CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/977,881 filed 18 Feb. 2020, titled ANTIVIRAL COMPOUNDS, the entirety of which is incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 17, 2021, is named 1223-US-NP_SL.txt and is 777 bytes in size.

BACKGROUND OF THE INVENTION

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 of lower respiratory tract infections in infancy and childhood with 0.5% to 2% of those infected requiring hospitalization.

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.

Examples of pyrrolo[2,3-d]pyrimidine compounds useful for treating viral infections are described in U.S. 2012/0009147 A1 (Cho et al.), U.S. 2012/0020921 A1 (Cho et al.), WO 2008/089105 A2 (Babu et al.), WO 2008/141079 A1 (Babu et al.), WO 2009/132135 A1 (Butler et al.), WO 2010/002877 A2 (Francom), WO 2011/035231 A1 (Cho et al.), WO 2011/035250 A1 (Butler et al.), WO 2011/150288 A1 (Cho et al.), WO 2012/012465 (Cho et al.), WO 2012/012776 A1 (Mackman et al.), WO 2012/037038 (Clarke et al.), WO 2012/087596 A1 (Delaney et al.), and WO 2012/142075 A1 (Girijavallabhan et al.).

Thus, there is a need for compositions and methods for treating Pneumoviridae viral infections, such as HRSV 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

In some embodiments, the present disclosure provides a compound of Formula (II):

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

Base is

[Image Omitted]

R^1Aand R^2Aare each independently:
- (A) C_1-2alkyl optionally substituted with 1 to 3 R^1B,
- (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 R^1C, or
- (C) phenyl, wherein each R^1Bis independently halogen, —OH, —NH₂, C_1-6alkoxy, methoxyethoxy, C_3-8cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and each R^1Cis independently C_1-3alkyl;

R³is —N(H)R^3Aor —N═C(R^3B)(R^3C); R^3Ais H, —CH₂OP(O)(OH)₂, or —C(O)R^3D, wherein R^3Dis C_1-3alkyl 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 C_1-3alkyl; R^3Bis H or C_1-3alkyl; R^3Cis —N(R^3C1)(R^3C2); R^3C1and R^3C2are each independently H or C_1-6alkyl; or R^3C1and R^3C2together 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 C_1-6alkyl;

R^4Ais O or S;

R^4Band R^4Care each independently
- (A) —OH;
- (B) —OR^4B1, wherein R^4B1is C_1-6alkyl optionally substituted with 1 to 3 R^4B2groups, or C_6-12aryl, wherein each R^4B2group is independently C_1-6alkoxy, —S—R^4B3or —S(O)₂—R^4B3, and each R^4B3group is independently C_1-6alkyl;
- (C)

[Image Omitted]

wherein m is 0, 1, 2, 3, 4, or 5; and each R^4Dis independently C_1-3alkyl optionally substituted with 1 to 3 R^4D1groups, C_1-3alkoxy optionally substituted with 1 to 3 R^4D2groups, or —C(O)N(R^4D3)₂, wherein each R^4D1group is independently —NH₂or —C(O)OR^4D3, each R^4D2is independently C_1-3alkoxy, and each R^4D3is independently C_1-3alkyl;

- (D)

[Image Omitted]

wherein R^4E1and R^4E2are each independently H or C_1-6alkyl, R^4F1and R^4F2are each independently H or C_1-6alkyl, or R^4F1and R^4F2together are oxo, R^4Gis C_1-12alkyl optionally substituted with 1 to 3 R^4G1, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G2, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R^4G3, or —C(O)R^4G4, each R^4G1is independently —OH, C_1-6alkyl, C_1-3alkoxy, —(CH₂OCH₂)_1-5—CH₃, —N(R^4G8)₂, —OP(O)(OH)₂, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R^4G10, or phenyl, each R^4G2is independently C_1-6alkyl, C_1-3haloalkyl, —OH or —NH₂, each R^4G3is independently halogen or C_1-3alkyl, each R^4G4is independently C_1-12alkyl, each R^4G8is independently C_1-6alkyl, each R^4G9is independently C_1-3haloalkyl, —OH or —NH₂, and each R^4G10is independently C_1-3haloalkyl; or

- (E) —(OP(O)(OH))_1-2—OH; and

R^5Aand R^5Bare each C_1-6alkyl substituted with —OP(O)(OH)₂.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 Flaviviridae virus infection.

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.

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.

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.

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.

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.

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 a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

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.

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.

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

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

“Alkyl” is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., C_1-8alkyl) or 1 to 8 carbon atoms (i.e., C_1-8alkyl) or 1 to 6 carbon atoms (i.e., C_1-6alkyl) or 1 to 4 carbon atoms (i.e., C_1-4alkyl). 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), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 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.

“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 C_1-6. 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.

“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.

“Hydroxy” refers to —OH.

“Halo” or “halogen” as used herein refers to fluoro (—F), chloro (—Cl), bromo (—Br) and iodo (—I).

“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, C_1-4haloalkyl is a C_1-4alkyl wherein one or more of the hydrogen atoms of the C_1-4alkyl 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.

“Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C_3-20cycloalkyl), 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 bicyclo[3.1.0]hexane and bicyclo[2.1.1]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, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

“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., bicyclic 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[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like.

“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 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 10-membered 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.

“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, 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.

A “compound of the present disclosure” includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) and (IIn), including the compounds of the Examples.

“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.

“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.

“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.

“Prophylaxis” refers to preventing or retarding the progression of clinical illness in patients suffering from a viral infection.

“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 eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyperreactivity consequent to other drug therapy, pulmonary vascular 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.

“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.

“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.

“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 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.

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.

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, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington: The Science and Practice of Pharmacy, 21^stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

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 X is C₁-C₄alkyl). Also included are base addition salts, such as sodium or potassium salts.

Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n 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.

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, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I respectively. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O 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.

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 form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1:1.

“Racemates” refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

“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).

“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.

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 “—SO₂CH₂—” is equivalent to “—CH₂SO₂—” 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 “C_u-v” or (C_u-C_v) indicates that the following group has from u to v carbon atoms. For example, “C_1-6alkyl” and “C₁-C₆alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms.

“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.

“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

The present disclosure provides compounds of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) and (IIn).

In some embodiments, the present disclosure provides a compound of Formula (II):

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

Base is

[Image Omitted]

R^1Aand R^2Aare each independently:
- (A) C_1-12alkyl optionally substituted with 1 to 3 R^1B
- (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 R^1C, or
- (C) phenyl, wherein each R^1Bis independently halogen, —OH, —NH₂, C_1-6alkoxy, methoxyethoxy, C_3-8cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and each R^1Cis independently C_1-3alkyl;

R³is —N(H)R^3Aor —N═C(R^3B)(R^3C); R^3Ais H, —CH₂OP(O)(OH)₂, or —C(O)R^3D, wherein R^3Dis C_1-6alkyl 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; R^3Bis H or C_1-3alkyl; R^3Cis —N(R^3C1)(R^3C2); R^3C1and R^3C2are each independently H or C_1-6alkyl; or R^3C1and R^3C2together 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 C_1-6alkyl;

R^4Ais O or S;

R^4Band R^4Care each independently
- (A) —OH;
- (B) —OR^4B1, wherein R^4B1is C_1-6alkyl optionally substituted with 1 to 3 R^4B2groups, or C_6-12aryl, wherein each R^4B2group is independently C_1-6alkoxy, —S—R^4B3or —S(O)₂—R^4B3, and each R^4B3group is independently C_1-6alkyl;
- (C)

[Image Omitted]

wherein m is 0, 1, 2, 3, 4, or 5; and each R^4Dis independently C_1-3alkyl optionally substituted with 1 to 3 R^4D1groups, C_1-3alkoxy optionally substituted with 1 to 3 R^4D2groups, or —C(O)N(R^4D3)₂, wherein each R^4D1group is independently —NH₂or —C(O)OR^4D3, each R^4D2is independently C_1-3alkoxy, and each R^4D3is independently C_1-3alkyl;

- (D)

[Image Omitted]

wherein R^4E1and R^4E2are each independently H or C_1-6alkyl, R^4F1and R^4F2are each independently H or C_1-6alkyl, or R^4F1and R^4F2together are oxo, R^4Gis C_1-12alkyl optionally substituted with 1 to 3 R^4G1, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G2, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R^4G3, or —C(O)R^4G4, each R^4G1is independently —OH, C_1-6alkyl, C_1-3alkoxy, —(CH₂OCH₂)_1-5—CH₃, —N(R^4G8)₂, —OP(O)(OH)₂, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R^4G10, or phenyl, each R^4G2is independently C_1-6alkyl, C_1-3haloalkyl, —OH or —NH₂, each R^4G3is independently halogen or C_1-3alkyl, each R^4G4is independently C_1-12alkyl, each R^4G8is independently C_1-6alkyl, each R^4G9is independently C_1-3haloalkyl, —OH or —NH₂, and each R^4G10is independently C_1-3haloalkyl; or

- (E) —(OP(O)(OH))_1-2—OH; and

R^5Aand R^5Bare each C_1-6alkyl substituted with —OP(O)(OH)₂.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein Base is

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein Base is

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein Base is

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently: (A) C_1-12alkyl optionally substituted with 1 to 3 R^1B, (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 R^1C, or (C) phenyl, wherein each R^1Bis independently —OH, —NH₂, C_1-6alkoxy, methoxyethoxy, C_3-8cycloalkyl, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and each R^1Cis independently C_1-3alkyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare C_1-12alkyl optionally substituted with 1 to 3 R^1B. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare 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 R^1B. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^1Bcan independently be methoxy, methoxyethoxy, morpholinyl, —OH, or —NH₂. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare 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), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each ethyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each isopropyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each 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 R^1C, wherein each R^1Cis independently C_1-3alkyl, hydroxy, or halogen. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each 4 to 6 membered heterocyclyl having 1 heteroatom selected from N and O, wherein the 4 to 6 membered heterocyclyl is optionally substituted with 1 R^1C, wherein each R^1Cis independently C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each oxetanyl, tetrahydropyranyl or piperidinyl, each optionally substituted with 1 R^1C, wherein each R^1Cis independently C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^1Cis methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently oxetanyl, tetrahydropyranyl, or piperidinyl optionally substituted with methyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R³is —N(H)R^3Aor —N═C(R^3B)(R^3C), R^3Ais H, —CH₂OP(O)(OH)₂, or —C(O)R^3D, wherein R^3Dis C_1-6alkyl 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 C_1-3alkyl, R^3Bis H or C_1-3alkyl, R^3Cis —N(R^3C1)(R^3C2), R^3C1and R^3C2are each independently H or C_1-6alkyl, or R^3C1and R^3C2together 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 C_1-6alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R³is —N(H)R^3A, and R^3Ais H, —CH₂OP(O)(OH)₂, or —C(O)R^3D, wherein R^3Dis C_1-6alkyl 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 C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R³is —N(H)R^3Aand R^3Ais H, —CH₂OP(O)(OH)₂, or —C(O)R^3D, wherein R^3Dis C_1-3alkyl optionally substituted with 1 methoxy, or piperidine optionally substituted with methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^3Ais H. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R³is —NH₂. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R³is —N═C(R^3B)(R^3C), wherein R^3Bis H or methyl, R^3Cis —N(R^3C1)(R^3C2), R^3C1and R^3C2are each independently H or methyl, or R^3C1and R^3C2together with the atom to which they are attached form piperazine, optionally substituted with methyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Ais O or S. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Ais O. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Ais S.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis —OH.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis —OR^4B1, wherein R^4B1is C_1-6alkyl optionally substituted with 1 to 3 R^4B2groups, or C_6-12aryl, wherein each R^4B2group is independently C_1-6alkoxy, —S—R^4B3, or —S(O)₂—R^4B3, and each R^4B3group is independently C_1-6alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4B1is C_1-6alkyl optionally substituted with 1 to 3 R^4B2groups. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4B2group is independently C_1-6alkoxy, —S—R^4B3, or —S(O)₂—R^4B3, and each R^4B3group is independently C_1-6alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4B1is C_1-6alkyl optionally substituted with 1 to 3 R^4B2groups, wherein each R^4B2group is independently C_1-6alkoxy, —S—R^4B3, or —S(O)₂—R^4B3, and each R^4B3group is methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis —O—C_1-6alkyl optionally substituted with methoxy, methylthio or methylsulfonyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis

[Image Omitted]

wherein m is 0, 1, 2, 3, 4, or 5; and each R^4Dis independently C_1-3alkyl optionally substituted with 1 to 3 R^4D1groups, C_1-3alkoxy optionally substituted with 1 to 3 R^4D2groups, or —C(O)N(R^4D3)₂, wherein each R^4D1group is independently —NH₂or —C(O)OR^4D3, each R^4D2is independently C_1-3alkoxy, and each R^4D3is independently C_1-3alkyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; and each R^4Dis independently C_1-3alkyl optionally substituted with 1 R^4D1group, C_1-3alkoxy optionally substituted with methoxy, or —C(O)N(R^4D3)₂, wherein each R^4D1group is independently —NH₂or —C(O)OR^4D3, and each R^4D3is independently C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein m is 0.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis:

[Image Omitted]

wherein R^4E1and R^4E2are each independently H or C_1-6alkyl, R^4F1and R^4F2are each independently H or C_1-6alkyl, or R^4F1and R^4F2together are oxo, R^4Gis C_1-12alkyl optionally substituted with 1 to 3 R^4G1, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G2, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R^4G3, or —C(O)R^4G4, each R^4G1is independently —OH, C_1-6alkyl, C_1-3alkoxy, —(CH₂OCH₂)_1-5—CH₃, —N(R^4G8)₂, —OP(O)(OH)₂, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R^4G10, or phenyl, each R^4G2is independently C_1-6alkyl, C_1-3haloalkyl, —OH or —NH₂, each R^4G3is independently halogen or C_1-3alkyl, each R^4G4is independently C_1-12alkyl, each R^4G8is independently C_1-6alkyl, each R^4G9is independently C_1-3haloalkyl, or —NH₂; and each R^4G10is independently C_1-3haloalkyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis:

[Image Omitted]

and

the other of R^4Band R^4Cis:

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4E1and R^4E2are each independently H or C_1-6alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4E1and R^4E2are each independently H or methyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4F1and R^4F2are each independently H or C_1-6alkyl, or R^4F1and R^4F2together are oxo. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4F1and R^4F2are each independently H or methyl, or R^4F1and R^4F2together are oxo. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4F1and R^4F2together are oxo.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis:

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis:

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis C_1-12alkyl optionally substituted with 1 to 3 R^4G1In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or 2-ethyl-butyl, each optionally substituted with 1 to 3 R^4G1.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G1is independently —OH, C_1-6alkyl, C_1-3alkoxy, —(CH₂OCH₂)_1-5—CH₃, —N(R^4G8)₂, —OP(O)(OH)₂, C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G9, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R^4G10, or phenyl, wherein each R^4G8is independently C_1-6alkyl, each R^4G9is independently C_1-3haloalkyl, or —NH₂, and each R^4G10is independently C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G1is independently —OH, C_1-6alkyl, C_1-3alkoxy, —(CH₂OCH₂)_1-5—CH₃, —N(R^4G8)₂, —OP(O)(OH)₂, C_4-6cycloalkyl optionally substituted with 1 to 3 R^4G9, 4 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from N and O, optionally substituted with 1 to 3 R^4G10, or phenyl, wherein each R^4G8is independently C_1-6alkyl, each R^4G9is independently C_1-3haloalkyl or —NH₂, and each R^4G10is independently C_1-3haloalkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G1is independently —OH, methyl, OMe, —(CH₂OCH₂)₂—CH₃, —N(iPr)₂, —OP(O)(OH)₂, cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with —NH₂or CF₃, oxetanyl, piperidinyl optionally substituted with CF₃or CH₂CF₃, tetrahydropyranyl, morpholinyl, or phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis methyl optionally substituted with R^4G1, ethyl optionally substituted with morpholinyl or —N(R^4G8)₂, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C_1-3alkyl, isobutyl optionally substituted with —OH or —OP(O)(OH)₂, wherein R^4G1is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with R^4G9, oxetanyl, piperidinyl optionally substituted with R^4G10tetrahydropyranyl, or phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G8is C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G8is isopropyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G9is C_1-3haloalkyl or —NH₂. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G9is —CF₃or —NH₂. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G10is C_1-3haloalkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4G10is —CF₃or 2,2,2-trifluoroethyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis methyl optionally substituted with R^4G1, ethyl optionally substituted with morpholinyl or —N(C_1-3alkyl)₂, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C_1-3alkyl, isobutyl optionally substituted with —OH or —OP(O)(OH)₂, wherein R^4G1is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with —NH₂or C_1-3haloalkyl, oxetanyl, piperidinyl optionally substituted with C_1-3alkyl or C_1-3haloalkyl, tetrahydropyranyl, or phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis C_3-7cycloalkyl optionally substituted with 1 to 3 R^4G2. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1 to 3 R^4G2. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G2is independently C_1-6alkyl, C_1-3haloalkyl or —NH₂. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G2is tert-butyl, —CF₃or —NH₂.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R^4G3. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R^4G3. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis a 4-6 membered heterocyclyl having 1 to 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R^4G3. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with 1 to 3 R^4G3. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G3is independently halogen or C_1-3alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G3is independently F, methyl or ethyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis —C(O)R^4G4. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein each R^4G4is independently C_1-12alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis —C(O)C_1-6alkyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis —C(O)-tert-butyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis —(OP(O)(OH))_1-2—OH. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein one of R^4Band R^4Cis —(OP(O)(OH))_1-2—OH and one of R^4Band R^4Cis —OH.

In some embodiments, the compound can be represented by Formula (II), (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R^5Aand R^5Bare each —CH₂OP(O)(OH)₂. In some embodiments, the compound can be represented by Formula (II) or (IIa), wherein R^5Ais —CH₂OP(O)(OH)₂. In some embodiments, the compound can be represented by Formula (II) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R^5Bis —CH₂OP(O)(OH)₂.

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (IIa):

[Image Omitted]

wherein R^5Ais —CH₂OP(O)(OH)₂.

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (IIb):

[Image Omitted]

wherein R^5Bis-CH₂OP(O)(OH)₂.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein

- R^1Aand R^2Aare 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, isopentyl, oxetanyl, tetrahydropyranyl, piperidinyl optionally substituted with methyl, or phenyl;
- R³is —N(H)R^3Aor —N═C(R^3B) (R^3C); R^3Ais H, —C(H)₂OP(O)(OH)₂, or —C(O)R^3D; R^3Dis methyl, ethyl optionally substituted with methoxy, isopropyl, or piperidinyl optionally substituted with methyl; R^3Bis H or methyl; R^3Cis —N(R^3C1)(R^3C2); R^3C1and R^3C2are independently H or methyl; or R^3C1and R^3C2together with the atom to which they are attached form a piperazinyl optionally substituted with methyl;
- R^4Ais O or S; and
- R^4Band R^4Care each independently
- (A) —OH;
- (B) —O—C_1-6alkyl optionally substituted with methoxy, methylthio or methylsulfonyl;
- (C)

[Image Omitted]

- wherein m is 0, 1 or 2; and each R^4Dis independently C_1-3alkyl optionally substituted with 1 R^4D1group, C_1-3alkoxy optionally substituted with methoxy, or —C(O)N(R^4D3)₂, wherein each R^4D1group is independently —NH₂or —C(O)OR^4D3and each R^4D3is independently C_1-3alkyl; or
- (D)

[Image Omitted]

- wherein R^4E1and R^4E2are each independently H or methyl, R^4F1and R^4F2are each independently H or methyl, or R^4F1and R^4F2together are oxo, R^4Gis methyl optionally substituted with R^4G1, ethyl optionally substituted with morpholinyl or —N(C_1-3alkyl)₂, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C_1-3alkyl, isobutyl optionally substituted with —OH or —OP(O)(OH)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently —NH₂, C_1-6alkyl, or C_1-3haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C_1-3alkyl, tetrahydrofuranyl, tetrahydropyranyl, or —C(O)C_1-6alkyl, and R^4G1is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with —NH₂or C_1-3haloalkyl, oxetanyl, piperidinyl optionally substituted with C_1-3haloalkyl, tetrahydropyranyl, or phenyl.

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIc):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IId):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IId):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIf):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIg):

[Image Omitted]

wherein m is 0 or 1.

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIh):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIi):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIj):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIk):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIm):

[Image Omitted]

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be represented by Formula (IIn):

[Image Omitted]

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently ethyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently isopropyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis ethyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis n-propyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis isopropyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis n-butyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis t-butyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^4Gis 2-ethyl-butyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl, R^4Gis methyl optionally substituted with R^4G1, ethyl optionally substituted with morpholinyl or —N(C_1-3alkyl)₂, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C_1-3alkyl, isobutyl optionally substituted with —OH or —OP(O)(OH)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently —NH₂, C_1-6alkyl, or C_1-3haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C_1-3alkyl, tetrahydrofuranyl, tetrahydropyranyl, or —C(O)C_1-6alkyl, and R^4G1is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with —NH₂or C_1-3haloalkyl, oxetanyl, piperidinyl optionally substituted with C_1-3alkyl or C_1-3haloalkyl, tetrahydropyranyl, or phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis methyl optionally substituted with R^4G1, ethyl optionally substituted with morpholinyl or —N(C_1-3alkyl)₂, n-propyl optionally substituted with methoxy or morpholinyl, isopropyl, n-butyl optionally substituted with C_1-3alkyl, isobutyl optionally substituted with —OH or —OP(O)(OH)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 3 groups each independently —NH₂, C_1-6alkyl, or C_1-3haloalkyl, oxetanyl, pyrrolidinyl optionally substituted with 1 to 3 methyl, piperidinyl optionally substituted with halogen or C_1-3alkyl, tetrahydrofuranyl, tetrahydropyranyl, or —C(O)C_1-6alkyl, and R^4G1is cyclopropyl, cyclobutyl, cyclohexyl optionally substituted with —NH₂or C_1-3haloalkyl, oxetanyl, piperidinyl optionally substituted with C_1-3alkyl or C_1-3haloalkyl, tetrahydropyranyl, or phenyl.

In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or isopentyl, and R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, and R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each methyl, and R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each ethyl, and R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each isopropyl, and R^4Gis 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), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, and R^4Gis methyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis ethyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis n-propyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis isopropyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis n-butyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk) (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis t-butyl. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein R^1Aand R^2Aare each independently methyl, ethyl, or isopropyl, R^4Gis 2-ethyl-butyl.

The compounds of the present disclosure include the compounds of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, and Table 1I. In some embodiments, the compound can be represented by Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) or (IIn), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, and Table 1I:

TABLE 1A

Compounds

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TABLE 1B

Compounds

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TABLE 1C

Compounds

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TABLE 1D

Compounds

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TABLE 1E

Compounds

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TABLE 1F

Compounds

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TABLE 1G

Compounds

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TABLE 1H

Compounds

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TABLE 1H

Compounds

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In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure:

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In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure:

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