 2H), 2.37 - 2.18 (m, 2H), 1.66 - 1.47 (m, 3H), 1.36 (s, 9H), 1.21 (d, J = 7.5 Hz, 5H). 19F NMR (376 MHz, DMSO-d6) o -68.52 (t, J = 10.3 Hz). ~O~NH2 .2HCI F3C..._.,.N.__)

[0292] (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl alaninate dihydrochloride. The product (3.52 g) was prepared in a manner similar to that described for Intermediate 13. 1H NMR (400 MHz, DMSO-d6) o 8.67 (s, 3H), 4.44 - 3.75 (m, 5H), 3.49 - 2.81 (m, 4H), 2.00 - 131 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 1.61 (m, SH), 1.43 (d, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) 8 -63.30 (d, J = 443.2 Hz).

[0293] (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl (( 4- nitrophenoxy)(phenoxy)phosphoryl)alaninate. The product (4.25 g) was prepared in a manner similar to that described for Intermediate 35. 1H NMR (400 MHz, DMSO-d6) 8 8.32 - 8.24 (m, 2H), 7.53 - 7.40 (m, 2H), 7.39 (ddd, J = 8.1, 6.8, 3.1 Hz, 2H), 7.24 (ddd, J = 17.4, 6.5, 1.6 Hz, 3H), 6.69 (ddd, J= 13.7, 10.0, 8.4 Hz, lH), 4.07-3.92 (m, IH), 3.88-3.77 (m, 2H), 3.08 (qd, J = 10.3, 1.6 Hz, 2H), 2.87 - 2.79 (m, 2H), 2.25 - 2.14 (m, 2H), 1.56 - 1.39 (m, 3H), 1.26 - 1.08 (m, SH). 31P NMR (162 MHz, DMSO-d6) 8-1.26, -1.49. 19F NMR (376 MHz, DMSO-d6) 8 - 68.45 (td, J = 10.2, 2.4 Hz). LCMS: MS mlz = 546.27 [M+ 1]; ]; tR = 1.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 37. O-Ethyl-3,3-difluoropiperidin-4-yl (( 4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate Boc~l 0 ')<'oA..,,.NHCbz F F I

[0294] tert-Butyl 4-( ( ( (benzyloxy )carbonyl)-L-alanyl)oxy )-3,3-difluoropiperidine-1- carboxylate. To a mixture of N-Cbz-L-alanine (2.0 g, 8.96 mmol), tert-butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate (2.12 g, 8.96 mmol), and EDCI (1.67 g, 10.75 mmol) in acetonitrile (20 mL) was added DMAP (1.64 g, 13.44 mmol). Then the mixture was stirred at room temperature for 15 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc 50 to 100% in hexanes) to afford the product. 19F NMR (377 MHz, Chloroform-d) 8 -114.32 (m), -117.73 - -121.11 (m). LCMS: MS mlz = 343.14 [M+ 1-Boc], 386.82 (M+l-t-Bu); 1R = 1.23 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 l00A, 50 x 3.0 mm; Solvents: 132 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2- 100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. H,~7 0 y 0 ~,_..NHCbz F F I

[0295] 3,3-difluoropiperidin-4-yl ((benzyloxy)carbonyl)-L-alaninate. To a mixture of tertButyl 4-((((benzyloxy)carbonyl)-L-alanyl)oxy)-3,3-difluoropiperidine-l-carboxylate (330 mg, 0.746 mmol) in DCM (5 mL) was added 4 M HCL in dioxane (0.9 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 2 h, concentrated in vacuo, co-evaporation with DCM several times, and dried under high vacuum for 15 h to afford the product. 1H NMR (400 MHz, Chloroform-d) o 7.33 (m, 5H), 5.59 (m, lH), 5.27 - 5.01 (m, 3H), 4.53 - 4.25 (m, lH), 3.12 (m, lH), 3.03 - 2.76 (m, 2H), 2.73 (s, lH), 1.94 (s, lH), 1.80 (s, lH), 1.41 (d, J= 7.2 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) o -114.66 (dd, J= 245.9, 61.8 Hz), -119.63. l~l a YoA,_..NHCbz F F I

[0296] 1-ethyl-3,3-difluoropiperidin-4-yl ((benzyloxy)carbonyl)-L-alaninate. A mixture of 3,3-difluoropiperidin-4-yl ((benzyloxy)carbonyl)-L-alaninate (450 mg, 1.190 mmol), acetaldehyde (0.194 mL, 2.629 mmol), and acetic acid (0.15 mL, 2.629 mmol) in DCM (9 mL) was stirred for 20 min at room temperature and sodium cyanoborohydride (330 mg, 5.258 mmol) was added. The resulting mixture was stirred for 1 h and purified by preparative HPLC (Phenominex Gemini l0u Cl8 1 lOA 250 x 21.2 mm column, 20-80% acetonitrile (0.1 % TFA) / water (0.1% TFA) gradient) to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) o 10.18 (bs, 2H), 7.38 (m, 5H), 6.19 (m, lH), 5.47 - 5.26 (m, lH), 4.33 (m, lH), 3.82-2.98 (m, 6H), 2.30 (s, lH), 2.16 (s, lH), 1.42 (m, 3H), 1.31 (td, J = 7.3, 1.5 Hz, 3H). LCMS: MS mlz = 371.27 [M+l]; tR = 0.66 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2- 100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μ L / min. 133 WO 2021 / 168038 CA 03171497 2022-08-16 l~l a \<'0A.,,,NH2 F F I PCT / 0S2021 / 018458

[0297] 1-ethyl-3,3-difluoropiperidin-4-yl L-alaninate. A mixture of l-ethyl-3,3- difluoropiperidin-4-yl ((benzyloxy)carbonyl)-L-alaninate (450 mg, 0.929 mmol) and 20% Pd(OH)2 / C in THF (10 mL) was stirred at room temperature under H2 gas for 1 h, filtered, concentrated in vacuo, co-evaporated with DCM several time, and dried under high vacuum for 1 h to afford the product. LCMS: MS mlz = 23 7. 09 [M+ 1]; tR = 0 .15 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XBC 18 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. l Q \I °')~J:h F F I ~- N02

[0298] (1-Ethyl-3,3-difluoropiperidin-4-yl ((4-nitrophenoxy)(phenoxy)phosphoryl)-Lalaninate. Methylene chloride (10 mL) was added to the syrup of 1-ethyl-3,3-difluoropiperidin- 4-yl L-alaninate (480 mg, 1.37 mmol) and TEA (0.190 mL, 0.370 mmol) was added to achieve a solution, which was cooled to -78 °C and phenyl dichlorophosphate (0.205 mL, 1.370 mmol) was added quickly. Triethylamine (0.190 mL, 1.37 mmol) was added over 30 min at -78 °C. The resulting mixture was stirred for 30 min at the same temperature and 4-nitrophenol (191 mg, 1.370 mmol) added in one portion. Then triethylamine (0.190 mL, 1.370 mmol) was added over 30 min at -78 ° C. Then the mixture was stirred for 2 h at room temperature, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc Oto 100% in hexanes) to give the product. 1H NMR (400 MHz, Chloroform-cl) 8 8.29 - 8.15 (m, 2H), 7.44 - 7.28 (m, 4H), 7.27 - 7.11 (m, 3H), 5.03 (m, lH), 4.34 - 4.14 (m, lH), 3.94 - 3.75 (m, lH), 2.88 (s, lH), 2.63-2.49 (m, 4H), 2.39 (m, lH), 2.03 - 1.93 (m, IH), 1.93 - 1.77 (m, IH), 1.44 (m, 3H), 1.09 (td, J = 7.2, 1.0 Hz, 3H). 31P NMR (162 MHz, Chloroform-cl) 8 -3.21, -3.26, -3.32, -3.46. 19F NMR (377 MHz, Chloroform-cl) 8 -110.50 (d, J= 244.0 Hz), -116.76 (m). LCMS: MS mlz = 514.29 [M+l]; tR = 0.80 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic 134 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 38. 4-nitrophenyl-N ,N'-ethyl L-alaninatephosphorodiamidate

[0299] To a solution of ethyl L-alaninate HCl salt (1. 8 g, 11. 72 mmol) in DCM (20 mL) was added 4-nitrophenyl phosphorodichloridate (1.5 g, 5.86 mmol) in one portion. The resulting mixture was cooled to 0 °C and triethylamine (2.37 g, 23.44 mmol) was added dropwise. The resulting mixture was stirred for 30 min after removal of ice bath and was stirred for overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 417.93 [M+ 1], tR = 1.23 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.02 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex C 18, 2.6u 11 0A, 100 x 4.6 mm; Solvents: A: Water with 0.1 % TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2- 98% B with 8.5 min gradient at 1.5 mL / min. Intermediate 39. benzyl (( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate N02 Q~O OO-P-0 uo~NH

[0300] Phenyl dichlorophosphate (1.49 mL, 10 mmol) was dissolved in 20 mL anhydrous dichloromethane and stirred under atmospheric nitrogen in an ice bath. L-Alanine benzyl ester HCl (2.2 g, 10 mmol) was added to the reaction solution in one portion and stirred for 10 min. Triethylamine (3 mL, 22 mmol) was dissolved in 5 mL of anhydrous dichloromethane and added to the reaction dropwise. The reaction mixture was stirred for 2 h. p-Nitrophenol (1.25 g, 135 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 9 mmol) was added in one portion. Triethylamine (1.5 mL, 11 mmol) was dissolved in 3 mL of anhydrous dichloromethane and added to the reaction dropwise. The reaction mixture was stirred for 1 h, and was diluted with dichloromethane (10 mL) and washed with water (3 x 10 mL). Organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (4 g SiO2 Combiflash HP Gold Column, 0-30% ethyl acetate / hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to afford the product. 1 H NMR ( 400 MHz, chloroform-d) 8 8.24 - 8.10 (m, 2H), 7.40- 7.10 (m, 12H), 5.14 (m, 2H), 4.19 (m, lH), 3.87 (m, IH), 1.47- 1.36 (m, 3H). 31P NMR (162 MHz, chloroform-d) 8 -3.15, -3.29. LCMS: MS mlz = 457.1 [M+l]; 455.1 [M-1], tR = 1.45 min; LC system: Thermo Dionex ultimate 3000 UHPLC; Column: Phenomenex Kinetex 2.6μ Cl8 l00A, 50 x 3 mm; Solvents: A: Water with 0.1 % acetic acid, B: Acetonitrile with 0.1% acetic acid; Gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5- 100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% Bat 2 mL / min. HPLC: tR = 4.03 min; HPLC system: Agilent 1100 series; Column: Phenomenex Gemini 5μ Cl8 110A, 50 x 4.6 mm; Solvent: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2-98% Bin 5 min at 2 mL / min. Intermediate 40. 4-nitrophenyl-N ,N'-methyl L-alaninatephosphorodiamidate -o .:- H ~ 0 HN-P-0 ,''x~Ho 0 0 N02

[0301] Triethylamine (3.68 mL, 26.4 mmol) was added to a solution of methyl L-alaninate hydrochloride (1.63 g, 12.0 mmol) and 4-nitrophenyl phosphorodichloridate (1.5 g, 5.9 mmol) in dichloromethane (23 mL) at 0 °C under an argon atmosphere. After 3 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1HNMR (400 MHz, chloroform-di) 8.25 - 8.16 (m, 2H), 7.38 (dd, J 9.3, 1.0 Hz, 2H), 4.17 - 3.95 (m, 2H), 3.73 (br s, 6H), 3.61 (br t, J 10.0 Hz, 2H), 1.42 (s, 3H), 1.40 (s, lH). 31P NMR (162 MHz, chloroform-di) 8 7.82 (s). LCMS: MS mlz = 389.98 [M+l], tR = 1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% 136 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 2.81 min; HPLC system: Agilent 1100 series; Column: Gemini 5μC18110A, 50x4.6mm; Solvents: Acetonitrilewith0.l¾TFA, Waterwith 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL / min. Intermediate 41. methyl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate -0 "' H ~ 0 HN-P-0 v6Q N02

[0302] Phenyl dichlorophosphate (2.81 mL, 18.9 mmol) and triethylamine (5.38 mL, 37.9 mmol) were sequentially added to a suspension of methyl L-alaninate hydrochloride (2.64 g, 18.9 mmol) in dichloromethane (100 mL) at 0 °C. After 1 h, 4-nitrophenol (2.64 g, 18.9 mmol) and triethylamine (2.64 mL, 18.9 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 2.5 h, the reaction mixture was diluted with dichloromethane (100 mL), washed with saturated a aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, chloroform-d1) 8 8.25 - 8.18 (m, 2H), 7.43 - 7.29 (m, 4H), 7.29 - 7.15 (m, 3H), 4.24 -4.07 (m, lH), 3.97 (br q, J 9.8 Hz, lH), 3.70 (s, 3H), 1.45 - 1.35 (m, 3H). 31P NMR (162 MHz, chloroform-d1) 8 -3.12 (s), -3.17 (s). LCMS: MS mlz = 380.98 [M+l], 1R = 1.59 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.49 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1 % TFA, Water with 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL / min. Intermediate 42. methyl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate 137 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0303] 4-Nitrophenyl phosphorodichloridate (2.00 g, 7.81 mmol) and triethylamine (2.18 mL, 15.6 mmol) were sequentially added to a suspension of methyl L-alaninate hydrochloride (1.091 g, 18.9 mmol) in dichloromethane (23 mL) at 0 °C under an argon atmosphere. After 1 h, benzyl alcohol (0.810 mL, 7.81 mmol) and triethylamine (1.09 mL, 7.81 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 1 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated an aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1HNMR (400 MHz, chloroform-d1) & 8.32- 8.09 (m, 2H), 8.32- 8.09 (m, 7H), 5.15 (app t, J= 8.4 Hz, 2H), 4.70 (s, lH), 4.07 - 3.93 (m, lH), 3.73 - 3.65 (m, 3H), 1.42 - 1.31 (m, 3H). 31P NMR (162 MHz, chloroform-d1) & 2.23 (s), 2.15 (s). LCMS: MS mlz = 394.9[M+l], tR = 1.34 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl}phenoxy}(4- nitrophenoxy)phosphoryl)-L-alaninate \ 0 lt) a ~II ,,lo~~:q N02

[0304] To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc Oto 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-cl) & 8.26 - 8.18 (m, 138 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, lH), 5.01 (m, lH), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H). 31P NMR (162 MHz, Chloroform-cl) 8 -3.13, - 3.21. MS mlz = 480 (M+H). LCMS: MS mlz = 480.26 [M+l]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C 18 1 00A, 50 x 3 .0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 44. oxetan-3-yl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate = 0 r-r0 0N)l_O~ 6-J O H V

[0305] oxetan-3-yl ((benzyloxy)carbonyl)-L-alaninate. To a mixture of ((benzyloxy)carbonyl)-L-alanine (1.8 g, 8.1 mmol), 3-hydroxyoxetane (0.5 g, 6.75 mmol) and lEthyl- 3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (1.68 g, 8. 77 mmol) in acetonitrile (100 mL) was added 4-(Dimethylamino)pyridine (DMAP, 1.24 g, 10.12 mmol). Then the mixture was stirred at room temperature for 2 h, then the reaction mixture was diluted with EtOAc, washed with brine, dried organic solvent over sodium sulfate, and then concentrated in vacuum. The obtained residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, Chloroform-cl) 8 7.40 - 7.28 (m, SH), 5.47 (p, J = 5.9 Hz, lH), 5.30 (d, J = 8.0 Hz, lH), 5.10 (s, 2H), 4.88 (t, J = 7.1 Hz, 2H), 4.62 (ddd, J = 17.5, 7.7, 5.3 Hz, 2H), 4.41 (p, J = 7.3 Hz, lH), 1.44 (d, J = 7.3 Hz, 3H). LCMS: MS mlz = 280.04 [M+l], tR = 1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 2.82 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex C 18, 2.6u 11 0A, 100 x 4.6 mm; Solvents: A: Water with 0.1 % TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2-98% B with 8.5 min gradient at 1.5 mL / min. rYO~NH2 6-J 0

[0306] oxetan-3-yl L-alaninate. Dissolved oxetan-3-yl ((benzyloxy)carbonyl)-L-alaninate (0.1 g, 0.36 mmol) in DCM (5 mL), to the solution was added 15 mg of Pd-C (10%, wet), the reaction flask was degassed and then charged with H2 balloon, stirred at RT for 2 h, the reaction 139 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 mixture was then filtered, solvent was evaporated under vacuum, the residue was dried on high vacuum for 5 min to afford the product. 1HNMR (400 MHz, Chloroform-cl) o 5.42 (p, J = 5.7 Hz, lH), 4.87 (t, J = 6.9 Hz, 2H), 4.65 -4.54 (m, 2H), 3.58 (qd, J = 7.0, 2.1 Hz, lH), 1.49 (d, J = 7.1 Hz, 2H), 1.34 (dd, J = 7.2, 2.1 Hz, 3H). Q~ OO-P-0 O(l__o~NH Q N02

[0307] oxetan-3-yl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To a solution of oxetan-3-yl L-alaninate (120 mg, 0.83 mmol) in DCM (10 mL) was added phenyl phosphorodichloridate (175 mg, 0.83 mmol) in one portion. The resulting mixture was cooled to 0 °C and triethylamine (252 mg, 2.49 mmol) was added dropwise. The resulting mixture was stirred for 30 min after removal of ice bath and cooled to 0 °C and para-nitrophenol (115 mg, 0.83 mmol) was added in one portion and triethylamine (252 mg, 2.49 mmol) was added dropwise. The resulting mixture was stirred for 30 min after removal of ice bath, diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 423.06 [M+ l], tR = 1.25 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C 18 1 00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.15 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex Cl 8, 2.6u l l0A, 100 x 4.6 mm; Solvents: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 - 98% B with 8.5 min gradient at 1.5 mL / min. Intermediate 45. propyl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate ~o ~ HN-{f

[0308] propyl (tert-butoxycarbonyl)-L-alaninate. N-(3-Dimethylaminopropyl)-N'ethylcarbodiimide hydrochloride (6.08 g, 31.71 mmol) was added to a solution ofBoc-Ala-OH (5 g, 26.43 mmol) and n-propyl alcohol (6.02 mL, 80.6 mmol) in acetonitrile (125 mL) at RT. After 15 min, 4-(dimethylamino)pyridine (3.23 g, 26.43 mmol) was added. After 16 h, the 140 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 reaction mixture was concentrated to half the volume, and the mixture was diluted with ethyl acetate (250 mL) and the resulting mixture was washed with saturated aqueous sodium carbonate solution (2 x 200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography eluting with 0-20% EtOAc in hexane to afford the product. 1HNMR (400 MHz, Acetonitrile-d3) 8 5.57 (s, lH), 4.19 -3.92 (m, 3H), 1.63 (h, J= 7.1 Hz, 2H), 1.40 (s, 9H), 1.30 (d, J= 7.3 Hz, 3H), 0.93 (t, J= 7.4 Hz, 3H). LCMS: MS mlz = 231.60 [M+ l], tR = 1. 10 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min- 1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. ~o -=- oHNH3c1

[0309] propyl L-alaninate hydrochloride. 4 M Hydrochloric acid solution in dioxane (16.91 mL) was added to propyl (tert-butoxycarbonyl)-L-alaninate (3.91 g, 16.91 mmol) in dichloromethane (10 mL) at RT. After 16 h, reaction mixture was concentrated under reduced pressure to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) 8 8.45 (s, 3H), 4.22 - 4.11 (m, 2H), 4.11 - 3.99 (m, lH), 1.68 (dtd, J = 14.0, 7.4, 6.6 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). LCMS: MS mlz = 131.94 [M+ l], tR = 0.32 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 I00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min.

[0310] propyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. Phenyl dichlorophosphate (0.89 mL, 5.97 mmol) in dichloromethane (12 mL) was added dropwise over 15 minutes to a solution of propyl L-alaninate hydrochloride (1.0 g, 5.97 mmol) in dichloromethane (12 mL) at 0 °C. After the addition was complete, triethylamine (2.0 mL, 14.32 mmol) in dichloromethane (2.5 mL) was added over 5 minutes. After 3.5 h, 4-nitrophenol (0.83 g, 5.97 mmol) and triethylamine (1.0 mL, 7.16 mmol) were then sequentially added at 0 °C, and 141 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 the resulting mixture was then allowed to warm to RT. After 2 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) o 8.28 - 8.20 (m, 2H), 7.49 - 7.35 (m, 4H), 7.31- 7.19 (m, 3H), 4.72 - 4.56 (m, lH), 4.14 -4.02 (m, lH), 3.99 (td, J= 6.6, 2.5 Hz, 2H), 1.58 (dtdd, J= 13.9, 7.4, 6.5, 0.9 Hz, 2H), 1.31 (ddd, J= 7.1, 4.2, 1.1 Hz, 3H), 0.88 (t, J= 7.4 Hz, 3H). 31P NMR (162 MHz, Acetonitrile-d3) o -2.12, -2.22. LCMS: MS mlz = 409.12 [M+ 1], tR = 1.15 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 5.73 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrilewith 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. Intermediate 46. oxetan-3-ylmethyl ((4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate

[0311] oxetan-3-ylmethyl ((benzyloxy)carbonyl)-L-alaninate. To a mixture of ((benzyloxy)carbonyl)-L-alanine (6.08 g, 27.24 mmol), oxetan-3-ylmethanol (2 g, 22.7 mmol) and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (5.66 g, 29.51 mmol) in acetonitrile (100 mL) was added 4-(Dimethylamino)pyridine (DMAP, 4.16 g, 34.05 mmol). Then the mixture was stirred at room temperature for 2 h, the reaction mixture was then diluted with EtOAc, washed with brine, dried organic solvent over sodium sulfate, and then concentrated in vacuum. The obtained residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 280.04 [M+ l], tR = 1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 2.88 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex Cl 8, 2.6u ll0A, 100 x 4.6 mm; Solvents: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 98% B with 8.5 min gradient at 1.5 mL / min. 142 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 0 ~ 0 r('NH2 0

[0312] oxetan-3-ylmethyl L-alaninate. Dissolved oxetan-3-ylmethyl ((benzyloxy)carbonyl)L- alaninate (2.2 g, 8 mmol) in DCM (25 mL), to the solution was added 500 mg of Pd-C (10%, wet), the reaction flask was degassed and then charged with H2 balloon, stirred at RT for 2 h, the reaction mixture was then filtered, solvent was evaporated under vacuum, the residue was dried on high vacuum for 5 min to afford the product. 1H NMR (400 MHz, Chloroform-cl) o 4.77 (dd, J = 7.9, 6.3 Hz, 2H), 4.44 (td, J = 6.1, 2.5 Hz, 2H), 4.38 4.23 (m, 2H), 3.55 (q, J = 7.0 Hz, lH), 3.34 - 3.19 (m, lH), 1.31 (d, J = 7.0 Hz, 3H). Q~ oo-P-o 0 ':('0~NHQ N02

[0313] oxetan-3-ylmethyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To a solution of oxetan-3-ylmethyl L-alaninate (1.19 g, 7.11 mmol) in DCM (20 mL) was added phenyl phosphorodichloridate (1.5 g, 7.11 mmol) in one portion. The resulting mixture was cooled to 0 °C and triethylamine (1.44 g, 14.22 mmol) was added drop wise. The resulting mixture was stirred for 30 min after removal of ice bath and cooled to 0 °C and para-nitrophenol (0.99 g, 7.1 mmol) was added in one portion and triethylamine (1.44 g, 14.22 mmol) was added dropwise. The resulting mixture was stirred for 30 min after removal of ice bath, diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 437.14 [M+l], tR = 1.25 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 IO0A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 3.36 min; HPLC system: Agilent 1290 II; Column: Phenomenex Kinetex C18, 2.6u 110A, 100 x 4.6 mm; Solvents: A: Water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; Gradient: 2 - 98% B with 8.5 min gradient at 1.5 mL / min. 143 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 47. cyclobutyl ((4-nitrophenoxy}(phenoxy)phosphoryl}-L-alaninate Q \I 0-_)(r~~o N02

[0314] To a solution ofL-Alanine, cyclobutyl ester (1.8 g, 10 mmol) in DCM (10 mL) under a nitrogen atmosphere in an ice bath was added phenyl phosphorodichloridate (2.1 g, 10 mmol) in one portion. Then triethylamine (1.11 g, 11 mmol) was added dropwise. The resulting mixture was stirred for 2 h after removal of ice bath and cooled to 0 °C and para-nitrophenol (2.5 g, 18 mmol) was added in one portion and triethylamine (1.11 g, 11 mmol) was added dropwise. The resulting mixture was stirred for 2 h after removal of ice bath, diluted with EtOAc, washed with 5% aqueous citric acid solution twice, followed by washing with brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. MS mlz = 422.0 (M+Ht.

[0315] Resolution of the Sp and Rp diastereomers. The product was purified via chiral preparatory HPLC (Chiralpak IA,150 x 4.6 mm, Heptane 70%, IPA 30%) to form Intermediate 48 and Intermediate 49: Q 11 °'-o~~~o N02 N02 Intermediate 48. First Eluting Diastereomer of Intermediate 47: 1H NMR ( 400 MHz, Methanold4) o 8.33-8.23 (m, 2H), 7.52 -7.33 (m, 4H), 7.33-7.17 (m, 3H), 4.96-4.85 (m, lH), 4.07-3.96 (m, lH), 2.27 (m, 2H), 2.07-1.91 (m, 2H), 1.83-1.70 (m, lH), 1.70-1.55 (m, lH), 1.32 (ddd, J= 7.2, 5.3, 1.2 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) o 1.36. LCMS: MS mlz = 421.05 [M+l], tR = 1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 IO0A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min- 3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 8.07 min; HPLC system: Chiralpak IC, 150 x 4.6 mm, 5 micron, 144 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 CN=IC00CD-QC005, 1 CV=2.49 mL, CV#l, Col Valve: Position 3, 15 mL / 15 min@ 1 mL / min. Pmax=300 bar; Solvent Valves: D: Heptane 70%, #6: IPA Intermediate 49. Second Eluting Diastereomer of Intermediate 47: 1HNMR (400 MHz, Methanol-d4) o 8.33-8.23 (m, 2H), 7.52 -7.33 (m, 4H), 7.33-7.17 (m, 3H), 4.96-4.85 (m, lH), 4.07-3.96 (m, lH), 2.27 (m, 2H), 2.07-1.91 (m, 2H), 1.83-1.70 (m, lH), 1.70-1.55 (m, lH), 1.32 (ddd, J = 7.2, 5.3, 1.2 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) o 1.59. LCMS: MS mlz = 420.90 [M+ l], tR = 1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1 % acetic acid, water with 0.1 % acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min- 3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2 μL / min. HPLC: tR = 11.50 min; HPLC system: Chiralpak IC, 150 x 4.6 mm, 5 micron, CN=IC00CD-QC005, 1 CV=2.49 mL, CV#l, Col Valve: Position 3, 15 mL / 15 min@ 1 mL / min. Pmax=300 bar; Solvent Valves: D: Heptane 70%, #6: IPA 30%. Intermediate 50. methyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl}-L-alaninate F. F o~*F O 0 1•P-O F , 0~NH

[0316] L-Alanine methyl ester hydrochloride (14 g, 100 mmol) was mixed with 50 mL of anhydrous DCM and stirred under atmospheric nitrogen in an ice bath. Phenyl dichlorophosphate (16.4 mL, 110 mmol) was added to the reaction dropwise, and the reaction mixture was stirred for 30 mins. Triethylamine (29.4 mL, 210 mmol) was mixed with 20 mL anhydrous DCM and added to the reaction dropwise. Reaction was stirred for 1 hr. Pentafluorophenol (18.4 g, 100 mmol) was added in one portion. Triethylamine (14.7 mL, 105 mmol) was mixed with 30 mL of anhydrous DCM and added to reaction dropwise. The reaction mixture was stirred for 16 hrs at RT.

[0317] Reaction was diluted with DCM (50 mL) and washed with water (5xl0 mL). Organic was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give solid. Isopropyl ether (130 mL) was added to solid. Big pieces of solid were broke down and then sonicated for 20 mins, after which the mixture was then stirred for 24 hrs.

[0318] Solid was collected and washed with small amount of isopropyl ether (30 mL). Solid was dried under high vacuum to give the product. 1H NMR (400 MHz, chloroform-d) o 7.40 - 145 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 7.32 (m, 2H), 7.28 - 7.19 (m, 3H), 4.20 (m, lH), 3.96- 3.85 (m, lH), 3.74 (s, 3H), 1.47 (d, J= 7.1 Hz, 3H). 31P NMR (162 MHz, chloroform-d) 8 -1.62. 19F NMR (376 MHz, chloroform-d) 8 - 153.82 (dd, J= 18.5, 2.7 Hz), -159.99 (td, J= 21.8, 3.8 Hz), -162.65 (dd, J= 22.2, 17.6 Hz). LCMS: MS mlz = 425.9 [M+l], 423.9 [M-1], tR = 1.68 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; Column: Phenomenex Kinetex 2.6μ Cl8 l00A, 50 x 3 mm; Solvents: A: Water with 0.1% acetic acid, B: Acetonitrile with 0.1% acetic acid; Gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% Bat 2 mL / min. HPLC: tR = 3.76 min; HPLC system: Agilent 1100 series; Column: Phenomenex Gemini 5μ C18 110A, 50 x 4.6 mm; Solvent: A: Water with 0.1% TFA, B: Acetonitrile with 0.1 % TFA; Gradient: 2-98% B in 5 min at 2 mL / min. Intermediate 51. isopropyl (( 4-(2-methoxyethoxy)phenoxy)( 4-nitrophenoxy)phosphoryl}-Lalaninate )-o -~ H <il 0~,::Xh ,-,0-------0~ 9-N02

[0319] 4-Nitrophenyl phosphorodichloridate (503 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes to a solution ofL-alanine isopropyl ester hydrochloride (329 mg, 1.97 mmol) in dichloromethane (20 mL) at 0 °C. After addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, 4-(2- methoxy-ethoxy)phenol (331 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, Methanol-d4) 8 8.32 - 8.24 (m, 2H), 7.51 - 7.39 (m, 2H), 7.24 - 7.12 (m, 2H), 6.97 - 6.90 (m, 2H), 4.94 (heptd, J = 6.2, 3.2 Hz, lH), 4.12 - 4.07 (m, 2H), 4.05 - 3.93 (m, lH), 3.76 - 3.68 (m, 2H), 3.41 (d, J = 0.5 Hz, 3H), 1.32 (td, J = 7.1, 1.2 Hz, 3H), 1.19 (dt, J= 6.3, 2.0 Hz, 6H). 31P NMR (162 MHz, Methanol-d4) 8 -0.86, -1.06. LCMS: MS mlz = 483.06 [M+ l], tR = 1.39 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min- 1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 5.58 146 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. Intermediate 52. butyl (( 4-nitrophenoxy}(phenoxy)phosphoryl}-L-alaninate ~o ~ H 'i? 0 HN-P-0 o-60 N02

[0320] Phenyl dichlorophosphate (0.89 mL, 5.97 mmol) in dichloromethane (12 mL) was added dropwise over 15 minutes to a solution of butyl L-alaninate hydrochloride (CAS# 81305- 85-3, 1.0 g, 5.97 mmol) in dichloromethane (12 mL) at 0 °C. After the addition was complete, triethylamine (2.0 mL, 14.32 mmol) in dichloromethane (2.5 mL) was added over 5 minutes. After 3.5 h, 4-nitrophenol (0.83 g, 5.97 mmol) and triethylamine (1.0 mL, 7.16 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 2 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, methanol-d4) 8 8.31 - 8.23 (m, lH), 7.52 7.34 (m, 2H), 7.32 7.18 (m, 2H), 4.04 (td, J = 6.6, 2.7 Hz, 2H), 1.60 1.48 (m, lH), 1.40- 1.26 (m, 3H), 0.89 (t, J= 7.4 Hz, 2H). 31P NMR (162 MHz, methanol-d4) 8 -1.36, - 1.59. LCMS: MS mlz = 423.13 [M+l], tR = 1.22 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2- 100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 53. 3-Methoxypropyl ((4-nitrophenoxy}(phenoxy)phosphoryl}-L-alaninate 0 'o~o~NH2

[0321] 3-Methoxypropyl L-alaninate. To a mixture of Cbz-L-alanine (2.80 g, 12.54 mmol), 3-methoxypropanol (1.00 mL, 10.45 mmol), and EDCI (2.11 g, 13.59 mmol) in acetonitrile (40 mL) was added DMAP (1.92 g, 15.68 mmol). Then the mixture was stirred at room temperature 147 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 for 15 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc 0 to 50% in hexanes, 35 min run) to give a Cbz-L-alanine ester (2. 78 g), which was dissolved in THF (20 mL) and 20% Pd(OH)2 (800 mg, 1.14 mmol) added at room temperature. The resulting mixture was stirred at room temperature for 4 h under a hydrogen gas atmosphere, filtered, concentrated in vacuo, and dried under high vacuum to afford the product. 1H NMR ( 400 MHz, Chloroform-d) 8 4.28 - 4.14 (m, 2H), 3.55 (q, J= 7.0 Hz, lH), 3.43 (t, J= 6.2 Hz, 2H), 3.32 (s, 3H), 1.98-1.85 (m, 4H), 1.33 (d, J= 7.0 Hz, 3H). LCMS mlz = 161.98 (M+H), tR = 0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Q~ o O-P-0 'o~o~~H Q N02

[0322] 3-Methoxypropyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To a solution of 3-Methoxypropyl L-alaninate (1.32 g, 8.20 mmol) in DCM (20 mL) was added phenyl phosphorodichloridate (1.23 mL, 8.20 mmol) in one portion quickly at -78 °C. Then triethylamine (1.14 mL, 8.20 mmol) was added over 5 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C. p-Nitrophenol (1.14 g, 8.20 mmol) was added in one portion and triethylamine (1.14 mL, 8.20 mmol) added over 5 min at - 78 °C. The resulting mixture was stirred for 2 h after removal of dry ice bath. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc Oto 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-d) 8 8.26 - 8.19 (m, 2H), 7.36 (m, 4H), 7.27 -7.15 (m, 3H), 4.20 (m, 2H), 4.17 - 4.06 (m, lH), 3.91 (m, lH), 3.40 (m, 2H), 3.30 (m, 3H), 1.87 (m, 2H), 1.40 (m, 3H). 31P NMR (162 MHz, Chloroform-d) 8 -3.07, -3.10. LCMS: mlz = 439.l l (M+H). tR = 1.36 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 I00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min 148 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 54. methyl (2S)-2-(((benzyloxy)carbonyl)amino )-3-( 4-(((((S)-1-methoxy-1- oxopropan-2-yl)amino )( 4-nitrophenoxy)phosphoryl)oxy)phenyl}propanoate ~)(:N;H z~o-lo- oq~ 0 I A - / O N02

[0323] L-Alanine methyl ester hydrochloride (275 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes to a solution of 4-nitrophenyl phosphorodichloridate (504 mg, 1.97 mmol) in dichloromethane (20 mL) at 0 °C. After addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 60 minutes, N-carbobenzyloxyL- tyrosine methyl ester (649 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 3 hr, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1HNMR (400 MHz, Methanol-d4) o 8.34 - 8.17 (m, 2H), 7.53 - 7.37 (m, 2H), 7.37- 7.09 (m, 9H), 5.02 (s, 2H), 4.43 (dd, J= 9.4, 5.2 Hz, lH), 4.19- 3.97 (m, lH), 3.70 (s, 3H), 3.62 (d, J = 4.4 Hz, 3H), 3.16 (dd, J= 14.0, 5.4 Hz, lH), 2.93 (dd, J = 14.1, 9.8 Hz, lH), 1.32 (td, J = 7.3, 1.2 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) o -1.30, -1.51. LCMS: MS m / z = 616.03 [M+ 1], tR = 1.63 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 IO0A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min- 1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 5.81 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ Cl8 1 l0A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. Intermediate 55. (S)-Tetrahydrofuran-3-yl (( 4-nitrophenoxy){phenoxy) 10, 0 ~O~NH2

[0324] (S)-Tetrahydrofuran-3-yl-L-alaninate. To a mixture of N-Cbz-L-alanine (3.31, 14.83 mmol), (S)-THF-3-ol (1.0 mL, 12.34 mmol), and EDCI (2.49 g, 16.04 mmol) in acetonitrile (20 mL) was added DMAP (2.26 g, 18.51 mmol). Then the mixture was stirred at room temperature 149 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 for 15 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc 0 to 80% in hexanes) to give a Cbz-L-alanine 4-THF ester, which was dissolved in THF (20 mL) and 20% palladium hydroxide (433 mg, 0.617 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h under H2 gas, filtered, and concentrated in vacuo, co-evaporated with DCM multiple times, and dried 15 h under high vacuum to afford the product. 1H NMR (400 MHz, Chloroform-d) o 5.37 - 5.29 (m, lH), 3.97 - 3.77 (m, 4H), 3.61 - 3.52 (m, lH), 2.27 - 2.12 (m, lH), 2.02 (dt, J = 12.8, 5.6 Hz, lH), 1.76 (s, 2H), 1.34 (dd, J= 7.1, 1.5 Hz, 3H). LCMS mlz = 159.94 (M+H), tR = 0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C 18 1 00A, 50 x 3 .0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Q~ U.0~tQ N02

[0325] (S)-Tetrahydrofuran-3-yl (( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To a solution of(S)-Tetrahydrofuran-3-yl-L-alaninate (1.45 g, 9.10 mmol) in DCM (20 mL) was added phenyl phosphorodichloridate (1.37 mL, 9.10 mmol) in one portion quickly at -78 °C. Then triethylamine (1.27 mL, 9.10 mmol) was added over 5 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C. p-Nitrophenol (1.27 g, 9.10 mmol) was added in one portion and triethylamine (1.27 mL, 9.10 mmol) added over 5 min at -78 °C. The resulting mixture was stirred for 2 h after removal of dry ice bath. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc Oto 100% in hexanes) to afford the product. 1HNMR (400 MHz, Chloroform-d) o 8.22 (m, 2H), 7.49 - 7.31 (m, 4H), 7.30 - 7.12 (m, 3H), 5.29 (m, 1H), 4.14 (m, 1H), 4.00 - 3.79 (m, 4H), 3.82- 3.60 (m, 1H), 2.17 (m, 1H), 1.95 (m, lH), 1.40 (m, 3H). 31P NMR (162 MHz, Chloroform-d) o -3.18, -3.20. LCMS: mlz = 437.05 (M+H), tR = 1.41 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2- 100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. 150 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 56. 3-morpholinopropyl (( 4-nitrophenoxy}(phenoxy)phosphoryl}-L-alaninate o> \_N ~o ~ \__.-- 0 f / \ II 0 HN-P-0 o-60 N02

[0326] 4-Nitrophenyl phosphorodichloridate (503 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes to a solution of 3-morpholinopropyl L-alaninate hydrochloride (496 mg, 1.97 mmol) in dichloromethane (20 mL) at 0 °C. After addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, phenol (185 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, Methanol-d4) 8 8.32 - 8.24 (m, 2H), 7.51 - 7.39 (m, 2H), 7.24 - 7.12 (m, 2H), 6.97 - 6.90 (m, 2H), 4.94 (m, lH), 4.12 - 4.07 (m, 2H), 4.05 - 3.93 (m, lH), 3.76 - 3.68 (m, 2H), 3.41 (d, J= 0.5 Hz, 3H), 1.32 (td, J= 7.1, 1.2 Hz, 3H), 1.19 (dt, J= 6.3, 2.0 Hz, 6H). 31P NMR (162 MHz, Acetonitrile-d3) 8 -2.12, -2.22. LCMS: MS mlz = 494.35 [M+l], tR = 1.03 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Intermediate 57. (R)-Tetrahydrofuran-3-yl (( 4-nitrophenoxy}(phenoxy) 00 0 ·,,0~NH2

[0327] (R)-Tetrahydrofuran-3-yl-L-alaninate. To a mixture of N-Cbz-L-alanine (3 .31 g, 14.83 mmol), (R)-THF-3-ol (1.0 mL, 12.34 mmol), and EDCI (2.49 g, 16.04 mmol) in acetonitrile (20 mL) was added DMAP (2.26 g, 18.51 mmol). Then the mixture was stirred at room temperature for 15 h, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel 151 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 chromatography (EtOAc Oto 50% in hexanes, 35 min run) to give a Cbz-L-alanine ester (2. 78 g), which was dissolved in THF (20 mL) and 20% Pd(OH)2 (433 mg, 0.617 mmol) added at room temperature. The resulting mixture was stirred at room temperature for 4.5 h under a hydrogen atmosphere, filtered, concentrated in vacuo, and dried under high vacuum to afford the product. 1HNMR (400 MHz, Chloroform-cl) 8 5.32 (ddt, J= 6.5, 4.3, 1.9 Hz, lH), 3.98- 3.78 (m, 4H), 3.56 (q, J= 7.0 Hz, lH), 2.19 (<ltd, J= 13.7, 8.4, 6.4 Hz, lH), 2.05 1.92 (m, lH), 1.79 (s, 2H), 1.34 (d, J= 7.0 Hz, 3H). LCMS: mlz = 159.92 (M+H), tR = 0.21 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C 18 1 00A, 50 x 3 .0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. Q~ 0 oO-P-0 0,,0~~Hq N02

[0328] (R)-Tetrahydrofuran-3-yl ( ( 4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To a solution of (R)-Tetrahydrofuran-3-yl-L-alaninate (1.66 g, 10.44 mmol) in DCM (40 mL) was added phenyl phosphorodichloridate (1.56 mL, 10.44 mmol) added in one portion quickly at -78 °C. Then triethylamine (1.45 mL, 10.44 mmol) was added over 5 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C. pNitrophenol (I .45 g, 10.44 mmol) was added in one portion and triethylamine (1 .45 mL, 10.44 mmol) added over 5 min at -78 °C. The resulting mixture was stirred for 2 h after removal of dry ice bath. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-cl) 8 8.22 (m, 2H), 7.43 7.31 (m, 4H), 7.25 - 7.14 (m, 3H), 5.29 (m, lH), 4.21 - 4.10 (m, lH), 3.93 - 3.79 (m, 4H), 3.79 - 3.71 (m, lH), 2.17 (m, lH), 1.97 - 1.85 (m, lH), 1.44 - 1.37 (m, 3H). 31P NMR (162 MHz, Chloroform-cl) 8 -3.24, -3.26. LCMS: mlz = 437.02 (M+H), tR = 1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XBC 18 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. 152 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 58. methyl (chloro(phenoxy)phosphorothioyl}-L-alaninate Q~ 0 0-P-CI 'o~~H

[0329] Thiophosphoryl chloride (5.08 mL, 50.0 mmol) and triethylamine (6.97 mL, 50.0 mmol) were sequentially added to a solution of phenol (4.70 mg, 50.0 mmol) in TBME (72 mL) at -78 °C under an argon atmosphere. The reaction mixture was then allowed to warm to RT. After 1 h, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (72 mL) and L-alanine methyl ester hydrochloride (6.97 mg, 50.0 mmol) was added. The resulting suspension was cooled to -78 °C and triethylamine (13.9 mL, 100 mmol) was added dropwise. The reaction mixture was then allowed to warm to RT. After 16 h, the reaction mixture was concentrated under reduced pressure and TBME (100 mL) was added to the residue. The resulting white solids were removed by vacuum filtration and the filtrate was concentrated under reduced pressure to afford the product used directly in the next step. 1H NMR (400 MHz, chloroform-d1) 8 7.45 - 7.12 (m, 5H), 4.67 - 4.44 (m, lH), 4.44 - 4.24 (m, lH), 3.81 (s, 1.5H), 3. 78 (s, 1.5H), 1.53 (app t, .J = 6.8 Hz, 3H). 31P NMR (162 MHz, chloroform-d1) 8 64.78 (s), 64.63 (s). Intermediate 59. Cyclohexyl ((((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl}amino )( 4- nitrophenoxy)phosphoryl}-L-alaninate and cyclohexyl ((((S)-1-cyclohexyloxy-1-oxopropan- 2-yl)amino )( 4-nitrophenoxy)phosphoryl}-L-alaninate

[0330] To a solution of (S)-1-( cyclohexyloxy )-1-oxopropan-2-aminium chloride Intermediate 11 (680 mg, 3.27 mmol) in THF (10 mL) was added 4-nitrophenyl phosphorodichloridate (838 mg, 3.27 mmol) in one portion. The resulting mixture was cooled in ice bath and triethylamine (1.0 mL, 6.54 mmol) in THF (2 mL) was added over 30 min. The resulting mixture was stirred under ice bath for 1.5 hand (S)-1-(2-ethylbutoxy)-l-oxopropan-2-aminium chloride (687 mg, 3.27 mmol) was added in one portion and triethylamine (1.0 mL, 6.54 mmol) in THF (2 mL) 153 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 added over 30 min under ice bath. The resulting mixture was stirred under ice bath for 1.5 h, diluted with EtOAc, washed with water and brine, concentrated in vacuo, and the resulting residue purified by preparative HPLC (Phenomenex Gemini-NX 10μ C18 110° A 250 x 30 mm column, 0%-100% acetonitrile / water gradient in 25 min run) to afford the product. 1H NMR (400 MHz, Chloroform-d) c5 8.20 (m, 2H), 7.38 (m, 2H), 4.77 (m, lH), 4.15 -3.91 (m, 4H), 3.60 (m, 2H), 1.91 1.77 (m, 2H), 1.75 1.67 (m, 2H), 1.51 (m, 2H), 1.45 1.23 (m, 15H), 0.88 (m, 6H). 31P NMR (162 MHz, Chloroform-d) c5 8.04. LCMS: MS mlz = 528.10 [M+ 1]. Intermediate 60. 4-nitrophenyl-N,N'-cyclohexyl L-alaninatephosphorodiamidate

[0331] (S)-cyclohexyl 2-aminopropanoate hydrochloride. L-Alanine (891 mg, 10 mmol) was mixed with cyclohexanol (10 mL). Trimethylsilyl chloride (12.7 mL, 100 mmol) was added dropwise and stirred for 20 mins. Reaction mixture was heated to 60 °C and stirred for 16 hrs. Reaction was concentrated under reduced pressure and azeotroped with toluene (5x) to give an oil. Hexanes (100 mL) was added and stirred for 15 hrs to give a solid which was collected, washed with hexanes (100 mL) and dried under high vacuum to give the product. 1H NMR (400 MHz, DMSO-d6) c5 8.45 (s, 3H), 4.77 (tt, J= 8.4, 3.7 Hz, lH), 4.02 (q, J= 7.2 Hz, lH), 1.71 (m, 4H), 1. 53 1.17 (m, 9H). -0- ll Ho -0 02N ••)?:00 0 0

[0332] 4-nitrophenyl-N ,N' -cycl ohexyl L-alaninatephosphorodiamidate. 4-Nitropheny 1 dichlorophosphate (256 mg, 1 mmol) was dissolved in anhydrous dichloromethane (10 mL) and stirred under atmosphere nitrogen in an ice bath. (S)-cyclohexyl 2-aminopropanoate hydrochloride (415 mg, 2 mmol) was added in one portion. Triethylamine (698 μL, 5 mmol) was added dropwise and stirred for 2 hrs. Reaction was diluted with dichloromethane (15 mL) and washed with 2% aqueous citric acid solution (20 mL). Organic was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column 0-50% ethyl acetate / hexanes) to afford the product. 1HNMR (400 MHz, DMSO-d6) c5 8.30- 8.13 (m, 2H), 7.49- 7.27 (m, 2H), 5.50 (m, 2H), 4.62 (m, 2H), 3.85 (m, 2H), 1.67 (m, 8H), 1.51- 1.18 (m, 18H). 31P NMR (162 MHz, DMSO-d6) c5 9.50. MS mlz = 526.0 [M+l], 524.1 [M-1]. 154 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Intermediate 61. 4-nitrophenyl-N ,N'-isopropyl L-alaninatephosphorodiamidate >- N02 o\__ / 0 n r-\ II ~ 0 HN-P-0 ~ I 0 --tNH -z 0

[0333] To a solution ofisopropyl L-alaninate HCl salt (1.97 g, 11.72 mmol) in DCM (20 mL) was added 4-nitrophenyl phosphorodichloridate (1.5 g, 5.86 mmol) in one portion. The resulting mixture was cooled to about O °C and triethylamine (2.37 g, 23.44 mmol) was added dropwise. The resulting mixture was stirred for about 30 min after removal of ice bath and was stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 445.96 [M+l]. Intermediate 62. 4-nitrophenyl-N ,N' -cyclo butylmethyl L-alaninatephosphorodiamidate q___ N02 0H / 10 1~μ 0 HN-P-0 ", I 0 -tNH ~ 0

[0334] To a solution of cyclobutylmethyl L-alaninate HCl salt (1.51 g, 7.8 mmol) in DCM (20 mL) was added 4-nitrophenyl phosphorodichloridate (1 g, 3.9 mmol) in one portion. The resulting mixture was cooled to O °C and triethylamine (1.58 g, 15.6 mmol) was added dropwise. The resulting mixture was stirred for 30 min after removal of ice bath and was stirred for overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. LCMS: MS mlz = 497.98 [M+l]. 155 Intermediate 63. (lr,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl ((4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate BocHN11•Q-o }' )-<NHCbz

[0335] (lr ,4S)-4-( (tert-butoxycarbonyl)amino )cyclohexyl ( (benzyloxy)carbonyl)-Lalaninate. 4-Dimethylaminopyridine (2.84 g, 23 mmol) was added to a solution oftert-butyl ((lr,4r)-4-hydroxycyclohexyl)carbamate (4.00 g, 19.0 mmol) and ((benzyloxy)carbonyl)-Lalanine (4.98 g, 22.0 mmol), and EDCI (3.13 g, 20.0 mmol) in acetonitrile (100 mL) at RT. After 4 h, the reaction mixture was diluted with dichloromethane (200 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, CDCh) o 7.40 - 7.28 (m, SH), 5.29 (hr d, J = 7.7 Hz, lH), 5.10 (s, 2H), 4.78 - 4.60 (m, lH), 4.47 - 4.19 (m, 2H), 3.45 (s, lH), 2.08 - 1.89 (m, 4H), 1.54 1.34 (m, 14H), 1.28 1.16 (m, 2H). LCMS: MS mlz 420.99 [M+l]. BocHN1•·Q-o ~ H ca 0 HN-P-0 o-c\Q N02

[0336] (lr ,4S)-4-( ( tert-butoxycarbonyl)amino )cyclohexyl ( ( 4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. A hydrogen balloon was appended to a flask containing a solution of (lr,4S)-4-((tert-butoxycarbonyl)amino )cyclohexyl ((benzyloxy)carbonyl)-L-alaninate (1.96 g, 4.66 mmol) and palladium on carbon (10% wt, 2.0 g) in tetrahydrofuran (50 mL) at RT under an argon atmosphere. The vessel was evacuated and refilled with hydrogen atmosphere (3 x) and the reaction mixture was stirred vigorously. After 1.5 h, the reaction mixture was filtered through a pad of Celite™ and the filtrate was concentrated under reduced pressure to afford the crude Cbz-deprotected material. The crude residue was taken up into dichloromethane (23 mL) and the resulting mixture was cooled to O °C. Phenyl dichlorophosphate (0.70 mL, 4.7 mmol) and triethylamine (0.66 mL, 4.7 mmol) were sequentially added. After 1 h, 4-nitrophenol (660 mg, 4.74 mmol) and triethylamine (0.66 mL, 4.7 mmol) were then added. After 1.5 h, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude 156 Date Re9ue / Date Received 2024-02-02 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1HNMR (400 MHz, chloroform-d1) o 8.26-8.18 (m, 2H), 7.43 -7.30 (m, 4H), 7.25 - 7.17 (m, 3H), 4.77 - 4.58 (m, lH), 4.40 (br s, lH), 4.18 -3.99 (m, lH), 3.93 -3.80 (m, lH), 3.44 (br s, lH), 2.07 1.87 (m, 4H), 1.52 1.36 (m, 14H), 1.30 1.16 (m, 2H). 31P NMR (162 MHz, chloroform-d1) o -3.15 (s). LCMS: MS mlz = 563.88 [M+ 1]. Intermediate 64. (Or,4S)-4-((tert-butoxycarbonyl}amino)cyclohexyl}methyl ((4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate Method 1.

[0337] ( (lr ,4S)-4-( (tert-butoxycarbonyl)amino )cyclohexyl)methyl ( (benzyloxy) carbonyl)L- alaninate. Cbz-L-Alanine (223 mg, 1.00 mmol) was dissolved in anhydrous MeCN (10 mL). trans-l-(Boc-amino)-4-(hydroxymethyl)cyclohexane (229 mg, 1.00 mmol) and EDCI (230 mg, 1.2 mmol) were added to the reaction, which was then stirred for 25 min. DMAP (122 mg, 1 mmol) was added in one portion, and the reaction was stirred for 4 h. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with 5% aqueous citric acid solution (2 x 5 mL), followed with brine (10 mL). Organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-40% ethyl acetate / hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give the product. 1H NMR (400 MHz, chloroform-d) o 7.41 - 7.27 (m, 5H), 5.29 (d, J= 7.6 Hz, lH), 5.11 (s, 2H), 4.47 -4.24 (m, 2H), 3.96 (d, J= 6.6 Hz, 2H), 3.37 (bs, lH), 2.03 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H), 1.44 (m, 12H), 1.10 (m, 4H). Boc.._NH QO H~ 0 , Q ~N-P-0 I 0 u N02

[0338] ( (1 r ,4S)-4-( (tert-butoxycarbonyl)amino )cyclohexyl)methyl ( ( 4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. ((lr,4S)-4-((tertbutoxycarbonyl) amino)cyclohexyl)methyl ((benzyloxy) carbonyl)-L-alaninate (348 mg, 0.800 157 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran. Degussa type 10% Palladium on carbon (25 mg) was added to the reaction and then stirred under atmospheric hydrogen for 3 h. Palladium on carbon was filtered off, and the filtrate was used in the next reaction without further purification. Phenyl dichlorophosphate (119 μL, 0.800 mmol) was dissolved in 15 mL anhydrous dichloromethane and stirred under atmospheric nitrogen in an ice bath. The filtrate from above was then added to the reaction solution dropwise and then stirred for 30 min. Triethylamine (120 μL, 0.88 mmol) was added dropwise and stirred for 1 h. p-Nitrophenol (100 mg, 0.72 mmol) was added in one portion. Triethylamine (123 μL, 0.88 mol) was added dropwise, and the reaction mixture was stirred for 2 hat RT. The reaction mixture was then diluted with dichloromethane (10 mL) and washed with water (3 x 10 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-40% ethyl acetate / hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give the product. 1H NMR (400 MHz, chloroform-ct) o 8.27 - 8.18 (m, 2H), 7.44 - 7.30 (m, 4H), 7.27 - 7.17 (m, 3H), 4.35 (s, IH), 4.22 - 4.06 (m, IH), 3.99 - 3.88 (m, 2H), 3.85 (t, J= 10.6 Hz, IH), 3.36 (s, IH), 2.03 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H), 1.48-1.36 (m, 12H), 1.15 - 0.98 (m, 4H). 31P NMR (162 MHz, chloroform-ct) o 3.12, 3.13. LCMS: MS mlz = 478.2 [M+l]. Method 2.

[0339] ( (lr ,4S)-4-( ( tert-butoxycarbonyl)amino )cyclohexyl)methyl ( (benzyloxy )carbonyl)L- alaninate. trans-I-( (tert-Butoxycarbonyl)amino )-4-(hydroxymethyl )cyclohexane ( 510 mg, 2.18 mmol) followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (509 g, 2.62 mmol) were added to a solution of Z-Ala-OH (489 g, 2.18 mmol) in acetonitrile (22 mL) at RT. After 30 min, 4-(dimethylamino)pyridine (267 mg, 2.18 mmol) was added. After 18 h, the reaction was diluted with ethyl acetate (100 mL) and the resulting mixture was washed with 10% aqueous citric acid (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography eluting with 0-50% methanol in ethyl acetate to afford the product. 1HNMR (400 MHz, Chloroform-ct) o 7.41 - 7.29 (m, 5H), 5.28 (s, IH), 5.11 (s, 2H), 4.46-4.27 (m, 2H), 3.96 (d, J= 6.6 Hz, 2H), 3.37 (s, IH), 2.03 (s, 2H), 1.78 (s, 2H), 1.56 158 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (s, 2H), 1.44 (s, 9H), 1.42 (d, J= 7.2 Hz, 3H), 1.08 (t, J= 9.7 Hz, 4H). LCMS: MS mlz = 434.87 [M+l], 1R = 1.21 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min- 1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 5.96 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 l I0A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. :::--0}---( +O O O .·NH, }-NH 0

[0340] ((lr,4S)-4-((tert-butoxycarbonyl)amino )cyclohexyl)methyl L-alaninate. Palladium on carbon (198 mg, 10 wt%) was added to a solution of ((1r,4S)-4-((tertbutoxycarbonyl )amino )cyclohexyl)methyl ((benzyloxy )carbonyl )-L-alaninate (719 g, 1.65 mmol) in tetrahydrofuran (24 mL) that was purged with argon. The mixture was then purged with hydrogen and stirred at RT. After 1 h, the mixture was filtered through celite, the filter was rinsed with tetrahydrofuran, and the volatiles were removed under reduce pressure to obtain the product. 1H NMR (400 MHz, Chloroform-d) 8 4.38 (s, lH), 4.02 - 3.85 (m, 2H), 3.55 (q, J= 7.0 Hz, IH), 3.38 (s, lH), 2.04 (d, J = 7.1 Hz, 2H), 1.83 - 1.73 (m, 2H), 1.63 (s, 2H), 1.44 (s, I0H), 1.34 (d, J= 7.0 Hz, 3H), 1.09 (t, J= 10.0 Hz, 4H). LCMS: MS mlz = 300.93 [M+l], 1R = 0.65 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%- 2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. -o ' __: ::- }----( 0 ~ 0 0 HN-~-0 -Y-}-NH u{j Q N02

[0341] ( (lr ,4S)-4-( (tert-butoxycarbonyl)amino )cyclohexyl)methyl ( ( 4- nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate. To ((lr,4S)-4-((tertbutoxycarbonyl) amino)cyclohexyl)methyl L-alaninate (553 mg, 1.65 mmol) in tetrahydrofuran (24 mL) at 0°C was added a solution of phenyl dichlorophosphate (247 μL, 1.65 mmol) in dichloromethane (30 mL) slowly over 15 min. After the addition was complete, triethylamine 159 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (0.26 mL, 1.82 mmol) was added dropwise. After 1 h, 4-nitrophenol (240 mg, 1.65 mmol) and triethylamine (0.26 mL, 1.82 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 1 h, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (3 x 75 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford the product. 1HNMR (400 MHz, Chloroform-d) 8 8.23 (ddd, J= 9.3, 1.3, 0.6 Hz, 2H), 7.44 - 7.31 (m, 4H), 7.25 -7.16 (m, 3H), 4.36 (s, lH), 4.22-4.06 (m, lH), 3.96- 3.90 (m, 2H), 3.84 (t, J= 10.6 Hz, lH), 3.36 (s, lH), 2.02 (s, 2H), 1.83 - 1.68 (m, 2H), 1.57 (s, 2H), 1.44 (s, 9H), 1.41 (dd, J = 7.1, 3.2 Hz, 3H), 1.06 (t, J = 9.6 Hz, 3H). 31P NMR (162 MHz, Chloroform-d) 8 -3.13 (d, J= 2.9 Hz). LCMS: MS mlz = 577.8 [M+l], tR = 1.28 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 6.35 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18110A, 50x4.6mm; Solvents: Acetonitrilewith0.1%TFA, Waterwith0.1%TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. Intermediate 65. 4-nitrophenyl-N ,N'-butryl L-alaninatephosphorodiamidate

[0342] butyl (tert-butoxycarbonyl)-L-alaninate. Boc-L-alanine (380 mg, 2.0 mmol) was dissolved in anhydrous MeCN (10 mL). 1-Butanol (920 μL, 10.0 mmol) and EDCI (460 mg, 2.4 mmol) were added to the reaction which was then stirred for 15 min. DMAP (240 mg, 2.0 mmol) was added in one portion, and the reaction was stirred for 14 h. The reaction mixture was diluted reaction with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 10 mL), followed with brine (5 mL). The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-20% ethyl acetate / hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give the product. 1H NMR (400 MHz, chloroform-d) 8 5.04 (m, lH), 4.29 (m, lH), 4.18 - 4.07 (m, 2H), 1.67 - 1.59 (m, 2H), 1.44 (s, 9H), 1.38 (m, SH), 0.93 (t, J = 7.4 Hz, 3H). 160 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458

[0343] 4-nitrophenyl-N,N'-butryl L-alaninatephosphorodiamidate. Butyl (tertbutoxycarbonyl)- L-alaninate (291 mg, 1.18 mmol) was dissolved in 7 mL of 4 M HCl in dioxane and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give an oil which was then dissolved in anhydrous dichloromethane (10 mL) and stirred under atmospheric nitrogen in an ice bath. 4-Nitrophenyl phosphorodichloridate (152 mg, 0.59 mmol) was added in one portion, and the reaction was stirred for 10 min. Triethylamine (270 μL, 1.95 mmol) was dissolved in 1 mL of anhydrous dichloromethane and added to the reaction solution dropwise. The reaction mixture was stirred for 1 h. Triethylamine (270 μL, 1.95 mmol) was dissolved with 700 μL of anhydrous dichloromethane and added to reaction dropwise. The reaction mixture was stirred for 16 hat RT. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (3 x 20 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (12 g SiO2 Combiflash HP Gold Column, 0-50% ethyl acetate / hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give the product. 1H NMR (400 MHz, chloroform-d) c5 8.27 8.15 (m, 2H), 7.43 7.34 (m, 2H), 4.19 3.98 (m, 5H), 3.80 3.61 (m, lH), 3.58 (m, 2H), 1.67 - 1.59 (m, 4H), 1.45 - 1.30 (m, l0H), 0.93 (m, 6H). 31P NMR (162 MHz, chloroformd) c5 7.93. LCMS: MS mlz = 474.0 [M+l]. Intermediate 66. methyl (2S)-2-(((benzyloxy)carbonyl)amino )-3-( 4-(((((S)-1-isopropoxy-1- oxopropan-2-yl}amino )( 4-nitrophenoxy)phosphoryl}oxy)phenyl}propanoate () )--o}--( \I TONAH O~ :oN- 6-oo~ 0 I A - / O N02

[0344] 4-Nitrophenyl phosphorodichloridate (504 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes to a solution ofL-alanine isopropyl ester hydrochloride (330 mg, 1.97 mmol) in dichloromethane (20 mL) at 0 °C. After addition was 161 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 60 minutes, Ncarbobenzyloxy- L-tyrosine methyl ester (649 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, Methanol-d4) o 8.32 - 8.22 (m, 2H), 7.49 - 7.37 (m, 2H), 7.35 - 7.13 (m, 9H), 5.02 (s, 2H), 4.93 (pd,J= 6.3, 1.1 Hz, lH), 4.43 (dd, J= 9.4, 5.2 Hz, lH), 4.00 (<ltd, J = 10.1, 7.7, 6.5 Hz, lH), 3.70 (s, 3H), 3.15 (dd, J= 14.0, 5.4 Hz, lH), 2.93 (dd, J = 13.9, 9.6 Hz, lH), 1.32 (td, J = 7.2, 1.2 Hz, 3H), 1.20 - 1.16 (m, 6H). 31P NMR (162 MHz, Methanol-d4) o -1.26, -1.49. LCMS: MS mlz = 644.11 [M+l], tR = 1.56 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min- 2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 6.21 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1 % TFA, Water with 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. Intermediate 67. 2-morpholinoethyl (( 4-nitrophenoxy)(phenoxy)phosphoryl}-L-alaninate / \ 0\.__ / N> 0 ~ H ~ 0 HN-P-0 u6Q N02

[0345] 4-Nitrophenyl phosphorodichloridate (505 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes to a solution of 2-morpholinoethyl L-alaninate hydrochloride (496 mg, 1.97 mmol) in dichloromethane (20 mL) at 0 °C. After addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, phenol (185 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexanes to afford the product. 1H NMR (400 MHz, CDCh) o 8.28 - 8.14 (m, 2H), 7.41 - 7.29 (m, 4H), 7.24 - 7.16 (m, 4H), 6.87 - 6.81 162 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 (m, lH), 4.14-4.04 (bs, 2H), 2.61-2.57 (bs, 4H), 2.45 - 3.40 (bs, 4H), 1.42 (dt, J = 6.3, 2.0 Hz, 6H). 31P NMR (162 MHz, CDCh) o -2.70. LCMS: MS mlz = 480.27 [M+l], tR = 0.96 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 5.23 min; HPLC system: Agilent 1100 series; Column: Kinetx 2.6u l00A Cl 8, 100mm x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-8.5 min 2-98% ACN, 8.5 min-10.0 min 98% ACN at 1. 5 mL / min. Intermediate 68. 2-( diisopropylamino )ethyl (( 4-nitrophenoxy){phenoxy)phos phoryl)-Lalaninate

[0346] 2-( diisopropylamino )ethyl ( (benzyloxy)carbonyl)-L-alaninate. N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.06 g, 10.8 mmol) was added to a solution of Z-Ala-OH (2.00 g, 8.96 mmol) and 2-(diisopropylamino)ethanol (3.2 mL, 17.9 mmol) in acetonitrile (125 mL) at RT. After 10 min, 4-(dimethylamino)pyridine (1.09 g, 8.96 mmol) was added. After 2 d, the reaction mixture was concentrated to half the volume, and the mixture was diluted with ethyl acetate (100 mL) and the resulting mixture was washed with saturated aqueous sodium carbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography eluting with 0-20% methanol in ethyl acetate to afford the product. 1HNMR (400 MHz, Acetonitrile-d3) o 7.48 - 7.23 (m, SH), 5.96 (s, lH), 5.07 (s, 2H), 4.30-4.00 (m, 3H), 2.28 (t, J= 7.1 Hz, 2H), 2.14 (s, 6H), 1.73 (p, J= 6.9 Hz, 2H), 1.34 (d, J= 7.3 Hz, 3H). LCMS: MS mlz = 351.26 [M+l], tR = 1.05 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 lO0A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min- 2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 3.10 min; HPLC system: Agilent 1100 series; 163 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 Column: Gemini 5μC18110A, 50x4.6mm; Solvents: Acetonitrilewith0.l¾TFA, Waterwith 0.1% TFA; Gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN at 2 mL / min. -{ -(~o __: :- 0HNH2

[0347] 2-(diisopropylamino)ethyl L-alaninate. Palladium on carbon (587 mg, 10 wt¾) was added to a solution of 2-(diisopropylamino)ethyl ((benzyloxy)carbonyl)-L-alaninate (1.93 g, 5.52 mmol) in ethanol (50 mL) that was purged with argon. The mixture was then purged with hydrogen and stirred at RT. After 18 hr, the mixture was filtered through celite, the filter was rinsed with ethyl acetate, and the volatiles were removed under reduce pressure to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) 8 4.06 - 3.90 (m, 2H), 3.43 (q, J = 7.0 Hz, lH), 3.01 (hept, J = 6.5 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 1.22 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 6.6 Hz, 12H). LCMS: MS mlz= 217.01 [M+l], tR = 0.17 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. -{ --<N~O ::- \ \__.-- 0 II \ II 0 HN-P-0 o-OQ N02

[0348] 2-( diisopropylamino )ethyl ( ( 4-nitrophenoxy )(phenoxy )phosphoryl)-L-alaninate. 2- ( diisopropylamino )ethyl L-alaninate (511 mg, 2.43 mmol) in tetrahydrofuran (7 mL) was added dropwise over 15 minutes to a solution of phenyl dichlorophosphate (0.36 mL, 2.43 mmol) in tetrahydrofuran (25 mL) at 0°C. After the addition was complete, triethylamine (0.36 mL, 2.43 mmol) was added dropwise. After 90 min, 4-nitrophenol (337 mg, 2.43 mmol) and triethylamine ( 1. 0 mL, 7 .16 mmol) were then sequentially added at 0 °C, and the resulting mixture was then allowed to warm to RT. After 17 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the product. 1H NMR (400 MHz, Acetonitrile-d3) 8 8.29 - 8.18 (m, 2H), 7.49 - 7.35 (m, 4H), 7.30 - 7.21 (m, 164 CA 03171497 2022-08-16 WO 2021 / 168038 PCT / 0S2021 / 018458 3H), 4.71 - 4.52 (m, lH), 4.12 - 3.99 (m, 2H), 4.00 - 3.83 (m, 3H), 3.06 - 2.86 (m, 2H), 2.56 (td, J = 7.0, 3.8 Hz, 2H), 1.31 (ddd, J = 7.1, 4.7, 1.1 Hz, 4H), 0.94 (d, J = 6.5 Hz, 13H). 31P NMR (162 MHz, Acetonitrile-d3) 8 -2.15, -2.30. LCMS: MS mlz = 494.25 [M+ l], tR = 1.27 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-Cl8 l00A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1 % formic acid, water with 0.1 % formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL / min. HPLC: tR = 3.97 min; HPLC sys...

Claims

89990955 406 CLAIMS:

1. A compound of Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof, wherein: Base is , or ; R1A and R2A are each independently: (A)C1-12 alkyl optionally substituted with 1 to 3 R1B, (B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R1C, or (C) phenyl, wherein each R1B is independently -OH, -NH2, C1-6 alkoxy, methoxyethoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and each R1C is independently C1-3 alkyl; R3 is -N(H)R3A or -N=C(R3B)(R3C); R3A is H, -CH2OP(O)(OH)2, or -C(O)R3D, wherein R3D is C1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C1-3 alkyl; CA 3171497 Date reçue / Received date 2025-04-22 89990955 407 R3B is H or C1-3 alkyl; R3C is -N(R3C1)(R3C2); R3C1 and R3C2 are each independently H or C1-6 alkyl; or R3C1 and R3C2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C1-6 alkyl; R4A is O or S; and R4B and R4C are each independently (A) -OH; (B) –OR4B1, wherein R4B1 is C1-6 alkyl optionally substituted with 1 to 3 R4B2 groups, or C6-12 aryl, wherein each R4B2 group is independently C1-6 alkoxy, -S-R4B3, or -S(O)2-R4B3, and each R4B3 group is independently C1-6 alkyl; (C) , wherein m is 0, 1, 2, 3, 4, or 5; and each R4D is independently C1-3 alkyl optionally substituted with 1 to 3 R4D1 groups, C1-3 alkoxy optionally substituted with 1 to 3 R4D2groups, or - C(O)N(R4D3)2, wherein each R4D1 group is independently -NH2 or -C(O)OR4D3, each R4D2 is independently C1-3 alkoxy, and each R4D3 is independently C1-3 alkyl; (D) , wherein R4E1 and R4E2 are each independently H or C1-6 alkyl, R4F1 and R4F2 are each independently H or C1-6 alkyl, or R4F1 and R4F2together are oxo, CA 3171497 Date reçue / Received date 2025-04-22 89990955 408 R4G is C1-12 alkyl optionally substituted with 1 to 3 R4G1, C3-7cycloalkyl optionally substituted with 1 to 3 R4G2, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R4G3, or -C(O)R4G4, each R4G1 is independently -OH, C1-6 alkyl, C1-3 alkoxy, -(CH2OCH2)1-5-CH3, -N(R4G8)2, -OP(O)(OH)2, C3-7 cycloalkyl optionally substituted with1 to 3 R4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R4G10, or phenyl, each R4G2 is independently C1-6 alkyl, C1-3 haloalkyl, or -NH2, each R4G3 is independently halogen or C1-3 alkyl; each R4G4 is independently C1-12 alkyl, each R4G8 is independently C1-6 alkyl, each R4G9 is independently C1-3 haloalkyl, or -NH2, and each R4G10 is independently C1-3 haloalkyl; or (E) -(OP(O)(OH))1-2-OH; and R5A and R5B are each C1-6 alkyl substituted with -OP(O)(OH)2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are C1-12 alkyl optionally substituted with 1 to 3 R1B.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, and isopentyl, each optionally substituted with 1 to 3 R1B.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein one of R4B and R4C is: ; and the other of R4B and R4C is: CA 3171497 Date reçue / Received date 2025-04-22 89990955 409 .

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R4F1 and R4F2 together are oxo.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4G is C1-12 alkyl optionally substituted with 1 to 3 R4G1.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R4G is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or 2-ethyl-butyl, each optionally substituted with 1 to 3 R4G1.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4G is C3-7 cycloalkyl optionally substituted with 1 to 3 R4G2.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4G is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1 to 3 R4G2.

10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4G is 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R4G3.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4G is a 4-6 membered heterocyclyl having 1 to 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R4G3.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4G is oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with 1 to 3 R4G3.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R5A and R5B are each -CH2OP(O)(OH)2. CA 3171497 Date reçue / Received date 2025-04-22 89990955 410 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIa): Formula (IIa), wherein R5A is -CH2OP(O)(OH)2.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIb): Formula (IIb) wherein R5B is -CH2OP(O)(OH)2.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1A and R2A are each independently methyl optionally substituted with methoxy, methoxyethoxy, or morpholinyl, ethyl optionally substituted with methoxy, n-propyl, isopropyl, CA 3171497 Date reçue / Received date 2025-04-22 89990955 411 n-butyl, isobutyl optionally substituted with -OH or -NH2, tert-butyl, isopentyl, oxetanyl, tetrahydropyranyl, piperidinyl optionally substituted with methyl, or phenyl; R3 is -N(H)R3A or -N=C(R3B) (R3C); R3A is H, -C(H)2OP(O)(OH)2, or -C(O)R3D; R3D is methyl, ethyl optionally substituted with methoxy, isopropyl, or piperidinyl optionally substituted with methyl; R3B is H or methyl; R3C is -N(R3C1)(R3C2); R3C1 and R3C2 are independently H or methyl; or R3C1 and R3C2 together with the atom to which they are attached form a piperazinyl optionally substituted with methyl; R4A is O or S; and R4B and R4C are each independently (A) –OH; (B) -O-C1-6 alkyl optionally substituted with methoxy, methylthio or methylsulfonyl; (C) , wherein m is 0, 1 or 2; and each R4D is independently C1-3 alkyl optionally substituted with 1 R4D1group, C1-3 alkoxy optionally substituted with methoxy, or - C(O)N(R4D3)2, wherein CA 3171497 Date reçue / Received date 2025-04-22 89990955 412 each R4D1 group is independently -NH2 or -C(O)OR4D3, and each R4D3 is independently C1-3 alkyl; or (D) , wherein R4E1 and R4E2 are each independently H or methyl; R4F1 and R4F2 are each independently H or methyl, or R4F1 and R4F2together are oxo; R4G is methyl optionally substituted with R4G1, ethyl optionally substituted with morpholinyl or -N(C1-3 alkyl)2, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C1-3 alkyl, isobutyl optionally substituted with -OH or -OP(O)(OH)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups independently -NH2, C1-6 alkyl, or C1-3 haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C1-3 alkyl, tetrahydrofuranyl, tetrahydropyranyl, or -C(O)C1-6 alkyl; and R4G1 is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with -NH2 or C1-3 haloalkyl, oxetanyl, piperidinyl optionally substituted with C1-3 haloalkyl, tetrahydropyranyl, or CA 3171497 Date reçue / Received date 2025-04-22 89990955 413 phenyl.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIc): Formula (IIc).

18. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, is represented by Formula (IId): Formula (IId).

19. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIe): CA 3171497 Date reçue / Received date 2025-04-22 89990955 414 Formula (IIe).

20. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIf): Formula (IIf).

21. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIg): Formula (IIg) wherein m is 0 or 1. CA 3171497 Date reçue / Received date 2025-04-22 89990955 415 22. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIh): Formula (IIh).

23. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIi): Formula (IIi).

24. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIj): Formula (IIj). CA 3171497 Date reçue / Received date 2025-04-22 89990955 416 25. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIk): Formula (IIk).

26. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIm): Formula (IIm).

27. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, represented by Formula (IIn): CA 3171497 Date reçue / Received date 2025-04-22 89990955 417 Formula (IIn).

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each methyl, ethyl, or isopropyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R1A and R2A are each isopropyl.

30. The compound of any one of claims 1-15 or 17-29, or a pharmaceutically acceptable salt thereof, wherein R4G is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or 2-ethyl-butyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R4G is methyl.

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 418 , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 419 , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 420 , , , , , , , , , , P O NH OO OO OO NN N NH2NH O O O O N CA 3171497 Date reçue / Received date 2025-04-22 89990955 421 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 422 , , , , , , OP O NH OONN N NH2 OO N OO O O CA 3171497 Date reçue / Received date 2025-04-22 89990955 423 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 424 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 425 , , , , , , , , , , P O NH OO OO OO NN N NH2NH O O O O N CA 3171497 Date reçue / Received date 2025-04-22 89990955 426 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 427 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 428 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 429 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 430 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 431 , , , , , , , , O OOONN N NH2 PHN O HO O O NOO CA 3171497 Date reçue / Received date 2025-04-22 89990955 432 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 433 , , , , , , , , O O OO NN N NH2 PONH O O O OO N CA 3171497 Date reçue / Received date 2025-04-22 89990955 434 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 435 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 436 , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 437 , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 438 , , , and .

33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 439 , , , , , , , , , , CA 3171497 Date reçue / Received date 2025-04-22 89990955 440 , , , , , , or .

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: CA 3171497 Date reçue / Received date 2025-04-22 89990955 441 .

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

36. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

37. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: . CA 3171497 Date reçue / Received date 2025-04-22 89990955 442 38. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

39. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

40. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

41. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: CA 3171497 Date reçue / Received date 2025-04-22 89990955 443 .

42. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is: .

43. A pharmaceutical formulation comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

44. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for treating a Pneumoviridae virus infection in a human in need thereof.

45. The use of claim 44, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

46. The use of claim 44, wherein the Pneumoviridae virus infection is human metapneumovirus infection.

47. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for treating a Picornaviridae virus infection in a human in need thereof. CA 3171497 Date reçue / Received date 2025-04-22 89990955 444 48. The use of claim 47, wherein the Picornaviridae virus infection is human rhinovirus infection.

49. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for treating a Flaviviridae virus infection in a human in need thereof.

50. The use of claim 49, wherein the Flaviviridae virus infection is a dengue virus infection.

51. The use of claim 49, wherein the Flaviviridae virus infection is a Yellow fever virus infection.

52. The use of claim 49, wherein the Flaviviridae virus infection is a West Nile virus infection.

53. The use of claim 49, wherein the Flaviviridae virus infection is a Zika virus infection.

54. The use of claim 49, wherein the Flaviviridae virus infection is a HCV infection.

55. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for treating a Filoviridae virus infection in a human in need thereof.

56. The use of claim 55, wherein the Filoviridae virus infection is an Ebola virus infection.

57. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Pneumoviridae virus infection.

58. The use of claim 57, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

59. The use of claim 57, wherein the Pneumoviridae virus infection is a human metapneumovirus infection. CA 3171497 Date reçue / Received date 2025-04-22 89990955 445 60. Use of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Picornaviridae virus infection.

61. The use of claim 60, wherein the Picornaviridae virus infection is a human rhinovirus infection.

62. Use of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Flaviviridae virus infection.

63. The use of claim 62, wherein the Flaviviridae virus infection is a dengue virus infection.

64. The use of claim 62, wherein the Flaviviridae virus infection is a Yellow fever virus infection.

65. The use of claim 62, wherein the Flaviviridae virus infection is a West Nile virus infection.

66. The use of claim 62, wherein the Flaviviridae virus infection is a Zika virus infection.

67. The use of claim 62, wherein the Flaviviridae virus infection is a HCV infection.

68. Use of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment in a human of a Filoviridae virus infection.

69. The use of claim 68, wherein the Filoviridae virus infection is an Ebola virus infection.

70. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Pneumoviridae virus infection in a human in need thereof. CA 3171497 Date reçue / Received date 2025-04-22 89990955 446 71. The compound of claim 70, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

72. The compound of claim 70, wherein the Pneumoviridae virus infection is a human metapneumovirus infection.

73. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Picornaviridae virus infection in a human in need thereof.

74. The compound of claim 73, wherein the Picornaviridae virus infection is a human rhinovirus infection.

75. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Flaviviridae virus infection in a human in need thereof.

76. The compound of claim 75, wherein the Flaviviridae virus infection is a dengue virus infection.

77. The compound of claim 75, wherein the Flaviviridae virus infection is a Yellow fever virus infection.

78. The compound of claim 75, wherein the Flaviviridae virus infection is a West Nile virus infection.

79. The compound of claim 75, wherein the Flaviviridae virus infection is a Zika virus infection.

80. The compound of claim 75, wherein the Flaviviridae virus infection is a HCV infection.

81. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Filoviridae virus infection in a human in need thereof.

82. The compound of claim 81, wherein the Filoviridae virus infection is an Ebola virus infection. CA 3171497 Date reçue / Received date 2025-04-22 89990955 447 83. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

84. The use of claim 83, wherein the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

85. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis in a human of an exacerbation of a respiratory condition by a viral infection, wherein the respiratory condition is chronic obstructive pulmonary disease.

86. The use of claim 85, wherein the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.

87. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

88. The compound of claim 87, wherein the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus. CA 3171497 Date reçue / Received date 2025-04-22